A1 Refereed original research article in a scientific journal
Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism
Authors: Spatola BN, Lerner AG, Wong C, dela Cruz T, Welch M, Fung WC, Kovalenko M, Losenkova K, Yegutkin GG, Beers C, Corbin J, Soros VB
Publisher: TAYLOR & FRANCIS INC
Publication year: 2020
Journal: mAbs
Journal name in source: MABS
Journal acronym: MABS-AUSTIN
Article number: ARTN 1838036
Volume: 12
Issue: 1
Number of pages: 16
ISSN: 1942-0862
DOI: https://doi.org/10.1080/19420862.2020.1838036(external)
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/51025539(external)
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-5MODIFIER LETTER PRIME-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 (alpha < 1). The uncompetitive mechanism of action enables TTX-030 to inhibit CD39 at the elevated ATP concentrations reported in the TME. Maximal inhibition of cellular CD39 ATPase velocity was 85%, which compares favorably to results reported for antibody inhibitors to other enzyme targets. The allosteric mechanism of TTX-030 was confirmed via mapping the epitope to a region of CD39 distant from its active site, which suggests possible models for how potent inhibition is achieved. In summary, TTX-030 is a potent allosteric inhibitor of CD39 ATPase activity that is currently being evaluated in clinical trials for cancer therapy.
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