Immunogenicity remains a barrier in biotherapeutic development, limiting exposure, efficacy, and safety and often constraining otherwise high-value biologic programs. The impact is particularly acute for non-human biologics as well as for those whose pharmacology inherently drives immunogenicity. ADAXION harnesses the B-cell checkpoint role of Siglec-2 (CD22) to selectively silence clonal B cell responses to a biotherapeutic while preserving drug pharmacology and normal immune function. This targeted, non–immunosuppressive approach suppresses ADA formation, enabling development of otherwise immunogenic biotherapeutics.  ADAXION is applying this technology to create hypoimmunogenic cytokine inhibitor bispecific antibodies and therapeutic enzymes for treatment of autoimmune and inflammatory diseases.

Interactions between sugar moieties on cancer cells and Siglecs on effector cells can impair tumour cell killing by therapeutic antibodies. Here, we describe approaches how interference with this checkpoint can improve tumour cell killing by myeloid effector cells—including the novel Ablec technology.

Tagworks is pioneering a new approach to ADCs, based on its Click-to-Release platform, that expands the ADC target scope to non- or slowly internalizing tumor antigens. Following extracellular tumor accumulation and blood clearance of a click-cleavable ADC, a tetrazine trigger molecule is administered i.v. that reacts with a trans-cyclooctene (TCO) linker, releasing the payload and allowing it to enter and kill surrounding tumor cells. This contribution covers the design considerations and functional characterization of our discovery-phase Click-to-Release ADCs.

Most approved and clinical-stage ADCs use tubulin or topoisomerase I inhibitor payloads. Resistance to these payload classes inevitably develops, highlighting the need for novel payloads with orthogonal mechanisms of action. Byondis is developing anti-folate–based ADCs and will present an update on this linker–drug platform and its lead program.

Pre-treatment vaccination in immunologically “cold” tumour models increases T-cell influx and promotes tumour nest infiltration following CD3 engager treatment. Even when composed of tumour-unrelated antigens, this combination therapy establishes a broadly inflamed TME, drives T-cell-mediated macrophage polarisation, and achieves effective tumour eradication. While the vaccine antigen is irrelevant for the primary response, induction of immune memory depends on the tumour’s inherent immunogenicity, with “cold” tumours requiring the presence of tumour-specific antigens.