Therapeutically targeting tumor myeloid cells has emerged as a complementary strategy to existing cancer immunotherapy approaches. The interaction of tumor-expressed CD47 with SIRPα (Signal Regulatory Protein-α, SIRPA) on macrophages, dendritic cells, and neutrophils inhibit key immune effector mechanisms. Targeting the SIRPα-CD47 axis represents a novel approach to enhance anti-tumor immunity by augmenting or reactivating critical tumor clearance mechanisms. While agents that target CD47 have shown promise in clinical trials, they present hematological toxicities and antigen sink issues that narrow their therapeutic application. Our approach targets SIRPα to focus on relevant mechanisms related to myeloid cell activation and increase of tumor cell phagocytosis while simultaneously avoiding the undesired effects of targeting CD47. Furthermore, SIRPγ, a close relative of SIRPα, is expressed on T cells and potentially co-stimulates T cell proliferation and is required for trans-endothelial T cell migration. We sought to develop an anti-SIRPα therapeutic that does not cross-react with SIRPγ and avoids potentially deleterious effects on T cell functions. Here, we describe APX701, a novel anti-SIRPα antibody generated using Apexigen's APXiMAB™ proprietary antibody discovery platform, and its differentiated properties as compared to other approaches targeting the SIRPα-CD47 interaction. APX701 binds to human SIRPα at a unique epitope with high affinity (Kd = 0.95nM) and with no detectable binding to SIRPγ expressed on primary human T cells. APX701 strongly binds to the major SIRPα variants—V1 and V2—and potently blocks their interaction with CD47, thereby allowing therapeutic targeting of SIRPα in a majority of patients. APX701 reverses SIRPα-mediated suppression of macrophage phagocytosis, resulting in potent destruction of a variety of tumor cells both as a single agent and in combination with anti-TAA (tumor associated antigen) antibodies including cetuximab, rituximab, and trastuzumab. Moreover, targeting SIRPα with APX701 does not interfere with T cell function, an effect previously observed following anti-CD47 treatment. Together, these data demonstrate the unique binding profile of APX701 and its ability to potently reactivate myeloid cell-mediated anti-tumor immunity. Our data support the development of APX701, a promising myeloid checkpoint inhibitor, for the treatment of cancer.

Citation Format: Ryan Alvarado, Sushma Krishnan, Minu K. Srivastava, Christine Tan, George Huang, Swati Jalgaonkar, Frances R. Bahjat, Erin L. Filbert, Xiaodong Yang. Targeting SIRPα with APX701, a Novel Myeloid Checkpoint Inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB177.