IgE antibodies exert pathogenic effects in allergies and protective anti-parasite immunity via high-affinity Fcε receptors on tissue-resident effector cells. We generated IgEs recognising cancer-associated antigens and translated the first-in-class agent to clinical testing. IgEs trigger pro-inflammatory effector recruitment and induction of hyperinflammatory macrophages to inhibit immunosuppression in the tumour microenvironment.
This talk will present ADC QSP bystander models incorporating both antigen-positive and antigen-negative cells. These models demonstrate that ADC modality may offer limited response durability if antigen-positive and antigen-negative cells grow independently. However, this limitation could potentially be overcome by stromal-targeting ADCs, as stromal cells are recruited to the tumor. Additionally, we will discuss the optimal ADC properties that balance efficacy across both cell populations.
Elimination of extracellular proteins is a compelling therapeutic modality. EpiTACs are bispecific antibodies in which one arm binds a target and the other arm leverages an EpiAtlas of tissue-enriched degrading receptors comprised of transmembrane ligases, cytokine/chemokine receptors, and internalizing receptors resulting in selective degradation of membrane and soluble proteins. EpiTACs elicit robust in-vitro and in-vivo activity in a target-, tissue- and disease-specific manner for a broad range of indications. Compelling data across multiple targets demonstrates that EpiTACs can degrade a target independent of mutational status, are better than neutralizing antibodies in preclinical models, and drive a survival benefit in preclinical tumor models.
We present a novel discovery platform that seamlessly combines in vivo immunisation with in vitro antibody discovery by leveraging a novel microfluidics-based semi-permeable capsule technology for recovery of natively-paired VH:VL (scFv) repertoires from millions of B cells derived from immunised animals and integrating it with our cutting-edge mammalian IgG display platform. This innovative capability enables iterative screening of original immune repertoires in final IgG format and early selection of highly developable, target-specific antibodies, thereby improving therapeutic discovery workflows.
Utilizing the ability of antibodies as delivery vehicles has resulted in a therapeutic modality known as antibody-drug conjugates or ADCs. As the field advances, new opportunities for antibody-mediated delivery are being explored. This talk will focus on our efforts to link chimeric protein degraders (aka PROTACs) to antibodies, their efficacy and safety, and how this general approach can expand the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
Add-on this optional pre-conference workshop to your main conference registration package and gain a comprehensive overview of antibody engineering in an easy-to-follow classroom setting to help you prepare for the main conference program.
- Workshop registration begins at 7:30 am
- Morning Break: ~10:30-10:50
WORKSHOP OVERVIEW
Today’s wealth of knowledge of antibody structures will be reviewed along with the genetics of diversity generation, to give insights into the best strategies for improving function. There is particular emphasis on the choice of a functional assay to effectively monitor the changes in a desired property, and the use of functional enrichment steps where a library approach is employed. Not only is amino acid sequence amenable to engineering, but glycan structures and other modifications may also be engineered. The course will focus on the engineering and enhancement of antibodies and antibody-like scaffolds. Examples will include work on antibody fragment affinity improvement by 100-fold to low pM affinity. Also, the engineering of bispecific antibodies by diverse approaches and the adaptation to generate Chimeric Antibody Receptor (CAR) constructs will be discussed. Expression platforms for producing antibodies for testing and for manufacture will also be covered. A background in biochemistry and molecular biology is useful, as the course is designed to progress rapidly from simple to advanced concepts.
INSTRUCTOR
David Bramhill, Ph.D., Founder, Bramhill Biological Consulting, LLC
WORKSHOP AGENDA
- Functions amenable to engineering: affinity, specificity, stability, solubility, immunogenicity
- The measure of success: functional assays
- Engineering by design
- Engineering by random mutation
- Designed libraries
- Display technologies
- Improving manufacturing by protein engineering methods
- Glycosylation engineering – function and homogeneity
- Other protein modifications
- Immunogenicity engineering
- Bispecific antibodies
- CAR-T strategies
- Expression of antibodies and fragments for discovery and testing
- Manufacturing platforms for antibodies and fragments
NOTE: The afternoon workshop “Introduction to Bispecific & Multispecific Antibodies” is an excellent complement to the morning introduction course.
For more information about presenting in this session, please contact Michael Keenan at Michael.Keenan@informa.com
At DJS Antibodies, part of AbbVie, we aim to develop first-in-class anti-GPCR antibodies to improve patient outcomes for serious diseases. The work presented compares various antigen formats and discovery methods for isolating single B-cells following immunization with our proprietary HEPTAD technology. By utilizing a diverse range of techniques, we aim to maximize the sequence landscape obtained from our immunizations, enhancing our ability to generate effective antibody candidates.
Alloy bispecific discovery services integrate best-in-class platforms with world class scientists to serve as an extension of your R&D team. Building on industry leading mouse platforms for fully human antibody discovery, Alloy has created Common Light Chain strains, ATX-CLC, to build bispecifics with better developability profiles by solving heavy and light chain pairing. Leveraging ATX-CLC Alloy supports bispecific discovery through format engineering and functional assessment to move candidates forward rapidly.
Abalone Bio’s Functional Antibody Selection Technology (FAST) platform combines biology and machine learning (ML) to identify and design functionally active antibody drugs. FAST simultaneously tests the entire diversity of antibody libraries directly for the desired function and produces library-scale sequence-function datasets that uniquely power generative protein language models to design novel active antibody sequences. FAST-discovered antibodies have been demonstrated to have agonist activity in vitro and in vivo.
IgA has the unique properly to turn neutrophils in cancer-killing immune cells. However, just like other myeloid cells, neutrophils express SIRPa as a checkpoint inhibition molecule, that interacts with CD47 on tumorcells as ‘don’t eat me’ signal. Our present research focusses on combining the targeting on GD2 on neuroblastoma with the block of CD47 in one, bispecific IgA molecule to maximally activate neutrophils.
Alchemab’s approach to developing therapeutic antibodies is based on the concept that the immune system is able to generate protective autoantibodies which drive unusual disease resilience. By deep sequencing the B Cell Receptor repertoires of groups of resilient individuals and looking for convergence antibody sequences shared in these individuals, we can identify those rare protective antibodies, identify the targets they bind and harness and develop them into novel therapies. This approach has been successfully applied in neurodegenerative conditions and examples will be presented.
Prominent among challenges faced in the immunotherapeutics field across a spectrum of platforms is the need for improved understanding of the complex mechanisms involved in their operation at multiple levels of the immune system. We have been working to address one aspect of this challenge with respect to immune cell signaling networks, aiming to construct comprehensive yet actionable models for their how they govern effectiveness of immunotherapeutic modalities. This presentation will describe certain new findings, including in applications to antibody glycosylation and to chimeric antigen receptor T cells.
To enable neoantigen peptides to serve as payloads in antibody-mediated targeted delivery strategies, we have developed a unique peptide tag (pTag)-scFv loading strategy that facilitates modular drug cargo loading. I will present our work on developing a novel CD40 agonistic antibody designed to bind both CD40 and the pTag-neoantigen cargo. We have explored the utility of this approach to expand CD8 and CD4 T cells in vivo and control tumor growth in lung and colorectal cancer models. Additionally, I will present unpublished data on the use of this platform for other drug modalities.
At OmniAb, we build, shape and mine custom, naturally optimized immune repertoires in divergent species to discover next generation biotherapeutics. We use high throughput phenotypic screening augmented by an AI-guided NGS workflow to navigate the vast sequence space and find high quality leads, bypassing extensive ex-vivo engineering. We demonstrate how we discovered developable anti-NKp46 binders with broad epitope coverage and affinities as building blocks for NK cell engager multispecifics.
Although antibodies are actively explored as therapeutic for bacterial infections, their narrow specificity poses a challenge due to the broad diversity between bacterial species. We reveal that conversion of highly specific anti-staphylococcal IgGs into IgM induced cross-reactivity with a range of bacterial species.
HVEM, a member of the TNF receptor superfamily (TNFRSF14), interacts with several molecules, including BTLA, CD160, and LIGHT. HVEM is expressed not only on hematopoietic cells but also on non-hematopoietic cells, which allows it to regulate both the priming phase of T cells in the draining lymph node and the effector phase of the T cell response at the inflamed tissue site. The engagement of HVEM with BTLA provides negative signals, while LIGHT engagement delivers bidirectional positive costimulatory signals, promoting T cell survival and effector functions.
By levering its platform Mabylon generates and engineers multispecific antibodies which target and neutralize exogenous allergens, providing long-term protection against allergic reactions. By deriving our variable regions from human subjects, we ensure the targeting of the most relevant allergens and epitopes. MY006, our trispecific anti-peanut antibody built from patient-derived monoclonal antibodies will start first-in-human trials by the end of 2025.
Bispecific antibody clinical development remains rife with challenges, including nuanced pharmacology, limited translatability of preclinical findings, frequent on-target toxicity, and convoluted dosing regimens. Here we argue that trimer formation on the molecular level are but a proxy for the actual driver of pharmacology. The formation of immunological synapses between tumor cells and T cells involves a coordinated cascade of molecular and cellular interactions that extend beyond the initial antigen-binding event. This cascade includes the survey of potential target cells within the tumor microenvironment, the slowing of T-cell movement upon identification, and the establishment cell-to-cell adhesion. Incorporating these cellular mechanisms into bsTCE QSP models offers promise for predicting long-term efficacy, resistance, and relapse in solid tumors.
The rapid evolution of SARS-CoV-2 has resulted in continuous escape from traditional IgG-based monoclonal antibody (mAb) therapeutics, suggesting that new antibody engineering and delivery strategies are required to keep pace with viral evolution. In this presentation, I will describe the discovery and engineering of multi-specific antibodies with broad and potent activity against SARS-CoV-2 variants and the in vivo delivery of these constructs using mRNA technology.
In this talk, we present the CHO Edge System, which integrates a glutamine synthetase (GS)-CRISPR knockout CHO host, a hyperactive transposase, libraries of characterized genetic elements to control cellular functions, and computational tools for rational vector design and multi-omics analysis. We present case studies highlighting the impact of these tools to optimize expression for both standard monoclonal and bispecific antibodies.
Antibody Fragment Drug Conjugates (FDCs), a new product class tailored for solid tumours promise many advantages over ADCs including rapid tumour penetration and faster systemic clearance. However, these have been technologically-challenging to apply in oncology. Our novel approach enables high-Drug:Antibody Ratios (DARs) whilst retaining effective binding and other favourable biophysical properties. To achieve this, single-chain Fvs and other recombinant antibody formats must be considered in context with complex linker-payload chemical moieties. This platform technology has led to our lead product, ANT-045 is a cMET-targeted FDC addressing a wide range of solid tumours. ANT-045 demonstrates superior tumour cure efficacy in cMET high, moderate and low CDX and PDX gastric cancer xenograft models and better tolerability compared to the leading competitor ADCs. In a non-GLP, non-human primate study, ANT-045 was well tolerated demonstrating no signs of the usual dose-limiting adverse effects seen with ADCs (neutropenia, thrombocytopenia) with a predicted half-life in humans of around 12-14 hours supporting a viable clinical dosing strategy with a wide therapeutic window. Insights into how FDCs behave in vivo through quantitative and qualitative imaging/uptake studies and toxicological parameters will be shared and how these have informed our follow-up products.
We show AAV delivery of full-length antibodies targeting GA-dipeptide proteins in C9orf72 ALS/FTD BAC-transgenic mice reduces repeat associated non-AUG (RAN) protein levels, improves behavior and neuropathology, and increases survival. AAV delivery of high-affinity antibodies is a novel strategy to achieve broad and sustained CNS expression and biodistribution of therapeutic antibodies. These data open new possibilities for developing AAV-antibody therapies as a novel approach for C9orf72 ALS/FTD and other neurodegenerative disorders.
The inability of antibodies to penetrate the blood-brain barrier is a key limitation to their use in diverse applications. We are developing bispecific antibodies that engage either CD98hc or transferrin receptor, which results in the transport of IgGs and other biologics into the CNS. We will highlight our findings related to the unique advantages of CD98hc and transferrin receptor bispecific antibodies, especially related to the impact of target engagement in the CNS on pharmacokinetics and CNS distribution. Finally, we will discuss our recent findings on applications of bispecific antibodies for targeted CNS drug delivery.
Fibrosis can affect multiple organs in the human body and significantly threaten human health. Early diagnosis and intervention are crucial for preventing disease progression. However, very few treatments are available to patients. Next-generation medications with novel mechanisms of action are demanded to broaden the responding patient population and improve the therapeutic index. WNT1-inducible signaling pathway protein 1 (WISP1, also known as CCN4), a matricellular protein, was identified as a novel drug target for fibrosis through analysis of the transcriptomic data of human cirrhotic livers. I will present the preclinical studies of targeting WISP1 for treating tissue fibrosis.
Add-on this pre-conference training course to your main conference registration package for an additional fee and gain a comprehensive overview of antibody engineering in an easy-to-follow classroom setting to help you prepare for the main conference program.
- Training course registration begins at 8:00am.
- Break Schedule:
- AM Break: 10:30-11:00;
- Lunch: 12:30-1:30;
- PM break: 3:00-3:30
TRAINING COURSE OVERVIEW
Today’s wealth of knowledge of protein structures will be reviewed along with the genetics of diversity generation of antibodies, to give insights into the best strategies for improving protein function. There is particular emphasis on the choice of a functional assay to effectively monitor the changes in a desired property, and the use of functional enrichment steps where a library approach is employed. Not only is amino acid sequence amenable to engineering, but glycan structures and other modifications may also be engineered. The course will focus on the engineering and enhancement of antibodies and antibody-like scaffolds. Examples will include work on antibody fragment affinity improvement by 100-fold to low pM affinity. Also, the engineering of bispecific antibodies by diverse approaches and the adaptation to generate Chimeric Antibody Receptor (CAR) constructs will be discussed. Expression platforms for producing antibodies for testing and for manufacture will also be covered. A background in biochemistry and molecular biology is useful, as the course is designed to progress rapidly from simple to advanced concepts.
INSTRUCTOR
David Bramhill, Ph.D., Founder, Bramhill Biological Consulting, LLC and Research Corporation Technologies
COURSE AGENDA
- Functions amenable to engineering: affinity, specificity, stability, solubility, immunogenicity
- The measure of success: functional assays
- Engineering by design
- Engineering by random mutation
- Designed libraries
- Display technologies
- Improving manufacturing by protein engineering methods
- Glycosylation engineering – function and homogeneity
- Other protein modifications
- Immunogenicity engineering
- Bispecific antibodies
- Antibody-drug conjugates (ADCs)
- CAR-T strategies
- Expression of antibodies and fragments for discovery and testing
- Manufacturing platforms for antibodies and fragments
Current approaches to mine functional immune responses are generally limited in quality or throughput. To address these limitations, our group established high-throughput functional screening platforms for natively paired antibodies and T cell receptors generated in vivo. Here we will share several case studies of immune mining and engineering from in vivo leads.
In this presentation, Dr. Reichert will provide an update on the antibody therapeutics currently in late-stage clinical studies, as well as those in regulatory review and recently approved. Trends observed in the burgeoning early-stage pipeline, popular formats and mechanisms of action, as well as common and obscure targets for antibody therapeutics will also be discussed.
Introducing a novel FACS-based strategy paired with our AbTheneum platform, this presentation showcases a workflow to deliver higher yield of hits from a discovery campaign. By combining high-precision cell isolation with a robust engine for parallel screening and sequencing of all IgGs, we reveal how this synergy boosts hit rates and diversity, even in challenging low-titer conditions across various campaigns.
Targeting tumors with γ9δ2T cells resulted in poor clinical outcomes, mainly due to the low affinity of γ9δ2TCRs for tumor antigens. We have developed affinity-enhanced γ9δ2TCRs, which led significantly improved tumor control in both in vitro and in vivo preclinical models, paving the way for next-generation γ9δ2TCR-based immunotherapies.
DNTH103 is an investigational, fully human, half-life extended, potent monoclonal antibody engineered to selectively target the classical pathway by inhibiting only the active form of the C1s protein, to enable a more convenient subcutaneous, self-administered injection dosed as infrequently as once every two weeks. Additionally, selective inhibition of the classical complement pathway may lower patient risk of infection from encapsulated bacteria by preserving immune activity of the lectin and alternative pathways. DNTH103 is in development for Myasthenia Gravis, CIDP and MMN.
We previously developed SMART-Ig® technology to efficiently remove soluble antigens from the blood. This time, we aimed for more efficient antigen removal by creating pH-dependent biparatopic antibodies that bind to different epitopes of a soluble monomeric antigen in a pH-dependent manner. These antibodies accelerated cellular uptake by forming larger immune complexes, successfully removing soluble antigens from the blood more efficiently.
(SMART-Ig® is a registered trademark of Chugai Pharmaceutical Co., Ltd.)
We show unique mechanisms of flexible homodimerization crucial for the inhibitory function of checkpoint receptor PD-1 and LAG-3, and identified a novel cell surface receptor potently modulating myeloid-associated Type-I IFN responses. These efforts laid the foundation for developing novel immunotherapies for cancer and autoimmune diseases.
A subset of cow antibodies have a heavy chain “ultralong” CDR3 region that can be over 70 amino acids in length, with a disulfide-bonded “knob” domain that protrudes far from the antibody surface. These knob domains can be produced independently of the antibody to generate tiny, high affinity, binding fragments. The novel genetics, structural biology, and biomedical applications of ultralong CDR3 antibodies will be discussed.
Developed by a core group of AbTherx scientists and acquired by Gilead Sciences in 2023, Atlas™ Mice are a suite of transgenic mouse technologies for human antibody discovery. AbTherx has worldwide rights to this novel platform, successfully developing technologies that express the full diversity of human antibody HC and k-LC repertoires, enable the development of bispecific antibodies through a novel binary fixed light chain, and use natural mechanisms to generate long CDRH3 antibodies to address challenging drug targets.
Successful and efficient discovery and engineering of biologic therapeutics requires diversity and quality in the initial library of antibodies. This presentation will showcase the integration of the versatile platforms and processes of AlivaMab Biologics and Ablexis and our ‘fit-for-purpose’ philosophy. Empowered by a growing suite of AlivaMab® Mouse strains, we enable the discovery and engineering of next-generation modalities including fully human single-domain antibodies, common light chain discovery using a unique approach, and TCRm antibodies. Our comprehensive, integrated antibody discovery and engineering platforms consistently deliver molecules with the critical attributes required for successful drug development.
Primary mouse B cells were engineered so their heavy and kappa variable-chain loci were scarlessly overwritten by their respective human antibody variable-chain genes. These B cells proliferated in vivo to generate potent neutralizing plasma, and affinity matured to develop broader, more potent, and more bioavailable HIV-1 and SARS-CoV-2 neutralizing antibodies. This approach improves the clinical utility of antibodies and biologics, enables more human-like vaccine models, and suggests new cell-based therapies.
For more information about presenting in this session, please contact Michael Keenan at Michael.Keenan@informa.com
For more information about presenting in this session, please contact Michael Keenan at Michael.Keenan@informa.com
ADCs are a rapidly expanding class of therapeutics with 7 new approvals in the past 6 years. However, they have a long history with many failures in the clinic. This presentation will use a quantitative systems pharmacology approach to highlight the major delivery challenges with ADCs in solid tumors, and how recent successes can be used to inform the design of the next wave of clinical approvals.
This topic explores the revolutionary potential of the genome-edited mouse, where endogenous VH and VL genes are replaced by fully human VH and VL genes in situ, enabling the generation of fully human antibody molecules. When combined with Biointron's AbDrop microfluidic technology-enhanced single B cell screening, this approach allows for the high-throughput and efficient discovery of antibody drug molecules.
Monoclonal antibodies struggle to achieve potent complement activation due to the need for multivalent C1q binding, resulting in the underutilization of complement as a therapeutic mechanism. We have recently described an innovative approach involving bispecific single domain antibodies, BiCE™, which efficiently recruit and activate C1. We now present the 2nd generation BiCE™ IgG molecules that exhibit superior complement-mediated cell killing compared to competing technologies, holding great therapeutic potential.
emp BIOTECH has developed first-in-class Protein G solid phases that can tolerate Cleaning-In-Place (CIP) with sodium hydroxide. No loss in binding capacity was observed after 50 CIP cycles. The resins have been optimized for the purification of human monoclonal IgG. The new products are expected to be launched in Q1 of 2025.
Broadly neutralizing antibodies are the major goal of a universal influenza vaccine. This presentation will focus on the identification of a class of broadly neutralizing antibodies targeting a membrane-proximal anchor epitope of the influenza virus hemagglutinin (HA) protein. I will discuss the challenges of identifying antibodies against membrane-proximal epitopes, how vaccines can induce anchor-specific antibodies, and how anchor-targeting antibodies can be engineered to improve binding breadth and potency.
Single domain antibodies (sdAbs) are about one-tenth the size of standard antibodies and have several advantages for therapeutic development. We have generated numerous sdAbs from llamas immunized with tau or α-synuclein proteins. The presentation will highlight our key findings to date and ongoing studies.
Using the Pfenex Expression Technology®, we achieved 15g/L of a modified VHH molecule engineered for site-specific ADC conjugation. The innovative Pfenex platform, based on P. fluorescens, produces various antibody formats including Fab's and novel Picobodies™. The platform effectively utilizes multiple genetic elements, host strains, and automated workflows to optimize protein expression from early research through full commercialization, with six approved products to date.
The discovery of broad and potently neutralizing antibodies against highly immunoevasive viruses like HIV can reveal conserved sites of viral vulnerability. Guided by such extraordinary antibodies, we can rationally design vaccine immunogens that focus the humoral response toward these vulnerable regions in order to reliably induce durable and escape-resistant immunity.
Add-on this optional pre-conference workshop to your main conference registration package and gain a comprehensive overview of bispecific and multispecific antibodies t in an easy-to-follow classroom setting to help you prepare for the main conference program.
