Table 1.

Advantages and disadvantages for targeting adenosine generation (CD39 and CD73) and adenosine signaling (A1, A2A, A2B, and A3 adenosine receptors) pathways

Therapeutic target—localizationPotential advantagesPotential disadvantages
CD39
  • B cells, NK cells, activated T cells, particularly Tregs, endothelial cells, solid tumors, and certain leukemias.

  • Rate-limiting step converting ATP to AMP

  • Increased expression in some cancer types

  • Antibody therapies and small-molecule inhibitors [polyoxometalate-1 (POM-1)] improve antitumor immunity and in some cases display anticancer potential in murine models.

  • Lack humanized antibodies

  • POM-1 displays proven selectivity for CD39, difficult to determine potential off-target effects in humans.

  • Possible side effects due to total loss of CD39.

CD73
  • Endothelium and epithelium, stromal cells, Tregs, MDSC, B cells, CD8+ T cells, tumor correlating with increased metastasis.

  • Multifunctionality of CD73

    • Generation of adenosine from AMP

    • Immunosuppressive environment

    • Angiogenesis

    • Involved in lymphocyte adhesion

    • Migration of immune and tumor cells

  • Inhibition promotes antitumor immunity.

  • Direct relationship with several types of cancers and proven anticancer properties.

  • Use as a predictive biomarker to dictate therapeutic efficacy of adenosine-mediated therapies.

  • Current lack of humanized antibodies.

  • Development of antibodies that target multiple functions of CD73 will be necessary for maximal efficacy.

  • Highly abundant CD73 expression may lead to alternative deleterious effects not identified in murine models.

  • Given the above and the longer half-life of intact mAb, smaller fragments or small-molecule inhibitors might be required.

A1
  • Broad distribution, particularly abundant in nerves, heart, and kidneys.

  • A1 adenosine receptor antagonists and agonists have undergone clinical testing, i.e., Rolofylline, Tonapofyline, and GW493838.

  • A1 adenosine receptor shown to regulate ER expression in certain breast cancer subtypes.

  • Disappointing clinical outcomes and discontinuation of testing in the treatment of nerve injury and prevention of heart and renal failure.

  • Areas of highest distribution on host tissue are unrelated to practical cancer targets.

A2A
  • Broad distribution, particularly immune cells NK, CD4+, and CD8+ T cells, macrophages as well as endothelium.

  • High-affinity adenosine receptor expressed on immune cells.

  • Antagonism promotes antitumor immunity, enhancing cytotoxic functions of CD8+ T cells and NK cells.

  • A2A adenosine receptor antagonists and display excellent safety profiles in clinical testing for neurodegenerative diseases.

  • Small-molecular inhibitors show appropriate tissue penetrance and bioavailability but short half-life ranging in hours.

  • Therapeutic efficacy specific to highly hypoxic adenosine-mediated tumors.

A2B
  • Broad distribution, particularly endothelium, MDSCs, DCs also apparent in some cancer types.

  • HIF1α-driven A2B adenosine receptor expression in response to the hypoxic tumor microenvironment.

  • Antagonists display anticancer, antiangiogenesis, and enhanced immune efficacy.

  • Low-affinity adenosine receptor, may be necessary to block others, particularly A2A adenosine receptor, in concert for efficacy.

A3
  • Broad distribution, particularly the nervous and cardiovascular system as well as immune cell subsets, highly expressed in liver and colon cancers.

  • CF101 A3 adenosine receptor agonist in clinical trial for the treatment of autoimmune disorders such as psoriasis and rheumatoid arthritis.

  • CF102 A3 adenosine receptor agonist in clinical trial for treatment of liver cancer.

  • Good safety profile and increased survival in initial clinical testing.

  • Development of therapeutic resistance by directly targeting cancer cells.

  • Off-target effects have not been established, potential agonists of immune cells can lead to activation-induced cell death or autoimmunity.