Abstract 5627: BALB/c-hCD3E transgenic mice to evaluate humanCD3-bispecific antibodies

Abstract

Abstract T cell-mediated immunotherapy is an attractive strategy for treatment of various tumors. T-cell bispecific antibody (TCB) can binds tumor associated antigen (TAA) and CD3 molecule (especially epsilon chain, CD3ϵ), and directs target specific killing of cells carrying the TAA. However, there is a challenge to evaluate the therapeutic efficacy of TCB due to the lack of immune competent animal that have both human immune system and TAA. Considering that CD3ϵ plays a critical role in formation and function of the TCR-CD3 complex while human CD3ϵ (hCD3ϵ) shares only 47% homology with mouse CD3ϵ (mCD3ϵ) in the extracellular domain, we established a CD3ϵ BAC transgenic model (BALB/c-hCD3E) carrying hCD3E gene and its entire regulatory sequence to meet this need. These transgenic mice co-express human and mouse CD3ϵ in over 90% of T-cells. Besides, the expression pattern of hCD3ϵ in spleen and thymus of BALB/c-hCD3E mice are similar with mCD3ϵ in wild type mice. With a normal immune system, splenic T cells from this strain could be activated by either anti-hCD3ϵ or anti-mCD3ϵ antibodies to produce IFNγ, IL2 and TNFα in vitro. We also tested the T cell-dependment cellular cytotoxicity on BALB/c-hCD3E mice use blinatumomab (bscCD19xCD3), the results shown significant anti-tumor effect. It's worth noting that further knockout of mCd3e in BALB/c-hCD3E mice cause remarkable reduce of splenic T cells, strong tumor inhibition of anti-mCTLA4 was observed in BALB/c-hCD3E but not BALB/c-hCD3E/mCd3e-KO mice, demonstrate that mCD3ϵ is indispensable for T-cell development and function in BALB/c-hCD3E transgenic mice. Taken together, these findings indicate that BALB/c-hCD3E mice with intact mCd3e is a novel and valuable model to assessing the therapeutic efficacy of TCBs. Citation Format: Cunxiang Ju, Mingkun Zhang, Dongjing Jia, Rui Mao, Jing Tang, Shuai Li, Jing Zhao, Xiang Gao. BALB/c-hCD3E transgenic mice to evaluate humanCD3-bispecific antibodies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5627.