title: Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk.
abstract: The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody.
authors.affiliation: Translational Medicine Research Institute and International Joint Cancer Institute, The Second Military Medical University, Shanghai, P. R. China. Department of Clinical Medicine, The Second Military Medical University, Shanghai, P. R. China. Department of Medical Imaging, Xi'an PLA 451 Hospital, Xi'an, Shaanxi, P. R. China. Department of Interventional Oncology, Xi'an PLA 451 Hospital, Xi'an, Shaanxi, P. R. China. hus@aftertumor.com zhuwd@aftertumor.com.
authors.forename: Shi
authors.initials: S
authors.lastname: Hu
authors.affiliation: Cancer Center, PLA General Hospital, PLA Postgraduate School of Medicine, Beijing, P. R. China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Cardiology, PLA General Hospital, PLA Postgraduate School of Medicine, Beijing, P. R. China.
authors.forename: Weihao
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Medical Imaging, Xi'an PLA 451 Hospital, Xi'an, Shaanxi, P. R. China. School of Basic Medicine, Xi'an Jiao Tong University, Xi'an, Shaanxi, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan. School of Medicine and Pharmacology, The University of Western Australia, Crawley, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cruz
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Australia.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Berezov
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jorissen
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Medical Imaging, Xi'an PLA 451 Hospital, Xi'an, Shaanxi, P. R. China. Department of Interventional Oncology, Xi'an PLA 451 Hospital, Xi'an, Shaanxi, P. R. China. hus@aftertumor.com zhuwd@aftertumor.com.
authors.forename: Wangdong
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011897:Random Allocation; D020239:Receptor Cross-Talk / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D066246:ErbB Receptors; D007074:Immunoglobulin G; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C491743:MET protein, human