- Workshop registration begins at 12:30 pm
- Afternoon Break: ~ 3:30-3:50
WORKSHOP OVERVIEW
This workshop covers the key aspects of bispecific antibody design, how best to achieve desired therapeutic function, and then explores the challenges posed for manufacturing such complex molecules. The various parameters for a bispecific antibody are each examined – valency and affinity for engaging each individual target, optimum physical distances for desired binding and outcome, requirement for Fc function(s) or not, etc. A discussion of antibody formats that may be especially applicable to rapid screening of the optimum valency, affinity, spacing, etc., of each specific binding component is included. It is aimed to provide even beginners with explanations of the nomenclature and science.
INSTRUCTOR
David Bramhill, Ph.D., Founder, Bramhill Biological Consulting, LLC
WORKSHOP TOPICS TO BE DISCUSSED
- Review of Antibody Structure, Fc Function(s)
- Fundamental Bispecific Antibody Design Considerations
- Symmetric vs. Asymmetric Formats – Valency of Target Binding
- Is Fc Function Required for a Particular Bi-specific Antibody Therapeutic?
- Aligning Format with Desired Bispecific Antibody Function
- Examples of a Variety of Bispecific Antibody Applications, from T-Cell Engagers to crossing the blood-brain barrier
- Manufacturing Multi-subunit Bispecific Antibody Molecules
WHAT WILL YOU LEARN?
- Gain an overview of the key aspects for design parameters for Bi-specific Antibodies.
- Scientific terms and acronyms relating to Bi-specific Antibody will be defined and explained.
T cell-engaging (TCE) multispecific antibodies demonstrate great clinical efficacy, though their molecular complexity is a challenge for drug manufacturability, developability, and obtaining desirable PK/PD properties. Here, we showcase the discovery and engineering of novel anti-CD3 heavy chain-only antibodies (HCAbs), which demonstrate T cell cytotoxicity comparable to clinically validated TCEs when paired with IgG or TCR modalities. This work introduces a flexible new tool for enabling this important class of biologics.
This presentation highlights efforts to develop novel transport vehicle (TV) enabled antibodies for AD that target microglia function. We’ve developed distinct transport vehicle platforms that can be differentially applied to antibodies to increase brain exposure, improve biodistribution, and enhance activity of Fab-mediated target engagement.
Payload resistance is a critical concern for ADCs. Combinations may be beneficial but therapeutic windows are limited. Hummingbird Bioscience's dual-payload ADC platform is a targeted, single-agent approach designed to overcome resistance and maximize therapeutic window. HMBD-802, an anti-HER2 dual-payload ADC shows robust efficacy in trastuzumab deruxtecan resistant models and good tolerability.
The talk will focus on our pre-clinical and clinical experience with CD27 monoclonal antibodies and consider how their therapeutic activity might be improved.
As a new addition this year, we're excited to announce this Early Career Scientists session taking place on the morning of December 15, the day before the main conference. Are you within 10 years of completing your Master’s or Ph.D. and under the age of 35? If so, unlock a range of exclusive benefits by selecting the "Early Career Scientist" pass when you register. This session will spotlight short, novel research presentations from early career scientists in the antibody engineering and therapeutics community. You’ll also hear an inspiring career journey from a distinguished mid-career scientist, plus enjoy the opportunity to connect and network with peers. You’ll also receive free admission to the afternoon pre-conferences workshops on December and the opportunity to present a free poster during the main conference. Please Note: Access to the early career scientists session is only available to those who register for the main conference by selecting the “Early Career Scientist” pass. All passes subject to approval by conference organizers.
To be considered for a short oral presentation in this session, or for general information about this session, please contact Michael Keenan at Michael.keenan@informa.com
If you are interested in sponsoring this session, please contact Blake Shuka at Blake.Shuka@informa.com
Protillion combines ML-guided antibody design technology with purpose-built chip-based high-throughput instrumentation to tackle challenging problems in therapeutic protein engineering. The platform is capable of characterizing the binding affinity of up to 10^6 antibody variants in a 2-day automated run. This unique approach enables identification of better antibody candidates that meet challenging product profiles, including pH-dependent binding, cross-species reactivity, and stringent developability.
Each immune complex is unique and affects its own set of Fc functions. To treat the antibody as a sum of two independent domains, the Fab and Fc, is fraught with false assumptions that could negatively impact therapeutic development. SeromYx’s high-throughput GCLP platform enables the empirical and comprehensive determination of the antigen-specific Fc functional profile of therapeutic antibodies uncovering vital insights into their safety and immune mechanisms of efficacy upfront.
SAIL66, a next-generation tri-specific T-cell engager targeting CLDN6, CD3, and CD137, was developed using proprietary Dual-Ig® technology. Dual-Ig® enables unique ability to CD3 and CD137, but not simultaneously. SAIL66 demonstrates remarkable selectivity, avoiding cross-reactivity with related CLDN family. In vitro and in vivo studies reveal SAIL66's superior T cell activation and enhanced anti-tumor efficacy compared to conventional TCEs.
Growth differentiation factor 15 (GDF-15) is a stress induced cytokine that causes anorexia and weight loss, and higher circulating levels are associated with cachexia and reduced survival in patients with cancer. Inhibition of GDF-15/GFRAL biological activity reverses cachexia in numerous preclinical tumor models, and ponsegromab (a novel, first in class humanized monoclonal anti-GDF15 antibody) is being developed as a therapeutic agent for cancer cachexia.
IgM is the first antibody in humoral immune response and appeared early in evolution. With high valency, IgM pentamers exhibit superior avidity, significant receptor clustering, potent effector function (CDC and ADCP) and provide opportunity for treatment of infectious disease, cancer and auto-immune disorders. Engineered IgMs have strong potential as therapeutic agents, and many biotechnical challenges of production and characterization have been resolved. Key topics and case studies will be presented.
InduPro leverages inherent and induced proximity of cell surface proteins to discover novel biology and enable therapeutic development. We demonstrate that re- location of immunomodulatory proteins into or out of the immune synapse using select bi-specific antibodies can alter T cell activation. Application of this approach to dampen T cell signaling for the treatment of autoimmune disease will be presented.
In vitro assays play a central role in biotherapeutic drug development by enabling critical insights into target identification, mechanism of action, and safety profiling. This presentation will provide an in-depth exploration of strategic application of in vitro assays through real-world case studies, illustrating their essential role in optimizing lead selection, assessing risks, and advancing drug candidates in ADC, TCE and autoimmune diseases therapeutics.
We provide an advanced, integrated high-throughput droplet sorting platform that accelerates antibody discovery. This platform supports high-performance screening against both soluble and transmembrane antigens. By harnessing plasma cells of the most popular species—not limited to mouse, rabbit, human, alpaca, etc.—whether fresh or in-vitro activated—the system enables direct acquisition of natural or genetically modified antibodies with exceptional specificity and affinity. Its sensitive, versatile , and high-throughput design further facilitates the discovery of functional antibodies, streamlining the development process from initial screening to therapeutic application.
Stellabody® is a single point mutation in the CH3 region that facilitates “on-target assembly” of immune biologics that transforms killing or agonistic potency in multiple immune protein formats i.e. mAbs, bispecific antibodies, Fc-fusions and novel scaffolds. Stellabody biologics mediate greatly (10-100x) enhanced potency in head-to-head comparisons with the equivalent standard biologic including standard-of-care mAbs in oncology on primary patient-derived clinical samples and targets in infection and immunology.
Xencor has created a growing set of bispecific antibodies, using principles of avidity-driven selectivity to improve therapeutic index. Building on these modalities are additional efforts to explore T cell costimulation via signal 2 to potentiate anti-tumor activity of T cells.
To better harness the anti-tumor activity of T cells on top of immune checkpoint inhibition, we generated a PD-L1/CD28 bispecific antibody using our κλ-body platform to promote antitumor function through a dual mechanism of action, immune checkpoint inhibition and T cell co-stimulation. In this presentation, we provide in vitro and in vivo evidence to confirm the safety and efficient anti-tumor activity of this dual-targeting strategy.
DuoBody®-EpCAMx4-1BB is a novel, clinical stage, bispecific antibody targeting EpCAM and 4-1BB designed to boost antitumor responses conditionally in EpCAM-expressing tumors. By crosslinking EpCAM on tumor cells with 4-1BB on immune cells, DuoBody-EpCAMx4-1BB enhances T-cell activation, proliferation, and antitumor activity in preclinical studies. DuoBody-EpCAMx4-1BB is co-developed by BioNTech and Genmab. The preclinical characterization of DuoBody-EpCAMx4-1BBB will be presented.
Alector is a leader in the field of Neuroimmunology - harnessing the brain's immune system to cure neurogenerative disorders. Here we describe our Neuroimmunology pipeline and our novel Blood-brain barrier crossing technology (ABC) designed to further enhance brain delivery of antibody and protein therapeutics to address neurodegenerative diseases.
ATUM’s antibody platform combines ML/AI with production quality expression systems and robust analytics. Antibodies are designed in silico, assisted by AI and knowledge base, synthesized at scale in commercially relevant platforms, and are characterized for functionality and developability features simultaneously. ML models built on these datasets which are built specifically to “learn”, are highly predictive and generate new designs for high-specificity antibodies with developability properties for process development, scale-up, and manufacturing.
Deep Screening is a novel high throughput method for the rapid and massive parallel screening of biologics. It enables the experimental collection of up to 10^9 scFv sequences paired with binding affinities in a 3 day experiment, identifying hits where traditional methods fail. Here we will present recent work conducted at Sortera.
The cytosolic Fc receptor TRIM21 uses antibodies to target proteins for degradation inside the cell. This activity provides potent immune protection by destroying incoming viral particles and underpins “Trim-Away” technology. In my talk I will discuss our recent work on the molecular mechanism of cytosolic antibody-mediated degradation and the use of Trim-Away degraders to remove tau aggregates in vivo in a mouse model of Alzheimer’s Disease.
While some of the best selling drugs of all time are biologics, several other modalities have been propelled into the limelight by continued innovations that have the potential to outcompete biologics. My talk will focus on the exciting new areas in biologics development through the lens of early-stage therapeutics investing.
Tau is inextricably linked to a group of clinically diverse neurodegenerative diseases termed tauopathies. The ratio balance of the major tau splicing isoform groups (3R- and 4R-tau) is critical in maintaining healthy neurons. An imbalance causing excess 4 R tau is associated with diseases such as progressive supranuclear palsy. The work presented in this talk covers the generation of a novel 4R-tau specific “degrabody” capable of degrading 4R tau in iPSC derived neurons to probe its potential role in neurodegeneration.
Immune-stimulating antibody conjugates (ISACs) utilize an innate immune agonist to promote lymphocyte activation in the tumor microenvironment, ultimately resulting in tumor regression and immune memory. While this technology has elicited powerful efficacy in various preclinical models, there have been a number of clinical setbacks and disappointments that have tempered the enthusiasm for this technology. We will describe the current state of the field of ISAC technology and will describe new ISAC designs that are being employed by our lab to overcome some of the reported clinical challenges. Specifically, we will focus on the role of Fc-gamma receptors in the efficacy and toxicity of ISACs.
Plasmodium falciparum RH5 (PfRH5) is the most advanced blood-stage malaria vaccine candidate, with proven efficacy both in pre-clinical and early clinical studies and the potential to elicit strain-transcending antibody responses. From clinical trial PBMCs, we isolated and functionally characterised a large panel of anti-RH5 IgG monoclonal antibodies to better understand the features of the PfRH5 vaccine-induced antibody response. We selected a diverse subset of these mAbs to determine their efficacy against P. falciparum clinical isolates from natural infection.
Oxidative stress occurs in many autoimmune diseases which give rise to oxidative post translationally modified (oxPTM) neoepitopes that are recognized by the immune system as ‘non-self’. The detection of autoantibodies against oxPTM neoepitopes, might improve early diagnosis and monitoring of disease activity. Importantly, oxPTM neoepitopes accumulating in the diseased tissue can be exploited for targeting therapeutic specifically to diseased tissue. Studies on musculoskeletal diseases and type 1 diabetes will be reviewed.
Characterizing the binding parameters (ka, kd, KD) of antibody:receptor interactions is crucial in drug discovery. However complex Abs and/or receptors are not always amenable to traditional biophysical methods (i.e., SPR, BLI, etc.), necessitating cell-based binding assays. We developed a pre-equilibrium assay to simultaneously determine the binding kinetics of up to 30 therapeutic Abs on living cells.
We will discuss the key challenges in creating and deploying machine learning for biologics discovery. While creating complex models for discovery and development is becoming commonplace, managing the entire ML model lifecycle is essential for effective use in therapeutic research and maximizing AI investment returns. Discover how a unified platform can streamline AI use in biologics discovery, from model training to consumption.
Pancreatic ductal adenocarcinoma (PDAC) is an immunologically cold disease. Increasing immune cell trafficking and activation in PDAC are therefore important for understanding response to immune checkpoint therapies (ICT). Mathematical modeling of the tumor microenvironment (TME) allows us to elucidate the features of PDAC that can determine responsiveness to ICT. By integrating mathematical models with spatial data from patients, we can identify the specific mechanisms in the TME that regulate immune cell trafficking during ICT treatment.
99% of a dose of an ADC is eliminated by normal tissues, causing efficacy limiting toxicities. Shasqi has developed an approach to overcome this problem by separating tumor binding from the payload and enabling selective payload activation at the tumor using click chemistry. This approach maximizes efficacy and therapeutic index by reducing toxicities.
The Lysosome Targeting Chimera (LYTAC) is a targeted protein degradation modality that utilizes receptor-mediated endocytosis to drive internalization and lysosome-mediated degradation of extracellular target proteins. In this presentation, we will disclose application of Lycia’s platform to design and generate small molecule conjugate and fully biologic LYTACs that promote strong in vitro and in vivo depletion of protein targets of interest.
2025 marks 50 years since the discovery of monoclonal antibodies, almost 75 years after Paul Ehrlich’s proposal of a ‘magic bullet’ to selectively target disease-causing organisms. Monoclonal antibodies have been a magic bullet tackling tough-to-treat diseases, but many promising targets remain undruggable. Novel antibody drug conjugates, as well as receptor-based shuttles and protein degraders, approaches using antibodies are poised to unlock many of these targets.
OmniHub significantly enhances the operational efficiency of antibody discovery workflows by automating data handling. This reduces manual effort, provides standardization, and minimizes errors. OmniHub integrates machine learning (ML) and artificial intelligence (AI) tools, along with bioinformatics pipelines, to create a comprehensive interface that allows internal and partner scientific teams to collaborate through shared data visualization and analysis. As a result, OmniHub lays the foundation for innovative and collaborative scientific discovery.
Identifying novel epitopes naturally targeted by the human antibody repertoire is an important component of immunogen design aimed at eliciting protective antibodies to infectious disease. I will describe techniques used to survey and characterize monoclonal antibodies generated in response to experimental vaccines in human clinical trials.
Thermo Fisher Scientific’s GeneArt Protein Expression Services offer scalability, reproducibility, and speed in transient expression of recombinant antibodies. We give insight in the technical as well as experimental design process to develop an automated platform with end-to-end traceability in a fully integrated workflow starting from single nucleotides to deliver a purified and polished antibody product.
We have developed a droplet-microfluidic single-cell-based platform for the repertoire biobanking and expression of the antibodies of up to one million human B cells in HEK cells. This cognate biobank represents 80% of the input cells, the robustness of this format enables any screening process including droplet microfluidic sorting.
This technology is applied for the direct discovery of tumor-reactive antibodies from tumor-infiltrating B cells in cell-based assays.
This presentation will explore how Adimab has revolutionized antibody discovery, growing from an innovative startup into a leading platform technology company. We will examine key technological breakthroughs in our platform, focusing on synthetic antibody library evolution, advances in multispecific generation, and novel approaches to developability optimization. Join us to learn how Adimab's engineering-driven approach is shaping the future of therapeutics.
The Dropzylla® Technology is a high-throughput microfluidic platform designed for the cloning of antibody repertoires. These recombinant repertoires are used to identify best-in-class antibodies targeting cancer and viral infections. MTx’ lead program, AntiBKV, is a highly effective and safe neutralizing antibody to treat BK virus infections in kidney transplant recipients. The oncology program aims to discover novel antibody-target pairs directly from tumor B cells.
Discovery of biotherapeutics against challenging targets such as integral membrane proteins, membrane protein complexes, and heavily glycosylated surface proteins using display technologies remains a challenge. We have utilized therapeutic-ready phage- and yeast-display platforms expressing a diversity of formats to pan against both cells and virus-like particles. Using these novel reagents and protocols, we have managed to discover biotherapeutics to traditionally display "unfriendly" targets.
Twist Biopharma Solutions, a division of twist Bioscience, combines HT DNA synthesis technology with expertise in antibody engineering to provide end-to-end antibody discovery solutions — from gene synthesis to antibody optimization. The result is a make-test cycle that yields better antibodies against challenging targets from immunization, libraries, and machine learning. Twist Biopharma Solutions will continue to optimize and expand its discovery, library synthesis and screening capabilities in partnership with others to further utilize their make-test cycle.
Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies has shown anti-tumor activity in human trials but can be associated with significant off-tumor toxicities. We designed and validated a tandem Fc-free tumor-specific 4-1BB agonist antibody fused to an engineered albumin sequence with high FcRn binding and favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor microenvironment. The antibody exhibited prolonged circulating half-life and in vivo tumor inhibition with no evidence of 4-1BB-associated toxicity when administered as purified protein or nucleoside-modified mRNA encoding the antibody.
Early-stage biotech companies must walk a fine line between innovation and risk management. For some companies, this means working with a clinically validated MOA and differentiating from first movers based on target and indication selection or significant functional improvements. As part of the highly active T-cell engager field, our team has successfully created multiple differentiated platforms.
Quickly obtaining qualified clones from multiple antibody generation technologies is crucial for advancing functional antibodies that eventually constitute the therapeutics of tomorrow.
ImCheck has created a set of bispecific antibodies, exploring different formats and valency to modulate anti-BTN3A agonist potency. Building on these modalities allowed to explore Vγ9Vδ2 T cell stimulation via BTN3A-mediated signal 1, immune checkpoint blocking and cis/trans anchoring to potentiate anti-tumor activity.
Obexelimab is a CD19 x FcgRIIb bifunctional monoclonal antibody resulting in an inhibitory effect, rather than depletion, across B cell lineage (pro-B cells, pre-B cells, B cells, plasmablasts and CD19-expressing plasma cells). It mimics natural antigen-antibody complex for inhibition of B cells. It is being developed for multiple I&I indications for autoimmune diseases. Clinical data from obexelimab-treated patients and relevant mechanisms of action will be discussed.
The therapeutic potential of T cell engagers (TCE) has been limited by a narrow safety window, with excess cytokine release and on-target toxicity limiting their clinical usefulness. Our Tumor-Microenvironment Activated Therapeutics (T-MATE™) platform overcomes these challenges by utilizing a pH-dependent conformational switch. This innovative mechanism attenuates TCE activity at physiological pH while preserving full potency within the tumor microenvironment, enabling a new class of safe and effective TCE therapeutics.
This presentation highlights the development of ARGX-117, a recycling anti-C2 antibody designed to inhibit complement activation. We trace its journey from laboratory innovation to phase 2 proof-of-concept studies, showcasing its potential as a therapeutic strategy for multifocal motor neuropathy patients.
T cell engaging antibodies (TCEs) are effective therapeutics for patients with diverse malignancies when adequately targeted to tumor biomass. We show that ML methods can support the efficient design of TCEs, including via boolean logic, targeting co-expressed tumor antigens and sparing healthy tissues expressing either antigen, even at high receptor densities. Overall, we demonstrate how AI/ML design with rapid, closed loop wet-lab characterization supports the systematic design of safe and effective TCEs.
Despite advances in cancer therapeutics, new protein targets and targeting approaches for drug development are needed. We developed a high-resolution proximity proteomics technology using photocatalyst-generated reactive probes to label discrete cell surface protein microenvironments. Combined with quantitative mass spectrometry, we characterize plasma membrane protein interactomes and integrate proximity proteomics data with clinical protein expression profiles through computational graphs and graph convolutional neural networks (GCNNs). This membrane interactomics (MInt) database enables the unbiased identification of inherently proximal surface antigens in tumor microenvironments and facilitates precise dual-targeting of malignant cells. Utilizing our platform to identify proteins inherently proximal to EGFR on tumor cells, we identified CDCP1 as a TAPA (tumor associated proximity antigen) of interest. Our findings led to the development of IDP-001, a novel bispecific ADC targeting EGFR and CDCP1, anticipated to enter clinical trials in 2026. Identification and characterization of IDP-001 will be presented.
This talk describes the regulation of energy balance and appetite beyond traditional hormonal mechanisms. We discuss Peptide Predictor, a computational tool that identified BRINP2-Related Peptide (BRP), an anorexigenic peptide cleaved by PCSK1. BRP significantly reduces food intake and obesity through a unique central signaling pathway, without affecting other metabolic behaviors. This discovery highlights the potential of peptide prediction platforms in uncovering new metabolic regulatory mechanisms and biological pathways.
The central role of FcRn in regulating IgG persistence and transport provides opportunities for therapy. In particular, the depletion of IgG using FcRn antagonists represents a new class of therapeutics to treat antibody-mediated autoimmunity. Recent developments related to the modulation of IgG levels, including mechanistic aspects of FcRn antagonism, will be presented.
Antibodies blocking the immunosuppressive receptor PD-1 on immune cells or its major ligand PD-L1 on tumor and stromal cells have become foundational in oncology. Their wide-ranging applications are now extending across more than 20 cancer types, and from advanced to earlier stages of cancer. The discovery of biomarkers predicting therapeutic response/resistance holds promise for further advancing this mode of cancer therapy.
ALL has become a model disease for novel immunotherapeutic approaches Here, we report on our studies using antibodies of either IgG1 or IgA2 isotype to mediate killing of ALL cells in vitro and in PDX models. These results suggest to investigate the clinical efficacy of IgA antibodies in combination with myeloid checkpoint blockade in ALL.
