Targeting macrophage checkpoint inhibitor SIRPa for anticancer therapy. JCI insight Liu, J. n., Xavy, S. n., Mihardja, S. n., Chen, S. n., Sompalli, K. n., Feng, D. n., Choi, T. S., Agoram, B. n., Majeti, R. n., Weissman, I. L., Volkmer, J. P. 2020


The SIRPa-CD47 interaction provides a macrophage immune checkpoint pathway that plays a critical role in cancer immune evasion across multiple cancers. Here, we report the engineering of a humanized anti-SIRPa monoclonal antibody (1H9) for antibody target cancer therapy. 1H9 has broad activity across a wide range of SIRPa variants. Binding of 1H9 to SIRPa blocks its interaction with CD47, thereby promoting macrophage-mediated phagocytosis of cancer cells. Pre-clinical studies in vitro and in vivo demonstrate that 1H9 synergizes with other therapeutic antibodies to promote phagocytosis of tumor cells and inhibit tumor growth in both syngeneic and xenograft tumor models, leading to survival benefit. Thus, 1H9 can potentially act as a universal agent to enhance therapeutic efficacy when used in combination with most tumor-targeting antibodies. We report for the first time, a comparison of anti-SIRPa and anti-CD47 antibodies in CD47/SIRPa double humanized mice, and found that 1H9 exhibits a substantially reduced antigen-sink effect due to the limited tissue distribution of SIRPa expression. Toxicokinetic studies in non-human primates show that 1H9 is well tolerated with no treatment-related adverse effects noted. These data highlight the clinical potential of 1H9 as a pan-therapeutic with the desired properties when used in combination with tumor-targeting antibodies.

View details for DOI 10.1172/jci.insight.134728

View details for PubMedID 32427583