Antibody-drug conjugates with HER2-targeting antibodies from synthetic antibody libraries are highly potent against HER2-positive human gastric tumor in xenograft models

Wei Ying Kuo, Hung Ju Hsu, Chun Yi Wu, Hong Sen Chen, Yu Chi Chou, Yueh Liang Tsou, Hung Pin Peng, Jhih Wei Jian, Chung Ming Yu, Yi Kai Chiu, Ing Chien Chen, Chao Ping Tung, Michael Hsiao, Chia Lung Lin, Yong Alison Wang, Andrew H.J. Wang, An Suei Yang

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8 引文 斯高帕斯(Scopus)

摘要

HER2-ECD (human epidermal growth factor receptor 2–extracellular domain) is a prominent therapeutic target validated for treating HER2-positive breast and gastric cancer, but HER2-specific therapeutic options for treating advanced gastric cancer remain limited. We have developed antibody-drug conjugates (ADCs), comprising IgG1 linked via valine-citrulline to monomethyl auristatin E, with potential to treat HER2-positive gastric cancer in humans. The antibodies optimally selected from the ADC discovery platform, which was developed to discover antibody candidates suitable for immunoconjugates from synthetic antibody libraries designed using antibody-antigen interaction principles, were demonstrated to be superior immunoconjugate targeting modules in terms of efficacy and off-target toxicity. In comparison with the two control humanized antibodies (trastuzumab and H32) derived from murine antibody repertoires, the antibodies derived from the synthetic antibody libraries had enhanced receptor-mediated internalization rate, which could result in ADCs with optimal efficacies. Along with the ADCs, two other forms of immunoconjugates (scFv-PE38KDEL and IgG1-AL1-PE38KDEL) were used to test the antibodies for delivering cytotoxic payloads to xenograft tumor models in vivo and to cultured cells in vitro. The in vivo experiments with the three forms of immunoconjugates revealed minimal off-target toxicities of the selected antibodies from the synthetic antibody libraries; the off-target toxicities of the control antibodies could have resulted from the antibodies’ propensity to target the liver in the animal models. Our ADC discovery platform and the knowledge gained from our in vivo tests on xenograft models with the three forms of immunoconjugates could be useful to anyone developing optimal ADC cancer therapeutics.

原文英語
頁(從 - 到)153-165
頁數13
期刊mAbs
11
發行號1
DOIs
出版狀態已發佈 - 1月 2 2019
對外發佈

ASJC Scopus subject areas

  • 免疫學和過敏
  • 免疫學

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