Abstract 1884: HFB9-2, a novel Galectin 9 neutralizing antibody for the treatment of AML and other cancers
Authors: Margall Germain , David Muriel , Prigent Julie , Lee Dean , Xu Wenhua , Pi Joyce , Cai Xing , Zhou He , Raue Andreas , Beltraminelli Nicola , Chen Mingjie , Wu Jia , Feng Mingfang , Paci Angelo , Delahousse Julia , Saada Véronique , de Botton Stéphane , Busson Pierre , Beq Stephanie , Adrian Francisco , Schweizer Liang , Lu Yun-Yueh 
Published: July 2021

Abstract
Monoclonal antibodies targeting immune checkpoints have demonstrated clinical success in a range of tumor types; however sustained responses are achieved 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 in the tumor microenvironment that renders tumors resistant to current chemo and 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. Previously, we have described the characterization of an anti-human Gal-9 antibody, HFB9-2, with sub-nanomolar affinity for human, murine and cynomolgous Gal-9. HFB9-2 blocks the interaction of Gal-9 with its receptors TIM3 and CD44, leading to inhibition of Gal-9 mediated Th1 cell apoptosis and regulatory T cell expansion. HFB9-2 demonstrated significant anti-tumor efficacy and increased survival in a WEHI-164 syngeneic model as a single agent and in combination with anti-PD1 antibody. HFB9-2 is well tolerated in cynomolgous monkeys after administered by intravenous infusion as a single dose of 10, 50, 200 mg/kg, with no adverse effects and a NOAEL of 200 mg/kg. HFB9-2 developability profile assessment does not anticipate any stability and manufacturing issues.
We hypothesize that targeting Gal-9 represents a valuable strategy to reduce immunosuppression and improve clinical response in selected cancer patients, in particular AML. 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. Analysis of AML patient serum samples demonstrated that Gal-9 expression was significantly higher than in healthy controls and that dropped at complete remission. Higher levels of Gal-9 were found in French-America-British (FAB) type M4 and M5 AML samples, and the lowest levels were observed in M3. To better understand the role for Gal-9 in the development of AML, we implanted primary human AML cells from different donors in M-NSG mice (NOD-Prkdcscid Il2rgem1). We demonstrate that the engraftment of primary human AML cells in these mice resulted in high levels of human Gal-9 in their serum that were detectable 2 weeks after intravenous implantation. The serum levels of Gal-9 increased over time following the increase of hCD45+ AML cells. Further analysis to evaluate the effect of Gal-9 neutralization in AML progression after primary and secondary engraftment with HFB9-2 are currently ongoing.
The data presented here provide evidence that neutralization of Gal-9 with HFB9-2 blocks key immunosuppressive mechanisms known to favor cancer progression and to limit the efficacy of current immunotherapies, and together with the data obtained in AML patient samples position Gal-9 neutralization as a promising anticancer approach.
Citation Format: Germain Margall, Muriel David, Julie Prigent, Dean Lee, Wenhua Xu, Joyce Pi, Xing Cai, He Zhou, Andreas Raue, Nicola Beltraminelli, Mingjie Chen, Jia Wu, Mingfang Feng, Angelo Paci, Julia Delahousse, Véronique Saada, Stéphane de Botton, Pierre Busson, Stephanie Beq, Francisco Adrian, Liang Schweizer, Yun-Yueh Lu. HFB9-2, a novel Galectin 9 neutralizing antibody for the treatment of AML and other cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1884.