Abstract 5204: Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity

Abstract

Abstract CD47 is a well-studied target for cancer immunotherapy. Blocking of CD47 binding to its receptor, SIRPα, on macrophages leads to inhibition of macrophage activation and phagocytosis. Several monoclonal anti-CD47 antibodies are currently in various stages of clinical development. However, since CD47 is also expressed on normal cells such as red blood cells and platelets, anti-CD47 antibodies also caused on-target side effects during clinical evaluations, such as anemia and red blood cell hemagglutination. To minimize the on-target side effects of anti-CD47 antibodies, we have generated anti-CD47 prodrugs. By screening a phage peptide library, we identified peptides that can specifically block the anti-CD47 antibody binding activity. These peptides were fused to the humanized anti-CD47 antibody via a linker containing protease substrate sequences to derive the anti-CD47 antibody prodrug. We demonstrated that these anti-CD47 antibody prodrugs had significantly diminished CD47 binding activity and were unable to block CD47:SIRPα interaction. Upon cleavage of the anti-CD47 antibody prodrug with proteases, the antibody regained full activities in both binding to CD47 and blocking CD47:SIRPα interaction. Importantly, we showed that the anti-CD47 antibody prodrug had minimal hemagglutination and RBC binding activities. Since different tumors may have different types of protease activities, anti-CD47 prodrugs with different types of protease substrates have been generated to demonstrate that the anti-CD47 prodrug can be used for treating various tumor types. These data suggest that novel anti-CD47 antibody prodrugs are promising candidates for the next generation anti-CD47 therapeutics with improved safety profile. Citation Format: Richard Zhang, Haishan Lin. Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5204.