Within the past decade, therapies that activate and engage T cells have changed the landscape of treatment of hematological malignancies. Successful T cell engaging antibodies target antigens selectively expressed on tumours with minimal/no expression in other tissues and are potent molecules that can eliminate malignant cells to achieve long-term benefit. Several bispecific T cell engagers have been approved in hematological malignancies. Recent research evaluates multispecific T cell engagers targeting several tumour-associated antigens.

The choice of an appropriate tumour-specific target and CD3 affinity are important considerations for the development of effective and safe CD3 bispecific antibodies (bsAbs). The immune checkpoint protein B7H4 shows high expression in various solid cancers, while expression is low or absent in normal tissues. Therefore, B7H4 provides an attractive target for a CD3 bsAb. This presentation will focus on the preclinical development of DuoBody-CD3-H101GxB7H4, which is currently being investigated in a first-in-human clinical trial for the treatment of solid tumours known to express B7H4 (NCT05180474).

This presentation will review current and emerging strategies to facilitate high-throughput bispecific antibody production, before considering their potential application during a biopharmaceutical discovery campaign. Screening in bispecific format during earlier stages may: i. enable empirical screening to identify or prioritise target pairings during target validation stages, ii. widen protein design space to maximise chances of success, or iii. result in early screening data being more predictive of lead molecule properties.

Agonistic antibodies present a compelling approach to treating diseases driven by defective signaling pathways, but their discovery has been severely limited by the difficulty of identifying epitopes that successfully trigger receptor signaling. Using a combination of experimental and computational approaches, we successfully generated bispecific agonist antibodies that activate a heteromeric receptor complex with the objective to treat human vasculopathies. Our approach has shown to be applicable across diseases and targets.

Complement activation is playing a pathogenic role in several human diseases. The importance of complement in this process is underscored by the successful implementation of complement inhibitory therapies. However, all these therapies work systemically, while the complement activation is occurring only locally. Therefore with my team we are developing bispecific antibody based complement inhibitors that only inhibit locally and leave systemic complement intact to fight infections.

Data from our Phase 2 clinical data with mitazalimab in first line pancreatic cancer show how CD40 targeting can be a game changer in immuno-oncology. The key learnings have been translated into the Neo-X-Prime platform with the lead compound ATOR-4066 targeting CD40 and CEACAM5 demonstrating superior anti-tumour activity and a unique mode of action.