Abstract 4789: Development of IMC-002, a next-generation anti-CD47 mAb: an affinity optimized antibody with enhanced safety and therapeutic efficacy in preclinical models

Abstract CD47, a broadly expressed transmembrane glycoprotein, interacts with SIRPα to inhibit macrophage-mediated phagocytosis. Its overexpression on cancer cells is associated with poor prognosis, making the CD47-SIRPα axis a promising target for cancer immunotherapy. While blocking this pathway enhances macrophage-driven anti-tumor responses, clinical translation is hindered by challenges such as hematological toxicity and rapid drug clearance due to CD47 expression on normal cells, including red blood cells.IMC-002, a fully human IgG4 monoclonal antibody targeting CD47, was screened for an optimized affinity to balance therapeutic efficacy and safety. Comparative studies with Hu5F9 and 13H3 demonstrated IMC-002’s enhanced selectivity and unique binding profile. In a tumor-RBC co-culture system, IMC-002 exhibited superior binding to CD47+ tumor cells while showing significantly reduced binding to normal cells, including RBCs, platelets, and CD3+ immune cells, compared to Hu5F9. The tumor selectivity and lack of binding to CD47 on RBCs by IMC-002 appear to result from differences in its binding site. Studies investigating the roles of CD47 clustering, Rh complex, Integrin β1, lipid rafts, and glycosylation revealed that O-glycosylation significantly influences IMC-002’s selective binding to CD47. Antibody structure simulations and antigen binding docking analyses confirmed that IMC-002 engages distinct epitopes and adopts a unique binding orientation compared to Hu5F9. Supporting this mechanism, enzymatic removal of O-glycans on RBCs in vitro increased IMC-002 binding, and in-silico epitope mapping identified an O-glycosylation site within the predicted binding region. We evaluated the therapeutic potential of IMC-002 in various solid tumor models through both in vitro and in vivo studies. In vitro functional assays demonstrated that IMC-002 significantly enhanced macrophage-mediated phagocytosis of tumor cells, both as a monotherapy and in combination with standard of care (SoC) treatment. In vivo, IMC-002 exhibited dose-dependent anti-tumor activity in mouse models of triple-negative breast cancer (TNBC), hepatocellular carcinoma (HCC), and biliary tract cancer (BTC). Furthermore, in non-human primates, IMC-002 was well-tolerated, with no hematological toxicity observed at doses up to 100 mg/kg, and exhibited a pharmacokinetic profile consistent with typical therapeutic antibodies. In conclusion, IMC-002 demonstrated exceptional efficacy and safety, attributed to its unique binding site and mechanism of action. These findings provide strong support for its clinical development as a cancer therapeutic. Phase 1a trials confirmed IMC-002's superior safety profile, and ongoing Phase 1b trials are evaluating its efficacy in combination with standard-of-care therapies in patients with HCC and TNBC. Citation Format: Jiyea Choi, Ji-Eun Park, A-Ra Jeon, Heewook Shin, Yeonsun Yu, HyeHyeon Jang, Hyesun Lee, Jiyoung Yoon, Sung Ho Kim, Heung Tae Kim. Development of IMC-002, a next-generation anti-CD47 mAb: an affinity optimized antibody with enhanced safety and therapeutic efficacy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4789.