Na+/K+–adenosine triphosphatase (NKA) is a transmembrane protein consisting of three subunits: a, b, g. A progressive decline of NKA activity exacerbates neurodegeneration in the aging process. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (897DVEDSYGQQWTYEQR911) of the NKAa1 subunit. It was demonstrated that DR5-12D produced therapeutic effects against neurodegenerative diseases. Therefore, DR5-12D may represent a new therapeutic strategy for neurodegenerative diseases.
The key components of Synaffix’s proprietary ADC technology GlycoConnect®, HydraSpace®, and the toxSYN® platform enabling ADCs with best-in-class therapeutic index potential will be presented. Next, an overview on the pipeline of more than 16 GlycoConnect® ADCs that are rapidly being advanced by our partners will be provided, followed by sharing clinical development insights on the most advanced assets.
The discovery of agonistic antibody drugs has been severely limited by the difficulty of identifying epitopes that support the productive engagement of the signaling complex. Using a combination of experimental and computational approaches, we generated agonist antibodies that activate the ALK1 pathway to treat vasculopathies. The techniques we developed can generate agonist antibodies against any heteromeric receptor complex, opening new opportunities to treat many human diseases with precision biologics drugs.
The FORCE™ platform was designed to enhance delivery of oligonucleotide to muscle for the treatment of neuromuscular disorders by conjugating them to an antigen-binding fragment (Fab) that is selective for the human transferrin receptor 1 (TfR1). In this presentation, we introduce the properties and modularity of the FORCE platform and provide evidence of translation between pre-clinical models and clinical proof of concept in myotonic dystrophy type 1 (DM1) with DYNE-101.
Proteins mediate the critical processes of life and beautifully solve the challenges faced during the evolution of modern organisms. Our goal is to design a new generation of proteins that address current-day problems not faced during evolution. In contrast to traditional protein engineering efforts, which have focused on modifying naturally occurring proteins, we design new proteins from scratch to optimally solve the problem at hand. Increasingly, we develop and use deep learning methods to design amino acid sequences that are predicted to fold to desired structures and functions. We also produce synthetic genes encoding these sequences and characterize them experimentally. In this talk, I will describe several recent advances in computational protein design.
Key considerations in starting and investing in companies focused on antibody- based therapeutics include the importance of choosing the right target, molecule attributes and format, clinical indication, investors and team. I will also discuss the differences in drug discovery at large biotech/pharma versus at a smaller company including portfolio considerations.
Barzolvolimab is a first-in-class anti-KIT monoclonal antibody designed to inhibit activation of and deplete mast cells (MC) through an allosteric mechanism. Barzolvolimab contains Fc-modifications resulting in decreased FcyR binding and enhanced pharmacokinetics. Here we describe its discovery through Phase 2 clinical development and highlight its use in patients with MC-driven disorders.
Chain exchange technologies can be used to generate binder-format matrices of bispecific antibodies. Similar to the optimization of bsAbs, chain-exchange can also generate ADC-matrices by combining different binders, formats, attachment-positions and payloads. As an example, a Her2-ADC matrix with payloads attached in different formats, positions and stoichiometries reveals that ‘format-defines-function’ applies not only to bsAbs but also to ADCs.
Artificial intelligence (AI) is transforming antibody discovery and engineering. Ailux's platform synergistically combines the best of our comprehensive wet lab, AtlaX proprietary database, and three AI engines. We will explore a series of case studies that exemplify our AI-driven approach for tackling hard targets, engineering challenging molecules, and accelerating conventional discovery campaigns. This presentation provides our realistic and evidence-based perspective on AI’s impact on the industry.
At-line nanoparticle-based molecular structure analyses were performed on antibody samples in Clarified Fermentation Broth using ProteometerTM kits, which provide rapid analytical tests for titer, aggregates, and charge variants. The Novilytic Proteometer's nanotechnology is for Process R&D and Discovery scientists/engineers who need a more efficient method of molecular structure analysis. Unlike LC/MS instruments, Proteometers provide fast, accurate, and quantifiable molecular data in-process without sample preparation or Protein A purification.
Asymmetric bispecific antibodies have a great potential for becoming the next big leap for antibodies, but present challenges for purification. One way to purify these molecules is by using avidity effects on affinity protein A and protein L resins. In this presentation, we show newly developed tools and a systematic approach that can be used to achieve high purity of the correctly paired antibody in the capture step.
IgA can be a well-suited isotype for therapeutic application in oncology due to its capacity to activate myeloid cells, especially neutrophils. However, therapeutic use is limited through issues with developability, pharmacokinetics, and in vivo translatability. In my talk, I will address the steps we have taken to employ IgA optimally for oncology.
Bispecifics and multispecifics that use only one light chain are a preferred format in view of manufacturability. We have established straightforward procedures to generate common light chain multispecifics from existing monospecific therapeutic antibodies, and we have also implemented an approach to obtain 2-in-1 symmetric antibodies where the light and heavy chain bind to different targets. We demonstrate that for bispecific multivalent T cell engagers the placement geometry of the binding modules is pivotal in controlling potency and mitigating cytokine release.
Wheeler Bio’s Modular CMC platform aims to provide biologics drug substance partners with flexible, tailored-made CMC development solutions across all stages of a molecule’s life cycle. Primarily developed for early-stage discovery organizations and Newco’s, Wheeler Bio is expanding its Modular CMC technology stack to include late-stage process design and biosimilar programming elements, offering similar flexibility, speed and service to partners. Aaron Pilling, Ph.D. will be presenting “Modular CMC” in the context of Wheeler Bio’s growth and expansion plans which include a new development and manufacturing facility, located in Oklahoma City’s growing Biotechnology hub.
MYTX-011 is an investigational, pH-sensitive, vcMMAE ADC. It has been designed to benefit a broader population of patients whose tumors express lower/moderate levels of cMET. MYTX-011 drives increased internalization and cytotoxicity and shows robust activity in xenograft models across a range of levels of cMET expression. Early clinical data demonstrate a differentiated profile: extended PK, low free MMAE release, and low incidence of side effects commonly associated with vcMMAE ADCs.
The design and implementation of phage display antibody libraries for discovery and optimization of antibodies, called ALTHEA Libraries, will be presented. The potentail of these antibody discovery platforms will be illustrated with two case studies: (1) isolation and optimization of broadly anti-SARS-CoV-2 neutralizing antibodies and (2) generation and characterization of a panel of anti-PD-1 antibodies with diverse binding and functional profiles.
IgG-based therapeutics may eliminate a target via Fc-mediated effector mechanisms. However, there is a need for more potent formats. The TandemAb concept combines structural elements of IgA with that of IgG, and results in tailored designs with favorable plasma half-life and engagement of effector molecules that can eradicate tumor cells and bacteria.
Immunocore has developed ImmTAAI, a new class of bispecific protein therapeutic designed to deliver targeted immunomodulation to treat autoimmune diseases. The effector domain comprises an agonistic anti-PD-1 VHH, which is biologically active only when target-bound and does not compete with natural ligand (PD-L1/L2), providing a wide therapeutic index. Using this targeted approach we have developed a novel bispecific molecule which specifically targets pancreatic beta cells to potentially treat type 1 diabetes.
Explore how Alloy Therapeutics' ATX-Gx™ Humanized Mouse Platform accelerates therapeutic antibody discovery with unmatched strain diversity and affordability. Focused on the ATX-GKH strain, featuring enhanced immune responses and superior antibody output, this technology empowers partners to build robust pipelines, delivering high-affinity candidates against challenging targets with proven clinical success.
Immunogenicity risk assessment is an essential step in bringing therapeutic drugs to the market. ProImmune's risk management tools evaluate immunogenic epitopes and the corresponding functional T cell responses that can lead to unwanted immune responses. Case studies will highlight how the integrated platform is used to address key questions in the drug development phase.
Explore how Heavy Chain Only Antibodies (HCAb) function as versatile building blocks for bispecifics. Understand the potential of fully human HCAbs derived from Harbour Mice® in developing bispecifics with outstanding druggability. Delve into the next-generation HBICE® bispecific platform for immune cell engagement. Discover emerging technology platforms on the horizon. Examine an engaging case study of HBICE® from concept to IND.
Degrader antibody conjugates (DACs) combine the unique strengths of ADCs with selective protein degraders. Our state-of-the-art platform enables DACs broadly. Degraders with different mechanisms of action and diverse structures can be delivered in antigen-dependent manner opening exciting opportunities for this novel therapeutic modality.
A recent clinical trial involving MOv18 IgE, provided tantalising evidence of IgE’s potential for the treatment of cancer. Epsilogen is conducting a phase Ib trial in which translational data will be collated to further understand mechanisms associated with IgE therapy. In addition, Epsilogen has established a pipeline of anti-tumoral IgEs and two novel platforms: bispecific IgE and a hybrid antibody which combines the effector functions of IgE and IgG.
Many antibody-based drug candidates require additional engineering such as affinity maturation, humanization, cross-reactivity and improved stability for optimal therapeutic efficacy. Here, we discuss TumblerTM, a validated CDR shuffling approach for customizable antibody optimization. This method utilizes diversity from our in-house libraries and near-parental sequence space CDR variants, grafted into a human framework, to minimize redundancy and maximize functional diversity. The talk will highlight a variety of engineering successes, including affinity maturation, induction of cross-binding, and humanization campaigns. The presentation will also showcase how Tumbler maximizes diversity and provides valuable insights about sequence-activity relationships. With over a dozen successful project outcomes across a diverse set of targets, Tumbler offers a robust and flexible antibody engineering solution to help accelerate therapeutic candidates through the drug development process.
PolyMap is a high-throughput method for mapping thousands of protein-protein interactions in a single tube. Here we probe antibody libraries isolated from human donors against a set of SARS-CoV-2 spike variants to demonstrate how PolyMap can be used to profile immune responses, map epitopes of hundreds of antibodies, and select functionally distinct clones for therapeutics.
Radiolabeled antibodies are essential in cancer theranostics and radio-immunotherapy (RIT) due to their high specificity for cancer antigens. While promising, RIT faces challenges including long half-life leading to prolonged radioactivity exposure. This presentation explores strategies to improve RIT efficacy and safety, including combination therapies with drugs that modulate radiation response or interact with the immune system, as well as antibody modifications, and optimized administration techniques.
This session will explore effective strategies for accelerating lead selection from a diverse panel of antibodies. Key techniques presented include proprietary methods for leveraging the unique immune system of rabbits, early epitope landscape profiling, and the use of IPA's in silico-driven humanization workflow. This approach combines thorough risk assessment, early de-risking, and high-throughput, in vitro kinetic profiling, resulting in the rapid delivery of optimized antibodies ready for clinical development.
Natural killer (NK) cells play a vital role in the human innate immune system and NK cell engagers are being explored as a promising approach for cancer and autoimmune disease immunotherapy. Using AvantGen's Germliner™ Library Collection, we've isolated and developed a panel of highly specific fully human CD16a antibodies that exhibit potent activities in killing target cells in various NK cell engager formats.
Protecting antibody innovations globally faces increasing challenges, both due to different laws in different countries as well as evolving legal standards, particular in the US and Europe. My talk will focus on potential strategies to a) cover products, b) throw patent obstacles in front of biosimilars and c) generate third party licenses for platform technologies.
T-cell engaging bispecific antibodies have had tremendous success in treating hematologic tumors but have shown limited efficacy in solid tumors. Alternative strategies for engaging the immune system employing safe and tunable bispecific antibodies are needed to overcome the challenges of solid tumors. In this presentation, we describe the bispecific platforms developed at Rondo Therapeutics and highlight progress on our lead program, RNDO-564, a CD28 x Nectin-4 bispecific antibody for treatment of metastatic bladder cancer.
To date, over 150 drugs have been approved by the FDA for treating or preventing autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Despite this comprehensive arsenal of therapies, there remains a significant unmet medical need for many patient groups. Elasmogen has designed a first-in-class soloMER drug conjugate tailor-made for autoimmune and inflammatory diseases. This innovative treatment utilizes a super-potent, novel-acting multivalent anti-TNFα soloMER to site-deliver an anti-inflammatory JAK inhibitor payload, Tofacitinib.
Most preclinical models fail to predict the clinical PK of antibodies and related molecules. To develop models for antibody PK studies, The Jackson Laboratory created a series of transgenic humanized models incorporating several genetic modifications. These models were shown to be effective in assessing the clinical half-life of WT and Fc-modified antibodies and allow efficient lead selection and prediction of the clinical PK parameters of therapeutic antibody candidates.
Biocytogen provides a unique, fully characterized library of fully human antibody binders targeting over 1,000 druggable proteins. Several bispecific ADC assets, utilizing a common light chain and our proprietary Top1 payload, are now in clinical trials. RenNano mice generate fully-human nanobodies for next-generation ADC.
The pathogenicity of autoreactive antibodies has been demonstrated for many autoimmune diseases and the isotype/subclass profile can potentially influence the disease pathophysiology. Although often overlooked, IgA autoantibodies are increasingly recognized in different autoimmune indications. Here, we describe the development of anti-IgA monoclonal antibodies that can actively remove IgA from the circulation and block binding of IgA to its main Fc receptor FcαRI. Given the abundancy of IgA in human serum (1-3 mg/mL), both Fab and Fc engineering were optimized to design a monoclonal antibody with the desired properties.
The unique cell-to-cell crosslinking action of T-cell engagers (TCEs) poses challenges for in vitro to in vivo translation. Recent advances in QSP models of TCEs capture key biophysical details of crosslinking, enabling rational techniques for first-in-human dose selection and efficacious dose prediction from in vitro potency assays and preclinical animal studies. This talk will review these developments and explain how QSP models can support and accelerate TCE development.
Mast cells (MCs) are key players in many allergic and inflammatory diseases. Briquilimab is a monoclonal antibody that binds to c-Kit, blocking stem cell factor from binding and activating c-Kit, leading to MC apoptosis and depletion. Pharmacokinetic and pharmacodynamic evaluation of briquilimab in non-human primates and in murine disease models of asthma and dermatitis suggest that briquilimab-mediated depletion of MCs is well-tolerated, protects against MC activation from various stimuli, and significantly reduces tissue inflammation.
Immunostimulatory antibody conjugates (ISACs) often rely on Fcγ receptor (FcγR) interactions to activate immune cells and drive tumor regression. However, these interactions may also contribute to immune-related side effects. To address this, we are developing deglycosylated ISACs that bypass FcγR binding. Tested in HER2+ breast and Trop2+ pancreatic cancer models, these ISACs maintained potent tumor-specific immune activation while potentially minimizing off-target effects. Ongoing studies are exploring the link between immunogenicity and FcγR binding.
CD3 bispecifics are clinically validated modalities, but none of the 9 approved molecules incorporates a costimulatory signal for optimal T-cell activation. EvolveImmune has integrated natural CD2 costimulation and affinity-tuned CD3 engagement into our EVOLVE platform, which induces sustained T-cell activation and potent redirection against tumor cells, whilst limiting T-cell exhaustion.
The field of therapeutic antibody engineering is on the brink of a transformative leap forward with the advent of Geneious-Luma-supported computational design. This cutting-edge platform promises unparalleled precision and efficiency in the discovery of next-generation multispecific antibodies (msAbs). This talk will delve into the myriad challenges inherent in researching and developing therapeutic msAbs, and will showcase how the Geneious-Luma computational design platform adeptly addresses these challenges, paving the way for more successful biologics drug treatments.
It is relatively straightforward to select antibodies or VHHs that bind targets, but much more challenging to generate antibodies with functional activity. Here we describe the use of TripleBar’s microfluidics system to select functional CD3 activating antibodies from Specifica’s Generation 3 library platform.
Multivalent interactions enable complex molecular recognition and signaling processes, such as the initiation of the classical complement pathway (CCP). This presentation gives an overview on how the CCP is initiated through antigen-dependent oligomerization of IgGs and subsequent recognition and activation of the multivalent zymogen C1. The presented kinetic model may serve as a basis for optimizing antibody-engineering and PK/PD modelling.
Groundbreaking immunotherapies known as immune checkpoint inhibitors mobilize the immune system against cancer by blocking the protein interactions that suppress immune cell activation. However, limited response rates to these therapies necessitate the development of new molecules that act through alternative mechanisms. Here, we describe the discovery and design of multispecific antibody fusion proteins incorporating single-domain shark antibodies that improve upon clinical drugs, presenting a novel modality to advance cancer treatment.
The inability of large molecule therapeutics to cross the blood-brain barrier has remained a major obstacle for the treatment of neurological disorders. Numerous strategies have aimed to increase brain exposure of biotherapeutics; approaches which utilize transport across the BBB via the rich capillary network are expected to significantly increase exposure in the brain and additionally result in broad distribution throughout the brain. Our approach utilizes the Transport Vehicle (TV), which binds to receptors, such as the transferrin receptor (TfR) and CD98hc, present on the BBB via modifications to the Fc region of an IgG. The TV-targeted receptors are expressed on brain vascular endothelial cells and enable transport of bound molecules across the BBB to reach target cells in the brain parenchyma. The molecular architecture of the TV platform is highly modular and enables the delivery of numerous types of biotherapeutics, including antibodies, enzymes, proteins, and oligonucleotides with the potential to meaningfully increase drug concentrations and target engagement in the CNS for the treatment of neurological disorders.
Regulatory T cells (Tregs) are naturally occurring immune cells that modulate immune responses and promote tissue homeostasis. Treg dysfunction is characteristic of many chronic autoimmune and inflammatory diseases. Sonoma Biotherapeutics genetically engineers and expands patients’ Tregs as a “living therapy” with antigen receptors that target diseased tissue to regulate inappropriate immune responses, reducing inflammation and facilitating tissue repair without compromising host defense.
To address the limited therapeutic window of several targeted cancer therapies we developed a chemical cleavage reaction (Click-to-Release) that allows in vivo control over drug activity. It enables controlled on-target cleavage of ADCs in the TME through a click reaction with a trigger molecule given in a second step, expanding the target scope to non-internalizing receptors. And it enables off-target deactivation of radioimmunotherapy, by selective radiolabel cleavage and clearance from circulating radioimmunotherapeutics, decreasing bone marrow toxicity. This contribution will cover examples from both ends of the therapeutic window.
The tumor microenvironment is complex, frequently immune suppressive and has become established as a critical determinant of response to antibody therapy. Understanding the tumor microenvironment in patients, including the contribution of host factors such as body composition and metabolic dysregulation on its inflammatory status, and modelling these effectively will likely be critical to advancing drug development and combination strategies. Here we will present data demonstrating that metabolic modifiers can alter the tumour immune environment in patients and then using preclinical models that this can be used in combination therapy to enhance response to immune checkpoint blockade.
This presentation will describe pre-clinical data from Regeneron’s clinical approaches to enhancing anti-tumor efficacy of T cells, focusing on the combination of costimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of T cell targeted enhancement strategies in pre-clinical development will be discussed.
Here I will describe how innovative techniques in mass spectrometry provide unique novel insights into our humoral immune response. In our body we produce every day huge amounts of antibodies, of which many end up in circulation. Humans can make about trillions of distinct antibody clones, all exhibiting a different sequence, recognizing distinct antigens. We recently developed new LC-MS based antibody repertoire profiling methods for studying immunoglobulins in a quantitative manner. By now, we analysed a variety of samples (sera, milk and saliva) from both healthy as well as diseased donors, allowing us to make some paradigm-shifting observations of which several I will highlight in this talk.
The extracellular proteome plays central roles in health and disease. Harnessing TfR1, a constitutive, rapidly internalizing receptor, we developed Transferrin Receptor Targeting Chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins. In two applications, TransTACs enabled the targeting of drug-resistant EGFR-driven lung cancer and reversible control of CAR-T cells. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of extracellular proteins and for targeted cancer therapy.
At Lightcast we are developing a next-generation technology platform that enables the direct, precise interrogation of single cell heterogeneity, interactions and functional dynamics at scale. Across a broad range of disciplines from basic and translational research to drug discovery, we provide the freedom to accelerate discovery and apply novel biological insights. This session will provide an overview of the technology and explore the potentially powerful impact in understanding and applying single cell functional understanding in some key areas of cancer therapeutics.
We present our forward translation strategy for evaluating off-the-shelf T cell engagers in combination with costimulatory agonists, employing advanced humanized mouse models to enhance preclinical insights. Our approach bridges the gap between preclinical and clinical research, showcasing the translational relevance of our findings. Additionally, we will share first-in-human Phase 1 clinical data supporting the predictive value of our preclinical platform and its potential to inform therapeutic development. This integrated strategy underscores the promise of our platform in advancing immunotherapeutic approaches
The development of antibody-based therapeutics necessitates precise target engagement to minimize off-target effects and ensure optimal safety profiles. This presentation outlines a systematic de-risking strategy leveraging multiple New Approach Methodologies (NAMs) platforms, with an emphasis on the Retrogenix® Cell Microarray Technology and in vitro safety profiling in both human and non-human primary cells. This comprehensive approach is designed to effectively identify and mitigate potential liabilities.
ADCs and TCEs are important therapeutic modalities. This presentation covers ADC & TCE antibody discovery from BsAb molecular design and antibody discovery platform selection to fit-for-purpose screening and characterization. We share our extensive experience in TCEs, highlighting key considerations for TCE optimization, such as epitope selection, affinity tuning, and PK. For ADCs, we showcase innovative early candidate screening platforms, including high-throughput internalization assays and bio-conjugation, ADC killing and stability assays.
DuoBody®-EpCAMx4-1BB (BNT314/GEN1059) is an investigational Fc-silenced bispecific antibody (bsAb) designed to boost antitumor immune responses through EpCAM-dependent 4-1BB agonist activity. EpCAMx4-1BB bispecific enhanced T cell proliferation, activation and cytotoxic capacity of activated T cells in vitro and exhibited antitumor activity in vivo. Moreover, combining EpCAMx4-1BB with PD-1/PD-L1 axis blockade potentiated all these responses. These data provide preclinical rationale for the clinical evaluation of DuoBody-EpCAMx4-1BB.
