Development of DPP-4-resistant CXCL9-Fc and CXCL10-Fc chemokines for effective cancer immunotherapy

• 成果类型: Article
• 署名作者: Lugassy, Jennie; Saleh, Noor Abdala -; Jarrous, Ghada; Turky, Abeer; Saidemberg, Daniel; Bahar, Gabriela Ridner -; Berger, Nir; On, Dana Bar -; Taura, Tetsuya; Wilson, David; Karin, Nathan; Steinman, Lawrence
• 署名单位: Technion Israel Institute of Technology; Teva Pharmaceutical Industries; Teva Pharmaceutical Industries; Teva Pharmaceutical Industries USA
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8492
• DOI: 10.1073/pnas.2501791122
• 发表日期: 2025-04-22
• 关键词: ifn-gamma; t-cells; tumor-immunity; nk cells; cxcr3; ip-10; polarization; inhibition; survival; receptor

摘要

CXCR3 is a chemokine receptor for three ligands: CXCL9, CXCL10, and CXCL11. Accumulating evidence, including data presented here, suggests that the interaction between CXCL9/CXCL10 and CXCR3 not only attracts CXCR3+ T cells but also cell killing. One of the homeostatic mechanisms that may limit this cycle is the cleavage of the two N- terminal amino acids of these chemokines by Dipeptidyl Peptidase IV (DPP- 4). The modified chemokines retain their ability to bind CXCR3 but no longer activate it, becoming competitive antagonists to native CXCL9/CXCL10. To develop a and CXCL10- Fc rendered them fully active CXCR3 agonists, yet resistant to DPP- 4 cleavage. Preclinical evaluations imply that they offer significant therapeutic potential in cancer immunotherapy.