CD73 is a cell surface enzyme that converts adenosine monophosphate to adenosine, a well-known immunosuppressive mediator that inhibits the cytotoxic function of T cells and natural killer cells. Tumors utilize this mechanism to escape attack by the immune system. Many attempts were made to antagonize the enzyme activity of CD73, including antibody drugs and small molecules. However, most current CD73 enzyme blockers were screened against tumor membrane CD73 and focused only on the membrane format of CD73. Our recent findings show that not only the membrane enzyme on tumor cells, but also the soluble format of CD73 shed off by tumor cells play important roles in generating immunosuppressive adenosine. To reverse the immune suppression exerted by CD73, both the membrane and the soluble format need to be blocked. We screened hundreds of anti-CD73 antibodies against soluble CD73 presented in tumor patient (CRC/LC/HCC/Melanoma) serum, and two candidates GB7002-01 and GB7002-04 were selected with great inhibition potency against tumor membrane CD73 and soluble CD73 in patient serum. GB7002-01/04 exhibited superior T cell proliferation promoting abilities in immune suppressive environment. To be precise, GB7002-01/04 totally reversed the T cell proliferation suppressive effects of pathological concentration of AMP. Moreover, this release of immune suppression was translated to better tumor killing by PBMC in the presence of GB7002-01/04. Humanized GB7002-01/04 has been put into in vivo efficacy study, preliminary toxicity and PK study. As we are observing anti-tumor efficacy, safety, and stability of these two candidates, they are promising agents for extended clinical exploration in several cancer indications.

Citation Format: Jijun Yuan. Dual CD73 enzyme blocker to reverse immune suppression [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 5652.