Abstract 6056: A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing approach

Abstract

CD73, an ecto-5'-nucleotidase, plays a major role in de-phosphorylation of the extracellular adenosine monophosphate (AMP) to adenosine, which in turn is a potent immunosuppressive metabolite that modulates the immune reaction within the tumor microenvironment (TME). High concentration of adenosine, predominantly signaling through the A2A receptor, suppress innate and adaptive immune cell responses, leading to tumor escape of immune surveillance. Recent studies have shown a significant overexpression of CD73 in solid tumors alongside it's functional upregulation by inflammatory mediators and hypoxia. Thus, inhibition of CD73 enzymatic activity and its surface expression in the TME may improve anti-tumor immune activity. To test this hypothesis, we designed and developed a fully human antibody with unique structure to recognize CD73. This antibody can block the enzymatic activity of CD73 in addition to reducing the surface expression of CD73. Both enzymatic and non-enzymatic dependent functions of CD73 were significantly dampened. The antibody demonstrates a superior anti-tumor activity over reference antibodies in in-vitro and in-vivo models. Our findings indicate that the antibody has promising potential as an effective therapy for PD-1/PD-L1 nonresponsive or refractory patients, as well as a broader patient population that may benefit from a unique mechanism of action of CD73-targeting antibody. Citation Format: Xin Gan, Lei Shi, Qianqian Shan, Fei Chen, Yun He, Yiping Rong, Qiumei Du. A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing approach [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 6056.

The Role of Metabolism in Tumor Immune Evasion: Novel Approaches to Improve Immunotherapy

“…CS3005 and DZD2269 [ 156 ] are A2AR inhibitors whose clinical trials were initiated in 2020. Regarding preclinical development, there are also various agents being tested: ES002 is an anti-CD39 monoclonal antibody; HBM1007 [ 157 ], PT199, and AK119 [ 158 ] are anti-CD73 monoclonal antibodies; AK123 is an anti-PD-1/CD73 bi-specific monoclonal antibody [ 158 ]; CB-708 [ 159 ], OP-5244 [ 160 ], OR-558 [ 161 ], and ORIC-533 as CD73 inhibitors [ 162 ], and AB745 [ 163 ], ARX001822 [ 164 ] and RVU330 [ 165 ] as A2AR antagonists.…”