A CD47 Antibody with Minimized Erythrocyte and Thrombocyte Toxicities

Min Pei¹Xiao-Dong Dai²Xiao-Fan Jiang³Cai-Yi Yuan³Jie Tan⁴Kai-Feng He³Guo-Jian Liu⁵Jin-Di Zhu²Huan-Huan Li⁴Ai-Ling Pan³Ya-Ru Wang⁶Yi-Li Chen⁴Xiao-Jia Chen¹Chunhe Wang^5*

• ¹Jinan University, Guangzhou, China
• ²Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, China
• ³Nanjing University of Chinese Medicine, Nanjing, China
• ⁴Shanghai Mabstone Biotechnology Co Ltd, Shanghai, China
• ⁵Dartsbio Pharmaceuticals Ltd., Zhongshan, China
• ⁶ShanghaiTech University, Shanghai, China

Blockade of the CD47/SIRPα axis has emerged as a promising approach to enhance macrophage-mediated anti-tumor activities in cancer immunotherapy. However, the clinical application of early CD47 antibodies has been associated with significant hematotoxicities, including hemagglutination, anemia, and thrombopenia. Although several CD47 antibodies have generally avoided hemagglutination, anemia, and thrombopenia remain, mediated possibly by enhanced phagocytosis of erythrocytes and thrombocytes. 1B2-10 is a humanized CD47-neutralizing antibody generated by mouse immunization and phage display technologies. It was evaluated in both in vitro assays, tumor xenograft models, and cynomolgus monkeys to confirm the efficacy and safety profiles and in silico studies revealed the binding epitopes of 1B2-10. 1B2-10 showed minimized binding to erythrocytes and thrombocytes, caused no hemagglutination, and reduced phagocytosis of erythrocytes in vitro. It enhanced macrophage-mediated phagocytosis of tumor cells and showed potent antitumor effects as a monotherapy or in combination with a PD-1 antibody in tumor models. In cynomolgus monkeys, 1B2-10 at 120 mg/kg single dose, and 100 mg/kg repeated doses, caused no significant hematotoxicities. The molecular principles underlying the reduced erythrocyte binding of 1B2-10 were elucidated through in silico studies, revealing two critical N-linked glycans masked epitopes. These findings indicate favorable efficacy and safety profiles for 1B2-10, with great therapeutical potentials for cancers. Based on these studies, 1B2-10 has been renamed as DS003 and is currently advancing through Phase I clinical trials in China to further evaluate its safety profile and preliminary efficacy in human subjects.