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.
AZD4635是一种强效、选择性的口服腺苷2A受体（A2AR）抑制剂，Ki值为1.7nM[1]。AZD4635能增加CD8 T细胞上的激活标志物CD25（IL2Rα）的表达，并提高CD4和CD8 T细胞上颗粒酶B的表达，从而改善免疫激活[2]。AZD4635已被广泛用于不同动物模型，以降低肿瘤负荷并增强抗肿瘤免疫[3]。
在体外，使用3µM的AZD4635处理30分钟，显著逆转了5µM的5'-（N-乙基羧基酰胺）腺苷（NECA）对树突状细胞的免疫抑制作用，并增加了卵清蛋白（OVA）的表达[4]。在抗CD3和抗CD28单克隆抗体刺激下，联合使用抗PD-L1抗体（10µg/ml）和AZD4635（0.2µM）处理6小时，增强了CD8 T细胞功能，并增加了IL-2和IFN-γ的分泌[5]。
在体内，在多发性骨髓瘤小鼠模型中，每日一次灌胃给予AZD4635（25mg/kg），持续15天，并联合sodium polyoxotungstate（POM-1）和抗CD73抗体治疗，增强了脾脏中的T细胞活化，并提高了脾脏和骨髓中IFN-γ和单核细胞的水平[6]。