We will present the progress of our Radio-DARPin therapeutics, designed for selective delivery of radioisotopes to tumors and surface engineered to limit uptake in healthy tissues such as kidneys. We will highlight MP0712, our DLL3-targeted candidate advancing to first-in-human trials, and our Radio-DARPin program targeting membrane-proximal MSLN. Both programs are tailored to deliver 212-Pb, a potent alpha particle-emitting isotope, and are co-developed with our partner Orano Med.
Inhibitory checkpoint receptor (IR) agonists have the potential to restore immune homeostasis for patients with autoimmunity but are limited by their ability to non-discriminately bind activating FcγRs. IR agonists anchored to FcγRIIb, the inhibitory Fc receptor, have the potential to provide superior agonism by avoiding inflammatory cytokine responses and limiting APC activation. Discovery and development of a Dual-cell Bidirectional PD-1 FcγRIIb agonist antibody that activates multiple inhibitory pathways in more than one cell type to regulate both sides of the immune cell synapse will be discussed.
The paucity of dendritic cells in the tumor microenvironment is considered to be a limiting factor to immune checkpoint blockade efficacy in patients with cancer. These cells can be expanded in vivo by the growth factor FLT3L, however, used in its native form, FLT3L requires daily dosing up to 14 days, hampering its broader use in the clinic. Here we developed a FLT3L with effectorless NG2LH Fc fusion to improve drug-like properties that allows for sustained expansion of dendritic cells upon a single injection, and stimulation of antitumour immunity when combined with an adjuvant and checkpoint blockade in preclinical models. By easing dosing constraints, FLT3L-Fc NG2LH could facilitate exploration of FLT3L based immunotherapies in cancer patients.
Ion channels are an important target class which are under-served by biologics. Maxion have shown that small cys rich peptides with ion-channel modulating activity can be inserted into antibody CDRs while retaining their function. The resulting molecules modulate ion channel activity while benefitting from the optimal drug-like properties of antibodies. This presentation will illustrate the generation and optimisation of KnotBody inhibitors to therapeutically relevant ion channel targets.
Developability is a critical, yet often overlooked, aspect of the pipeline for therapeutic antibody development. Specifica utilizes highly functional antibody libraries for the identification of developable, drug-like antibodies (IgG or VHH) directly from discoveryor maturation campaigns. In this presentation we describe the latest advances to both our library designs and our pipelines to identify antibody leads with improved developability.
After vaccination, responding B cells may differentiate along the extrafollicular path, which leads to the production of short-lived plasmablasts, or along the germinal center (GC) route, which leads to the generation of long-lived plasma cells and memory B cells. GCs are the primary site of affinity maturation, the process whereby the binding affinity of induced antibodies to vaccine antigens increases with time after vaccination. We have recently shown that mRNA vaccination against SARS-CoV-2 in humans can elicit a GC reaction that engages pre-existing memory B cell clones and de novo ones that can target new epitopes, broadening the spectrum of vaccine-induced protective antibodies. These findings raised the following important questions: (1) What are the dynamics of vaccine-induced GC B cell responses in humans? (2) Do responding GC B cells accumulate somatic hypermutations (SHM) after mRNA vaccination? (3) Can a GC reaction be remounted upon repeat mRNA vaccination? These are some of the questions I will discuss in my presentation.
T-cell engaging bispecific antibodies have had tremendous success in treating hematologic tumors but have shown limited efficacy in solid tumors. Alternative strategies for engaging the immune system employing safe and tunable bispecific antibodies are needed to overcome the challenges of solid tumors. In this presentation, we describe the bispecific platforms developed at Rondo Therapeutics and highlight progress on our lead program, RNDO-564, a CD28 x Nectin-4 bispecific antibody for treatment of metastatic bladder cancer.
Add-on this optional pre-conference workshop to your main conference registration package and gain a comprehensive overview of antibody engineering in an easy-to-follow classroom setting to help you prepare for the main conference program.
- Workshop registration begins at 7:30 am
- Morning Break: ~10:30-10:50
WORKSHOP OVERVIEW
Today’s wealth of knowledge of antibody structures will be reviewed along with the genetics of diversity generation, to give insights into the best strategies for improving function. There is particular emphasis on the choice of a functional assay to effectively monitor the changes in a desired property, and the use of functional enrichment steps where a library approach is employed. Not only is amino acid sequence amenable to engineering, but glycan structures and other modifications may also be engineered. The course will focus on the engineering and enhancement of antibodies and antibody-like scaffolds. Examples will include work on antibody fragment affinity improvement by 100-fold to low pM affinity. Also, the engineering of bispecific antibodies by diverse approaches and the adaptation to generate Chimeric Antibody Receptor (CAR) constructs will be discussed. Expression platforms for producing antibodies for testing and for manufacture will also be covered. A background in biochemistry and molecular biology is useful, as the course is designed to progress rapidly from simple to advanced concepts.
INSTRUCTOR
David Bramhill, Ph.D., Founder, Bramhill Biological Consulting, LLC
WORKSHOP AGENDA
- Functions amenable to engineering: affinity, specificity, stability, solubility, immunogenicity
- The measure of success: functional assays
- Engineering by design
- Engineering by random mutation
- Designed libraries
- Display technologies
- Improving manufacturing by protein engineering methods
- Glycosylation engineering – function and homogeneity
- Other protein modifications
- Immunogenicity engineering
- Bispecific antibodies
- CAR-T strategies
- Expression of antibodies and fragments for discovery and testing
- Manufacturing platforms for antibodies and fragments
NOTE: The afternoon workshop “Introduction to Bispecific & Multispecific Antibodies” is an excellent complement to the morning introduction course.
Chugai has established various proprietary antibody engineering technologies. To effectively maximize the value of these established technologies, we have been applying them sequentially to multiple targets across disease areas. Several examples will be shared in this presentation.
FcRn functions as a recycling receptor to maintain levels of IgG and albumin. Efgartigimod (Vyvgart™) is a FcRn antagonist approved for treatment of IgG driven diseases. In this talk the engineering of a next-generation FcRn blocker with prolonged duration of effect will be discussed. Moreover, we describe the development of an anti-IgA monoclonal antibody that can actively remove IgA from the circulation. Given the abundancy of IgA in human serum (1-3 mg/mL), both Fab and Fc engineering were needed.
Fibrosis can affect multiple organs in the human body and significantly threaten human health. Early diagnosis and intervention are crucial for preventing disease progression. However, very few treatments are available to patients. Next-generation medications with novel mechanisms of action are demanded to broaden the responding patient population and improve the therapeutic index. WNT1-inducible signaling pathway protein 1 (WISP1, also known as CCN4), a matricellular protein, was identified as a novel drug target for fibrosis through analysis of the transcriptomic data of human cirrhotic livers. I will present the preclinical studies of targeting WISP1 for treating tissue fibrosis.
Recent breakthroughs in cancer immunotherapy have highlighted the potential of leveraging natural killer (NK) cells for cancer treatment, with NK cell engagers (NKCEs) emerging as a promising strategy. We will present the discovery of a panel of Nkp80 engagers, and the subsequent engineering of a trifunctional NKCE that targets HER2 on cancer cells while engaging Nkp80 and CD16a on NK cells (HER2-NKCE). HER2-NKCE demonstrated potent antitumor activity against HER2-positive cancer cells, with picomolar-range potency. It effectively targeted a range of HER2 expression levels, inducing NK cell activation and cytokine secretion exclusively in the presence of HER2-expressing cancer cells, significantly outperforming the HER2 antibody Trastuzumab. Moreover, the dual-engagement of Nkp80 and CD16a led to a robust immune response. Importantly, HER2-NKCE exhibited target-dependent cytotoxicity against cancer cells, while sparing HER2-positve normal cells, thereby minimising on-target off-tumor effect.
Abalone Bio’s Functional Antibody Selection Technology (FAST) platform is driven by a powerful combination of large-scale activity measurement and machine learning (ML) to identify and design activating antibody drugs against challenging targets. In combination with Abalone’s developability ML models, this enables the design of novel, therapeutically active and highly developable antibody sequences. Agonists for multiple GPCRs, including CB2, were identified using FAST, which have macrophage-modulating, anti-inflammatory activities in vitro and ex vivo in human precision-cut liver slices, and therapeutic activity in animal models of neuropathic pain and advanced liver cirrhosis. These antibodies activate their target through non-orthosteric mechanisms involving novel binding-function relationships that would have been difficult to discover without using large-scale activity-first selection methods like Abalone’s FAST platform.
Add-on this optional pre-conference workshop to your main conference registration package and gain a comprehensive overview of bispecific and multispecific antibodies t in an easy-to-follow classroom setting to help you prepare for the main conference program.
- Workshop registration begins at 12:30 pm
- Afternoon Break: ~ 3:30-3:50
WORKSHOP OVERVIEW
This workshop covers the key aspects of bispecific antibody design, how best to achieve desired therapeutic function, and then explores the challenges posed for manufacturing such complex molecules. The various parameters for a bispecific antibody are each examined – valency and affinity for engaging each individual target, optimum physical distances for desired binding and outcome, requirement for Fc function(s) or not, etc. A discussion of antibody formats that may be especially applicable to rapid screening of the optimum valency, affinity, spacing, etc., of each specific binding component is included. It is aimed to provide even beginners with explanations of the nomenclature and science.
INSTRUCTOR
David Bramhill, Ph.D., Founder, Bramhill Biological Consulting, LLC
WORKSHOP TOPICS TO BE DISCUSSED
- Review of Antibody Structure, Fc Function(s)
- Fundamental Bispecific Antibody Design Considerations
- Symmetric vs. Asymmetric Formats – Valency of Target Binding
- Is Fc Function Required for a Particular Bi-specific Antibody Therapeutic?
- Aligning Format with Desired Bispecific Antibody Function
- Examples of a Variety of Bispecific Antibody Applications, from T-Cell Engagers to crossing the blood-brain barrier
- Manufacturing Multi-subunit Bispecific Antibody Molecules
WHAT WILL YOU LEARN?
- Gain an overview of the key aspects for design parameters for Bi-specific Antibodies.
- Scientific terms and acronyms relating to Bi-specific Antibody will be defined and explained.
The development of antibody-based medicines can be accelerated by enhancing both our understanding and predictive power of antibody-antigen binding. For both purposes, affinity datasets from mutational scans are an important resource, but the factors driving affinity remain insufficiently understood. To address this, we present a multi-modal dataset of antigen and VHH interface variants, that captures changes in binding affinity, protein stability, and expression levels. We observe that the affinity change introduced by most mutations is largely explained by changes in stability rather than interaction-specific effects. Using this data, we confirm that structure-conditioned inverse folding models perform well in predicting the relative stability of protein variants. Finally, we quantify the ability of inverse folding models to capture interface changes of paratope variants and detect little predictive power for the interface changes in epitope variants. Our findings highlight the importance of high-quality, information rich datasets in advancing protein engineering efforts.
We present JAM, a protein design system capable of designing antibodies de novo with therapeutic-grade affinities, function, and early-stage developability for soluble and multipass membrane protein targets. For GPCRs, we show de novo designed antibodies have single-digit nM to picomolar binding affinities, and while most are functional antagonists, remarkably, a subset are agonists -- marking an important milestone in the field.
We will present our practical, platform-driven strategies for generating POC-stage antibodies targeting emerging targets in chronic diseases and oncology. These innovative antibody candidates have the potential to de-risk drug development and address unmet patient needs. Leveraging AI-powered platforms, we enable the discovery and engineering of next-generation antibodies with distinct mechanisms of action, novel modalities, and optimized drug-like properties.
Etcembly is the first company to leverage generative AI to discover and engineer T cell receptor (TCR) biologics for cancer immunotherapy. Using our proprietary machine learning platform, EMLyTM, we predicted the TCR-pHLA interface from sequence alone, leading to the discovery of our lead molecule, ETC-101, a TCR that recognises the PRAME cancer antigen peptide in complex with HLA-A*02. We show that ETC-101, which was designed in silico, was able to signal effectively to elicit T cell activation when expressed as a full-length TCR and was specific to its target peptide. Further predictions from EMLyTM enabled rapid affinity enhancement of the parent molecule by >5 million-fold, resulting in an ETC-101 TCR variant with picomolar affinity. When this high affinity variant was expressed as a bispecific T cell engager, ETCer (Etcembly’s T Cell Engaging Receptor), ETC-101 exhibited strong efficacy and was able to induce robust T cell-mediated cytotoxicity against a panel of target cancer cells. Early preclinical assessment and cross-reactivity screening of the ETC-101 ETCer also demonstrated a promising safety profile, and the suitability of this candidate TCR for advancement into translational development. Our data validates the strong predictive capability of our AI platform EMLyTM in TCR discovery and engineering. Functional characterisation of our lead TCR molecule ETC-101 demonstrates its potential as a novel drug candidate for the treatment of PRAME-positive cancer indications.
This talk will explore cutting-edge strategies for antibody display selections, highlighting their impact on the discovery of novel potential therapeutics, for established and novel format of antibodies: from Fab to VHH. The presentation will cover advancements in display technology approaches to optimize the selection of antibodies with precise features, presenting case studies demonstrating successful applications (e.g., anti-ID, pH sensitivity, specific epitope recognition). Future directions and unmet needs in the field to accelerate precision medicine and the development of new therapies will also be covered.
This presentation will explore how Adimab has revolutionized antibody discovery, growing from an innovative startup into a leading platform technology company. We will examine key technological breakthroughs in our platform, focusing on synthetic antibody library evolution, advances in multispecific generation, and novel approaches to developability optimization. Join us to learn how Adimab's engineering-driven approach is shaping the future of therapeutics.
Quick feedback on what people designed and produced and how these act in the system is essential for the development of novel molecules and formats, but this is challenging. Rigaku developed a 'Molecular projector, MoleQlyze' that can image large molecules and complexes in a solution without prerequisite information and crystallization/freezing/fixation/labeling processes. This enables overnight direct epitope mapping, molecular defects and aging monitoring during culture and purification processes, nucleotide-protein quantitation of vector complexes, and observation of defects in particles with the molecular 3D image under given conditions.
For more information about presenting in this session, please contact Michael Keenan at Michael.Keenan@informa.com
A recent clinical trial involving MOv18 IgE, provided tantalising evidence of IgE’s potential for the treatment of cancer. Epsilogen is conducting a phase Ib trial in which translational data will be collated to further understand mechanisms associated with IgE therapy. In addition, Epsilogen has established a pipeline of anti-tumoral IgEs and two novel platforms: bispecific IgE and a hybrid antibody which combines the effector functions of IgE and IgG.
At OmniAb, we build, shape and mine custom, naturally optimized human immune repertoires in divergent species to discover next generation biotherapeutics. Using our high throughput single B cell screening xPloration platform combined with an AI-guided NGS workflow, we identify drug-like leads, bypassing extensive ex-vivo engineering. We show examples of campaigns across various animal platforms that yielded broad and complementary epitope coverage of disparate specific targets, with a range of affinities, and favorable developability characteristics, increasing options for our partners.
Effective and specific non-opioid therapeutics for chronic pain with high efficacy and no side effects are urgently needed. We have reported that mouse scFv95, a small molecule specifically recognizing and blocking P2X4R, is a promising candidate for further characterization and humanization. Nine humanized scFv (hscFv) variants against an extracellullar fragment of human P2X4 were generated via CDR grafting using E. coli production and His-Tag protein purification. Affinity measurement by ELISA and SDS indicates binding affinity in the nanomolar range. More than 2/3 of humanized small molecules showed higher affinity than the parental protein. Octet measurements further revealed the lead HC3-LC3 had binding kinetics of KD = 2.5 × 10–9 M. No endotoxin or in vivo toxicity is noted. Functional validation in vivo in a trigeminal nerve injury model finds reversal of pain related behaviors within two weeks after a single dose (4 mg/kg, intranasal). The details of the development and characterization of a lead P2X4 hscFv HC3-LC3 small molecule provided here constitute an original method whereby durable reversal of nerve injury hypersensitivity can be accomplished. This study opens new avenues for research to develop humanized non-opioid therapeutic interventions for chronic pain.
ADCs and TCEs are important therapeutic modalities. This presentation covers ADC & TCE antibody discovery from BsAb molecular design and antibody discovery platform selection to fit-for-purpose screening and characterization. We share our extensive experience in TCEs, highlighting key considerations for TCE optimization, such as epitope selection, affinity tuning, and PK. For ADCs, we showcase innovative early candidate screening platforms, including high-throughput internalization assays and bio-conjugation, ADC killing and stability assays.
Biocytogen provides a unique, fully characterized library of fully human antibody binders targeting over 1,000 druggable proteins. Several bispecific ADC assets, utilizing a common light chain and our proprietary Top1 payload, are now in clinical trials. RenNano mice generate fully-human nanobodies for next-generation ADC.
Despite advances in cancer therapeutics, new protein targets and targeting approaches for drug development are needed. We developed a high-resolution proximity proteomics technology using photocatalyst-generated reactive probes to label discrete cell surface protein microenvironments. Combined with quantitative mass spectrometry, we characterize plasma membrane protein interactomes and integrate proximity proteomics data with clinical protein expression profiles through computational graphs and graph convolutional neural networks (GCNNs). This membrane interactomics (MInt) database enables the unbiased identification of inherently proximal surface antigens in tumor microenvironments and facilitates precise dual-targeting of malignant cells. Utilizing our platform to identify proteins inherently proximal to EGFR on tumor cells, we identified CDCP1 as a TAPA (tumor associated proximity antigen) of interest. Our findings led to the development of IDP-001, a novel bispecific ADC targeting EGFR and CDCP1, anticipated to enter clinical trials in 2026. Identification and characterization of IDP-001 will be presented.
For more information about presenting in this session, please contact Michael Keenan at Michael.Keenan@informa.com
A bispecific ADC targeting EGFR x HER3 was discovered, named PM1300, which has an asymmetric 1+1 IgG-like structure and optimized affinity. This allows for preferential binding to EGFR/HER3 double-positive cancer cells, rather than EGFR single-positive cells. This may significantly contribute to minimizing safety risk that is common for EGFR-targeting agents. Furthermore, this also significantly increased internalization efficiency and in vivo efficacy against EGFR/HER3 double positive tumor compared to 2+2 format ADC indicating a superior therapeutical window.
Amanitin-based ADCs (ATACs) offer a novel mode of action in targeted cancer therapy, distinct from traditional cytotoxic agents. With precisely engineered backbones, they enable the development of highly effective low DAR (Drug-to-Antibody Ratio) species, optimizing stability and therapeutic impact. Amanitin selectively inhibits RNA polymerase II, halting mRNA synthesis and inducing apoptosis. This unique mechanism targets both proliferating and quiescent tumor cells, tackling a key challenge in modern oncology: therapeutic resistance. HDP-101, a BCMA-ATAC, is in a Phase I/IIa trial for relapsed or refractory multiple myeloma. Currently in its sixth cohort, the study has shown promising results, including one complete remission and notable biological activity in several patients. Other ATAC portfolio candidates include HDP-102, an anti-CD37 ADC for non-Hodgkin lymphoma, and HDP-103, an anti-PSMA ADC for prostate cancer, showcasing the platform's versatility in addressing hard-to-treat malignancies.
This presentation will highlight the development of AT65474, a CLDN6-targeting ADC leveraging AxcynDOT™, a novel payload platform with enhanced potency and safety. AT65474 employs site-specific conjugation via AxcynCYS™ technology to achieve highly uniform DAR4 profiles (>97%), improving consistency and efficacy. We will present preclinical data demonstrating potent anti-tumor activity in CLDN6-positive CDX and PDX models, broad in vitro cytotoxicity across drug-resistant lines, and favorable safety in GLP toxicology studies. Key lessons in payload optimization, linker stability, and overcoming regulatory hurdles for IND readiness will also be shared, underscoring our approach to next-generation ADC development.
MabPair is a novel technology for making the next generation antibody combination products that are capable of targeting multiple molecules and pathways. The core technology is based on an antibody engineering platform that enables the production of two full length IgG molecules from a single production cell line. The technology platform can be used to develop therapeutic antibody products that contain a mixture of two different antibodies in a predefine ratio through the conventional antibody manufacture process. MabPair products can offer compelling advantages over bispecific antibodies or conventional antibody combination including abilities to achieve different level of target coverage for the two antibodies, full flexibility in choice of different Fc backbones for antibody effector function and pharmacokinetics profiles, streamlined regulatory and clinical development paths, and single-entity pricing power. Recently our first MabPair product was approved in China by NMPA. The talk will describe the process of generating MabPair products with case studies that highlight the unique feature of the platform and its potential applications in different therapeutic settings.
TfR1 is involved in iron uptake and cell growth. Many cancers express TfR1, but TfR1-targeted agents have safety risks. KK2260 is a REGULGENT™ technology-based bispecific antibody targeting TfR1 and EGFR. KK2260 resulted in EGFR-binding dependent TfR1 downregulation and demonstrated potent anticancer effect against EGFR-expressing tumors. Clinical study is ongoing (NCT06248411).
For more information about presenting in this session, please contact Michael Keenan at Michael.Keenan@informa.com
We present JAM, a protein design system capable of designing antibodies de novo with therapeutic-grade affinities, function, and early-stage developability for soluble and multipass membrane protein targets. For GPCRs, we show de novo designed antibodies have single-digit nM to picomolar binding affinities, and while most are functional antagonists, remarkably, a subset are agonists -- marking an important milestone in the field.
The development of antibody-based therapeutics necessitates precise target engagement to minimize off-target effects and ensure optimal safety profiles. This presentation outlines a systematic de-risking strategy leveraging multiple New Approach Methodologies (NAMs) platforms, with an emphasis on the Retrogenix® Cell Microarray Technology and in vitro safety profiling in both human and non-human primary cells. This comprehensive approach is designed to effectively identify and mitigate potential liabilities.
Machine learning is revolutionizing antibody engineering by leveraging generative AI models that incorporate systematically varied experimental data. Here, we utilize an iterative sparse dataset to affinity mature an antibody while simultaneously minimizing polyreactivity, increasing titer, increasing Tm, and reducing aggregation through multiobjective optimization. This innovative approach bypasses traditional methods, accelerating therapeutic development with precision and efficiency.
