A novel humanized antibody targeting CD39 that enhances anti-tumor immunity and the efficacy of cancer immunotherapy.

Abstract

e14508 Background: Immunotherapy using immune-checkpoint inhibitors (ICIs) has shown remarkable clinical efficacy in patients with cancer. However, it is crucial to utilize appropriate combination of immunotherapy for patient condition, as most patients do not benefit or sustain responses of immunotherapy. We focused on CD39 that is highly expressed in some tumors and tumor infiltrating immune cells (e.g. exhausted T cells and Tregs) as a target for cancer immunotherapy. CD39 is an ectoenzyme that converts extracellular ATP to immunosuppressive adenosine. Since the ATP-adenosine pathway is a key modulator of innate and adaptive immunity within the tumor microenvironment (TME), we presume that anti-CD39 antibodies suppress the production of adenosine and limit the immunosuppressive state in TMEs. Methods: Anti-human CD39 antibodies were screened by sorting B cells of mice immunized with human CD39 protein. The obtained clones that inhibit enzyme activity of CD39 were humanized on IgG1 and IgG4. PBMC were used in proliferation and functional assays. The anti-tumor effect was investigated with mouse xenograft model. Results: Analyzing gene expression profiles from TCGA data, high CD39 expression is associated with a poor prognosis in several cancers. There was a strong correlation between them in multiple myeloma treated with chemotherapies. The expression of CD39 was upregulated in some cancer cell lines treated with chemotherapeutic agents. A novel humanized anti-CD39 antibody, BP1202, which has a high affinity for the recombinant CD39 protein (KD: 481 pM) and inhibits the enzyme activity of CD39 expressed on a cancer cell line (IC50: 1 nM) and human Tregs. The antibody showed a high potency to enhance T cell activity including their proliferation, cytokine production, and cytotoxicity against a cancer cell line. We examined the anti-tumor effect of BP1202 in vivo using tumor-bearing mice and found that the combination treatment of BP1202 with chemotherapeutic agents significantly reduced tumor volume. Conclusions: We developed a new humanized antibody that enhances anti-tumor immunity by inhibiting CD39 expressed on exhausted T cells and intra-tumor T cells. These data suggest the scientific rationale for the clinical development of BP1202 and their use in combination with ICIs, with ATP-adenosine pathway inhibitors, and with chemotherapies. BP1202 is currently being developed as a new antibody agent for cancer immunotherapy.