Uncoupling therapeutic from effects for safer and effective CTLA4 humanized mice immunotherapy-related adverse anti-CTLA-4 antibodies in  

作　　者：Xuexiang Du Mingyue Liu Juanjuan Su Peng Zhang Fei Tang Peiying Ye Martin Devenport Xu Wang Yan Zhang Yang Liu Pan Zheng 

机构地区：[1]Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC 20010, USA [2]Oncolmmune, Inc., Rockville, MD 20852, USA

出　　处：《Cell Research》2018年第4期433-447,共15页细胞研究（英文版）

摘　　要：Anti-CTLA-4 monoclonal antibodies （mAbs） confer a cancer immunotherapeutic effect （CITE） but cause severe immunotherapy- related adverse events （irAE）. Targeting CTLA-4 has shown remarkable long-term benefit and thus remains a valuable tool for cancer immunotherapy if the irAE can be brought under control. An animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. Here, we report such a model using mice harboring the humanized Ctla4 gene. in this model, the clinically used drug, Ipiiimumab, induced severe irAE especially when combined with an anti-PD-1 antibody; whereas another mAb, L3DIO, induced comparable CITE with very mild irAE under the same conditions. The irAE corresponded to systemic T cell activation and resulted in reduced ratios of regulatory to effector T cells （Treg/Teff） among autoreactive T cells. Using mice that were either homozygous or heterozygous for the human allele, we found that the irAE required biallelic engagement, while CITE only required monoallelic engagement. As with the immunological distinction for monoallelic vs bi-allelic engagement, we found that bi-allelic engagement of the Ctla4 gene was necessary for preventing conversion of autoreactive T cells into Treg cells. Humanization of L3DIO, which led to loss of blocking activity, further increased safety without affecting the therapeutic effect. Taken together, our data demonstrate that complete CTLA-4 occupation, systemic T cell activation and preferential expansion of self-reactive T cells are dispensable for tumor rejection but correlate with irAE, while blocking B7- CTLA-4 interaction impacts neither safety nor efficacy of anti-CTLA-4 antibodies. These data provide important insights for the clinical development of safer and potentially more effective CTLA-4-targeting immunotherapy.

关 键 词：免疫疗法 人性化 治疗学 CTLA4 安全 抗体 老鼠 CTLA-4 

分 类 号：Q753[生物学—分子生物学] S858.325.3[农业科学—临床兽医学]