Dual A2A/A2B Adenosine Receptor Antagonist M1069 Counteracts Immunosuppressive Mechanisms of Adenosine and Reduces Tumor Growth In Vivo.

Autor:	Schiemann K; The Healthcare Business of Merck KGaA, Darmstadt, Germany., Belousova N; EMD Serono, Billerica, Massachusetts., Matevossian A; EMD Serono, Billerica, Massachusetts., Nallaparaju KC; EMD Serono, Billerica, Massachusetts., Kradjian G; EMD Serono, Billerica, Massachusetts., Pandya M; EMD Serono, Billerica, Massachusetts., Chen Z; EMD Serono, Billerica, Massachusetts., Aral E; EMD Serono, Billerica, Massachusetts., Krauel EM; EMD Serono, Billerica, Massachusetts., Petrova E; The Healthcare Business of Merck KGaA, Darmstadt, Germany., Boesler C; The Healthcare Business of Merck KGaA, Darmstadt, Germany., Kitzing T; The Healthcare Business of Merck KGaA, Darmstadt, Germany., Lecomte M; The Healthcare Business of Merck KGaA, Darmstadt, Germany., Wagner C; The Healthcare Business of Merck KGaA, Darmstadt, Germany., Blayo AL; Domain Therapeutics SA, Strasbourg, France., Schann S; Domain Therapeutics SA, Strasbourg, France., Huck B; EMD Serono, Billerica, Massachusetts., Moisan J; EMD Serono, Billerica, Massachusetts., Zaynagetdinov R; EMD Serono, Billerica, Massachusetts.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Nov 04; Vol. 23 (11), pp. 1517-1529.
DOI:	10.1158/1535-7163.MCT-23-0843
Abstrakt:	While A2A adenosine receptor (AR) was considered as a major contributor to adenosine-mediated immunosuppression, A2B, having the lowest affinity to adenosine, has also emerged as a potential contributor to tumor promotion. Therefore, in adenosine-rich tumor microenvironment (TME), where A2B could be complementary and/or compensatory to A2A, simultaneous targeting of A2A and A2B ARs can provide higher potential for cancer immunotherapy. We developed M1069-a highly selective dual antagonist of the A2A and A2B AR. In assays with primary human and murine immune cells, M1069 rescued IL2 production from T cells (A2A dependent) and inhibited VEGF production by myeloid cells (A2B dependent) in adenosine-high settings. M1069 also demonstrated superior suppression of the secretion of protumorigenic cytokines CXCL1, CXCL5, and rescue of IL12 secretion from adenosine-differentiated dendritic cells compared to an A2A-selective antagonist (A2Ai). In a one-way mixed lymphocyte reaction (MLR) assay, adenosine-differentiated human and murine dendritic cells treated with M1069 demonstrated superior T-cell stimulatory activity compared to dendritic cells differentiated in presence of A2Ai. In vivo, M1069 decreased tumor growth as a monotherapy and enhanced antitumor activity of bintrafusp alfa (BA) or cisplatin in syngeneic adenosinehi/CD73hi 4T1 breast tumor model, but not in the CD73 knockout 4T1 tumor model or in adenosinelow/CD73low MC38 murine colon carcinoma model. In summary, our dual A2A/A2B AR antagonist M1069 may counteract immune-suppressive mechanisms of high concentrations of adenosine in vitro and in vivo and enhance the antitumor activity of other agents, including BA and cisplatin. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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