Abstract A93: Development of blocking antibodies to human CD47 with lower side effects on RBCs and platelets

Abstract

Abstract CD47 is a major immune “checkpoint” molecule for macrophage activation. It is highly expressed on many types of cancers, including human acute myeloid leukemia (AML), non-Hodgkin’s lymphoma (NHL), and solid tumors such as small-cell lung cancer (SCLC). Binding of CD47 to its receptor, SIRPα, on macrophages leads to inhibition of macrophage activation and phagocytosis. CD47 overexpression is considered to be one of the mechanisms cancer cells employ to evade immune surveillance and correlates with poor prognosis in cancers. Several strategies have been used to block CD47 binding to SIRPα, including anti-CD47 blocking antibodies and SIRPα Fc proteins. However, since CD47 is also expressed on normal cells, a major concern is that these anti-CD47 antibodies may also induce platelet aggregation and red blood cell hemagglutination. In addition, since anti-CD47 antibodies bind to many different cell types in the peripheral circulation, the half-life for these antibody drugs could be lower. Here we report the generation and characterization of a panel of high-affinity anti-human CD47 blocking antibodies. The lead antibodies bound to human CD47 with sub-nanomolar affinities and displayed a range of activities in blocking CD47/SIRPα interaction. These antibodies showed robust activities in stimulating macrophage-mediated phagocytosis of cancer cells. Importantly, our antibodies did not induce red blood cell hemagglutination in in vitro assays. One of the lead antibodies demonstrates pH- dependent binding to human CD47. It has lower binding affinity to human CD47 at neutral pH but higher binding affinity to CD47 at more acidic pH, suggesting that this antibody may preferentially bind to CD47 in tumor microenvironment. Currently we are evaluating these anti-CD47 antibodies in preclinical efficacy and safety models. Citation Format: Richard Zhang, Haishan Lin. Development of blocking antibodies to human CD47 with lower side effects on RBCs and platelets [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A93.