Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers
- 306 Downloads
Adenosine suppresses antitumor immune responses via A2a and A2b receptors expressed on intratumoral immune cells. This effect is mediated by increased cyclic adenosine 5′-monophosphate (AMP) levels and phosphorylation of cyclic AMP response element binding protein (CREB). We conducted a phase 1, placebo-controlled, single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study to assess the safety, tolerability, pharmacokinetics (PK), including food effect (FE), and pharmacodynamics (PD) of oral AB928, a novel dual A2aR/A2bR antagonist, in healthy volunteers. AB928 doses between 10 and 200 mg once daily and 100 mg twice daily were evaluated. The study enrolled 85 subjects (randomized 3:1, AB928:placebo), 40 each in the SAD and MAD cohorts, and 5 in the FE cohort. AB928 was well tolerated up to the highest dose tested and did not affect any physiologic parameters potentially sensitive to adenosine inhibition. No safety concern was identified. The PK profile of AB928 was linear and dose-proportional, and a clear PK/PD correlation was demonstrated. Significant inhibition of adenosine receptor-mediated phosphorylated CREB was observed at peak plasma concentrations in all dose cohorts and at trough plasma concentrations in the higher-dose cohorts. AB928 plasma levels ≥1 μM were associated with ≥90% adenosine receptor inhibition. In the postprandial state, the rate of AB928 absorption decreased but the extent of absorption was unchanged. Together, these data support further clinical development of oral AB928 in cancer patients.
KeywordsAB928 Adenosine signaling Adenosine receptor antagonist Immunotherapy Oncology Healthy volunteers
The authors thank all of the healthy volunteers who participated in this study. We also thank PRA Health Sciences in the Netherlands for assistance with flow cytometry: Sijranke Post, Richard Draaijer, Tom Huizinga, Patrick Veerman, Frank Beltman, Riejanne Bax-Seigers, and Janet Stegehuis. Editorial assistance was provided by Marithea Goberville, PhD, Science Author, Inc.
Arcus Biosciences, Inc. (no grant number applies).
Compliance with ethical standards
Conflict of interest
LS, LJ, ML, DA, JJ, AR, JT, JP, MW, and JK are employees of Arcus Biosciences, Inc., and RT and GA are employees of PRA Health Sciences.
This study was conducted in the Netherlands in accordance with the ethical principles that have their origin in the Declaration of Helsinki,and complied with the International Conference on Harmonization E6 Guideline for Good Clinical Practice and the European Union CTD Directive, as incorporated into Dutch Law. The protocol was approved by the institutional review board. The data were analyzed by PRA Health Sciences (safety and PK) and Arcus Biosciences, Inc. (PD).
Informed consent was obtained from all individual participants included in the study.
- 5.Buisseret L, Pommey S, Allard B, Garaud S, Bergeron M, Cousineau I, Ameye L, Bareche Y, Paesmans M, Crown JPA, di Leo A, Loi S, Piccart-Gebhart M, Willard-Gallo K, Sotiriou C, Stagg J (2018) Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial. Ann Oncol 29:1056–1062CrossRefGoogle Scholar
- 6.Inoue Y, Yoshimura K, Kurabe N, Kahyo T, Kawase A, Tanahashi M, Ogawa H, Inui N, Funai K, Shinmura K, Niwa H, Suda T, Sugimura H (2017) Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget 8:8738–8751Google Scholar
- 9.Huang S, Apasov S, Koshiba M, Sitkovsky M (1997) Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90:1600–1610Google Scholar
- 11.Raskovalova T, Lokshin A, Huang X et al (2006) Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase a isozyme I (PKA I). Immunol Res36:91–99Google Scholar
- 18.Walters MJ, Tan JB, Becker A, Yi F, Park T, Leleti MR, Rosen B, Sharif E, Debien L, Young S, Lim WH, Garrido-Shaqfeh S, Jaen JC, Powers JP (2017) Characterization of the potent and selective A2R antagonist AB928 for the treatment of cancer. Cancer Res 77(13 Suppl):4572Google Scholar
- 19.DiRenzo D, Piovesan D, Narasappa N et al. AB928, a dual antagonist of the A2aR and A2bR adenosine receptors, relieves adenosine-mediated immune suppression. CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, New York, NY, USA; September 30–October 3, 2018. Abstract A124Google Scholar
- 20.Walters MJ, Piovesan D, Tan JB, DiRenzo D, Yin F, Miles D, Leleti MR, Park T, Soriano F, Sharif E, Schindler U, Powers JP (2018) Combining adenosine receptor inhibition with AB928 and chemotherapy results in greater immune activation and tumor control. Cancer Res 78(13 Suppl):5556Google Scholar
- 21.Ashok D, Seitz L, Tan JBL et al (2017) Characterization of AB928, a dual adenosine A2aR/A2bR antagonist that retains potency under conditions of high albumin and high receptor activation. J Immunother Cancer 5(Suppl 2):P6Google Scholar