TR1801‐ADC: a highly potent cMet antibody–drug conjugate with high activity in patient‐derived xenograft models of solid tumors

Autor: Marco Gymnopoulos, Oscar Betancourt, Vincent Blot, Ryo Fujita, Diana Galvan, Vincent Lieuw, Sophie Nguyen, Jeanette Snedden, Christine Stewart, Jose Villicana, Jon Wojciak, Eley Wong, Raul Pardo, Neki Patel, Francois D’Hooge, Balakumar Vijayakrishnan, Conor Barry, John A. Hartley, Philip W. Howard, Roland Newman, Julia Coronella
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Molecular Oncology, Vol 14, Iss 1, Pp 54-68 (2020)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12600
Popis: cMet is a well‐characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody–drug conjugates (ADCs). However, the clinical benefit from cMet‐targeted therapy has been limited. We developed a novel cMet‐targeted ‘third‐generation’ ADC, TR1801‐ADC, that was optimized at different levels including specificity, stability, toxin–linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site‐specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin–linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet‐expressing cell lines but also in medium‐to‐low cMet cell lines (40 000–90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low–medium cMet expression were also very responsive to TR1801‐ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801‐ADC had excellent efficacy with significant antitumor activity in 90% of tested patient‐derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single‐dose administration. Altogether, TR1801‐ADC is a new generation cMet ADC with best‐in‐class preclinical efficacy and good tolerability in rats.
Databáze: Directory of Open Access Journals
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