Anti-Claudin-2 Antibody-Drug Conjugates for the Treatment of Colorectal Cancer Liver Metastasis.

Autor: Tabariès S; Goodman Cancer Institute, McGill University, Montréal, Canada.; Department of Medicine, McGill University, Montréal, Canada., Robert A; National Research Council Canada, Montréal, Canada., Marcil A; National Research Council Canada, Montréal, Canada., Ling B; National Research Council Canada, Ottawa, Canada., Acchione M; National Research Council Canada, Montréal, Canada., Lippens J; National Research Council Canada, Montréal, Canada., Pagé M; National Research Council Canada, Montréal, Canada., Fortin A; National Research Council Canada, Montréal, Canada., Meury L; National Research Council Canada, Montréal, Canada., Coutu M; National Research Council Canada, Montréal, Canada., Annis MG; Goodman Cancer Institute, McGill University, Montréal, Canada.; Department of Medicine, McGill University, Montréal, Canada., Girondel C; Goodman Cancer Institute, McGill University, Montréal, Canada.; Department of Medicine, McGill University, Montréal, Canada., Navarre J; Goodman Cancer Institute, McGill University, Montréal, Canada.; Department of Medicine, McGill University, Montréal, Canada., Jaramillo M; National Research Council Canada, Montréal, Canada., Moraitis AN; National Research Council Canada, Montréal, Canada., Siegel PM; Goodman Cancer Institute, McGill University, Montréal, Canada.; Department of Medicine, McGill University, Montréal, Canada.; Department of Biochemistry, McGill University, Montréal, Canada.
Jazyk: angličtina
Zdroj: Molecular cancer therapeutics [Mol Cancer Ther] 2024 Oct 01; Vol. 23 (10), pp. 1459-1470.
DOI: 10.1158/1535-7163.MCT-23-0393
Abstrakt: We have previously demonstrated that Claudin-2 is required for colorectal cancer (CRC) liver metastasis. The expression of Claudin-2 in primary CRC is associated with poor survival and highly expressed in liver metastases. Claudin-2 also promotes breast cancer liver metastasis by enabling seeding and cancer cell survival. These observations support Claudin-2 as a potential therapeutic target for managing patients with liver metastases. Antibody-drug conjugates (ADC) are promising antitumor therapeutics, which combine the specific targeting ability of monoclonal antibodies with the potent cell killing activity of cytotoxic drugs. Herein, we report the generation of 28 anti-Claudin-2 antibodies for which the binding specificities, cross-reactivity with claudin family members, and cross-species reactivity were assessed by flow cytometry analysis. Multiple drug conjugates were tested, and PNU was selected for conjugation with anti-Claudin-2 antibodies binding either extracellular loop 1 or 2. Anti-Claudin-2 ADCs were efficiently internalized and were effective at killing Claudin-2-expressing CRC cancer cells in vitro. Importantly, PNU-conjugated-anti-Claudin-2 ADCs impaired the development of replacement-type CRC liver metastases in vivo, using established CRC cell lines and patient-derived xenograft (PDX) models of CRC liver metastases. Results suggest that the development of ADCs targeting Claudin-2 is a promising therapeutic strategy for managing patients with CRC liver-metastatic disease who present replacement-type liver metastases.
(©2024 American Association for Cancer Research.)
Databáze: MEDLINE