Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism

The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known as CD39, is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a...

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Bibliographic Details
Published in:mAbs 2020-01, Vol.12 (1), p.1838036-1838036
Main Authors: Spatola, Bradley N, Lerner, Alana G, Wong, Clifford, Dela Cruz, Tracy, Welch, Megan, Fung, Wanchi, Kovalenko, Maria, Losenkova, Karolina, Yegutkin, Gennady G, Beers, Courtney, Corbin, John, Soros, Vanessa B
Format: Article
Language:English
Subjects:
allosteric regulation
ATP
CD39
enzyme inhibitor
enzyme kinetics
enzyme mechanism
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Summary:The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known as CD39, is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a broad set of cancer indications. CD39 processes pro-inflammatory extracellular ATP to ADP and AMP, which is then processed by Ecto-5'-nucleotidase/CD73 to immunosuppressive adenosine. Directly inhibiting the enzymatic function of CD39 via an antibody has the potential to unleash an immune-mediated anti-tumor response via two mechanisms: 1) increasing the availability of immunostimulatory extracellular ATP released by damaged and/or dying cells, and 2) reducing the generation and accumulation of suppressive adenosine within the TME. Tizona Therapeutics has engineered a novel first-in-class fully human anti-CD39 antibody, TTX-030, that directly inhibits CD39 ATPase enzymatic function with sub-nanomolar potency. Further characterization of the mechanism of inhibition by TTX-030 using CD39 human melanoma cell line SK-MEL-28 revealed an uncompetitive allosteric mechanism (α 
ISSN:1942-0862
1942-0870
DOI:10.1080/19420862.2020.1838036