Therapeutic applications of a novel humanized monoclonal antibody targeting chemokine receptor CCR9 in pancreatic cancer

Abstract

The relative failure of immune checkpoint inhibitors in pancreatic ductaladenocarcinoma (PDAC) despite having a dense, immunosuppressivetumor microenvironment highlights the need to target alternate/escapepathways. 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 evalu-ated in vitro and in vivo. CCR9 expression on PDAC cells/tissues, immunecomponents of patient-derived organoids (PDOs), and antibody-dependentcell-mediated cytotoxicity were examined. In PANC-1 and MIA PaCa-2cell lines, we demonstrated highest CCR9 expression; however, no directcytotoxic effect was observed with SRB2 treatment. In PANC-1 cells, NKcell-mediated cytotoxicity was promoted by SRB2. Dose-dependent SRB2cytotoxicity was observed in PDAC PDOs. In patient-derived xenograftmouse models, cytotoxicity of SRB2 monotherapy and in combination withoxaliplatin was also shown. In humanized immune-competent mousemodels, SRB2 efficacy was similar to other drugs, but two mice in thiscohort had complete tumor regression. Our current studies suggest thattherapeutic targeting of CCR9 may improve PDAC outcomes, and addi-tional studies are underway to evaluate SRB2 for clinical use.