Abstract 5312: BSI-082, a fully human anti-SIRPα antibody with both high specificity and broad coverage of SIRPα variant populations
Authors: Peng Zeyu , Liu Jinyu , Dai Wenwen , Liu Xiaodong F. , Xia Shukai , Li Hongyan , Shi Lei , Davis Hugh M. , Chen Mingjiu , Ma Mark Z. 
Published: June 2022

Abstract
Background: SIRPα is an inhibitory immunoreceptor, expressed on macrophages that interacts with CD47 expressed on tumor cells to release a “don't eat me” signal, resulting in immune evasion of tumor cells. Antibodies targeting CD47 or SIRPα are expected to block the CD47/SIRPα signaling pathway, thereby stimulating macrophage-based phagocytosis of tumor cells. Anti-CD47 antibodies usually have side effects related to anemia and thrombocytopenia since CD47 is expressed on normal cells, including red blood cells and platelets. Targeting SIRPα on the macrophage is an alternative approach to blocking CD47/SIRPα signaling without the side effects observed in anti-CD47 antibody treatment. In addition to SIRPα there are two other members of the SIRP family - SIRPβ and SIRPγ. These isoforms share high sequence homology with SIRPα but have very different functionality. Moreover, SIRPα is polymorphic in humans, among which SIRPαV1, SIRPαV2 and SIRPαV8 are the main SIRPα variants in diverse ethnic groups. Together, the key challenge of anti-SIRPα antibody discovery is to identify lead candidates that specifically bind to SIRPα and block the SIRPα/CD47 interaction while also recognizing the majority of SIRPα variants.
Experimental procedures: Humanized mice were used for immunization and the proprietary H3 (High-throughput, High-content and High-efficiency) antibody screening platform was used to identify a lead candidate - BSI-082. Affinity was measured by SPR while specificity of antibodies to SIRPα and blocking activity of CD47/SIRPα were evaluated by ELISA and FACS. Functional activity of antibodies was investigated using monocyte-derived macrophages and Raji cells in the presence of Rituximab with and without anti-SIRPα antibody. Antibody internalization was evaluated by using the Biosion SynTracer™ antibody discovery platform.
Results: BSI-082 is a fully human IgG1/κ mAb that binds to SIRPα and blocks the SIRPα/CD47-mediated signaling pathway. BSI-082 is a highly selective SIRPα binder with very weak or no binding to SIRPβ and no binding to SIRPγ. In addition, BSI-082 binds three main SIRPα variants (V1, V2 and V8) with high affinity. Through antibody engineering, BSI-082 harbors an engineered Fc domain that prevents FcγR binding and enhances FcRn binding, thus significantly reducing ADCC while also extending half-life. In the presence of rituximab, BSI-082 promotes macrophage-mediated phagocytosis. BSI-082 exhibits effective internalization, which would deplete SIRPα on macrophages and enhance immune response.
Conclusion: BSI-082 exhibits best-in-class biophysical properties, SIRPα specificity, broad SIRPα variant binding and superior functional characteristics, supporting the initiation of development activities including manufacturing and IND-enabling studies.
Citation Format: Zeyu Peng, Jinyu Liu, Wenwen Dai, Xiaodong F. Liu, Shukai Xia, Hongyan Li, Lei Shi, Hugh M. Davis, Mingjiu Chen, Mark Z. Ma. BSI-082, a fully human anti-SIRPα antibody with both high specificity and broad coverage of SIRPα variant populations [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 5312.