Unbiased discovery of antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma

Ribeiro, J.; Pages-Geli, C.; Meglan, A.; Velarde, J.; Blandin, J.; Vaccaro, K.; Wienclaw, T.; Fernandez-Guzman, P.; Hahn, C. K.; Crespo, M.; Weiskopf, K.

doi:10.1101/2024.11.13.623229

bioRxiv · 10.1101/2024.11.13.623229

Unbiased discovery of antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma

Ribeiro, J.·Pages-Geli, C.·Meglan, A.·Velarde, J.·Blandin, J.·Vaccaro, K.·Wienclaw, T.·Fernandez-Guzman, P.·Hahn, C. K.·Crespo, M.·Weiskopf, K.

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Abstract

Macrophages are critical effectors of antibody therapies for lymphoma, but the best targets for this purpose remain unknown. Here, we sought to define a comprehensive repertoire of cell surface antigens that can be targeted to stimulate macrophage-mediated destruction of B-cell lymphoma. We developed a high-throughput assay to screen hundreds of antibodies for their ability to provoke macrophages to attack B-cell lymphoma cells. Across both mouse and human systems, we identified multiple unappreciated targets of opsonization as well as putative immune checkpoints. We used this information to engineer a compendium of 156 bispecific antibodies, and we identified dozens of bispecifics that dramatically stimulate macrophage-mediated cytotoxicity of lymphoma cells. Among these, a bispecific comprising a SIRP decoy domain and a CD38-targeting arm (WTa2d1xCD38) exhibited maximal efficacy while minimizing the risk of hematologic toxicity. This bispecific stimulated robust anti-tumor responses in multiple xenograft models of aggressive B-cell lymphoma. Our approach can be directly applied to other cancers to rapidly discover bispecific antibodies that leverage anti-tumor responses by macrophages or other innate immune cells.

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Ribeiro, J., Pages-Geli, C., Meglan, A., Velarde, J., Blandin, J., Vaccaro, K., Wienclaw, T., Fernandez-Guzman, P., Hahn, C. K., Crespo, M., Weiskopf, K.. 2024-11-15. Unbiased discovery of antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma. https://doi.org/10.1101/2024.11.13.623229

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