Most preclinical models fail to predict the clinical PK of antibodies and related molecules. To develop models for antibody PK studies, The Jackson Laboratory created a series of transgenic humanized models incorporating several genetic modifications. These models were shown to be effective in assessing the clinical half-life of WT and Fc-modified antibodies and allow efficient lead selection and prediction of the clinical PK parameters of therapeutic antibody candidates.
neoSwitch is a yeast strain with the capacity to ‘switch’ between surface display and secretion. Antibody fragments are secreted at high titers in multi-well plates and the raw supernatant is compatible with biolayer interferometry. When combined with the Opentrons Flex, neoSwitch enables turnkey automation of key workflows, including protein purification.
Developability is a critical, yet often overlooked, aspect of the pipeline for therapeutic antibody development. Specifica utilizes highly functional antibody libraries for the identification of developable, drug-like antibodies (IgG or VHH) directly from discoveryor maturation campaigns. In this presentation we describe the latest advances to both our library designs and our pipelines to identify antibody leads with improved developability.
At Hooke Bio, we design tailored fluid flow systems that integrate all your cells of interest, transforming the way immunotherapies are developed and tested.
Powered by our cutting-edge Mera system, we deliver circulating dynamic flow over complex 3D organoid models, allowing for precise assessment of off-target and/or solid tumour effects.
Our advanced in vitro studies, both standard and customized, enable researchers to screen novel therapeutics, uncover mechanisms of action, and accelerate clinical trial design. By identifying safe, effective immunotherapies at the preclinical stage, Mera helps drive more successful treatments, fewer side effects, reduced drug failures, and better disease prediction.
For immunotherapy developers seeking rapid access to next-generation technology, Hooke Bio provides a cost-effective solution—delivering physiologically relevant, human-based immunologic models without the need for expensive equipment.
We also offer a full suite of traditional assays, including flow cytometry, cytokine analysis, and immunochemistry analysis, ensuring comprehensive support for your research.
Accelerate discovery. Reduce risks. Improve patient outcomes.
Partner with Hooke Bio and take your immunotherapy research to the next level.
This presentation highlights the development of ARGX-117, a recycling anti-C2 antibody designed to inhibit complement activation. We trace its journey from laboratory innovation to phase 2 proof-of-concept studies, showcasing its potential as a therapeutic strategy for multifocal motor neuropathy patients.
To date, over 150 drugs have been approved by the FDA for treating or preventing autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Despite this comprehensive arsenal of therapies, there remains a significant unmet medical need for many patient groups. Elasmogen has designed a first-in-class soloMER drug conjugate tailor-made for autoimmune and inflammatory diseases. This innovative treatment utilizes a super-potent, novel-acting multivalent anti-TNFα soloMER to site-deliver an anti-inflammatory JAK inhibitor payload, Tofacitinib.
Immunocore has developed ImmTAAI, a new class of bispecific protein therapeutic designed to deliver targeted immunomodulation to treat autoimmune diseases. The effector domain comprises an agonistic anti-PD-1 VHH, which is biologically active only when target-bound and does not compete with natural ligand (PD-L1/L2), providing a wide therapeutic index. Using this targeted approach we have developed a novel bispecific molecule which specifically targets pancreatic beta cells to potentially treat type 1 diabetes.
The central role of FcRn in regulating IgG persistence and transport provides opportunities for therapy. In particular, the depletion of IgG using FcRn antagonists represents a new class of therapeutics to treat antibody-mediated autoimmunity. Recent developments related to the modulation of IgG levels, including mechanistic aspects of FcRn antagonism, will be presented.
T cell-engaging antibodies (TCEs) are bispecific adaptor proteins that connect any kind of cytotoxic T cells with target cells for redirected lysis. One arm of a TCE binds a surface antigen on the target cell, the other arm binds to the invariant CD3 epsilon subunit of the T cell receptor complex. Over the last three years, TCEs have seen an unparalleled surge in FDA approvals. A total of nine TCEs are now approved in oncology that very effectively treat as a monotherapy B cell-derived leukemia, lymphomas and multiple myeloma, and solid tumors derived from uveal melanoma and small cell lung cancer. TCEs specific for the B cell antigens CD19 and BCMA --as are approved for the treatment of leukemia, lymphomas and multiple myeloma— can also mediate deep and lasting depletion of normal and autoimmune B cells. First studies showed that this can lead to compelling remissions by TCEs in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A spade of clinical studies with B cell-depleting TCEs is under way to further explore their therapeutic potential. This presentation will focus on the development and properties of CLN-978, a novel CD19/CD3-bispecific TCE which is in clinical trials with RA and SLE patients.
Barzolvolimab is a first-in-class anti-KIT monoclonal antibody designed to inhibit activation of and deplete mast cells (MC) through an allosteric mechanism. Barzolvolimab contains Fc-modifications resulting in decreased FcyR binding and enhanced pharmacokinetics. Here we describe its discovery through Phase 2 clinical development and highlight its use in patients with MC-driven disorders.
Recent studies highlight the critical role of Fcγ receptor (FcγR)-mediated mechanisms in the efficacy and toxicity of checkpoint monoclonal antibodies (mAbs). In this talk, I will present our findings on how FcγR interactions influence mAbs' anti-tumor activity and treatment toxicity. I will also discuss our antibody-engineering strategies to optimize these mechanisms, aiming to develop safer, more effective immunotherapies.
DuoBody®-EpCAMx4-1BB (BNT314/GEN1059) is an investigational Fc-silenced bispecific antibody (bsAb) designed to boost antitumor immune responses through EpCAM-dependent 4-1BB agonist activity. EpCAMx4-1BB bispecific enhanced T cell proliferation, activation and cytotoxic capacity of activated T cells in vitro and exhibited antitumor activity in vivo. Moreover, combining EpCAMx4-1BB with PD-1/PD-L1 axis blockade potentiated all these responses. These data provide preclinical rationale for the clinical evaluation of DuoBody-EpCAMx4-1BB.
Stellabody® is a single point mutation in the CH3 region that facilitates “on-target assembly” of immune biologics that transforms killing or agonistic potency in multiple immune protein formats i.e. mAbs, bispecific antibodies, Fc-fusions and novel scaffolds. Stellabody biologics mediate greatly (10-100x) enhanced potency in head-to-head comparisons with the equivalent standard biologic including standard-of-care mAbs in oncology on primary patient-derived clinical samples and targets in infection and immunology.
Multivalent interactions enable complex molecular recognition and signaling processes, such as the initiation of the classical complement pathway (CCP). This presentation gives an overview on how the CCP is initiated through antigen-dependent oligomerization of IgGs and subsequent recognition and activation of the multivalent zymogen C1. The presented kinetic model may serve as a basis for optimizing antibody-engineering and PK/PD modelling.
A growing number of antibodies in development are based on a complex format; however, its impact on pharmacokinetic (PK) properties remains underexplored. We systematically determined the pharmacokinetic properties of a relevant format space in vitro and in SDPK mouse studies, thereby revealing structure-PK relationships in non-specific clearance, mediated by FcRn-recycling.
Alchemab’s approach to developing therapeutic antibodies is based on the concept that the immune system is able to generate protective autoantibodies which drive unusual disease resilience. By deep sequencing the B Cell Receptor repertoires of groups of resilient individuals and looking for convergence antibody sequences shared in these individuals, we can identify those rare protective antibodies, identify the targets they bind and harness and develop them into novel therapies. This approach has been successfully applied in neurodegenerative conditions and examples will be presented.
At Monod Bio, we’ve developed the NovoBody platform, which leverages AI-assisted computational protein design to generate novel binding molecules that exploit the binding interfaces of existing antibodies (or ScFvs, or VHHs.) The process eliminates suboptimal properties of the original molecules while enhancing key functionalities without requiring extensive discovery campaigns. The result is small, single-chain, highly stable molecules that are easy to manufacture in both bacterial and mammalian cells, with customizable properties—including bispecific binding interfaces—for diverse life science applications.
The Dropzylla® Technology is a high-throughput microfluidic platform designed for the cloning of antibody repertoires. These recombinant repertoires are used to identify best-in-class antibodies targeting cancer and viral infections. MTx’ lead program, AntiBKV, is a highly effective and safe neutralizing antibody to treat BK virus infections in kidney transplant recipients. The oncology program aims to discover novel antibody-target pairs directly from tumor B cells.
We present a novel discovery platform that seamlessly combines in vivo immunisation with in vitro antibody discovery by leveraging a novel microfluidics-based semi-permeable capsule technology for recovery of natively-paired VH:VL (scFv) repertoires from millions of B cells derived from immunised animals and integrating it with our cutting-edge mammalian IgG display platform. This innovative capability enables iterative screening of original immune repertoires in final IgG format and early selection of highly developable, target-specific antibodies, thereby improving therapeutic discovery workflows.
Deep Screening is a novel high throughput method for the rapid and massive parallel screening of biologics. It enables the experimental collection of up to 10^9 scFv sequences paired with binding affinities in a 3 day experiment, identifying hits where traditional methods fail. Here we will present recent work conducted at Sortera.
PolyMap is a high-throughput method for mapping thousands of protein-protein interactions in a single tube. Here we probe antibody libraries isolated from human donors against a set of SARS-CoV-2 spike variants to demonstrate how PolyMap can be used to profile immune responses, map epitopes of hundreds of antibodies, and select functionally distinct clones for therapeutics.
ImCheck has created a set of bispecific antibodies, exploring different formats and valency to modulate anti-BTN3A agonist potency. Building on these modalities allowed to explore Vγ9Vδ2 T cell stimulation via BTN3A-mediated signal 1, immune checkpoint blocking and cis/trans anchoring to potentiate anti-tumor activity.
HVEM, a member of the TNF receptor superfamily (TNFRSF14), interacts with several molecules, including BTLA, CD160, and LIGHT. HVEM is expressed not only on hematopoietic cells but also on non-hematopoietic cells, which allows it to regulate both the priming phase of T cells in the draining lymph node and the effector phase of the T cell response at the inflamed tissue site. The engagement of HVEM with BTLA provides negative signals, while LIGHT engagement delivers bidirectional positive costimulatory signals, promoting T cell survival and effector functions.
T-cell engaging bispecific antibodies have had tremendous success in treating hematologic tumors but have shown limited efficacy in solid tumors. Alternative strategies for engaging the immune system employing safe and tunable bispecific antibodies are needed to overcome the challenges of solid tumors. In this presentation, we describe the bispecific platforms developed at Rondo Therapeutics and highlight progress on our lead program, RNDO-564, a CD28 x Nectin-4 bispecific antibody for treatment of metastatic bladder cancer.
To better harness the anti-tumor activity of T cells on top of immune checkpoint inhibition, we generated a PD-L1/CD28 bispecific antibody using our κλ-body platform to promote antitumor function through a dual mechanism of action, immune checkpoint inhibition and T cell co-stimulation. In this presentation, we provide in vitro and in vivo evidence to confirm the safety and efficient anti-tumor activity of this dual-targeting strategy.
Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies has shown anti-tumor activity in human trials but can be associated with significant off-tumor toxicities. We designed and validated a tandem Fc-free tumor-specific 4-1BB agonist antibody fused to an engineered albumin sequence with high FcRn binding and favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor microenvironment. The antibody exhibited prolonged circulating half-life and in vivo tumor inhibition with no evidence of 4-1BB-associated toxicity when administered as purified protein or nucleoside-modified mRNA encoding the antibody.
To enable neoantigen peptides to serve as payloads in antibody-mediated targeted delivery strategies, we have developed a unique peptide tag (pTag)-scFv loading strategy that facilitates modular drug cargo loading. I will present our work on developing a novel CD40 agonistic antibody designed to bind both CD40 and the pTag-neoantigen cargo. We have explored the utility of this approach to expand CD8 and CD4 T cells in vivo and control tumor growth in lung and colorectal cancer models. Additionally, I will present unpublished data on the use of this platform for other drug modalities.
Here I will describe how innovative techniques in mass spectrometry provide unique novel insights into our humoral immune response. In our body we produce every day huge amounts of antibodies, of which many end up in circulation. Humans can make about trillions of distinct antibody clones, all exhibiting a different sequence, recognizing distinct antigens. We recently developed new LC-MS based antibody repertoire profiling methods for studying immunoglobulins in a quantitative manner. By now, we analysed a variety of samples (sera, milk and saliva) from both healthy as well as diseased donors, allowing us to make some paradigm-shifting observations of which several I will highlight in this talk.
2025 marks 50 years since the discovery of monoclonal antibodies, almost 75 years after Paul Ehrlich’s proposal of a ‘magic bullet’ to selectively target disease-causing organisms. Monoclonal antibodies have been a magic bullet tackling tough-to-treat diseases, but many promising targets remain undruggable. Novel antibody drug conjugates, as well as receptor-based shuttles and protein degraders, approaches using antibodies are poised to unlock many of these targets.
At OmniAb, we build, shape and mine custom, naturally optimized immune repertoires in divergent species to discover next generation biotherapeutics. We use high throughput phenotypic screening augmented by an AI-guided NGS workflow to navigate the vast sequence space and find high quality leads, bypassing extensive ex-vivo engineering. We demonstrate how we discovered developable anti-NKp46 binders with broad epitope coverage and affinities as building blocks for NK cell engager multispecifics.
OneChain Immunotherapeutics is developing advance CAR-T cell therapies targeting T-acute lymphoblastic leukemia (T-ALL). The use of CHO-derived scFvs support affinity tuning, epitope mapping, and benchmarking against competing candidates, while humanized scaffolds enable CAR optimization. CHO-produced anti-idiotype antibodies provide precise CAR detection and functional characterization. This integrated system bridges antibody engineering and CAR-T development, offering a scalable and rational approach to next-generation cell therapy design.
Combining single function antibodies into a bi-specific or multi specific format can present unique challenges. Stoichiometry, overall layout (IgG like, asymmetrical) and affinity can all play a key role in the success of a design with the desired activity and therapeutic developability. From multiple examples, it is clear that each bispecific development program should be treated as unique and that strategies are required to identify the optimal format. Abzena has developed a screening cascade which first places a strong focus on intelligent bispecific design which considers avidity, spacing as well as the use of different technologies. In combination with in silico analysis to identify and engineer the best partners for developability we can provide screening on a minimal number of smart designs. By leveraging unparalleled expertise in antibody production, purification, analytics and functional bioassays, we can rapidly identify and advance the most promising bispecific candidates.
Targeting novel pathways demands more than affinity. We’ll present an integrated workflow combining phage display, epitope-focused lead selection, and custom functional assays adapted for medium-throughput screening. By comparing legacy antibodies to new leads across activity, stability, and formulation-readiness, we identified candidates ready for testing in disease models. This case study illustrates how parallel optimization of function and developability streamlines antibody advancement for emerging therapeutic targets.
ADCs and TCEs are important therapeutic modalities. This presentation covers ADC & TCE antibody discovery from BsAb molecular design and antibody discovery platform selection to fit-for-purpose screening and characterization. We share our extensive experience in TCEs, highlighting key considerations for TCE optimization, such as epitope selection, affinity tuning, and PK. For ADCs, we showcase innovative early candidate screening platforms, including high-throughput internalization assays and bio-conjugation, ADC killing and stability assays.
The AlivaMab® Mouse platform, a natural mammalian display platform, outperforms in vitro technologies by leveraging in vivo immune systems to generate high-specificity, high-affinity antibodies with reduced developability and immunogenicity risks. Harnessing both natural immune mechanisms and advanced engineering, the AlivaMab platforms accelerate the transition from discovery to clinical development, with multiple candidates now in trials. Successful delivery across a range of modalities positions it as a critical tool for addressing increasingly complex therapeutic designs.
Maximizing the efficiency of PK screening assays during biotherapeutic development is advantageous when supporting multiple engineered antibody candidates and multiple programs. A microfluidic 1-hour generic PK assay using 10 µL sample and compatibility to rodent or non-human primate matrices eliminates assay development between molecules and accelerates time to results. A case study for a custom drug-specific assay for ADCs or total antibody assays will also be presented.
Explore a flexible, low-investment approach to bispecific T-cell engager discovery that enables rapid hit ID, parallel program advancement, and compressed timelines. Learn how Alloy has invested in creating optimized components and sequence-first strategies to reduce risk with a platform that has taken 12 antibodies to the clinic.
Downregulation of targets limit the efficacy of monotargeted T cell engagers (TCE). ISB 2001, a first in class TCE targeting both CD38 and BCMA, demonstrated superior tumour cytotoxicity in vitro, in vivo and ex vivo using patient samples when compared to teclistamab. Clinically, ISB 2001 demonstrated an overall response rate of 75% across all dose levels and a favourable safety and tolerability profile in heavily pretreated patients with r/r MM.
SAIL66, a next-generation tri-specific T-cell engager targeting CLDN6, CD3, and CD137, was developed using proprietary Dual-Ig® technology. Dual-Ig® enables unique ability to CD3 and CD137, but not simultaneously. SAIL66 demonstrates remarkable selectivity, avoiding cross-reactivity with related CLDN family. In vitro and in vivo studies reveal SAIL66's superior T cell activation and enhanced anti-tumor efficacy compared to conventional TCEs.
T cell-engaging (TCE) multispecific antibodies demonstrate great clinical efficacy, though their molecular complexity is a challenge for drug manufacturability, developability, and obtaining desirable PK/PD properties. Here, we showcase the discovery and engineering of novel anti-CD3 heavy chain-only antibodies (HCAbs), which demonstrate T cell cytotoxicity comparable to clinically validated TCEs when paired with IgG or TCR modalities. This work introduces a flexible new tool for enabling this important class of biologics.
Bispecifics and multispecifics that use only one light chain are a preferred format in view of manufacturability. We have established straightforward procedures to generate common light chain multispecifics from existing monospecific therapeutic antibodies, and we have also implemented an approach to obtain 2-in-1 symmetric antibodies where the light and heavy chain bind to different targets. We demonstrate that for bispecific multivalent T cell engagers the placement geometry of the binding modules is pivotal in controlling potency and mitigating cytokine release.
Our multispecific CD3 Switch-DARPins are designed to overcome current limitations of T-cell engagers, such as the lack of clean targets and poor therapeutic windows. We developed Switch-DARPins that can mask the CD3-engaging moiety until a tumor target (or combination of targets) is bound. This allows for increased tumor specificity, the safer use of a potent CD3-binder with additional co-stimulatory function for enhanced efficacy, and the selection of new target combinations.
IL-2 is a potent cytokine essential for effective immune responses, but its use in cancer therapy is limited by toxicity. BON-001 was developed to overcome this by specifically targeting IL-2 to LAG3+ cells through a novel dual-binding antibody switch. In preclinical models, BON-001 effectively inhibits tumor growth, promotes expansion of tumor-specific CD8+ T cells, and shows strong combinatorial activity with anti-PD-1, supporting its potential as a therapeutic.
Plasmodium falciparum RH5 (PfRH5) is the most advanced blood-stage malaria vaccine candidate, with proven efficacy both in pre-clinical and early clinical studies and the potential to elicit strain-transcending antibody responses. From clinical trial PBMCs, we isolated and functionally characterised a large panel of anti-RH5 IgG monoclonal antibodies to better understand the features of the PfRH5 vaccine-induced antibody response. We selected a diverse subset of these mAbs to determine their efficacy against P. falciparum clinical isolates from natural infection.
By levering its platform Mabylon generates and engineers multispecific antibodies which target and neutralize exogenous allergens, providing long-term protection against allergic reactions. By deriving our variable regions from human subjects, we ensure the targeting of the most relevant allergens and epitopes. MY006, our trispecific anti-peanut antibody built from patient-derived monoclonal antibodies will start first-in-human trials by the end of 2025.
At DJS Antibodies, part of AbbVie, we aim to develop first-in-class anti-GPCR antibodies to improve patient outcomes for serious diseases. The work presented compares various antigen formats and discovery methods for isolating single B-cells following immunization with our proprietary HEPTAD technology. By utilizing a diverse range of techniques, we aim to maximize the sequence landscape obtained from our immunizations, enhancing our ability to generate effective antibody candidates.
Nanobodies are as powerful building blocks for immunotherapeutics. To facilitate nanobody discovery, we made transgenic LamaMice that expresses llama IgH molecules without association to Igκ or λ light chains. From immunized LamaMice we selected target-specific nanobodies using classical hybridoma and phage display technologies, single B cell screening, and direct cloning of the nanobody-repertoire. LamaMice represent a flexible and broadly applicable platform for selection of target-specific nanobodies.
In this talk, I will describe how hydrogel microparticles, combined with flow cytometry, offer a scalable platform for screening and isolating single cells based on their biological functions. This technology is unlocking new possibilities in antibody discovery by enabling direct functional characterization of antibody-secreting cells, including specificity, binding affinity, and interactions with target cells, while maintaining compatibility with existing lab infrastructure.
We have developed a powerful B cell screening platform that enables the identification of extremely rare antibody hits that possess a number of desirable features. We have successfully applied this to the discovery of antibody molecules from a range of animal species including mouse, rat, rabbit, llama, cow and human. Together with NGS expansion of the hit sequence space, we use a number of computational tools that help us go beyond the limitations of both wet-lab screening and indeed the in vivo immune response. These digital tools are helping us more efficiently identify and optimise hits with drug-like properties, accelerating their path to candidate selection and ultimately to patients.
Antibody Fragment Drug Conjugates (FDCs), a new product class tailored for solid tumours promise many advantages over ADCs including rapid tumour penetration and faster systemic clearance. However, these have been technologically-challenging to apply in oncology. Our novel approach enables high-Drug:Antibody Ratios (DARs) whilst retaining effective binding and other favourable biophysical properties. To achieve this, single-chain Fvs and other recombinant antibody formats must be considered in context with complex linker-payload chemical moieties. This platform technology has led to our lead product, ANT-045 is a cMET-targeted FDC addressing a wide range of solid tumours. ANT-045 demonstrates superior tumour cure efficacy in cMET high, moderate and low CDX and PDX gastric cancer xenograft models and better tolerability compared to the leading competitor ADCs. In a non-GLP, non-human primate study, ANT-045 was well tolerated demonstrating no signs of the usual dose-limiting adverse effects seen with ADCs (neutropenia, thrombocytopenia) with a predicted half-life in humans of around 12-14 hours supporting a viable clinical dosing strategy with a wide therapeutic window. Insights into how FDCs behave in vivo through quantitative and qualitative imaging/uptake studies and toxicological parameters will be shared and how these have informed our follow-up products.
