Abstract
The relative failure of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) despite having a dense, immunosuppressive tumor microenvironment highlights the need to target alternate/escape pathways. We have previously examined C–C chemokine receptor type 9 (CCR9) as a candidate immune checkpoint and developed a targeted, humanized monoclonal antibody (SRB2). Cytotoxicity of SRB2 was evaluated in vitro and in vivo. CCR9 expression on PDAC cells/tissues, immune components of patient-derived organoids (PDOs), and antibody-dependent cell-mediated cytotoxicity were examined. In PANC-1 and MIA PaCa-2 cell lines, we demonstrated highest CCR9 expression; however, no direct cytotoxic effect was observed with SRB2 treatment. In PANC-1 cells, NK cell-mediated cytotoxicity was promoted by SRB2. Dose-dependent SRB2 cytotoxicity was observed in PDAC PDOs. In patient-derived xenograft mouse models, cytotoxicity of SRB2 monotherapy and in combination with oxaliplatin was also shown. In humanized immune-competent mouse models, SRB2 efficacy was similar to other drugs, but two mice in this cohort had complete tumor regression. Our current studies suggest that therapeutic targeting of CCR9 may improve PDAC outcomes, and additional studies are underway to evaluate SRB2 for clinical use.
Document Type
Article
Publication Date
5-2025
Digital Object Identifier (DOI)
https://doi.org/10.1002/1878-0261.70062
Funding Information
This research was supported by NIH Training Grant T32CA160003 (HGM, AMR, and MMH), the Biospecimen Procurement and Translational Pathology Shared Resource, and the Flow Cytometry and Immune Monitoring Shared Resource of the University of Kentucky Markey Cancer Center.
Repository Citation
McDonald, Hannah G.; Reagan, Anna M.; Bailey, Charles J.; Gao, Mei; Gao, Muqiang; Solomon, Angelica L.; Cavnar, Michael J.; Pandalai, Prakash; Barry-Hundeyin, Mautin; Harper, Megan; Rueckert, Justin A.; Turrero, Ángela; Tobio, Araceli; Vidal, Anxo; Roca-Lema, Daniel; Álvarez-Coiradas, Elia; Garrido, Pablo; Simón, Laureano; and Kim, Joseph, "Therapeutic applications of a novel humanized monoclonal antibody targeting chemokine receptor CCR9 in pancreatic cancer" (2025). Markey Cancer Center Faculty Publications. 428.
https://uknowledge.uky.edu/markey_facpub/428
Notes/Citation Information
Molecular Oncology (2025) ª 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.