Abstract 4975: Using humanized B-hSIRPa/hCD47 mouse model to evaluate the efficacy and toxicity of CD47 and SIRPa antibodies

Abstract

Abstract Cancer immunotherapy is one of the most promising research areas in the field of cancer therapy. Along the IO drug development process, production of mouse models for in vivo efficacy evaluation has always been a rate-limiting step. Therefore, we generated a novel humanized knock-in mouse to evaluate the efficacy of human IO antibodies. CD47 is a transmembrane protein expressed in many human tissues. SIRPa, which is expressed on phagocytic cells, was identified as the receptor of CD47. Engagement of SIRPa by CD47 serves as “do not eat me” signal, inhibiting the phagocytic activity of macrophages. Antibodies interfering with the CD47-SIRPa interaction block inhibition and promote tumor destruction. While CD47 is a potential target for antibody development, side effects associated with CD47 blockade have emerged as a major concern, especially anemia. To evaluate the efficacy and toxicity of CD47 antibody, we generated a double humanized B-hSIRPa/hCD47 mouse. In this model, exon2 in mouse SIRPa and CD47 were replaced with the corresponding human sequences. In homozygous mice, mouse SIRPa and CD47 was absent and only human protein expression was detected, B-hSIRPa/hCD47 mice paired with genetically modified MC38-hCD47 cancer cells were used to screen CD47 antibodies by balancing their efficacy and toxicity. Antibodies with less toxicity exhibited minimal weight loss, minimal effects on blood cell and platelet production, and reduced ALT/AST elevation in mice. Thus, we demonstrated that these humanized mice could expedite and improve the development of safer CD47 antibodies. Humanized B-hSIRPa/hCD47 mice can also be used to evaluate the efficacy of antibodies targeting SIRPa. We also generated triple humanized B-hPD-1/hSIRPa/hCD47 and B-hPD-L1/hSIRPa/hCD47 mice that would be useful to develop combination therapies of PD-1/PD-L1 and SIRPa/CD47 antibodies. Humanized B-hSIRPa/hCD47 mice are a promising in vivo efficacy model for the development of CD47 and SIRPa antibodies that can be advanced to human clinical trials. Citation Format: Yanan Li, Chaoshe Guo, Jie Xiang, Qingcong Lin. Using humanized B-hSIRPa/hCD47 mouse model to evaluate the efficacy and toxicity of CD47 and SIRPa antibodies [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 4975.