Main Conference Day 1Tuesday, 10 June 2025 - BST (British Summer 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 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. Additionally, the talk will explore innovations across therapeutic modalities, with updates on mRNA-encoded antibodies and insights from our latest collaboration on peptide libraries and therapeutic peptide characterization.

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.

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.

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.