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Targeting CD73 with AB680 (Quemliclustat), a Novel and Potent Small-Molecule CD73 Inhibitor, Restores Immune
Dana Piovesan1, Joanne B L Tan1,2, Annette Becker1,3
1Arcus Biosciences, Hayward, California.
Abstract:
T cells play a critical role in the control of cancer. The development of immune checkpoint blockers (ICB) aimed at enhancing antitumor T-cell responses has revolutionized cancer treatment. However, durable clinical benefit is observed in only a subset of patients, prompting research efforts to focus on strategies that target multiple inhibitory signals within the tumor microenvironment (TME) to limit tumor evasion and improve patient outcomes. Adenosine has emerged as a potent immune suppressant within the TME, and CD73 is the major enzyme responsible for its extracellular production. CD73 can be co-opted within the TME to impair T-cell-mediated antitumor immunity and promote tumor growth. To target this pathway and block the formation of adenosine, we designed a novel, selective, and potent class of small-molecule inhibitors of CD73, including AB680 (quemliclustat), which is currently being tested in patients with cancer. AB680 effectively restored T-cell proliferation, cytokine secretion, and cytotoxicity that were dampened by the formation of immunosuppressive adenosine by CD73. Furthermore, in an allogeneic mixed lymphocyte reaction where CD73-derived adenosine had a dominant suppressive effect in the presence of PD-1 blockade, AB680 restored T-cell activation and function. Finally, in a preclinical mouse model of melanoma, AB680 inhibited CD73 in the TME and increased the antitumor activity of PD-1 blockade. Collectively, these data provide a rationale for the inhibition of CD73 with AB680 in combination with ICB, such as anti-PD-1, to improve cancer patient outcomes.
Insights
Targeting CD73 with the novel inhibitor AB680 restores T-cell function suppressed by adenosine in the tumor microenvironment. This approach enhances antitumor immunity and may improve outcomes when combined with immune checkpoint blockers like anti-PD-1.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- T cells are crucial for cancer control, but many patients do not benefit from current immune checkpoint blockers (ICB).
- The tumor microenvironment (TME) contains immunosuppressive factors, including adenosine produced by CD73, which hinders T-cell responses and promotes tumor growth.
- Targeting multiple inhibitory signals in the TME is essential to overcome tumor evasion and improve patient outcomes.
Purpose of the Study:
- To investigate the role of CD73-produced adenosine in suppressing T-cell-mediated antitumor immunity within the TME.
- To evaluate the efficacy of a novel, selective small-molecule inhibitor of CD73, AB680 (quemliclustat), in restoring antitumor T-cell function.
- To assess the potential of combining CD73 inhibition with ICB, such as anti-PD-1, for enhanced cancer treatment.
Main Methods:
- Development and characterization of a novel small-molecule inhibitor, AB680, targeting CD73.
- Assessment of AB680's ability to restore T-cell proliferation, cytokine secretion, and cytotoxicity in the presence of CD73-mediated adenosine suppression.
- Evaluation of AB680 in an allogeneic mixed lymphocyte reaction with PD-1 blockade to assess T-cell activation.
- Testing AB680 in a preclinical mouse melanoma model in combination with anti-PD-1 therapy.
Main Results:
- AB680 effectively restored T-cell proliferation, cytokine secretion, and cytotoxicity suppressed by CD73-derived adenosine.
- In the presence of PD-1 blockade, AB680 restored T-cell activation and function, overcoming the dominant suppressive effect of CD73-derived adenosine.
- In a preclinical melanoma model, AB680 inhibited CD73 within the TME and enhanced the antitumor activity of anti-PD-1 therapy.
Conclusions:
- CD73-derived adenosine is a significant immunosuppressive factor in the TME that limits T-cell-mediated antitumor immunity.
- The novel CD73 inhibitor AB680 effectively restores T-cell function suppressed by adenosine.
- Combining AB680 with ICB, such as anti-PD-1, shows promise for improving cancer patient outcomes by targeting multiple immunosuppressive pathways.
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