Species-Specific Involvement of Integrin alpha IIb beta 3 in a Monoclonal Antibody CH12 Triggers Off-Target Thrombocytopenia in Cynomolgus Monkeys

doi:10.1016/j.ymthe.2018.04.005

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	Species-Specific Involvement of Integrin alpha IIb beta 3 in a Monoclonal Antibody CH12 Triggers Off-Target Thrombocytopenia in Cynomolgus Monkeys
	Zhang, Yiting 6,7; Sun, Jianhua6 ; Tan, Minjia1,2,7 ; Liu, Yongzhen6 ; Li, Qian 1,2,7; Jiang, Hua 3; Wang, Huamao 3; Li, Zonghai 3; Wan, Wei 4,7; Jiang, Hualiang4,7
刊名	MOLECULAR THERAPY
	2018-06-06
卷号	26 期号:6 页码:1457-1470
ISSN号	1525-0016
DOI	10.1016/j.ymthe.2018.04.005
文献子类	Article
英文摘要	CH12 is a novel humanized monoclonal antibody against epidermal growth factor receptor variant III (EGFRvIII) for cancer treatment. Unfortunately, in pre-clinical safety evaluation studies, acute thrombocytopenia was observed after administration of CH12 in cynomolgus monkeys, but not rats. More importantly, in vitro experiments found that CH12 can bind and activate platelets in cynomolgus monkey, but not human peripheral blood samples. Cynomolgus monkey-specific thrombocytopenia has been reported previously; however, the underlying mechanism remains unclear. Here, we first showed that CH12 induced thrombocytopenia in cynomolgus monkeys through off-target platelet binding and activation, resulting in platelet destruction. We subsequently found that integrin alpha IIb beta 3 (which is expressed on platelets) contributed to this off-target toxicity. Furthermore, three-dimensional structural modeling of the alpha IIb beta 3 molecules in cynomolgus monkeys, humans, and rats suggested that an additional unique loop exists in the ligand-binding pocket of the alpha IIb subunit in cynomolgus monkeys, which may explain why CH12 binds to platelets only in cynomolgus monkeys. Moreover, this study supported the hypothesis that the minor differences between cynomolgus monkeys and humans can confuse human risk assessments and suggests that species differences can help the prediction of human risks and avoid losses in drug development.
资助项目	National New Drug Creation Program of China[2015ZX09501007-001] ; Independent Deployment Program of the Institute of Pharmaceutical Innovation of the Chinese Academy of Sciences[CASIMM0120163004] ; "Strategic Priority Research Program" of the Chinese Academy of Sciences[XDA12050305]
WOS关键词	INDUCED IMMUNE THROMBOCYTOPENIA ; DRUG-INDUCED THROMBOCYTOPENIA ; PLATELET ACTIVATION ; SAFETY ASSESSMENT ; LIGAND-BINDING ; THE-LITERATURE ; MODEL ; THERAPEUTICS ; FIBRINOGEN ; ABCIXIMAB
WOS研究方向	Biotechnology & Applied Microbiology ; Genetics & Heredity ; Research & Experimental Medicine
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000439687900009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279714]
专题	药物安全性评价中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ren, Jin; Gong, Likun
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Chem Prote Ctr, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes,Renji Hos, Shanghai 200032, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 5.Shanghai Jiao Tong Univ, Sch Med, Dept Biostat, Shanghai 200025, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China; 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Zhang, Yiting,Sun, Jianhua,Tan, Minjia,et al. Species-Specific Involvement of Integrin alpha IIb beta 3 in a Monoclonal Antibody CH12 Triggers Off-Target Thrombocytopenia in Cynomolgus Monkeys[J]. MOLECULAR THERAPY,2018,26(6):1457-1470.
APA	Zhang, Yiting.,Sun, Jianhua.,Tan, Minjia.,Liu, Yongzhen.,Li, Qian.,...&Gong, Likun.(2018).Species-Specific Involvement of Integrin alpha IIb beta 3 in a Monoclonal Antibody CH12 Triggers Off-Target Thrombocytopenia in Cynomolgus Monkeys.MOLECULAR THERAPY,26(6),1457-1470.
MLA	Zhang, Yiting,et al."Species-Specific Involvement of Integrin alpha IIb beta 3 in a Monoclonal Antibody CH12 Triggers Off-Target Thrombocytopenia in Cynomolgus Monkeys".MOLECULAR THERAPY 26.6(2018):1457-1470.