Patient-customized monoclonal antibody discovery platform for cancer therapy via neoepitope-specific antibody cocktails 2050

Description Cellular heterogeneity poses a major challenge to cancer treatment. While antibody therapies targeting individual tumor-associated antigens can be highly effective, they often fail in patients with heterogeneous tumors, as cells with low or no antigen expression escape targeting and develop resistance. Targeting multiple tumor-specific proteins with multiple antibodies can improve efficacy, but there are few widely expressed cancer-specific antigens. Neoepitopes, arising from mutations unique to tumor cells, are more abundant, but their patient-specific nature necessitates a customized approach. Here, we used directed evolution in yeast and phage display systems to engineer B16F10 melanoma neoepitope-specific antibodies from non-immune human antibody fragment libraries. We demonstrate proof-of-concept for a pipeline that supports rapid isolation and functional enhancement of multiple neoepitope peptide-targeted monoclonal antibodies and demonstrate their robust binding to B16F10 cells and potent effector functions in vitro. These antibodies were combined and evaluated in vivo for anti-cancer activity in tumor-bearing mice, where they suppressed B16F10 tumor growth and prolonged survival. These findings emphasize the potential for clinical application of patient-customized antibody cocktails in the treatment of the many cancers poorly addressed by current therapies. Funding Sources SD Ireland Cancer Research Fund PhD Innovation Program at Dartmouth NIH NIGMS grant P20-GM113132 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)