Abstract 5577: A novel CD73-blocking antibody reduces production of immunosuppressive adenosine and restores T cell function

Abstract

Adenosine is present at high concentrations in the tumor microenvironment and is immunosuppressive acting on multiple cell types, including suppression of effector T cells. CD73, an ectonucleotidase that converts AMP to adenosine, is expressed on a subset of B and T cells and is a major source of extracellular adenosine. Elevated CD73 expression has been observed in multiple tumor types and is prognostic in triple negative breast cancer supporting a role for CD73 in tumor progression1. Inhibiting catalytic activity of CD73 is an attractive therapeutic strategy to reduce adenosine-mediated suppression of tumor immunity. We developed two types of humanized monoclonal anti-CD73 antibodies. CPX-006 inhibits CD73 catalytic activity by competing directly with AMP for the active site with an affinity of 0.64 nM. CPX-016 is similar to anti-CD73 antibodies described by others2, and inhibits CD73 activity allosterically by binding to a distal site. This was demonstrated using CD73 expressing cells incubated with APCP, a non-hydrolyzable analog of AMP. APCP competes with CPX-006 for binding to CD73 in contrast to CPX-016. The CPX-016 mechanism requires higher order complexes and results in loss of inhibition at high CPX-016/CD73 ratios. In contrast, CPX-006 reduces catalytic activity completely in cell based assays to levels seen when CD73 gene is deleted using CRISPR technology and inhibition was unaffected at high CPX-006/CD73 ratios. In a functional assay, CPX-006 inhibited immune suppression of T cell function induced by exposure of human PBMCs to AMP through direct inhibition of catalytic activity with a mean EC50 of 137 nM (interferon gamma production) and 189 nM (T cell proliferation) (n=12 donors). We analyzed the prevalence of CD73 expression across tumor histologies by immunohistochemistry including renal cell carcinoma (RCC, n=62), non small cell lung cancer (NSCLC, n=68), melanoma (n= 68) and breast cancer (n=94). CD73 was found to be heterogeneously expressed on tumor cells, immune cells and other stromal elements within each of the histologies examined. Expression on tumor cell only was found in 15% of melanoma and 14% of squamous NSCLC cases. In contrast, tumor cell staining was found in a significant fraction of the adenocarcinoma sub-type of NSCLC (55%). Stromal cell staining to varying degrees was seen in all tumor tissues. In summary, we have a generated a therapeutic antibody, CPX-006, that utilizes a novel mechanism of binding to the CD73 active site to completely inhibit CD73 enzymatic activity and restore T cell function. The finding of CD73 expression on tumor cells and stromal cells in a variety of tumors suggest this as a potential new target for immunotherapy of these malignancies. 1. Loi et al., Proc Natl Acad Sci USA 2013; 110: 11091-11096. 2. Geoghegan et al., mAbs 2016; 8: 454-467. Citation Format: Emily C. Piccione, Glen Mikesell, Barbara Daine-Matsuoka, Kimberly Walter, Richard Miller, Ian McCaffery. A novel CD73-blocking antibody reduces production of immunosuppressive adenosine and restores T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5577. doi:10.1158/1538-7445.AM2017-5577

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

“…In June 2016, Bristol-Myers Squibb (BMS) launched a Phase I/IIa trial (NCT02754141) to assess the efficacy of BMS-986179, a human IgG2-IgG1 hybrid mAb that not only inhibits CD73-exerted AMP hydrolysis but also induces CD73 internalization (414). In April 2018, Corvus Pharmaceuticals initiated clinical evaluation (NCT03454451) of their humanized anti-CD73 mAb, CPI-006, which directly competes with AMP for the CD73 active site (415). Finally, in July 2018, Novartis listed a Phase I/Ib trial (NCT03549000) evaluating the efficacy of SRF373/NZV930, a human mAb that impedes CD73 activity via a currently undisclosed mechanism, and was pre-clinically developed by Surface Oncology before being exclusively licensed to Novartis for further clinical development.…”

Tregs: Where We Are and What Comes Next?

“…Several studies revealing the relationship between CD73 and clinical prognosis have sprung up ( 98 – 103 ). Further, anti-CD73 therapy alone ( 104 ) or combined with other inhibitory molecules ( 105 ) have produced inspiring benefits in preclinical models. Admittedly, these advancements may reflect the relationship between CD73 and tumor microenvironment rather than Tregs alone.…”

Targeting Metabolism of Extracellular Nucleotides via Inhibition of Ectonucleotidases CD73 and CD39

“…Four additional anti-CD73 mAbs are currently in phase I/II clinical trials across a range of advanced solid malignancies, as summarized in Table . These include CPI-006 (Corvus Pharmaceuticals), a humanized IgG1 mAb that binds with high affinity to the active site and blocks the enzymatic activity of CD73 without internalization; NZV930 (developed by Surface Oncology as SRF373 and subsequently licensed to Novartis), a fully human IgG4 mAb that inhibited tumor growth as a single agent and in combination with PD-1 inhibition in preclinical studies; TJ004309 (in-licensed by Tracon Pharmaceuticals from I-Mab, a company developing the same molecule in China as TJD5); , and GS-1423 (developed by Agenus as AGEN1423 and subsequently licensed to Gilead), a bispecific antibody against CD73 and transforming growth factor β (TGFβ). , …”