anti-tumor activity and toxicokinetics analysis of mgah22, an anti-her2 monoclonal antibody with enhanced fcγ receptor binding propertiesmgah22的抗肿瘤活性和毒性动力学分析anti-her2单克隆抗体与增强fcγ受体结合特性.pdfVIP

Nordstrom et al. Breast Cancer Research 2011, 13:R123 /content/13/6/R123 RESEARCH ARTICLE Open Access Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcg receptor binding properties 1* 1 1 1 1 1 1 Jeffrey L Nordstrom , Sergey Gorlatov , Wenjun Zhang , Yinhua Yang , Ling Huang , Steve Burke , Hua Li , 1 1 1,2 1 1 1 Valentina Ciccarone , Tengfei Zhang , Jeffrey Stavenhagen , Scott Koenig , Stanford J Stewart , Paul A Moore , Syd Johnson1 and Ezio Bonvini1 Abstract Introduction: Response to trastuzumab in metastatic breast cancer correlates with expression of the high binding variant (158V) of the activating Fcg receptor IIIA (CD16A). We engineered MGAH22, a chimeric anti-HER2 monoclonal antibody with specificity and affinity similar to trastuzumab, with an Fc domain engineered for increased binding to both alleles of human CD16A. Methods: MGAH22 was compared to an identical anti-HER2 mAb except for a wild type Fc domain. Antibody- dependent cell cytotoxicity (ADCC) assays were performed with HER2-expressing cancer cells as targets and human PBMC or purified NK cells as effectors. Xenograft studies were conducted in mice with wild type murine Fcg Rs; in mice lacking murine CD16; or in mice lacking murine CD16 but transgenic for human CD16A-158F, the low- binding variant. The latter model reproduces the differential binding between wild type and the Fc-optimized mAb for human CD16A. The JIMT-1 human breast tumor line, derived from a patient that progressed on trastuzumab therapy, was used in these studies. Sing