To address the limited therapeutic window of several targeted cancer therapies we developed a chemical cleavage reaction (Click-to-Release) that allows in vivo control over drug activity. It enables controlled on-target cleavage of ADCs in the TME through a click reaction with a trigger molecule given in a second step, expanding the target scope to non-internalizing receptors. And it enables off-target deactivation of radioimmunotherapy, by selective radiolabel cleavage and clearance from circulating radioimmunotherapeutics, decreasing bone marrow toxicity. This contribution will cover examples from both ends of the therapeutic window.
The key components of Synaffix’s proprietary ADC technology GlycoConnect®, HydraSpace®, and the toxSYN® platform enabling ADCs with best-in-class therapeutic index potential will be presented. Next, an overview on the pipeline of more than 16 GlycoConnect® ADCs that are rapidly being advanced by our partners will be provided, followed by sharing clinical development insights on the most advanced assets.
Immune-stimulating antibody conjugates (ISACs) utilize an innate immune agonist to promote lymphocyte activation in the tumor microenvironment, ultimately resulting in tumor regression and immune memory. While this technology has elicited powerful efficacy in various preclinical models, there have been a number of clinical setbacks and disappointments that have tempered the enthusiasm for this technology. We will describe the current state of the field of ISAC technology and will describe new ISAC designs that are being employed by our lab to overcome some of the reported clinical challenges. Specifically, we will focus on the role of Fc-gamma receptors in the efficacy and toxicity of ISACs.
We will present the progress of our Radio-DARPin therapeutics, designed for selective delivery of radioisotopes to tumors and surface engineered to limit uptake in healthy tissues such as kidneys. We will highlight MP0712, our DLL3-targeted candidate advancing to first-in-human trials, and our Radio-DARPin program targeting membrane-proximal MSLN. Both programs are tailored to deliver 212-Pb, a potent alpha particle-emitting isotope, and are co-developed with our partner Orano Med.
The cytosolic Fc receptor TRIM21 uses antibodies to target proteins for degradation inside the cell. This activity provides potent immune protection by destroying incoming viral particles and underpins “Trim-Away” technology. In my talk I will discuss our recent work on the molecular mechanism of cytosolic antibody-mediated degradation and the use of Trim-Away degraders to remove tau aggregates in vivo in a mouse model of Alzheimer’s Disease.
This presentation highlights efforts to develop novel transport vehicle (TV) enabled antibodies for AD that target microglia function. We’ve developed distinct transport vehicle platforms that can be differentially applied to antibodies to increase brain exposure, improve biodistribution, and enhance activity of Fab-mediated target engagement.
Tau is inextricably linked to a group of clinically diverse neurodegenerative diseases termed tauopathies. The ratio balance of the major tau splicing isoform groups (3R- and 4R-tau) is critical in maintaining healthy neurons. An imbalance causing excess 4 R tau is associated with diseases such as progressive supranuclear palsy. The work presented in this talk covers the generation of a novel 4R-tau specific “degrabody” capable of degrading 4R tau in iPSC derived neurons to probe its potential role in neurodegeneration.
Deficiencies in the hormone leptin or the leptin receptor (LEPR) causes morbid obesity in individuals with homozygous loss-of-function mutations in LEP or LEPR, and metabolic and liver disease in individuals with hypoleptinemia secondary to adipose loss. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We present translational data for a fully human monoclonal antibody (mAb) that activates the human LEPR and may provide clinical benefit in disorders associated with hypoleptinemia.
The tumor microenvironment is complex, frequently immune suppressive and has become established as a critical determinant of response to antibody therapy. Understanding the tumor microenvironment in patients, including the contribution of host factors such as body composition and metabolic dysregulation on its inflammatory status, and modelling these effectively will likely be critical to advancing drug development and combination strategies. Here we will present data demonstrating that metabolic modifiers can alter the tumour immune environment in patients and then using preclinical models that this can be used in combination therapy to enhance response to immune checkpoint blockade.
The development of Inno8, an oral hemophilia drug candidate, represents a significant advancement in hemophilia A treatment. Derived from llama and alpaca VHH fragments, it underwent iterative engineering cycles, resulting in enhanced thrombin-generation potential. Animal model screenings demonstrated improved pharmacokinetic and peroral properties, including enhanced half-life based on fatty-acid protraction and oral bioavailability. Inno8's selection for clinical testing holds promise for revolutionizing hemophilia A treatment and addressing chronic diseases with an antibody-based oral drug modality.
ALL has become a model disease for novel immunotherapeutic approaches Here, we report on our studies using antibodies of either IgG1 or IgA2 isotype to mediate killing of ALL cells in vitro and in PDX models. These results suggest to investigate the clinical efficacy of IgA antibodies in combination with myeloid checkpoint blockade in ALL.
IgA has the unique properly to turn neutrophils in cancer-killing immune cells. However, just like other myeloid cells, neutrophils express SIRPa as a checkpoint inhibition molecule, that interacts with CD47 on tumorcells as ‘don’t eat me’ signal. Our present research focusses on combining the targeting on GD2 on neuroblastoma with the block of CD47 in one, bispecific IgA molecule to maximally activate neutrophils.
IgG-based therapeutics may eliminate a target via Fc-mediated effector mechanisms. However, there is a need for more potent formats. The TandemAb concept combines structural elements of IgA with that of IgG, and results in tailored designs with favorable plasma half-life and engagement of effector molecules that can eradicate tumor cells and bacteria.
Targeting tumors with γ9δ2T cells resulted in poor clinical outcomes, mainly due to the low affinity of γ9δ2TCRs for tumor antigens. We have developed affinity-enhanced γ9δ2TCRs, which led significantly improved tumor control in both in vitro and in vivo preclinical models, paving the way for next-generation γ9δ2TCR-based immunotherapies.
IgE antibodies exert pathogenic effects in allergies and protective anti-parasite immunity via high-affinity Fcε receptors on tissue-resident effector cells. We generated IgEs recognising cancer-associated antigens and translated the first-in-class agent to clinical testing. IgEs trigger pro-inflammatory effector recruitment and induction of hyperinflammatory macrophages to inhibit immunosuppression in the tumour microenvironment.
IgM is the first antibody in humoral immune response and appeared early in evolution. With high valency, IgM pentamers exhibit superior avidity, significant receptor clustering, potent effector function (CDC and ADCP) and provide opportunity for treatment of infectious disease, cancer and auto-immune disorders. Engineered IgMs have strong potential as therapeutic agents, and many biotechnical challenges of production and characterization have been resolved. Key topics and case studies will be presented.
Join fellow attendees, speakers, exhibitors and poster presenters in the exhibit hall and conference area for an evening of food, drink, poster/exhibit viewing and networking.
Add-on this pre-conference training course to your main conference registration package for an additional fee and gain a comprehensive overview of antibody engineering in an easy-to-follow classroom setting to help you prepare for the main conference program.
- Training course registration begins at 8:00am.
- Break Schedule:
- AM Break: 10:30-11:00;
- Lunch: 12:30-1:30;
- PM break: 3:00-3:30
TRAINING COURSE OVERVIEW
Today’s wealth of knowledge of protein structures will be reviewed along with the genetics of diversity generation of antibodies, to give insights into the best strategies for improving protein function. There is particular emphasis on the choice of a functional assay to effectively monitor the changes in a desired property, and the use of functional enrichment steps where a library approach is employed. Not only is amino acid sequence amenable to engineering, but glycan structures and other modifications may also be engineered. The course will focus on the engineering and enhancement of antibodies and antibody-like scaffolds. Examples will include work on antibody fragment affinity improvement by 100-fold to low pM affinity. Also, the engineering of bispecific antibodies by diverse approaches and the adaptation to generate Chimeric Antibody Receptor (CAR) constructs will be discussed. Expression platforms for producing antibodies for testing and for manufacture will also be covered. A background in biochemistry and molecular biology is useful, as the course is designed to progress rapidly from simple to advanced concepts.
INSTRUCTOR
David Bramhill, Ph.D., Founder, Bramhill Biological Consulting, LLC and Research Corporation Technologies
COURSE AGENDA
- Functions amenable to engineering: affinity, specificity, stability, solubility, immunogenicity
- The measure of success: functional assays
- Engineering by design
- Engineering by random mutation
- Designed libraries
- Display technologies
- Improving manufacturing by protein engineering methods
- Glycosylation engineering – function and homogeneity
- Other protein modifications
- Immunogenicity engineering
- Bispecific antibodies
- Antibody-drug conjugates (ADCs)
- CAR-T strategies
- Expression of antibodies and fragments for discovery and testing
- Manufacturing platforms for antibodies and fragments
Prominent among challenges faced in the immunotherapeutics field across a spectrum of platforms is the need for improved understanding of the complex mechanisms involved in their operation at multiple levels of the immune system. We have been working to address one aspect of this challenge with respect to immune cell signaling networks, aiming to construct comprehensive yet actionable models for their how they govern effectiveness of immunotherapeutic modalities. This presentation will describe certain new findings, including in applications to antibody glycosylation and to chimeric antigen receptor T cells.
Pancreatic ductal adenocarcinoma (PDAC) is an immunologically cold disease. Increasing immune cell trafficking and activation in PDAC are therefore important for understanding response to immune checkpoint therapies (ICT). Mathematical modeling of the tumor microenvironment (TME) allows us to elucidate the features of PDAC that can determine responsiveness to ICT. By integrating mathematical models with spatial data from patients, we can identify the specific mechanisms in the TME that regulate immune cell trafficking during ICT treatment.
ADCs are a rapidly expanding class of therapeutics with 7 new approvals in the past 6 years. However, they have a long history with many failures in the clinic. This presentation will use a quantitative systems pharmacology approach to highlight the major delivery challenges with ADCs in solid tumors, and how recent successes can be used to inform the design of the next wave of clinical approvals.
The unique cell-to-cell crosslinking action of T-cell engagers (TCEs) poses challenges for in vitro to in vivo translation. Recent advances in QSP models of TCEs capture key biophysical details of crosslinking, enabling rational techniques for first-in-human dose selection and efficacious dose prediction from in vitro potency assays and preclinical animal studies. This talk will review these developments and explain how QSP models can support and accelerate TCE development.
Bispecific antibody clinical development remains rife with challenges, including nuanced pharmacology, limited translatability of preclinical findings, frequent on-target toxicity, and convoluted dosing regimens. Here we argue that trimer formation on the molecular level are but a proxy for the actual driver of pharmacology. The formation of immunological synapses between tumor cells and T cells involves a coordinated cascade of molecular and cellular interactions that extend beyond the initial antigen-binding event. This cascade includes the survey of potential target cells within the tumor microenvironment, the slowing of T-cell movement upon identification, and the establishment cell-to-cell adhesion. Incorporating these cellular mechanisms into bsTCE QSP models offers promise for predicting long-term efficacy, resistance, and relapse in solid tumors.
This talk will present ADC QSP bystander models incorporating both antigen-positive and antigen-negative cells. These models demonstrate that ADC modality may offer limited response durability if antigen-positive and antigen-negative cells grow independently. However, this limitation could potentially be overcome by stromal-targeting ADCs, as stromal cells are recruited to the tumor. Additionally, we will discuss the optimal ADC properties that balance efficacy across both cell populations.
While some of the best selling drugs of all time are biologics, several other modalities have been propelled into the limelight by continued innovations that have the potential to outcompete biologics. My talk will focus on the exciting new areas in biologics development through the lens of early-stage therapeutics investing.
Protecting antibody innovations globally faces increasing challenges, both due to different laws in different countries as well as evolving legal standards, particular in the US and Europe. My talk will focus on potential strategies to a) cover products, b) throw patent obstacles in front of biosimilars and c) generate third party licenses for platform technologies.
Key considerations in starting and investing in companies focused on antibody- based therapeutics include the importance of choosing the right target, molecule attributes and format, clinical indication, investors and team. I will also discuss the differences in drug discovery at large biotech/pharma versus at a smaller company including portfolio considerations.
Early-stage biotech companies must walk a fine line between innovation and risk management. For some companies, this means working with a clinically validated MOA and differentiating from first movers based on target and indication selection or significant functional improvements. As part of the highly active T-cell engager field, our team has successfully created multiple differentiated platforms.
As a new addition this year, we're excited to announce this Early Career Scientists session taking place on the morning of December 15, the day before the main conference. Are you within 10 years of completing your Master’s or Ph.D. and under the age of 35? If so, unlock a range of exclusive benefits by selecting the "Early Career Scientist" pass when you register. This session will spotlight short, novel research presentations from early career scientists in the antibody engineering and therapeutics community. You’ll also hear an inspiring career journey from a distinguished mid-career scientist, plus enjoy the opportunity to connect and network with peers. You’ll also receive free admission to the afternoon pre-conferences workshops on December and the opportunity to present a free poster during the main conference. Please Note: Access to the early career scientists session is only available to those who register for the main conference by selecting the “Early Career Scientist” pass. All passes subject to approval by conference organizers.
To be considered for a short oral presentation in this session, or for general information about this session, please contact Michael Keenan at Michael.keenan@informa.com
If you are interested in sponsoring this session, please contact Blake Shuka at Blake.Shuka@informa.com
T cell engagers (TCEs), a class of T cell-retargeting immunotherapy, are rapidly transforming clinical cancer care. Adapting these biotherapeutics to treat a wide range of oncology indications is an urgent clinical need, which has been, in part, limited by challenges including on-target, off-tumor toxicity and poor therapeutic index linked to aberrant cytokine release. Here we highlight the engineering of T cell engagers to address these outstanding challenges to clinical translation. We have adapted TCEs to (1) target the massive intracellular proteome and (2) selectivity expand and re-direct anti-viral T cells to eliminate cancer cells. Overall, this research provides new fundamental insights for generating optimized TCEs against a variety of targets with potentially improved therapeutic index.
Rondo has developed a robust discovery pipeline and characterized a panel of CD28 agonistic antibodies, designed for flexible engineering into bispecific antibodies targeting solid tumors. While T cell engagers (TCEs) have been successful in hematologic malignancies, their efficacy in solid tumors is limited. Targeted costimulatory agonistic antibodies may enhance T cell responses in the tumor microenvironment to overcome the efficacy limitations of CD3 bispecific antibodies. This highlights a potential paradigm shift with costimulatory bispecific antibodies for the treatment of solid tumors.
Yeast surface display using synthetic libraries is a popular tool but often suffer from non-productive sequences resulting in poor folding, suboptimal biophysical properties, and failures during selection. Such issues often necessitate extensive post-discovery engineering of antibody leads. To address this, we created a minimalistic Fab and VHH platform with varied, liability-purged HCDR3 sequences grafted into well-behaved scaffolds. This approach enables the selection of high-affinity, developable antibodies with good biophysical properties across multiple targets.
Antibodies blocking the immunosuppressive receptor PD-1 on immune cells or its major ligand PD-L1 on tumor and stromal cells have become foundational in oncology. Their wide-ranging applications are now extending across more than 20 cancer types, and from advanced to earlier stages of cancer. The discovery of biomarkers predicting therapeutic response/resistance holds promise for further advancing this mode of cancer therapy.
The discovery of broad and potently neutralizing antibodies against highly immunoevasive viruses like HIV can reveal conserved sites of viral vulnerability. Guided by such extraordinary antibodies, we can rationally design vaccine immunogens that focus the humoral response toward these vulnerable regions in order to reliably induce durable and escape-resistant immunity.
The inability of large molecule therapeutics to cross the blood-brain barrier has remained a major obstacle for the treatment of neurological disorders. Numerous strategies have aimed to increase brain exposure of biotherapeutics; approaches which utilize transport across the BBB via the rich capillary network are expected to significantly increase exposure in the brain and additionally result in broad distribution throughout the brain. Our approach utilizes the Transport Vehicle (TV), which binds to receptors, such as the transferrin receptor (TfR) and CD98hc, present on the BBB via modifications to the Fc region of an IgG. The TV-targeted receptors are expressed on brain vascular endothelial cells and enable transport of bound molecules across the BBB to reach target cells in the brain parenchyma. The molecular architecture of the TV platform is highly modular and enables the delivery of numerous types of biotherapeutics, including antibodies, enzymes, proteins, and oligonucleotides with the potential to meaningfully increase drug concentrations and target engagement in the CNS for the treatment of neurological disorders.
Proteins mediate the critical processes of life and beautifully solve the challenges faced during the evolution of modern organisms. Our goal is to design a new generation of proteins that address current-day problems not faced during evolution. In contrast to traditional protein engineering efforts, which have focused on modifying naturally occurring proteins, we design new proteins from scratch to optimally solve the problem at hand. Increasingly, we develop and use deep learning methods to design amino acid sequences that are predicted to fold to desired structures and functions. We also produce synthetic genes encoding these sequences and characterize them experimentally. In this talk, I will describe several recent advances in computational protein design.
Broadly neutralizing antibodies are the major goal of a universal influenza vaccine. This presentation will focus on the identification of a class of broadly neutralizing antibodies targeting a membrane-proximal anchor epitope of the influenza virus hemagglutinin (HA) protein. I will discuss the challenges of identifying antibodies against membrane-proximal epitopes, how vaccines can induce anchor-specific antibodies, and how anchor-targeting antibodies can be engineered to improve binding breadth and potency.
In this presentation, Dr. Reichert will provide an update on the antibody therapeutics currently in late-stage clinical studies, as well as those in regulatory review and recently approved. Trends observed in the burgeoning early-stage pipeline, popular formats and mechanisms of action, as well as common and obscure targets for antibody therapeutics will also be discussed.
Enhancing various modalities is at the leading edge of mAb development, however, research and development processes are becoming increasingly complex and unpredictable. It will change the situation if scientists can visualize a newly designed molecule just after a few days or confirm the mode of complex formation as well as epitope/paratopes based on 3D images in solution. EDT enables it not only for 3D images of the molecule but also for molecular flexibilities, dynamic characteristics, and even the internal ratio of components of a molecular complex.
Explore how Alloy Therapeutics' ATX-Gx™ Humanized Mouse Platform accelerates therapeutic antibody discovery with unmatched strain diversity and affordability. Focused on the ATX-GKH strain, featuring enhanced immune responses and superior antibody output, this technology empowers partners to build robust pipelines, delivering high-affinity candidates against challenging targets with proven clinical success.
emp BIOTECH has developed first-in-class Protein G solid phases that can tolerate Cleaning-In-Place (CIP) with sodium hydroxide. No loss in binding capacity was observed after 50 CIP cycles. The resins have been optimized for the purification of human monoclonal IgG. The new products are expected to be launched in Q1 of 2025.
The design and implementation of phage display antibody libraries for discovery and optimization of antibodies, called ALTHEA Libraries, will be presented. The potentail of these antibody discovery platforms will be illustrated with two case studies: (1) isolation and optimization of broadly anti-SARS-CoV-2 neutralizing antibodies and (2) generation and characterization of a panel of anti-PD-1 antibodies with diverse binding and functional profiles.
Twist Biopharma Solutions, a division of twist Bioscience, combines HT DNA synthesis technology with expertise in antibody engineering to provide end-to-end antibody discovery solutions — from gene synthesis to antibody optimization. The result is a make-test cycle that yields better antibodies against challenging targets from immunization, libraries, and machine learning. Twist Biopharma Solutions will continue to optimize and expand its discovery, library synthesis and screening capabilities in partnership with others to further utilize their make-test cycle.
At-line nanoparticle-based molecular structure analyses were performed on antibody samples in Clarified Fermentation Broth using ProteometerTM kits, which provide rapid analytical tests for titer, aggregates, and charge variants. The Novilytic Proteometer's nanotechnology is for Process R&D and Discovery scientists/engineers who need a more efficient method of molecular structure analysis. Unlike LC/MS instruments, Proteometers provide fast, accurate, and quantifiable molecular data in-process without sample preparation or Protein A purification.
At OmniAb, we build, shape and mine custom, naturally optimized immune repertoires in divergent species to discover next generation biotherapeutics. We use high throughput phenotypic screening augmented by an AI-guided NGS workflow to navigate the vast sequence space and find high quality leads, bypassing extensive ex-vivo engineering. We demonstrate how we discovered developable anti-NKp46 binders with broad epitope coverage and affinities as building blocks for NK cell engager multispecifics.
The therapeutic antibody market is rapidly growing due to unmet needs and increased awareness of targeted therapies. The availability of advanced techniques and platforms in the market speeds up the process of antibody drug discovery to meet the increasing demands. GenScript's MonoRab™ and TurboCHO™ platforms streamline development, reducing timelines and costs. This integrated approach delivers high-quality therapeutic antibodies faster, addressing urgent medical needs and advancing biopharmaceutical innovation.
Presenter #2:
The Development of a Novel CD8-targeting Lipid Nanoparticle to Transiently Engineer CD8+ T Cells in vivo Using mRNA to Express a CD19 CAR
Despite the success of ex vivo chimeric antigen receptor (CAR) T cell therapies, challenges in cell manufacturing, scalability, and the need for lymphodepleting chemotherapy highlight the necessity for an off-the-shelf in vivo CAR technology applicable to broader indications. To that aim, we developed CPTX2309, a novel in vivo anti-CD19 CAR mRNA product delivered by a CD8-targeted lipid nanoparticle (tLNP), optimized for pre-clinical performance and advancement to clinical development.
Stuart A. Sievers, Ph.D., Senior Director, Discovery Research, Capstan Therapeutics
Many antibody-based drug candidates require additional engineering such as affinity maturation, humanization, cross-reactivity and improved stability for optimal therapeutic efficacy. Here, we discuss TumblerTM, a validated CDR shuffling approach for customizable antibody optimization. This method utilizes diversity from our in-house libraries and near-parental sequence space CDR variants, grafted into a human framework, to minimize redundancy and maximize functional diversity. The talk will highlight a variety of engineering successes, including affinity maturation, induction of cross-binding, and humanization campaigns. The presentation will also showcase how Tumbler maximizes diversity and provides valuable insights about sequence-activity relationships. With over a dozen successful project outcomes across a diverse set of targets, Tumbler offers a robust and flexible antibody engineering solution to help accelerate therapeutic candidates through the drug development process.
