The ATP/Adenosine pathway in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. The ATPase 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 CD73, to immunosuppressive adenosine. Inhibiting the enzymatic function of CD39 has the potential to shift the immunosuppressive milieu of the TME in a 2-pronged fashion: 1) Enhancement of immunostimulatory extracellular ATP released by damaged and/or dying tumor cells and 2) Inhibition of the generation and accumulation of suppressive adenosine within the TME, thereby unleashing an immune-mediated anti-tumor response.
Tizona has generated a novel first-in-class fully human anti-CD39 antibody, TTX-030, that inhibits CD39 ATPase enzymatic function with sub-nanomolar affinity and potency. TTX-030 is specific for CD39 and binds to CD39+ cancer cell lines and primary human leukocytes with high affinity. TTX-030 is capable of inhibiting CD39 at elevated ATP concentrations reported in the TME. Enzymatic inhibition by TTX-030 has demonstrated: preservation of pro-inflammatory extracellular ATP, reduction of adenosine accumulation, and inhibition of phosphate release by a variety of CD39-expressing cells, including tumor cells and immune cells. In vitro functional assays using stimulated PBMCs exposed to exogenous ATP demonstrated increased proliferation of both CD4+ and CD8+ T cells in the presence of TTX-030 and increased secretion of the pro-inflammatory cytokines IFN-γ, TNF-α, and IL-2. Treatment of mice with a mouse-specific CD39 inhibitory antibody in a syngeneic tumor model significantly decreased tumor growth.
In summary, TTX-030 is a selective and potent CD39 enzymatic inhibitor, capable of preventing adenosine-mediated immune suppression and increasing T-cell activation. Inhibition of CD39 with TTX-030 represents a unique therapeutic target aimed at modulating the immunosuppressive TME in cancer.
Citation Format: Alana G. Lerner, Maria Kovalenko, Megan Welch, Tracy dela Cruz, Jeff Jones, Clifford Wong, Bradley Spatola, Meghan Eberhardt, Andrew Wong, Wanchi Fung, Leanna Lagpacan, Karolina Losenkova, Gennady Yegutkin, Vanessa Soros, John Corbin, Courtney Beers, Achim K. Moesta. Targeting CD39 with a first-in-class inhibitory antibody prevents ATP processing and increases T-cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5012.