In this study, we developed a novel T cell engager called Dual-Ig that enhances the efficacy of T cell bispecific antibodies by incorporating the co-stimulatory signal CD137. We applied Dual-Ig to an antibody successfully engineered to have high specificity for CLDN6, despite its similarity to other CLDNs. Promising preclinical data suggests that this approach may lead to significant therapeutic advances in the treatment of CLDN6-targeted cancers.

This presentation discusses the pivotal role of dendritic-T cell crosstalk in driving anti-tumor immunity and enhancing immunotherapy. I will highlight our recent studies that led to the development of new immunotherapies, harnessing dendritic cell-T cell interactions for optimal efficacy.

The use of therapeutic antibody-epitope conjugates (AECs) is a new therapeutic strategy for delivery of immunogenic viral epitopes and redirecting virus-specific CD8+ T cell activity toward cancer cells. The AECs rely on proteolytic release of these epitopes close to the tumour cell surface for presentation on HLA Class I molecules. In my presentation, I will cover how we genetically fused an EBV epitope preceded by a protease cleavage site to the protein termini and how we evaluated the potential of these AECs and their capacity to redirect the EBV-specific T cells in vitro and in vivo.

Multispecific antibodies are emerging as a leading class of biological therapeutics. Their capacity to simultaneously target two or more distinct disease pathways or bridge two different cells opens attractive new perspectives in terms of efficacy and selectivity that may potentially lead to better drug safety and an overall improved therapeutic index. We’ll showcase several differentiated Bispecific modalities that have advanced into clinical development and discuss how unique design elements allow us to engineer multispecifics with novel MOAs.

Cytokines emerged as promising molecules for therapeutic intervention in order to modulate the immune response. However, their often pleiotropic nature, combined with their high potency when administered systemically, restricts their therapeutic applicability. We have generated cytokine mimetics with tailor-made mode-of-actions based on multifunctional antibody derivatives.

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.

•  How can structural biology help with the design and screening?
•  How/Why the alternative format antibodies can achieve unique MoA, higher specificity and better activity?
• What are current hurdles to advance these alternative format molecules into and develop them in clinic?
  

We are at the dawn of a second wave of TCR-based biologics and cell therapies recognising peptide-MHC, which expands oncology target opportunities beyond traditional mAb targets. This talk will provide an update on the development of T-Therapeutics’ OpTiMus platform which is a novel mouse transgenic platform for discovery of fully human therapeutic TCRs and bispecifics. It will cover an overview of our state-of-the art discovery process with data on optimisation of our soluble bi-specific modality.

Whereas the T cell receptor (TCR) is generally considered an adaptive modality, αβ TCRs can also act as an innate receptor, engaging nonclonal ligands at germline-encoded sites. We designed a library of antibodies that target distinct germline-encoded variants of TCR variable β chain. In certain formats, these anti-Vβ TCR antibodies agonize the TCR and drive highly selective expansion and activation of Vβ T cell subsets with a novel memory-like effector phenotype. Using different multi-specific antibody formats we have developed dual T cell agonists and tumor-targeting T cell engagers with potent anti-tumour activity in solid tumors.

This talk will cover TCR discovery, computational selection, and affinity prediction. Results of in silico engineering success, reformatting into bispecific (ETCer) and T cell- killing assays will be shared.

Learnings from computational analysis of > 850,000 atom-atom contacts from >1800 structurally elucidated antibody-antigen complexes and >11000 functional antibodies will be presented and their impact for bi-and multispecific antibody design and the generation of novel in-silico designed humanized single-domain antibody phage display libraries with maximal functional diversity for generating fusion partners. Novel workflows for deep mining of antibody phage-display selections using ONT and dual UMI and immobilization free in solution analysis of antibody kinetics will be shown.