@article{c226460e17954e36849a0733cdb84b3e,
title = "Antibody-drug conjugates with HER2-targeting antibodies from synthetic antibody libraries are highly potent against HER2-positive human gastric tumor in xenograft models",
abstract = "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{\textquoteright} 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.",
keywords = "antibody-drug conjugate, high through antibody screening, human gastric cancer, immunotoxin, synthetic antibody library",
author = "Kuo, {Wei Ying} and Hsu, {Hung Ju} and Wu, {Chun Yi} and Chen, {Hong Sen} and Chou, {Yu Chi} and Tsou, {Yueh Liang} and Peng, {Hung Pin} and Jian, {Jhih Wei} and Yu, {Chung Ming} and Chiu, {Yi Kai} and Chen, {Ing Chien} and Tung, {Chao Ping} and Michael Hsiao and Lin, {Chia Lung} and Wang, {Yong Alison} and Wang, {Andrew H.J.} and Yang, {An Suei}",
note = "Funding Information: This work was supported by the Ministry of Science and Technology, Taiwan [MOST104-0210-01-09-02];Ministry of Science and Technology, Taiwan [MOST105-0210-01-13-01];Ministry of Science and Technology, Taiwan [MOST106-0210-01-15-02];Taiwan Protein Project [MOST105-0210-01-12-01];Taiwan Protein Project [MOST106-0210-01-15-04]; Funding Information: This research was supported by Academia Sinica and Ministry of Science and Technology [MOST104-0210-01-09-02, MOST105-0210-01-13-01, MOST106-0210-01-15-02] and by the Taiwan Protein Project [MOST105-0210-01-12-01 and MOST106-0210-01-15-04]. We would also like to thank the support from Program for Translational Innovation of Biopharmaceutical Development. We like to thank Dr. Yang, Chi Fan and National Center for Genome Medicine for experimental assistance. We like to thanks Taiwan mouse clinic in Academia Sinica for mouse serum biochemical analyses. Funding Information: This work was supported by the Ministry of Science and Technology, Taiwan [MOST104-0210-01-09-02];Ministry of Science and Technology, Taiwan [MOST105-0210-01-13-01];Ministry of Science and Technology, Taiwan [MOST106-0210-01-15-02];Taiwan Protein Project [MOST105-0210-01-12-01];Taiwan Protein Project [MOST106-0210-01-15-04]; This research was supported by Academia Sinica and Ministry of Science and Technology [MOST104-0210-01-09-02, MOST105-0210-01-13-01, MOST106-0210-01-15-02] and by the Taiwan Protein Project [MOST105-0210-01-12-01 and MOST106-0210-01-15-04]. We would also like to thank the support from Program for Translational Innovation of Biopharmaceutical Development. We like to thank Dr. Yang, Chi Fan and National Center for Genome Medicine for experimental assistance. We like to thanks Taiwan mouse clinic in Academia Sinica for mouse serum biochemical analyses. Publisher Copyright: {\textcopyright} 2018, {\textcopyright} 2018 The Author(s). Published by Taylor & Francis.",
year = "2019",
month = jan,
day = "2",
doi = "10.1080/19420862.2018.1541370",
language = "English",
volume = "11",
pages = "153--165",
journal = "mAbs",
issn = "1942-0870",
publisher = "Landes Bioscience",
number = "1",
}
