Abstract 498: ZL-1201, a differentiated CD47 therapeutic antibody with improved hematological safety profile

The interaction between CD47 that is overexpressed on tumor cells and SIRPα on macrophages facilitates a “don9t-eat-me” signal that inhibits macrophage-mediated phagocytosis of tumor cells. Blockade of the CD47/SIRPα interaction using antibodies against CD47 or SIRPα-Fc fusion proteins promotes phagocytosis and tumor cell destruction, which represents a promising strategy for tumor immunotherapy. However, CD47 is ubiquitously expressed on all cells including erythrocytes and platelets, which form a large antibody sink and lead to potential hematological toxicities. In fact, anemia and thrombocytopenia have been observed in non-human primates and tumor patients that are subjected to anti-CD47 treatment in preclinical and clinical studies. We have developed ZL-1201, a recombinant, humanized monoclonal antibody that specifically targets CD47. ZL-1201 was engineered to reduce Fc-mediated antibody effector function. Preclinical in vitro studies show that ZL-1201 displays potent binding to CD47 thereby blocking interaction with SIRPα and effectively facilitates macrophage-mediated phagocytosis of hematological and solid tumor cells. Importantly, ZL-1201 induces minimal red blood cell (RBC) phagocytosis and does not induce hemagglutination, though it does bind to human RBCs and platelets. In vivo studies demonstrate that ZL-1201 possesses potent antitumor efficacy in rodent xenograft tumor models, while displaying remarkably improved hematological safety profile as compared with the benchmark antibody in a toxicology study in cynomolgus monkeys. Thus, ZL-1201 treatment represents an effective CD47-targeting therapy with improved hematological safety consequences. A Ph1 dose escalation study to assess the safety of ZL-1201 is currently ongoing in patients with solid tumors, and future combination studies are planned for both hematologic and solid tumor indications. Citation Format: Bing Wan, Xu Fang, Shou Li, Wenhua Shi, Holly Li, David Bellovin, Lei Wang, Yusong Zhu, Yuan Lin, Shali Qi, Sophia Yin, Frank Tao, Lishan Kang, Omar Kabbarah, Haiying Zhou, Petter Veiby, James Yan, Karl Hsu. ZL-1201, a differentiated CD47 therapeutic antibody with improved hematological safety profile [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 498.