Main Conference Day 1 - European Time GMT+1
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.
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.
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.
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.
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 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.
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.
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.
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.