Monoclonal antibodies have transformed cancer therapy by enabling the selective targeting of tumor-associated antigens, reducing reliance on broadly toxic chemotherapies. However, not all surface receptors are well suited to conventional antibody approaches, particularly those that signal through ligand-induced dimerization. In these settings, symmetric antibodies can unintentionally mimic native signaling and paradoxically enhance tumor growth. This limitation is especially relevant for a number of clinically important receptor tyrosine kinases that are frequently amplified or overexpressed across multiple cancers and associated with poor outcomes despite available kinase inhibitors. A key question in the field is how to target these receptors effectively while avoiding agonism, resistance, and dose-limiting toxicities.
This Drug Discovery Award will leverage the power of biparatopic antibodies to target two key receptor tyrosine kinases. Biparatopic antibodies are engineered to engage two distinct epitopes on the same antigen, enabling receptor downregulation rather than activation, enhanced internalization, and improved suitability for antibody–drug conjugates. Using a high-throughput ribosome nanobody display platform, the team has generated extensive panels of high-affinity nanobody binders and is assembling them into mono- and biparatopic antibody formats. These constructs will be evaluated as antibody–drug conjugates in cellular and in vivo tumor models, alongside Fc-silent designs intended to mitigate off-target effects such as immune activation or mast cell degranulation.
By combining rational antibody engineering with targeted drug delivery, this project introduces an innovative strategy to overcome long-standing challenges in receptor-directed cancer therapy. Successful development of optimized biparatopic antibody–drug conjugates could provide potent, single-agent treatments for patients with target-amplified and -driven solid tumors with limited therapeutic options, ultimately expanding the clinical impact of antibody-based precision oncology.