AZD4635 is a potent, selective, and oral adenosine 2A receptor (A2AR) inhibitor, with a Ki value of 1.7nM [1]. AZD4635 can increase the expression of CD25 (IL2Ra), an activation marker on CD8 T cells, and increase the expression of granzyme B on CD4 and CD8 T cells to improve immune activation[2]. AZD4635 has been widely used in different animal models to reduce tumor burden and enhance antitumor immunity [3].
In vitro, AZD4635 treatment at 3µM for 30min significantly reversed the immunosuppressive effect of 5µM 5 '-(N-ethylcarboxamide) adenosine (NECA) on dendritic cells, and increased the expression of ovalbumin (OVA)[4]. After stimulation with anti-CD3 and anti-28 monoclonal antibodies, combined treatment with anti-PD-L1 antibody (10µg/ml) and AZD4635 (0.2 µM) for 6 hours enhanced CD8+ T cell function and increased IL-2 and IFN-γ secretion[5].
In vivo, AZD4635 (25mg/kg) administered by gavage once daily for 15 days in combination with sodium polyoxotungstate (POM-1) and anti-CD73 antibody treatment resulted in enhanced T cell activation in the spleen and increased IFN-γ and monocyte levels in the spleen and bone marrow in a mouse model of myeloma[6].
References:
[1] Borodovsky A, Wang Y, Ye M, et al. Preclinical pharmacodynamics and antitumor activity of AZD4635, a novel adenosine 2A receptor inhibitor that reverses adenosine mediated T cell suppression[J]. Cancer Research, 2017, 77(13_Supplement): 5580-5580.
[2] Budhu S, Mane M, Bah M A, et al. Optimizing breast cancer therapy by inhibiting the adenosine receptor and oxygen consumption[J]. Cancer Research, 2023, 83(7_Supplement): 2517-2517.
[3] Borodovsky A, Wang Y, Ye M, et al. Inhibition of A2AR by AZD4635 induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical models[J]. Cancer Research, 2018, 78(13_Supplement): 3751-3751.
[4] Borodovsky A, Barbon C M, Wang Y, et al. Small molecule AZD4635 inhibitor of A2AR signaling rescues immune cell function including CD103+ dendritic cells enhancing anti-tumor immunity[J]. Journal for Immunotherapy of Cancer, 2020, 8(2): e000417.
[5] Li J, Huang H H, Tu B, et al. Reversal of the CD8+ T-Cell exhaustion induced by chronic HIV-1 infection through combined blockade of the adenosine and PD-1 pathways[J]. Frontiers in Immunology, 2021, 12: 687296.
[6] Yang R, Elsaadi S, Misund K, et al. Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade[J]. Journal for immunotherapy of cancer, 2020, 8(1): e000610.