Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers

Seitz, Lisa; Jin, Lixia; Leleti, Manmohan R.; Ashok, Devika; Jeffrey, Jenna L.; Rieger, Aimee; Tiessen, Renger G.; Arold, Gerhard; Tan, Joanne; Powers, Jay P.; Walters, Matthew J.; Karakunnel, Joyson

doi:10.1007/s10637-018-0706-6

Cited by 46 publications

(39 citation statements)

References 20 publications

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“…NK cells express high A 2A R levels, specific A 2A R agonists, or ADO suppressed NK cells due to their cytokine production and cytotoxic function. 142 , 279 – 281 Intracellular cAMP concentration enhancement mediated by A 2A R is believed to be the predominant mechanism explaining how ADO suppresses NK cell activity (Fig. 4 ).…”

Section: Study and Progress Of Adenosine In The Nk Cell Cancer Immunomentioning

confidence: 99%

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Cao

Wang

Jin

et al. 2020

Sig Transduct Target Ther

100

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Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

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Section: Study and Progress Of Adenosine In The Nk Cell Cancer Immunomentioning

confidence: 99%

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Cao

Wang

Jin

et al. 2020

Sig Transduct Target Ther

100

View full text Add to dashboard Cite

show abstract

“…In a preclinical model of AT-3-OVA-bearing mice, AB-928 combined with chemotherapy by doxorubicin or oxaliplatin resulted in a significant reduction in the tumor growth rate when compared to chemotherapy alone [ 65 ]. In healthy volunteers, AB-928 was well tolerated up to the highest dose tested (200 mg once daily) and did not affect any physiologic parameters that are potentially sensitive to adenosine inhibition [ 66 ]. Researchers found that plasma levels of over 1 μM of the compound were associated with over 90% adenosine receptor inhibition [ 66 ].…”

Section: A 2a Ar Antagonists In Preclinical Andmentioning

confidence: 99%

“…In healthy volunteers, AB-928 was well tolerated up to the highest dose tested (200 mg once daily) and did not affect any physiologic parameters that are potentially sensitive to adenosine inhibition [ 66 ]. Researchers found that plasma levels of over 1 μM of the compound were associated with over 90% adenosine receptor inhibition [ 66 ]. These data resulted in further clinical development of oral AB-928 in cancer patients [ 66 ].…”

Section: A 2a Ar Antagonists In Preclinical Andmentioning

confidence: 99%

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Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists

et al. 2020

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The A2A adenosine receptor (A2AAR) plays critical roles in human physiology and pathophysiology, which makes it an important drug target. Previous drug-discovery efforts targeting the A2AAR have been focused on the use of A2AAR antagonists for the treatment of Parkinson’s disease. More recently, the A2AAR has attracted additional attention for its roles in immuno-oncology, and a number of A2AAR antagonists are currently used as lead compounds for antitumor drugs in both preclinical models and clinical trials. This review surveys recent advances in the development of A2AAR antagonists for cancer immunotherapy. The therapeutic potential of representative A2AAR antagonists is discussed based on both animal efficacy studies and clinical data.

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“…Adenosine and ATP acting at different classes of receptors often have opposite effects in cell proliferation or cell death. ATP and other adenine nucleotides have antitumor effects via the activation of the P2Y 1 receptor (P2Y 1 R) subtype [1,2], whereas adenosine induces cancer cell proliferation and growth of many types of tumors via the activation of the A 2B adenosine receptor (AR) [3,4,5,6,7,8,9,10]. The generation and degradation/removal of adenosine is a multi-step and balanced process in cells involving enzymes (Cluster of Differentiation 39 (CD39), CD73, CD26, adenosine deaminase, adenosine kinase, S-adenosyl homocysteine hydrolase) and nucleoside transporters [11], which are not the main topic of this review.…”

Section: Introductionmentioning

confidence: 99%

A2B Adenosine Receptor and Cancer

Gao

Jacobson

2019

IJMS

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There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A2BAR, coupled to both Gαs and Gαi G proteins, is one of the several GPCRs that are expressed in a significantly higher level in certain cancer tissues, in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various cancers, and the rationale of using A2BAR antagonists in cancer therapy.

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Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers

Cited by 46 publications

References 20 publications

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists

A2B Adenosine Receptor and Cancer

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