Abstract 496: Targeting CD73-adenosine axis for the treatment of multiple myeloma
Authors: Bian Gang , Hua Jiahui , Lin Ge , Bai Yu , Zhu Tianci , Jiang Bin , Mei Jay , Shan Bo , Hou Bing 
Published: April 2023

Abstract
Background: Currently, the commonly used and active agents such as proteasome inhibitors (PIs), immunomodulator (IMiDs), and CD38 antibody have significantly improved the prognosis of multiple myeloma (MM). However, MM is still considered incurable, and almost all MM patients eventually experience relapse. Relapsed/refractory MM (rrMM) remains a disease with an unmet need for additional therapeutic options, especially drugs with a novel mechanism of action. CD73 is a cell surface enzyme which is highly expressed in the tumor microenvironment. CD73, in concert with CD39, converts ATP to adenosine, which promotes the onset and progression of cancer via inhibiting T cells, NK cells, and DCs, inducing immunosuppressive cell types and enhancing their functions (Gao et al., 2014). Indeed, elevated levels of adenosine have been observed in various cancers, including MM (Ray A et al., 2022). ATG-037 is a highly potent and selective oral small molecule inhibitor of CD73. In this study, we evaluated the potential of ATG-037 in treating multiple myeloma.
Methods: The inhibition of enzyme function of recombinant and cell surface CD73 was evaluated by measuring the concentration of inorganic phosphate using Malachite Green. Reversal of AMP/adenosine-mediated human T cell suppression by CD73 inhibitors was determined in the presence of exogenous AMP. The in vivo efficacy was assessed in syngeneic myeloma models, J558 and MCP-11. The murine myeloma cells were implanted subcutaneously into BALB/c mice, and ATG-037 (100 mg/kg) or vehicle was orally administered BID starting day one post-implantation.
Results: ATG-037 demonstrated complete inhibition of CD73 activity without “hook effect”, whereas MEDI9447, a CD73 antibody, did not reach 100% inhibition and with reduced inhibition of CD73 activity at higher antibody concentrations. T cell proliferation and activation induced by CD3/CD28 activator were suppressed by extracellular 20 μM or 100 μM AMP, and the suppression was relieved by the addition of ATG-037. Furthermore, compared to the vehicle control, ATG-037 at 100 mg/kg exhibited significant tumor growth inhibition with a tumor growth inhibition (TGI) value of 30.88% on Day 16 after implantation in J558 model. ATG-037 (100 mg/kg) also demonstrated significant in vivo anti-tumor efficacy against MCP-11 myeloma compared with the vehicle control group, with a TGI value of 24.27% on Day 17 after implantation. ATG-037 treatment was well tolerated, with no significant body weight loss or severe adverse effects observed in both models.
Conclusion: ATG-037 demonstrated potent and complete CD73 enzyme inhibition without “hook effect”, restoring T cell functions from AMP-mediated suppression. And this is the first report that a CD73 inhibitor demonstrates in vivo efficacy in myeloma animal models. The single agent anti-myeloma efficacy of ATG-037 warrants further clinical investigation.
Citation Format: Gang Bian, Jiahui Hua, Ge Lin, Yu Bai, Tianci Zhu, Bin Jiang, Jay Mei, Bo Shan, Bing Hou. Targeting CD73-adenosine axis for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 496.