MGAH22的抗肿瘤活性和毒性动力学分析anti-HER2单克隆抗体与增强Fcgamma受体结合特性。

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杨张Nordstrom JL Gorlatov年代,W, Y,黄L,伯克年代,李H,市政债券同样V, T, Stavenhagen J, Koenig年代,斯图尔特SJ,摩尔PA,约翰逊年代,Bonvini E

MGAH22的抗肿瘤活性和毒性动力学分析anti-HER2单克隆抗体与增强Fcgamma受体结合特性。

乳腺癌研究》2011;13(6):二氯。doi: 10.1186 / bcr3069。Epub 2011年11月30日。

PubMed ID

22129105 (在PubMed

]

文摘

简介:对曲妥珠单抗在转移性乳腺癌与表达式的绑定变量(158 v)的激活Fcgamma iii a受体(CD16A)。我们工程MGAH22嵌合anti-HER2单克隆抗体与类似于曲妥珠单抗的特异性和亲和力,与Fc域工程增加人类CD16A绑定两个等位基因。方法:MGAH22相比是一个相同的anti-HER2马伯除了野生型Fc域。锁定细胞细胞毒性(ADCC)化验与her2表达癌细胞进行目标和人类PBMC或纯化NK细胞作为效应器。异种移植研究对小鼠与野生型小鼠FcgammaRs进行;在老鼠身上缺乏小鼠CD16;或在老鼠身上缺乏小鼠CD16但转基因对人类cd16a - 158 f,弱耦合变异。后者模型再现了野生型之间的微分绑定和Fc-optimized马伯人类CD16A。JIMT-1人类乳腺肿瘤,来源于对曲妥珠单抗治疗病人进展,这些研究中使用。单一和重复剂量毒性研究MGAH22管理在高剂量静脉注射在猕猴身上进行的。 RESULTS: The optimized Fc domain confers enhanced ADCC against all HER2-positive tumor cells tested, including cells resistant to trastuzumab's anti-proliferative activity or expressing low HER2 levels. The greatest improvement occurs with effector cells isolated from donors homozygous or heterozygous for CD16A-158F, the low-binding allele. MGAH22 demonstrates increased activity against HER2-expressing tumors in mice transgenic for human CD16A-158F. In single and repeat-dose toxicology studies in cynomolgus monkeys, a species with a HER2 expression pattern comparable to that in humans and Fcgamma receptors that exhibit enhanced binding to the optimized Fc domain, MGAH22 was well tolerated at all doses tested (15-150 mg/kg) and exhibited pharmacokinetic parameters similar to that of other anti-HER2 antibodies. Induction of cytokine release by MGAH22 in vivo or in vitro was similar to that induced by the corresponding wild type mAb or trastuzumab. CONCLUSIONS: The data support the clinical development of MGAH22, which may have utility in patients with low HER2 expressing tumors or carrying the CD16A low-binding allele.

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