MAIN CONFERENCE DEC. 16Monday, 16 December 2024 - PT (Pacific Time, GMT-08:00)

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.

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.

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.

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.

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.