Abstract 1658: Establishment of CD137 humanized mouse model for efficacy assessment of agonistic anti-CD137 therapeutic antibodies

Abstract

Abstract CD137 belongs to the TNF receptor super family, and its activation is essential to the function of T cells and NK cells. Multiple agonistic CD137 antibodies are currently being tested in humans with advanced cancer, which expected to become an important new immuno-oncology therapeutics in clinic. It is important to establish preclinical models for efficacy assessment of investigational CD137 antibodies before entering clinic. Currently available animal models cannot meet this need. Syngeneic mouse tumor models provide a useful platform for testing surrogate immuno-oncology therapies, but cannot be used for testing human therapeutic antibodies due to the species specificity; human immunity reconstituted models, by human PBMC or hematopoietic stem cell inoculation into immune deficient mice, suffering from highly variable responses, are not robust enough to provide a reliable system for efficacy studies. Establishing target humanized models by replacing mouse therapeutic target with human counterpart while maintaining normal mouse immunity is a practical approach to evaluate human therapeutic antibodies in vivo. Using CRISPR-Cas9 gene editing, we have engineered human CD137 knock-in model expressing chimeric human/mouse CD137 composed of human extracellular and transmembrane domains (Exon 4-7), with intact mouse signal peptide and intracellular domain. FACS analysis of splenocytes derived from homozygous knock-in mice showed that CD3/CD28 stimulated T cells only express chimeric CD137 reactive to human CD137 antibodies, but not mouse CD137; Yet the expression levels of the chimeric CD137 in the knock-in mice are generally lower than endogenous mouse protein in wild-type C57BL/6 mice. At present, we are testing the efficacy of reference human CD137 agonistic antibodies by treating these homozygous knock-in mice grafted with syngeneic MC38 tumor cells. Data will be presented at the conference. Citation Format: Davy Xuesong Ouyang, Gang Chen, Zhensheng Wang, Lei Zheng, Annie Xiaoyu An, Jean-Pierre Wery, Jay Liu, Xin Dong, Henry Q. X. Li. Establishment of CD137 humanized mouse model for efficacy assessment of agonistic anti-CD137 therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1658. doi:10.1158/1538-7445.AM2017-1658