Abstract 1551: First in class immunotherapy targeting Galectin-9 promotes T-cell activation and anti-tumor response against pancreatic cancer and other solid tumors
Authors: Linxiao Chen, Wei Wang, Akiko Koide, Joseph Bolen, George Miller, Shohei Koide
Journal: Cancer Research (2019)

Abstract Background: Pancreatic adenocarcinoma (PDA) is one of the deadliest forms of cancer, with a five-year survival rate at or below seven percent. Current immunotherapies show promise in treating other cancers, but success remains elusive for pancreatic cancer. Poor prognosis in pancreatic cancer is invariably linked to immune dysfunction. We have shown that in PDA, Galectin-9 (Gal-9) plays a significant role in facilitating a tumor-permissive immune microenvironment. Specifically, Gal-9 modulates immunosuppression via binding to multiple partner molecules (TIM-3, Dectin-1, CD44, CD206 etc). In light of these findings, we have developed and characterized first-in-class, therapeutic monoclonal antibodies to target Gal-9 and impede tumor growth. Methods: A proprietary synthetic, human antibody library was screened via phage display to identify high-affinity antibodies cross-reactive with human, cynomolgus and rodent Gal-9, to enable efficacy and toxicity studies. We used surface plasmon resonance and bead-based assays to measure antibody binding affinity. ELISA and cell-based approaches were used to demonstrate antibody blockade of Gal-9 binding to known ligands, inferring potential therapeutic efficacy. Efficacy in multiple IgG formats were assayed using KPC (Pdx1Cre; KrasG12D; Tp53R172H)-derived cancer cells implanted orthotopically into the pancreas of C57BL/6 mice. Patient-derived organotypic tumor spheroids (PDOTs) derived from PDA and other GI tumors, which recapitulate complex tumor architecture, were treated with anti-Gal-9 antibodies and resulting immune profile was analyzed via flow cytometry. Results: Our lead clinical candidate Gal-9 antibodies exhibit specific binding towards mouse, cynomolgus and human Gal-9 with KDvalues in the sub nanomolar range. These antibodies potently block Gal-9 interactions with known ligands such as CD206 and Dectin-1. These antibodies also inhibit Gal-9 mediated apoptosis of Jurkat cells. Mice bearing orthotopic pancreatic tumors treated with Gal-9 antibodies induced significant reduction in tumor size (p&amp;lt;0.005) compared with relevant controls. Immune profiling showed increased T cell activation and modulation of the monocytic compartment towards an immune permissive state. PDOTs showed similar immune profiles including an increase in type 1 inflammatory cytokines and effector T cell activation. Conclusions: Our Gal-9 lead therapeutic antibody has been identified, characterized and is being further assessed in expanding pre-clinical efficacy, molecular and safety studies in preparation for an IND filing. Our data demonstrate novel cancer immune biology with therapeutic implications of a first-in-class monoclonal antibody against Gal-9 to reverse immunosuppressive mechanisms contributing to tumor growth immune escape in pancreatic cancer and other solid tumors. Citation Format: Linxiao Chen, Wei Wang, Akiko Koide, Joseph Bolen, George Miller, Shohei Koide. First in class immunotherapy targeting Galectin-9 promotes T-cell activation and anti-tumor response against pancreatic cancer and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1551.