Abstract 6532: HFB9-2: A novel Gal-9 neutralizing antibody to reverse immune suppression in the tumor microenvironment

Abstract

Abstract Although monoclonal antibodies targeting immune checkpoints have demonstrated clinical success in a range of tumor types, sustained responses are only observed in a fraction of patients due to primary or secondary resistance to treatment. Recent evidence has implicated the pleiotropic immunosuppressive modulator Galactoside-binding lectin Galectin 9 (Gal-9) as a key factor present in the tumor microenvironment that renders tumors resistant to current immunotherapies. High Gal-9 expression has been reported in different types of cancer including hematological malignancies such as AML and ALL, and multiple solid tumors. We hypothesize that targeting Gal-9 may represent a valuable strategy to overcome resistance and improve clinical response in selected cancer patients. We present a monoclonal antibody, HFB9-2, that specifically binds to human Gal-9 with sub-nanomolar affinity, recognizes recombinant Gal-9 and Gal-9 produced by human tumor cells, and is cross-reactive with mouse and monkey Gal-9 orthologs. HFB9-2 blocks the interaction of Gal-9 with its receptors TIM3 and CD44 in a dose dependent manner. These two receptors have been described to mediate Gal-9-immunosuppressive signals in effector and regulatory T cells. Treatment of human PBMCs from healthy donors with HFB9-2 prevents Gal-9-induced Th1 cell apoptosis and suppresses the expansion of regulatory T cells. A humanized variant of HFB9-2, HFB9-2hz11, was generated and further characterized for its stability and pharmacokinetic profile. HFB9-2hz11 has a favorable developability profile. It demonstrated stability for at least 14 days at 40°C, as well as for several hours at low pH, and following several freeze-thaw cycles. High plasma exposures following a single dose administration to mice were observed. Furthermore, several preclinical in vivo studies are ongoing to demonstrate the efficacy of HFB-2hz11. Gal-9 has been reported to play a dual role in AML as both a self-renewal factor for leukemic stem cells and a suppressor of anti-cancer immunity, suggesting that Gal-9 neutralization represents an attractive therapeutic approach for treatment of AML patients. To explore this hypothesis, we have initiated a predictive biomarker discovery effort, using HiFiBiO's proprietary Drug Intelligent Science (DIS™) platform, using AML primary patient cells and integrating single-cell technology to identify patient subpopulations likely to respond to HFB9-2hz11. Potential novel biomarkers for patient stratification, that could be applied to other tumor indications, will be identified for AML patients. Altogether, the data presented here provide evidence that neutralization of Gal-9 with HFB9-2hz11 blocks key immunosuppressive mechanisms known to limit the efficacy of current immunotherapies and position HFB9-2hz11 as a drug candidate for clinical exploration in AML and other indications. Citation Format: Germain Margall, Rachel Pacherie, Julie Prigent, He Zhou, Francisco Adrian, Liang Schweizer, Andreas Raue, Roshan Kumar, Nicola Beltraminelli, Stéphanie Beq. HFB9-2: A novel Gal-9 neutralizing antibody to reverse immune suppression in the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6532.