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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2020.1838036 |
| _version_ | 1818481416689680384 |
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| author | Bradley N. Spatola Alana G. Lerner Clifford Wong Tracy dela Cruz Megan Welch Wanchi Fung Maria Kovalenko Karolina Losenkova Gennady G. Yegutkin Courtney Beers John Corbin Vanessa B. Soros |
| author_facet | Bradley N. Spatola Alana G. Lerner Clifford Wong Tracy dela Cruz Megan Welch Wanchi Fung Maria Kovalenko Karolina Losenkova Gennady G. Yegutkin Courtney Beers John Corbin Vanessa B. Soros |
| author_sort | Bradley N. Spatola |
| collection | DOAJ |
| description | 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-5ʹ-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 < 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. |
| first_indexed | 2024-12-10T11:34:47Z |
| format | Article |
| id | doaj.art-8bced6b671a140d282b142fc5d12124b |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-12-10T11:34:47Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-8bced6b671a140d282b142fc5d12124b2022-12-22T01:50:28ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2020.1838036Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanismBradley N. Spatola0Alana G. Lerner1Clifford Wong2Tracy dela Cruz3Megan Welch4Wanchi Fung5Maria Kovalenko6Karolina Losenkova7Gennady G. Yegutkin8Courtney Beers9John Corbin10Vanessa B. Soros11Antibody Development, Tizona Therapeutics, South San Francisco, CA, USAImmunology, Tizona Therapeutics, South San Francisco, CA, USAAntibody Development, Tizona Therapeutics, South San Francisco, CA, USAImmunology, Tizona Therapeutics, South San Francisco, CA, USAImmunology, Tizona Therapeutics, South San Francisco, CA, USAAntibody Development, Tizona Therapeutics, South San Francisco, CA, USAClinical Biomarkers, AbbVie, Redwood City, CA, USAMediCity Research Laboratory, University of Turku, Turku, FinlandMediCity Research Laboratory, University of Turku, Turku, FinlandImmunology, Tizona Therapeutics, South San Francisco, CA, USAAntibody Development, Tizona Therapeutics, South San Francisco, CA, USAAntibody Development, Tizona Therapeutics, South San Francisco, CA, USAThe 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-5ʹ-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 < 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.https://www.tandfonline.com/doi/10.1080/19420862.2020.1838036CD39ATPenzyme inhibitorenzyme kineticsenzyme mechanismallosteric regulation |
| spellingShingle | Bradley N. Spatola Alana G. Lerner Clifford Wong Tracy dela Cruz Megan Welch Wanchi Fung Maria Kovalenko Karolina Losenkova Gennady G. Yegutkin Courtney Beers John Corbin Vanessa B. Soros Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism mAbs CD39 ATP enzyme inhibitor enzyme kinetics enzyme mechanism allosteric regulation |
| title | Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism |
| title_full | Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism |
| title_fullStr | Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism |
| title_full_unstemmed | Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism |
| title_short | Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism |
| title_sort | fully human anti cd39 antibody potently inhibits atpase activity in cancer cells via uncompetitive allosteric mechanism |
| topic | CD39 ATP enzyme inhibitor enzyme kinetics enzyme mechanism allosteric regulation |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2020.1838036 |
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