Abstract 2905: A novel therapeutic antibody against CD73 that ameliorates the tumor microenvironment and improves the efficacy of cancer immunotherapy

Abstract

Abstract Background: CD73, also known as ecto-5’-nucleotidase (NT5E), is a GPI-anchored cell surface enzyme expressed on certain types of immune cells and tumor cells. This enzyme catalyzes the hydrolytic conversion of extracellular adenosine monophosphate (AMP) to adenosine (Ado) that suppresses tumor-infiltrating immune cells via the adenosine receptors, allowing tumors to escape the immune system. Here, we introduce a novel anti-human CD73 antibody called BP1200 that strongly blocks the generation of Ado by CD73 and thereby reverses immune suppression in tumors. Methods: We screened anti-CD73 antibodies by antigen-specific single B cell sorting from mice immunized with recombinant human CD73. CDRs of the antibodies that inhibit the enzyme activity of CD73 were engrafted into human IgG1 framework carrying the mutations of Fc silent. The proliferation and cytotoxicity of T cells were analyzed using human peripheral blood mononuclear cells (PBMC) in the presence of ATP. Efficacy of BP1200 in vivo was investigated by using mice bearing human CD73 knock-in-MC38 cells and mice implanted with human NSCLC cell line (NCI-H292) and PBMC. Results: The humanized anti-CD73 antibody (BP1200) binds to both human and cynomolgus CD73 expressed on cell surface with KD value of 0.2 nM (human CD73). BP1200 blocked the hydrolysis of AMP by CD73 expressed as both membrane-bound and soluble form without the hook effect. BP1200 induced internalization of CD73 and remarkably decreased the cell surface CD73, indicating that BP1200 inhibits the enzyme activity as well as downregulates the protein level of CD73 at the cell surface. BP1200 induced in vitro proliferation, cytokine production, and cytotoxic activity of T cells even in the presence of high level of ATP, suggesting that BP1200 enhances the T cell immunity in immunosuppressive tumor micro-envelopment (TME). In vivo studies showed that the combination treatment of BP1200 with anti-PD-1/PD-L1 antibodies remarkably retarded tumor growth. Moreover, the mice administrated with BP1200 and anti-PD-1 exhibited long-term immune memory effects that rendered them resistant to rechallenge with tumors. Conclusions: The novel anti-human CD73 antibody, BP1200, ameliorates immunosuppressive TME caused by adenosine and enhances antitumor immune responses. The combination of BP1200 and immune-checkpoint inhibitors for cancer treatment will be a promising therapeutic option in clinical practice. Citation Format: Noriko Matsumoto, Yuji Mishima, Toshifumi Obonai, Haruka Ban, Motoya Mie, Norihiro Nakamura. A novel therapeutic antibody against CD73 that ameliorates the tumor microenvironment and improves the efficacy of cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2905.