We present a comprehensive strategy for generating best-in-class anti-pMHC single-chain Fv (scFv) antibodies, from the discovery of anti-pHLA binders to the engineering of potent T-cell engagers. Our approach integrates advanced sorting techniques, bioinformatics-driven predictions, high-throughput screening, and protein engineering to develop highly specific and stable pMHC-targeting antibodies. This optimized pipeline enables the identification of therapeutic candidates with exceptional selectivity and antitumour activity, paving the way for new advancements in antibody-based cancer therapies.

Downregulation of targets limits 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 favorable safety and tolerability profile in heavily pretreated patients with r/r MM.

Tumour-targeted costimulatory CD28 bispecific antibodies represent a potential groundbreaking therapeutic approach for combating challenging solid tumours. Early human trials have demonstrated significant clinical efficacy of the PSMAxCD28 bispecific antibody when combined with anti-PD-1 treatment in patients with metastatic castration-resistant prostate cancer. Understanding the underlying mechanisms driving the potent synergy between these agents in enhancing responsiveness in mCRPC tumours, which are unresponsive to PD-1 inhibitors alone, is crucial. Concurrently, developing strategies to effectively manage safety concerns remains a top priority in advancing this innovative therapy.

This presentation focuses on the development of bispecific HER3 antibodies for cancer immunotherapy. We will describe the rationale behind HER3 targeting, outline the antibody formats explored, and summarise in vitro and in vivo findings that support their therapeutic potential. This session aims to highlight how this bispecific approach may offer a novel and promising option for the treatment of HER3-expressing cancers.

A peptide nucleic acid (PNA)-based pretargeting strategy for radionuclide therapy has been developed to reduce radioactivity uptake in non-tumour organs. The PNA pretargeting concept has successfully been demonstrated in preclinical mouse models using affibody molecules, DARPins, and monoclonal antibodies as the tumour-targeting agents. The pretargeting technology has further been optimised by engineering of the PNA probes and investigation of new bioconjugation methods.

We have developed an innovative pre-targeted radioimmunotherapy (PRIT) strategy using reconstituting half-antibodies to specifically target cancer cells. Our novel approach enhances specificity and reduces systemic toxicity by forming a complete antibody only at tumour sites, eliminating the need for a clearing agent. Utilising lead-212 as an in vivo alpha generator, this method maximises tumour cell destruction while minimising healthy tissue damage, offering significant therapeutic advantages over traditional PRIT methods.

Designed Ankyrin Repeat Proteins (DARPins) are promising protein-based delivery vectors for radiopharmaceuticals due to their small size and high specificity. This presentation showcases our development of Radio-DARPin Therapeutic (RDT) candidates with favourable tumour-to-kidney ratios through DARPin surface engineering and half-life modulation using different albumin binders. Combined with the alpha-emitting radioisotope 212Pb, we achieved high-energy deposition in tumours, while minimising kidney accumulation, highlighting RDTs’ potential as effective cancer treatments.

We engineered a novel Fc-fused bacterially derived IgE protease using Seismic’s proprietary machine learning enabled platform to reduce immunogenicity and improve manufacturability while maintaining selectivity and potency. The protease selectively cleaves IgE, eliminating it from circulation, from cell surface and immune complexes, and provides a novel therapeutic opportunity to treat IgE-mediated allergic and atopic diseases.

Recent developments in targeted protein degradation have provided great opportunities to eliminating extracellular protein targets using potential therapies with unique mechanisms of action and pharmacology. Among them, Lysosome-Targeting Chimeras (LYTACs) acting through mannose 6-phosphate receptor (M6PR) have been shown to facilitate degradation of several soluble and membrane-associated proteins in lysosomes with high efficiency. Herein we have developed a novel site-specific antibody conjugation approach to generate antibody mannose 6-phosphate (M6P) conjugates.

With the increased occurrence of cancer types exhibiting resistance to currently approved therapy methods and the limitation of the mechanisms of action of cytotoxic agents to three broad major categories, degraders are new potential candidates in the setting of antibody-drug-conjugates due to their possible introduction of new mode of actions and the targeting of new survival-critical proteins previously non-addressable.

To enhance the selectivity of cancer therapies, we present a single-cell atlas-guided approach to identify surface target pairs for dual-targeting biologics in colorectal cancer (CRC). Our computational pipeline prioritizes pairs that are highly co-expressed on CRC cells but show minimal co-expression in healthy tissues, thereby increasing the therapeutic window. We showcase this strategy by successfully de-risking CEACAM5, identifying an optimal partner for a highly tumor-specific combination.