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: Pia M Challita-Eid, Daulet Satpayev, Peng Yang, Zili An, Karen Morrison, Yuriy Shostak, Arthur Raitano, Rossana Nadell, Wendy Liu, Dawn Ratay Lortie, Linnette Capo, Alla Verlinsky, Monica Leavitt, Faisal Malik, Hector Aviña, Claudia I Guevara, Nick Dinh, Sher Karki, Banmeet S Anand, Daniel S Pereira, Ingrid B J Joseph, Fernando Doñate, Kendall Morrison, David R Stover
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 10 Pg. 3003-13 (05 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27013195 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Cell Adhesion Molecules
• Immunoconjugates
• Nectins
• Oligopeptides
• monomethyl auristatin E

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Blotting, Western
• Cell Adhesion Molecules (antagonists & inhibitors, metabolism)
• Cell Proliferation
• Drug Delivery Systems
• Drug Evaluation, Preclinical
• Flow Cytometry
• Humans
• Immunoconjugates (pharmacology)
• Immunoenzyme Techniques
• Macaca fascicularis
• Mice
• Mice, Inbred ICR
• Mice, SCID
• Nectins
• Neoplasms (drug therapy, enzymology, pathology)
• Oligopeptides (immunology)
• Rats
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays