title: Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models.
abstract: The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas the expression of nectin-4 in normal tissue was more limited. We generated a novel antibody-drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule-disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface-expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4-targeting ADCs. Cancer Res; 76(10); 3003-13. ©2016 AACR.
authors.affiliation: Agensys Inc., Santa Monica, California. pchallita@agensys.com.
authors.forename: Pia M
authors.initials: PM
authors.lastname: Challita-Eid
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Daulet
authors.initials: D
authors.lastname: Satpayev
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Zili
authors.initials: Z
authors.lastname: An
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Morrison
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Shostak
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Arthur
authors.initials: A
authors.lastname: Raitano
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Rossana
authors.initials: R
authors.lastname: Nadell
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Wendy
authors.initials: W
authors.lastname: Liu
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Dawn Ratay
authors.initials: DR
authors.lastname: Lortie
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Linnette
authors.initials: L
authors.lastname: Capo
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Alla
authors.initials: A
authors.lastname: Verlinsky
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Monica
authors.initials: M
authors.lastname: Leavitt
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Faisal
authors.initials: F
authors.lastname: Malik
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Hector
authors.initials: H
authors.lastname: Aviña
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Guevara
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Nick
authors.initials: N
authors.lastname: Dinh
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Sher
authors.initials: S
authors.lastname: Karki
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Banmeet S
authors.initials: BS
authors.lastname: Anand
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pereira
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Ingrid B J
authors.initials: IB
authors.lastname: Joseph
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Fernando
authors.initials: F
authors.lastname: Doñate
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Kendall
authors.initials: K
authors.lastname: Morrison
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Stover
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008252:Macaca fascicularis; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D000075983:Nectins; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000276:immunology*; D051381:Rats; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; D000075983:Nectins; D009842:Oligopeptides; C495575:monomethyl auristatin E