Successful and efficient discovery and engineering of biologic therapeutics requires diversity and quality in the initial library of antibodies. This presentation will showcase the integration of the versatile platforms and processes of AlivaMab Biologics and Ablexis and our ‘fit-for-purpose’ philosophy. Empowered by a growing suite of AlivaMab® Mouse strains, we enable the discovery and engineering of next-generation modalities including fully human single-domain antibodies, common light chain discovery using a unique approach, and TCRm antibodies. Our comprehensive, integrated antibody discovery and engineering platforms consistently deliver molecules with the critical attributes required for successful drug development.
Artificial intelligence (AI) is transforming antibody discovery and engineering. Ailux's platform synergistically combines the best of our comprehensive wet lab, AtlaX proprietary database, and three AI engines. We will explore a series of case studies that exemplify our AI-driven approach for tackling hard targets, engineering challenging molecules, and accelerating conventional discovery campaigns. This presentation provides our realistic and evidence-based perspective on AI’s impact on the industry.
We will discuss the key challenges in creating and deploying machine learning for biologics discovery. While creating complex models for discovery and development is becoming commonplace, managing the entire ML model lifecycle is essential for effective use in therapeutic research and maximizing AI investment returns. Discover how a unified platform can streamline AI use in biologics discovery, from model training to consumption.
In this talk, we present the CHO Edge System, which integrates a glutamine synthetase (GS)-CRISPR knockout CHO host, a hyperactive transposase, libraries of characterized genetic elements to control cellular functions, and computational tools for rational vector design and multi-omics analysis. We present case studies highlighting the impact of these tools to optimize expression for both standard monoclonal and bispecific antibodies.
This session will explore effective strategies for accelerating lead selection from a diverse panel of antibodies. Key techniques presented include proprietary methods for leveraging the unique immune system of rabbits, early epitope landscape profiling, and the use of IPA's in silico-driven humanization workflow. This approach combines thorough risk assessment, early de-risking, and high-throughput, in vitro kinetic profiling, resulting in the rapid delivery of optimized antibodies ready for clinical development.
Wheeler Bio’s Modular CMC platform aims to provide biologics drug substance partners with flexible, tailored-made CMC development solutions across all stages of a molecule’s life cycle. Primarily developed for early-stage discovery organizations and Newco’s, Wheeler Bio is expanding its Modular CMC technology stack to include late-stage process design and biosimilar programming elements, offering similar flexibility, speed and service to partners. Aaron Pilling, Ph.D. will be presenting “Modular CMC” in the context of Wheeler Bio’s growth and expansion plans which include a new development and manufacturing facility, located in Oklahoma City’s growing Biotechnology hub.
Immunogenicity risk assessment is an essential step in bringing therapeutic drugs to the market. ProImmune's risk management tools evaluate immunogenic epitopes and the corresponding functional T cell responses that can lead to unwanted immune responses. Case studies will highlight how the integrated platform is used to address key questions in the drug development phase.
Thermo Fisher Scientific’s GeneArt Protein Expression Services offer scalability, reproducibility, and speed in transient expression of recombinant antibodies. We give insight in the technical as well as experimental design process to develop an automated platform with end-to-end traceability in a fully integrated workflow starting from single nucleotides to deliver a purified and polished antibody product.
Introducing a novel FACS-based strategy paired with our AbTheneum platform, this presentation showcases a workflow to deliver higher yield of hits from a discovery campaign. By combining high-precision cell isolation with a robust engine for parallel screening and sequencing of all IgGs, we reveal how this synergy boosts hit rates and diversity, even in challenging low-titer conditions across various campaigns.
In vitro assays play a central role in biotherapeutic drug development by enabling critical insights into target identification, mechanism of action, and safety profiling. This presentation will provide an in-depth exploration of strategic application of in vitro assays through real-world case studies, illustrating their essential role in optimizing lead selection, assessing risks, and advancing drug candidates in ADC, TCE and autoimmune diseases therapeutics.
We provide an advanced, integrated high-throughput droplet sorting platform that accelerates antibody discovery. This platform supports high-performance screening against both soluble and transmembrane antigens. By harnessing plasma cells of the most popular species—not limited to mouse, rabbit, human, alpaca, etc.—whether fresh or in-vitro activated—the system enables direct acquisition of natural or genetically modified antibodies with exceptional specificity and affinity. Its sensitive, versatile , and high-throughput design further facilitates the discovery of functional antibodies, streamlining the development process from initial screening to therapeutic application.
Using the Pfenex Expression Technology®, we achieved 15g/L of a modified VHH molecule engineered for site-specific ADC conjugation. The innovative Pfenex platform, based on P. fluorescens, produces various antibody formats including Fab's and novel Picobodies™. The platform effectively utilizes multiple genetic elements, host strains, and automated workflows to optimize protein expression from early research through full commercialization, with six approved products to date.
ATUM’s antibody platform combines ML/AI with production quality expression systems and robust analytics. Antibodies are designed in silico, assisted by AI and knowledge base, synthesized at scale in commercially relevant platforms, and are characterized for functionality and developability features simultaneously. ML models built on these datasets which are built specifically to “learn”, are highly predictive and generate new designs for high-specificity antibodies with developability properties for process development, scale-up, and manufacturing.
Asymmetric bispecific antibodies have a great potential for becoming the next big leap for antibodies, but present challenges for purification. One way to purify these molecules is by using avidity effects on affinity protein A and protein L resins. In this presentation, we show newly developed tools and a systematic approach that can be used to achieve high purity of the correctly paired antibody in the capture step.
Natural killer (NK) cells play a vital role in the human innate immune system and NK cell engagers are being explored as a promising approach for cancer and autoimmune disease immunotherapy. Using AvantGen's Germliner™ Library Collection, we've isolated and developed a panel of highly specific fully human CD16a antibodies that exhibit potent activities in killing target cells in various NK cell engager formats.
Each immune complex is unique and affects its own set of Fc functions. To treat the antibody as a sum of two independent domains, the Fab and Fc, is fraught with false assumptions that could negatively impact therapeutic development. SeromYx’s high-throughput GCLP platform enables the empirical and comprehensive determination of the antigen-specific Fc functional profile of therapeutic antibodies uncovering vital insights into their safety and immune mechanisms of efficacy upfront.
Developed by a core group of AbTherx scientists and acquired by Gilead Sciences in 2023, Atlas™ Mice are a suite of transgenic mouse technologies for human antibody discovery. AbTherx has worldwide rights to this novel platform, successfully developing technologies that express the full diversity of human antibody HC and k-LC repertoires, enable the development of bispecific antibodies through a novel binary fixed light chain, and use natural mechanisms to generate long CDRH3 antibodies to address challenging drug targets.
OmniHub significantly enhances the operational efficiency of antibody discovery workflows by automating data handling. This reduces manual effort, provides standardization, and minimizes errors. OmniHub integrates machine learning (ML) and artificial intelligence (AI) tools, along with bioinformatics pipelines, to create a comprehensive interface that allows internal and partner scientific teams to collaborate through shared data visualization and analysis. As a result, OmniHub lays the foundation for innovative and collaborative scientific discovery.
Quickly obtaining qualified clones from multiple antibody generation technologies is crucial for advancing functional antibodies that eventually constitute the therapeutics of tomorrow.
The field of therapeutic antibody engineering is on the brink of a transformative leap forward with the advent of Geneious-Luma-supported computational design. This cutting-edge platform promises unparalleled precision and efficiency in the discovery of next-generation multispecific antibodies (msAbs). This talk will delve into the myriad challenges inherent in researching and developing therapeutic msAbs, and will showcase how the Geneious-Luma computational design platform adeptly addresses these challenges, paving the way for more successful biologics drug treatments.
At Lightcast we are developing a next-generation technology platform that enables the direct, precise interrogation of single cell heterogeneity, interactions and functional dynamics at scale. Across a broad range of disciplines from basic and translational research to drug discovery, we provide the freedom to accelerate discovery and apply novel biological insights. This session will provide an overview of the technology and explore the potentially powerful impact in understanding and applying single cell functional understanding in some key areas of cancer therapeutics.
This topic explores the revolutionary potential of the genome-edited mouse, where endogenous VH and VL genes are replaced by fully human VH and VL genes in situ, enabling the generation of fully human antibody molecules. When combined with Biointron's AbDrop microfluidic technology-enhanced single B cell screening, this approach allows for the high-throughput and efficient discovery of antibody drug molecules.
Alloy bispecific discovery services integrate best-in-class platforms with world class scientists to serve as an extension of your R&D team. Building on industry leading mouse platforms for fully human antibody discovery, Alloy has created Common Light Chain strains, ATX-CLC, to build bispecifics with better developability profiles by solving heavy and light chain pairing. Leveraging ATX-CLC Alloy supports bispecific discovery through format engineering and functional assessment to move candidates forward rapidly.
Explore how Heavy Chain Only Antibodies (HCAb) function as versatile building blocks for bispecifics. Understand the potential of fully human HCAbs derived from Harbour Mice® in developing bispecifics with outstanding druggability. Delve into the next-generation HBICE® bispecific platform for immune cell engagement. Discover emerging technology platforms on the horizon. Examine an engaging case study of HBICE® from concept to IND.
GenScript’s new AmMag™ Quatro Mini-1100 and Maxi-1400 systems, utilizing novel magnetic bead technology, provide automated, high-quality plasmid DNA purification. These advanced systems enhance throughput, yield, and reproducibility, handling culture volumes of up to 10 mL with the Mini-1100 and up to 200 mL with the Maxi-1400. Discover how these innovative solutions streamline workflows, delivering superior transfection-ready plasmid DNA and boosting lab efficiency and scalability.
It is relatively straightforward to select antibodies or VHHs that bind targets, but much more challenging to generate antibodies with functional activity. Here we describe the use of TripleBar’s microfluidics system to select functional CD3 activating antibodies from Specifica’s Generation 3 library platform.
Discovery of biotherapeutics against challenging targets such as integral membrane proteins, membrane protein complexes, and heavily glycosylated surface proteins using display technologies remains a challenge. We have utilized therapeutic-ready phage- and yeast-display platforms expressing a diversity of formats to pan against both cells and virus-like particles. Using these novel reagents and protocols, we have managed to discover biotherapeutics to traditionally display "unfriendly" targets.
We have developed a droplet-microfluidic single-cell-based platform for the repertoire biobanking and expression of the antibodies of up to one million human B cells in HEK cells. This cognate biobank represents 80% of the input cells, the robustness of this format enables any screening process including droplet microfluidic sorting.
This technology is applied for the direct discovery of tumor-reactive antibodies from tumor-infiltrating B cells in cell-based assays.
Abalone Bio’s Functional Antibody Selection Technology (FAST) platform combines biology and machine learning (ML) to identify and design functionally active antibody drugs. FAST simultaneously tests the entire diversity of antibody libraries directly for the desired function and produces library-scale sequence-function datasets that uniquely power generative protein language models to design novel active antibody sequences. FAST-discovered antibodies have been demonstrated to have agonist activity in vitro and in vivo.
Characterizing the binding parameters (ka, kd, KD) of antibody:receptor interactions is crucial in drug discovery. However complex Abs and/or receptors are not always amenable to traditional biophysical methods (i.e., SPR, BLI, etc.), necessitating cell-based binding assays. We developed a pre-equilibrium assay to simultaneously determine the binding kinetics of up to 30 therapeutic Abs on living cells.
Protillion combines ML-guided antibody design technology with purpose-built chip-based high-throughput instrumentation to tackle challenging problems in therapeutic protein engineering. The platform is capable of characterizing the binding affinity of up to 10^6 antibody variants in a 2-day automated run. This unique approach enables identification of better antibody candidates that meet challenging product profiles, including pH-dependent binding, cross-species reactivity, and stringent developability.
Groundbreaking immunotherapies known as immune checkpoint inhibitors mobilize the immune system against cancer by blocking the protein interactions that suppress immune cell activation. However, limited response rates to these therapies necessitate the development of new molecules that act through alternative mechanisms. Here, we describe the discovery and design of multispecific antibody fusion proteins incorporating single-domain shark antibodies that improve upon clinical drugs, presenting a novel modality to advance cancer treatment.
A subset of cow antibodies have a heavy chain “ultralong” CDR3 region that can be over 70 amino acids in length, with a disulfide-bonded “knob” domain that protrudes far from the antibody surface. These knob domains can be produced independently of the antibody to generate tiny, high affinity, binding fragments. The novel genetics, structural biology, and biomedical applications of ultralong CDR3 antibodies will be discussed.
Ion channels are an important target class which are under-served by biologics. Maxion have shown that small cys rich peptides with ion-channel modulating activity can be inserted into antibody CDRs while retaining their function. The resulting molecules modulate ion channel activity while benefitting from the optimal drug-like properties of antibodies. This presentation will illustrate the generation and optimisation of KnotBody inhibitors to therapeutically relevant ion channel targets.
The pathogenicity of autoreactive antibodies has been demonstrated for many autoimmune diseases and the isotype/subclass profile can potentially influence the disease pathophysiology. Although often overlooked, IgA autoantibodies are increasingly recognized in different autoimmune indications. Here, we describe the development of anti-IgA monoclonal antibodies that can actively remove IgA from the circulation and block binding of IgA to its main Fc receptor FcαRI. Given the abundancy of IgA in human serum (1-3 mg/mL), both Fab and Fc engineering were optimized to design a monoclonal antibody with the desired properties.
Inhibitory checkpoint receptor (IR) agonists have the potential to restore immune homeostasis for patients with autoimmunity but are limited by their ability to non-discriminately bind activating FcγRs. IR agonists anchored to FcγRIIb, the inhibitory Fc receptor, have the potential to provide superior agonism by avoiding inflammatory cytokine responses and limiting APC activation. Discovery and development of a Dual-cell Bidirectional PD-1 FcγRIIb agonist antibody that activates multiple inhibitory pathways in more than one cell type to regulate both sides of the immune cell synapse will be discussed.
Although antibodies are actively explored as therapeutic for bacterial infections, their narrow specificity poses a challenge due to the broad diversity between bacterial species. We reveal that conversion of highly specific anti-staphylococcal IgGs into IgM induced cross-reactivity with a range of bacterial species.
DuoBody®-EpCAMx4-1BB is a novel, clinical stage, bispecific antibody targeting EpCAM and 4-1BB designed to boost antitumor responses conditionally in EpCAM-expressing tumors. By crosslinking EpCAM on tumor cells with 4-1BB on immune cells, DuoBody-EpCAMx4-1BB enhances T-cell activation, proliferation, and antitumor activity in preclinical studies. DuoBody-EpCAMx4-1BB is co-developed by BioNTech and Genmab. The preclinical characterization of DuoBody-EpCAMx4-1BBB will be presented.
Monoclonal antibodies struggle to achieve potent complement activation due to the need for multivalent C1q binding, resulting in the underutilization of complement as a therapeutic mechanism. We have recently described an innovative approach involving bispecific single domain antibodies, BiCE™, which efficiently recruit and activate C1. We now present the 2nd generation BiCE™ IgG molecules that exhibit superior complement-mediated cell killing compared to competing technologies, holding great therapeutic potential.
We previously developed SMART-Ig® technology to efficiently remove soluble antigens from the blood. This time, we aimed for more efficient antigen removal by creating pH-dependent biparatopic antibodies that bind to different epitopes of a soluble monomeric antigen in a pH-dependent manner. These antibodies accelerated cellular uptake by forming larger immune complexes, successfully removing soluble antigens from the blood more efficiently.
(SMART-Ig® is a registered trademark of Chugai Pharmaceutical Co., Ltd.)
The discovery of agonistic antibody drugs has been severely limited by the difficulty of identifying epitopes that support the productive engagement of the signaling complex. Using a combination of experimental and computational approaches, we generated agonist antibodies that activate the ALK1 pathway to treat vasculopathies. The techniques we developed can generate agonist antibodies against any heteromeric receptor complex, opening new opportunities to treat many human diseases with precision biologics drugs.
T cell engaging antibodies (TCEs) are effective therapeutics for patients with diverse malignancies when adequately targeted to tumor biomass. We show that ML methods can support the efficient design of TCEs, including via boolean logic, targeting co-expressed tumor antigens and sparing healthy tissues expressing either antigen, even at high receptor densities. Overall, we demonstrate how AI/ML design with rapid, closed loop wet-lab characterization supports the systematic design of safe and effective TCEs.
Xencor has created a growing set of bispecific antibodies, using principles of avidity-driven selectivity to improve therapeutic index. Building on these modalities are additional efforts to explore T cell costimulation via signal 2 to potentiate anti-tumor activity of T cells.
Na+/K+–adenosine triphosphatase (NKA) is a transmembrane protein consisting of three subunits: a, b, g. A progressive decline of NKA activity exacerbates neurodegeneration in the aging process. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (897DVEDSYGQQWTYEQR911) of the NKAa1 subunit. It was demonstrated that DR5-12D produced therapeutic effects against neurodegenerative diseases. Therefore, DR5-12D may represent a new therapeutic strategy for neurodegenerative diseases.
Growth differentiation factor 15 (GDF-15) is a stress induced cytokine that causes anorexia and weight loss, and higher circulating levels are associated with cachexia and reduced survival in patients with cancer. Inhibition of GDF-15/GFRAL biological activity reverses cachexia in numerous preclinical tumor models, and ponsegromab (a novel, first in class humanized monoclonal anti-GDF15 antibody) is being developed as a therapeutic agent for cancer cachexia.
This talk describes the regulation of energy balance and appetite beyond traditional hormonal mechanisms. We discuss Peptide Predictor, a computational tool that identified BRINP2-Related Peptide (BRP), an anorexigenic peptide cleaved by PCSK1. BRP significantly reduces food intake and obesity through a unique central signaling pathway, without affecting other metabolic behaviors. This discovery highlights the potential of peptide prediction platforms in uncovering new metabolic regulatory mechanisms and biological pathways.
We show AAV delivery of full-length antibodies targeting GA-dipeptide proteins in C9orf72 ALS/FTD BAC-transgenic mice reduces repeat associated non-AUG (RAN) protein levels, improves behavior and neuropathology, and increases survival. AAV delivery of high-affinity antibodies is a novel strategy to achieve broad and sustained CNS expression and biodistribution of therapeutic antibodies. These data open new possibilities for developing AAV-antibody therapies as a novel approach for C9orf72 ALS/FTD and other neurodegenerative disorders.
The inability of antibodies to penetrate the blood-brain barrier is a key limitation to their use in diverse applications. We are developing bispecific antibodies that engage either CD98hc or transferrin receptor, which results in the transport of IgGs and other biologics into the CNS. We will highlight our findings related to the unique advantages of CD98hc and transferrin receptor bispecific antibodies, especially related to the impact of target engagement in the CNS on pharmacokinetics and CNS distribution. Finally, we will discuss our recent findings on applications of bispecific antibodies for targeted CNS drug delivery.
Alector is a leader in the field of Neuroimmunology - harnessing the brain's immune system to cure neurogenerative disorders. Here we describe our Neuroimmunology pipeline and our novel Blood-brain barrier crossing technology (ABC) designed to further enhance brain delivery of antibody and protein therapeutics to address neurodegenerative diseases.
The extracellular proteome plays central roles in health and disease. Harnessing TfR1, a constitutive, rapidly internalizing receptor, we developed Transferrin Receptor Targeting Chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins. In two applications, TransTACs enabled the targeting of drug-resistant EGFR-driven lung cancer and reversible control of CAR-T cells. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of extracellular proteins and for targeted cancer therapy.
Utilizing the ability of antibodies as delivery vehicles has resulted in a therapeutic modality known as antibody-drug conjugates or ADCs. As the field advances, new opportunities for antibody-mediated delivery are being explored. This talk will focus on our efforts to link chimeric protein degraders (aka PROTACs) to antibodies, their efficacy and safety, and how this general approach can expand the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
Degrader antibody conjugates (DACs) combine the unique strengths of ADCs with selective protein degraders. Our state-of-the-art platform enables DACs broadly. Degraders with different mechanisms of action and diverse structures can be delivered in antigen-dependent manner opening exciting opportunities for this novel therapeutic modality.
Elimination of extracellular proteins is a compelling therapeutic modality. EpiTACs are bispecific antibodies in which one arm binds a target and the other arm leverages an EpiAtlas of tissue-enriched degrading receptors comprised of transmembrane ligases, cytokine/chemokine receptors, and internalizing receptors resulting in selective degradation of membrane and soluble proteins. EpiTACs elicit robust in-vitro and in-vivo activity in a target-, tissue- and disease-specific manner for a broad range of indications. Compelling data across multiple targets demonstrates that EpiTACs can degrade a target independent of mutational status, are better than neutralizing antibodies in preclinical models, and drive a survival benefit in preclinical tumor models.
Single domain antibodies (sdAbs) are about one-tenth the size of standard antibodies and have several advantages for therapeutic development. We have generated numerous sdAbs from llamas immunized with tau or α-synuclein proteins. The presentation will highlight our key findings to date and ongoing studies.
The Lysosome Targeting Chimera (LYTAC) is a targeted protein degradation modality that utilizes receptor-mediated endocytosis to drive internalization and lysosome-mediated degradation of extracellular target proteins. In this presentation, we will disclose application of Lycia’s platform to design and generate small molecule conjugate and fully biologic LYTACs that promote strong in vitro and in vivo depletion of protein targets of interest.
The talk will focus on our pre-clinical and clinical experience with CD27 monoclonal antibodies and consider how their therapeutic activity might be improved.
A recent clinical trial involving MOv18 IgE, provided tantalising evidence of IgE’s potential for the treatment of cancer. Epsilogen is conducting a phase Ib trial in which translational data will be collated to further understand mechanisms associated with IgE therapy. In addition, Epsilogen has established a pipeline of anti-tumoral IgEs and two novel platforms: bispecific IgE and a hybrid antibody which combines the effector functions of IgE and IgG.
