Abstract 545: Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD20 for the treatment of B cell lineage cancer

Abstract

Abstract Tumor cells over expressing CD47 can evade immune surveillance through delivering a “Don’t eat me” signal to macrophages. Developing CD47-targeted modalities has been a hot pursue in the pharmaceutical industry. However due to the ubiquitous expression of CD47 in normal tissues, especially in red blood cells (RBC), severe antigenic sink as well as hemotoxicity including anemia set up a higher bar for this particular targeted therapy development. To overcome these hurdles, we have developed a bispecific recombinant antibody-trap, IMM0306, designed to simultaneously target CD47 and CD20 on B cells but avoid binding to human RBCs. Extensive in vitro characterization demonstrated that IMM0306 binds to both CD47 and CD20 with affinity 3-8 folds lower than either single-targeted molecule, but has strong pro-phagocytosis activity over CD47-positive target cells, and even stronger ADCC activity than Rituximab. Intriguingly, IMM0306 has no binding activity at all toward human RBCs, albeit much lower binding activity toward monkey RBCs. Treatment of tumor-implanted SCID mice with IMM0306 significantly inhibited tumor growth and led to eradication of the tumor cells from 5 out of 8 mice, which is much more effective than Rituximab and than co-administration of Rituximab and SIRPα-Fc (IMM01), although profound synergistic effect has been observed for the co-administration. Preclinical study in non-human primates demonstrated a favorable pharmacokinetic profile with no obvious hemotoxicity following single as well as multiple administrations at different dosage. Our study suggests that antibody-trap like IMM0306 might be an ideal approach for CD47-targeted immunotherapy development since selective avoidance of RBC mediated antigen-sink as well as anemia could be achieved along with the robust anti-tumor activity. Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Guangjun Liang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Jie Weng, Gui Zhao, Dandan Liu, Huiqin Guo, Chunmei Yang, Ruliang Zhang. Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD20 for the treatment of B cell lineage cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 545.