Direct Tumor Suppression by Anti-Basigin Antibody and Enhancement of Macrophage-Mediated Cancer Cell Phagocytosis under SIRPα Blockade.

Abstract

The transmembrane protein CD47 expressed on tumor cells suppresses Fcγ receptor-mediated antibody-dependent cellular phagocytosis (ADCP) through its interaction with signal regulatory protein α (SIRPα), a transmembrane protein expressed on phagocytic cells such as macrophages. Although blockade of the CD47-SIRPα interaction enhances the efficacy of tumor-targeting antibodies such as rituximab, its antitumor activity remains limited in cancers lacking defined tumor-associated antigens. In this study, we identified the membrane protein Basigin and SIRPα as broadly applicable therapeutic targets for cancer. We found that the 8H4 antibody, originally identified in the course of other research, recognized mouse Basigin, suppressed proliferation of diverse cancer cell types, and induced cancer cell death. Treatment with the 8H4 antibody indeed inhibited tumor growth in vivo. Moreover, combined treatment with the 8H4 antibody and an anti-SIRPα antibody that blocks the CD47-SIRPα interaction markedly enhanced macrophage-mediated ADCP against diverse cancer cell types in vitro. These results suggest that targeting Basigin, particularly in combination with SIRPα blockade, may provide a basis for the development of macrophage-mediated immunotherapies applicable to cancers in which tumor-associated antigens have not yet been identified.