The FORCE™ platform was designed to enhance delivery of oligonucleotide to muscle for the treatment of neuromuscular disorders by conjugating them to an antigen-binding fragment (Fab) that is selective for the human transferrin receptor 1 (TfR1). In this presentation, we introduce the properties and modularity of the FORCE platform and provide evidence of translation between pre-clinical models and clinical proof of concept in myotonic dystrophy type 1 (DM1) with DYNE-101.
The paucity of dendritic cells in the tumor microenvironment is considered to be a limiting factor to immune checkpoint blockade efficacy in patients with cancer. These cells can be expanded in vivo by the growth factor FLT3L, however, used in its native form, FLT3L requires daily dosing up to 14 days, hampering its broader use in the clinic. Here we developed a FLT3L with effectorless NG2LH Fc fusion to improve drug-like properties that allows for sustained expansion of dendritic cells upon a single injection, and stimulation of antitumour immunity when combined with an adjuvant and checkpoint blockade in preclinical models. By easing dosing constraints, FLT3L-Fc NG2LH could facilitate exploration of FLT3L based immunotherapies in cancer patients.
We show unique mechanisms of flexible homodimerization crucial for the inhibitory function of checkpoint receptor PD-1 and LAG-3, and identified a novel cell surface receptor potently modulating myeloid-associated Type-I IFN responses. These efforts laid the foundation for developing novel immunotherapies for cancer and autoimmune diseases.
We present our forward translation strategy for evaluating off-the-shelf T cell engagers in combination with costimulatory agonists, employing advanced humanized mouse models to enhance preclinical insights. Our approach bridges the gap between preclinical and clinical research, showcasing the translational relevance of our findings. Additionally, we will share first-in-human Phase 1 clinical data supporting the predictive value of our preclinical platform and its potential to inform therapeutic development. This integrated strategy underscores the promise of our platform in advancing immunotherapeutic approaches
Current approaches to mine functional immune responses are generally limited in quality or throughput. To address these limitations, our group established high-throughput functional screening platforms for natively paired antibodies and T cell receptors generated in vivo. Here we will share several case studies of immune mining and engineering from in vivo leads.
Primary mouse B cells were engineered so their heavy and kappa variable-chain loci were scarlessly overwritten by their respective human antibody variable-chain genes. These B cells proliferated in vivo to generate potent neutralizing plasma, and affinity matured to develop broader, more potent, and more bioavailable HIV-1 and SARS-CoV-2 neutralizing antibodies. This approach improves the clinical utility of antibodies and biologics, enables more human-like vaccine models, and suggests new cell-based therapies.
The rapid evolution of SARS-CoV-2 has resulted in continuous escape from traditional IgG-based monoclonal antibody (mAb) therapeutics, suggesting that new antibody engineering and delivery strategies are required to keep pace with viral evolution. In this presentation, I will describe the discovery and engineering of multi-specific antibodies with broad and potent activity against SARS-CoV-2 variants and the in vivo delivery of these constructs using mRNA technology.
Identifying novel epitopes naturally targeted by the human antibody repertoire is an important component of immunogen design aimed at eliciting protective antibodies to infectious disease. I will describe techniques used to survey and characterize monoclonal antibodies generated in response to experimental vaccines in human clinical trials.
After vaccination, responding B cells may differentiate along the extrafollicular path, which leads to the production of short-lived plasmablasts, or along the germinal center (GC) route, which leads to the generation of long-lived plasma cells and memory B cells. GCs are the primary site of affinity maturation, the process whereby the binding affinity of induced antibodies to vaccine antigens increases with time after vaccination. We have recently shown that mRNA vaccination against SARS-CoV-2 in humans can elicit a GC reaction that engages pre-existing memory B cell clones and de novo ones that can target new epitopes, broadening the spectrum of vaccine-induced protective antibodies. These findings raised the following important questions: (1) What are the dynamics of vaccine-induced GC B cell responses in humans? (2) Do responding GC B cells accumulate somatic hypermutations (SHM) after mRNA vaccination? (3) Can a GC reaction be remounted upon repeat mRNA vaccination? These are some of the questions I will discuss in my presentation.
MYTX-011 is an investigational, pH-sensitive, vcMMAE ADC. It has been designed to benefit a broader population of patients whose tumors express lower/moderate levels of cMET. MYTX-011 drives increased internalization and cytotoxicity and shows robust activity in xenograft models across a range of levels of cMET expression. Early clinical data demonstrate a differentiated profile: extended PK, low free MMAE release, and low incidence of side effects commonly associated with vcMMAE ADCs.
Chain exchange technologies can be used to generate binder-format matrices of bispecific antibodies. Similar to the optimization of bsAbs, chain-exchange can also generate ADC-matrices by combining different binders, formats, attachment-positions and payloads. As an example, a Her2-ADC matrix with payloads attached in different formats, positions and stoichiometries reveals that ‘format-defines-function’ applies not only to bsAbs but also to ADCs.
Payload resistance is a critical concern for ADCs. Combinations may be beneficial but therapeutic windows are limited. Hummingbird Bioscience's dual-payload ADC platform is a targeted, single-agent approach designed to overcome resistance and maximize therapeutic window. HMBD-802, an anti-HER2 dual-payload ADC shows robust efficacy in trastuzumab deruxtecan resistant models and good tolerability.
99% of a dose of an ADC is eliminated by normal tissues, causing efficacy limiting toxicities. Shasqi has developed an approach to overcome this problem by separating tumor binding from the payload and enabling selective payload activation at the tumor using click chemistry. This approach maximizes efficacy and therapeutic index by reducing toxicities.
Radiolabeled antibodies are essential in cancer theranostics and radio-immunotherapy (RIT) due to their high specificity for cancer antigens. While promising, RIT faces challenges including long half-life leading to prolonged radioactivity exposure. This presentation explores strategies to improve RIT efficacy and safety, including combination therapies with drugs that modulate radiation response or interact with the immune system, as well as antibody modifications, and optimized administration techniques.
Immunostimulatory antibody conjugates (ISACs) often rely on Fcγ receptor (FcγR) interactions to activate immune cells and drive tumor regression. However, these interactions may also contribute to immune-related side effects. To address this, we are developing deglycosylated ISACs that bypass FcγR binding. Tested in HER2+ breast and Trop2+ pancreatic cancer models, these ISACs maintained potent tumor-specific immune activation while potentially minimizing off-target effects. Ongoing studies are exploring the link between immunogenicity and FcγR binding.
This presentation will describe pre-clinical data from Regeneron’s clinical approaches to enhancing anti-tumor efficacy of T cells, focusing on the combination of costimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of T cell targeted enhancement strategies in pre-clinical development will be discussed.
T-cell engaging bispecific antibodies have had tremendous success in treating hematologic tumors but have shown limited efficacy in solid tumors. Alternative strategies for engaging the immune system employing safe and tunable bispecific antibodies are needed to overcome the challenges of solid tumors. In this presentation, we describe the bispecific platforms developed at Rondo Therapeutics and highlight progress on our lead program, RNDO-564, a CD28 x Nectin-4 bispecific antibody for treatment of metastatic bladder cancer.
CD3 bispecifics are clinically validated modalities, but none of the 9 approved molecules incorporates a costimulatory signal for optimal T-cell activation. EvolveImmune has integrated natural CD2 costimulation and affinity-tuned CD3 engagement into our EVOLVE platform, which induces sustained T-cell activation and potent redirection against tumor cells, whilst limiting T-cell exhaustion.
IgA can be a well-suited isotype for therapeutic application in oncology due to its capacity to activate myeloid cells, especially neutrophils. However, therapeutic use is limited through issues with developability, pharmacokinetics, and in vivo translatability. In my talk, I will address the steps we have taken to employ IgA optimally for oncology.
The therapeutic potential of T cell engagers (TCE) has been limited by a narrow safety window, with excess cytokine release and on-target toxicity limiting their clinical usefulness. Our Tumor-Microenvironment Activated Therapeutics (T-MATE™) platform overcomes these challenges by utilizing a pH-dependent conformational switch. This innovative mechanism attenuates TCE activity at physiological pH while preserving full potency within the tumor microenvironment, enabling a new class of safe and effective TCE therapeutics.
Oxidative stress occurs in many autoimmune diseases which give rise to oxidative post translationally modified (oxPTM) neoepitopes that are recognized by the immune system as ‘non-self’. The detection of autoantibodies against oxPTM neoepitopes, might improve early diagnosis and monitoring of disease activity. Importantly, oxPTM neoepitopes accumulating in the diseased tissue can be exploited for targeting therapeutic specifically to diseased tissue. Studies on musculoskeletal diseases and type 1 diabetes will be reviewed.
Mast cells (MCs) are key players in many allergic and inflammatory diseases. Briquilimab is a monoclonal antibody that binds to c-Kit, blocking stem cell factor from binding and activating c-Kit, leading to MC apoptosis and depletion. Pharmacokinetic and pharmacodynamic evaluation of briquilimab in non-human primates and in murine disease models of asthma and dermatitis suggest that briquilimab-mediated depletion of MCs is well-tolerated, protects against MC activation from various stimuli, and significantly reduces tissue inflammation.
Obexelimab is a CD19 x FcgRIIb bifunctional monoclonal antibody resulting in an inhibitory effect, rather than depletion, across B cell lineage (pro-B cells, pre-B cells, B cells, plasmablasts and CD19-expressing plasma cells). It mimics natural antigen-antibody complex for inhibition of B cells. It is being developed for multiple I&I indications for autoimmune diseases. Clinical data from obexelimab-treated patients and relevant mechanisms of action will be discussed.
InduPro leverages inherent and induced proximity of cell surface proteins to discover novel biology and enable therapeutic development. We demonstrate that re- location of immunomodulatory proteins into or out of the immune synapse using select bi-specific antibodies can alter T cell activation. Application of this approach to dampen T cell signaling for the treatment of autoimmune disease will be presented.
DNTH103 is an investigational, fully human, half-life extended, potent monoclonal antibody engineered to selectively target the classical pathway by inhibiting only the active form of the C1s protein, to enable a more convenient subcutaneous, self-administered injection dosed as infrequently as once every two weeks. Additionally, selective inhibition of the classical complement pathway may lower patient risk of infection from encapsulated bacteria by preserving immune activity of the lectin and alternative pathways. DNTH103 is in development for Myasthenia Gravis, CIDP and MMN.
Regulatory T cells (Tregs) are naturally occurring immune cells that modulate immune responses and promote tissue homeostasis. Treg dysfunction is characteristic of many chronic autoimmune and inflammatory diseases. Sonoma Biotherapeutics genetically engineers and expands patients’ Tregs as a “living therapy” with antigen receptors that target diseased tissue to regulate inappropriate immune responses, reducing inflammation and facilitating tissue repair without compromising host defense.
We present methods to keep the sequences of therapeutic antibody candidates as close as possible to the germline, for example by affinity maturation without any point mutagenesis.
Surface display of intact antibodies in mammalian cells engineered with somatic hypermutation machinery replicates key aspects of the adaptive immune system allowing affinity maturation via “natural” mutations in frameworks and insertions/deletions in CDRs. Human germline sequences from low affinity naïve human antibodies contain natural hotspots near key residues involved in low affinity interactions and the platform can convert these residues to higher affinity alternatives with better developability.
We evaluated the biophysical properties of 400 human B cell-derived mAbs using high-throughput screening assays. Overall, mAbs derivedfrom memory B cells and long-lived plasma cells (LLPCs) display reduced levels of polyreactivity, hydrophobicity, and thermal stability compared with naive B cell-derived mAbs. Somatic hypermutation (SHM) is inversely associated with all three biophysical properties. The developability profiles of the human B cell-derived mAbs are comparable with those observed for clinical mAbs
The tripartite beta-lactamase assay (TPBLA) developed in our laboratory allows the aggregation propensity of a peptide or protein to be quantified in vivo. Aggregation propensity is linked to a simple phenotypic read-out (bacterial resistance to b-lactam antibiotics) by grafting the protein/peptide of interest into an unstructured loop in beta-lactamase which is inactivated upon aggregation of the grafted sequence. In addition, the TPBLA can be used as a screen for directed evolution of problematic sequences and, when combined with next generation sequencing can provide insight into the mechanism of aggregation for disease-causing and therapeutic proteins.
Antibody discovery and lead selection require a careful analysis of affinity, epitope, specificity, and cross-reactivity. A-Alpha Bio’s AlphaSeq platform can measure these properties simultaneously for an entire antibody library by reprogramming yeast agglutination
with a next generation sequencing readout. In his talk, David will introduce the AlphaSeq platform along with specific use cases for biologics development.
To address the therapeutic limitations of both PD-1 and PD-L1 blockade, we have developed novel, fully human antibodies which block binding of both PD-ligands to PD-1, as well as of PD-L1 to
B7-1. The in vitro efficacy of these therapeutics equals or exceeds that of PD-1 blockade; however, when armed with effector function in vivo, these antibodies can regress both PD-1 sensitive “hot” and PD-1 resistant “cold” syngeneic tumors.
To address the therapeutic limitations of both PD-1 and PD-L1 blockade, we have developed novel, fully human antibodies which block binding of both PD-ligands to PD-1, as well as of PD-L1 to
B7-1. The in vitro efficacy of these therapeutics equals or exceeds that of PD-1 blockade; however, when armed with effector function in vivo, these antibodies can regress both PD-1 sensitive “hot” and PD-1 resistant “cold” syngeneic tumors.
Transforming growth factor-beta (TGFβ) signaling in solid tumors has recently been associated with primary resistance to checkpoint inhibition therapy. SRK-181 is a fully human antibody that selectively binds latent TGFβ1 and inhibits its activation. Our data demonstrate that inhibiting the TGFβ1 isoform with SRK-181 is sufficient to overcome primary resistance to anti-PD-1 in syngeneic mouse tumor models and has an improved safety profile compared to broad TGFβ inhibition.
Memo Therapeutics current pipeline features two antiviral antibody programs, one for the prevention of BK virus-associated nephritis in kidney transplant recipients and the other for the prevention of SARS-CoV-2 virus progression in patients at high risk for a severe course of COVID-19. Antibody discovery for both programs was performed using our microfluidic single-cell-based technology platform Dropzylla®. Dropzylla® expresses recombinant antibody repertoires of millions of memory B cells allowing the identification of virus-specific monoclonal antibodies in three weeks.
Pulmonary Arterial Hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy through vasodilation but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased in patients with idiopathic PAH and stimulates pulmonary vascular remodelling. Treatment with a human antibody targeting OPG attenuates pulmonary vascular remodelling associated multiple rodent models of PAH in the presence of standard of care vasodilator therapy. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.
Phagocytosis plays important roles both in homeostasis and under pathological condition. MerTK is a member of TAM receptor tyrosine kinase. Two stories will be presented by blocking or activating MerTK mediated phagocytosis. 1) Antibody blockade of MerTK prevents apoptotic cell clearance by macrophages, MerTK blockade increases tumor immunogenicity and enhances anti PDL1/PD1 therapy. 2) Unlike Fc receptor mediated phagocytosis, MerTK mediated phagocytic clearance is immunologically silent. We will describe a bi-specific antibody approach to harness MerTK for targeted clearance without inducing proinflammatory cytokine release associated with Fcreceptor engagement.
REGN4018 binds both MUC16 on tumor cells and CD3 on T cells. REGN4018 inhibited growth of human tumors in a xenogenic model and syngeneic models. Immuno-PET imaging demonstrated localization of REGN4018 in MUC16-expressing tumors as well as in T cell-rich organs. Toxicology studies in cynomolgus monkeys showed minimal and transient increases in serum cytokines and C-reactive protein following REGN4018 administration with no overt toxicity.
Bispecific antibody-mediated co-engagement of T cells with tumor antigens is now a validated therapeutic strategy. We have engineered modular Fc-containing bispecifics by coupling a robust and portable single-chain CD3 domain with full-length antibodies against promising cancer targets, and have also extended this Fc platform to generate multiple checkpoint inhibiting bispecifics and cytokine-Fc fusions. I will present case studies of several such bispecifics entering clinical development.
Bispecific antibodies are coming of age as therapeutics with two currently marketed and 100+ more bispecifics in clinical development. This presentation will focus on addressing challenges that may assist in the development of some bispecific antibodies. Firstly, intrinsic antibody heavy/light chain pairing preference were investigated and then used to facilitate the efficient production of bispecific IgG in single host cells. Secondly, a mutational strategy was devised to mitigate high viscosity of some monospecific and bispecific antibodies that may facilitate subcutaneous delivery.
AvibodiesTM comprise unique surface disulphides for precise loading of drug payloads (auristatins, maytansinoids) with superior tumor xenograft regression compared to conventional IgGs (targeting CD30). PK of Tag-72 targeted diabodies has been demonstrated in a first-in-man Phase 1 clinical biodistribution trial. With TagWorks NV2, Avibodies were shown to pre-target and upload tumors with the ADC-drug subsequently released by a systemic activator. In summary, Avipep’s novel AvibodyTM designsenable precise site-specific loading of drug and isotope payloads for cancer imaging and ADC therapy.
To enhance the selectivity of monoclonal antibodies for tumors over healthy tissues, we have developed an antibody masking system that utilizes coiled-coil peptide domains to sterically impede antigen binding. On exposure to tumor-associated proteases the coiled-coil domains can be cleaved and antibody function restored. The coiledcoil domain is a generalizable approach for antibody masking that results in antibody therapeutics with improved circulation half-lives, minimized systemic effects, and improved tumor targeting.
Antikor are addressing challenges of treating solid tumours with their innovative next-generation ‘miniaturized’ Antibody Drug Conjugates (ADC) called Fragment Drug Conjugates (FDCs). FDCs offer benefits due to their effective penetration, more-rapid delivery of high amounts of cytotoxic payload and fast clearance from normal tissues, resulting in better tolerability and therapeutic index. We’ll present data showing how the combination of antibody engineering and linker-payload design can be used to tailor the PK and tolerability properties of FDCs. Antikor has part-licenced its first product, an anti-HER2 FDC to development partner, Essex Biotechnology and Antikor’s exciting new flagship FDC product will be presented with compelling efficacy, tolerability and CMC data.
Adoptive transfer of genetically modified immune cells holds great promise for cancer immunotherapy. We have developed a widely adaptable technology to barcode and track targeted integrations of large non-viral DNA templates and applied it to perform pooled knockin screens in primary human T cells. Pooled knockin of dozens of unique barcoded templates into the T cell receptor (TCR)-locus revealed gene constructs that enhanced fitness in vitro and in vivo. We further developed pooled knockin sequencing (PoKI-seq), combining singlecell transcriptome analysis and pooled knockin screening to measure cell abundance and cell state ex vivo and in vivo, allowing for the accelerated discovery of next generation cell therapies.
Cytokines transmit critical environmental information into cells to mediate immune functions, and thus have great therapeutic potential, both to stimulate as well as to suppress the immune response for targeted disease treatment. However, the multifarious activities and unfavorable pharmaceutical properties of natural cytokines have limited their clinical performance. Here we describe new computational and experimental protein design technologies that are advancing the clinical translation of effective cytokine therapies.
To identify novel immunotherapy strategies we comprehensively profiled the expression programs and clonality of tumor infiltrating T-cells from 26 glioma patients using full-length single cell RNA sequencing. Using this methodology, we found a novel target expressed in subsets of tumor infiltrating T-cells, as well as NK cells. Functional genomics experiments validated the target’s role as an inhibitory immune checkpoint and prompted a comprehensive therapeutic antibody discovery effort that yielded multiple leads with favorable characteristics and potent pharmacology across both T- and NK-cell functional assays.
Emerging data point to a critical role for Fc-effector function across infectious diseases. These functions range from target pathogen opsinophagocytic clearance, infected cell cytotoxicity, pathogen mucin-trapping, to simple pathogen-growth arrest. Here, we developed a systems biology inspired Fc-engineering platform to generate Fc-libraries on any Fab of interest. Coupling any Fab to 80 distinct Fc domains, generates a library of Fc-variants to screen for Fab/Fc domains of greatest clinically benefit.
Antibody effector functions are often undesired for therapeutic antibodies when only antigen binding or neutralization would be ideal. By switching the native glycosylation site from position 297 to 298, we created alternative antibody glycosylation variants as a novel strategy to eliminate the effector functions. The lead mutant called “NNAS” (N297/S298N/T299A/Y300S) with the engineered glycosylation site at Asn298 shows no detectable binding to all mouse or human FcγRs by SPR analyses. The effector functions of the mutant are completely eliminated when measured in antibody-dependent cellular cytotoxicity (ADCC) and complementdependent cytotoxicity (CDC) assays. Structural study confirmed the successful glycosylation switch to the engineered Asn298 site
would cause a clash of N-glycans with FcγRs, resulting in loss of binding. In addition, the NNAS mutants of multiple antibodies retain binding to antigens and FcRn, exhibit comparable purification yields and thermal stability, and display normal circulation half-life in mice and non-human primate. Our work provides a novel approach for generating therapeutic antibodies devoid of any effector function with potentially lower immunogenicity.
ProbodyTM therapeutics are antibody prodrugs designed to remain predominantly inactive in the circulation until they are proteolytically activated in the tumor microenvironment, thereby widening the therapeutic index. Probody technology can be applied to multiple therapeutic modalities. Examples will be presented, including probodies based on checkpoint inhibitors, antibody drug conjugates, and T cell-engaging bispecifics.
IgG antibodies must be modified with an asparagine-linked (N-) glycan to bind Fc receptors and stimulate a cytotoxic response. It was known that altering the glycan composition impacted affinity, though it was unclear how. We determined that the IgG1 Fc N-glycans sample multiple conformations, and specific antibody features provide additional interactions that stabilize and preorganize the receptor-binding interface for optimal affinity.
This presentation will review the rapid progress that investigators have made isolating very potent human monoclonal antibodies for SARS-CoV-2 from the B cells of survivors and deploying them to the clinic.