a single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy单个蛋白水解低铰链内解理曲妥珠单抗免疫效应功能和体内疗效降低.pdfVIP

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a single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy单个蛋白水解低铰链内解理曲妥珠单抗免疫效应功能和体内疗效降低.pdf

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a single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy单个蛋白水解低铰链内解理曲妥珠单抗免疫效应功能和体内疗效降低

Fan et al. Breast Cancer Research 2012, 14:R116 /content/14/4/R116 RESEARCH ARTICLE Open Access A single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy 1 2 1 1 2 3 Xuejun Fan , Randall J Brezski , Ming Fa , Hui Deng , Allison Oberholtzer , Anneliese Gonzalez , 4 2 2 1* 1* William P Dubinsky , William R Strohl , Robert E Jordan , Ningyan Zhang and Zhiqiang An Abstract Introduction: Recent studies reported that human IgG antibodies are susceptible to specific proteolytic cleavage in their lower hinge region, and the hinge cleavage results in a loss of Fc-mediated effector functions. Trastuzumab is a humanized IgG1 therapeutic monoclonal antibody for the treatment of HER2-overexpressing breast cancers, and its mechanisms of action consist of inhibition of HER2 signaling and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC). The objective of this study is to investigate the potential effect of proteinase hinge cleavage on the efficacy of trastuzumab using both a breast cancer cell culture method and an in vivo mouse xenograft tumor model. Methods: Trastuzumab antibody was incubated with a panel of human matrix metalloproteinases, and proteolytic cleavage in the lower hinge region was detected using both western blotting and mass spectrometry. Single hinge cleaved trastuzumab (scIgG-T) was purified and evaluated for its ability to mediate ADCC and inhibition of breast cancer cell proliferation in vitro as well as anti-tumor efficacy in the mouse xenograft tumor model. Infiltrated immune cells were detected in tumor