Chen Shen-Jue, Foster William R, Jure-Kunkel Maria N, Girit Emel, Abraham Ralph, Hefta Laura J, Gao Shan, Yonan Christopher R, Lin Jun-Hsiang, Dambach Donna M
Discovery Toxicology, Bristol-Myers Squibb Research and Development, Route 206 & Province Line Road, Princeton, NJ 08543, United States.
Vet Immunol Immunopathol. 2008 Dec 15;126(3-4):377-81. doi: 10.1016/j.vetimm.2008.07.009. Epub 2008 Jul 31.
CD137 plays an important role as a co-stimulatory molecule in activated T cells. Agonistic CD137 specific antibodies have been investigated as therapeutic agents to promote tumor-specific immune responses by direct activation of T cells. As part of the pre-clinical pharmacological evaluation of cynomolgus monkeys, monkey CD137 was cloned and characterized. The deduced amino acid sequence encoded a full-length gene of 254 amino acids 95% identical to human CD137. Sequence variants identified in monkey CD137 include four splice variants lacking the transmembrane domain. These variants were detectable in human including two previously unreported variants. Two missense single nucleotide polymorphisms were detected present in 42 and 50% of 36 monkeys tested. In both monkey and human, mRNA expression of full-length CD137 and splice variants were significantly increased in peripheral blood mononuclear cells (PBMCs) upon stimulation by anti-CD3 antibodies. Recombinant monkey CD137 protein was bound with high affinity by an agonistic anti-human CD137 antibody but not by an anti-mouse CD137 antibody. In summary, compared to human, monkey CD137 showed distinct extracellular domain amino acid sequence and sequence polymorphisms. Thus, antibodies directed against epitopes in this extracellular domain could have differences in pharmacologic activity between cynomolgus monkeys and human or across individual cynomolgus monkeys.
CD137作为共刺激分子在活化T细胞中发挥重要作用。激动性CD137特异性抗体已被研究作为通过直接激活T细胞来促进肿瘤特异性免疫反应的治疗剂。作为食蟹猴临床前药理学评估的一部分，对猴CD137进行了克隆和表征。推导的氨基酸序列编码一个254个氨基酸的全长基因，与人CD137有95%的同一性。在猴CD137中鉴定出的序列变体包括四个缺乏跨膜结构域的剪接变体。这些变体在人类中也可检测到，包括两个以前未报告的变体。在36只受试猴子中，分别有42%和50%检测到两个错义单核苷酸多态性。在猴和人中，抗CD3抗体刺激后，外周血单核细胞（PBMCs）中全长CD137和剪接变体的mRNA表达均显著增加。重组猴CD137蛋白与激动性抗人CD137抗体高亲和力结合，但不与抗小鼠CD137抗体结合。总之，与人类相比，猴CD137显示出不同的细胞外结构域氨基酸序列和序列多态性。因此，针对该细胞外结构域表位的抗体在食蟹猴和人类之间或不同食蟹猴个体之间可能具有不同的药理活性。
