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Engineered SIRPa variants as immunotherapeutic adjuvants to anticancer antibodies. Science Weiskopf, K., Ring, A. M., Ho, C. C., Volkmer, J., Levin, A. M., Volkmer, A. K., Ozkan, E., Fernhoff, N. B., van de Rijn, M., Weissman, I. L., Garcia, K. C. 2013; 341 (6141): 88-91

Abstract

CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPa, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPa variants with approximately 50,000-fold increased affinity for human CD47 relative to wild-type SIRPa. As high-affinity SIRPa monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This "one-two punch" directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.

View details for DOI 10.1126/science.1238856

View details for PubMedID 23722425