quemliclustat (AB680)

P1/2, N=227, Active, not recruiting, Arcus Biosciences, Inc. | Trial completion date: Oct 2024 --> Jul 2025 | Trial primary completion date: Oct 2024 --> Jul 2025

P1/2, N=56, Recruiting, Jonsson Comprehensive Cancer Center | Suspended --> Recruiting

P3, N=610, Not yet recruiting, Arcus Biosciences, Inc.

P2, N=320, Recruiting, Gilead Sciences | Trial completion date: Sep 2026 --> Dec 2027 | Trial primary completion date: Sep 2026 --> Dec 2027

P1/2, N=173, Completed, Arcus Biosciences, Inc. | Active, not recruiting --> Completed

To test our hypothesis, we used the KrasG12D; PdxCre1 (KC) genetically engineered mouse (GEM) model and tested the utility of AB-680, a small molecule inhibitor targeting CD73, to inhibit PanIN progression...The scRNA-seq analysis showed that CD73 inhibition reduced M2 macrophages, acinar, and PanIN cell populations. CD73 inhibition enhanced immune surveillance and expanded unique clonotypes of TCR and BCR, indicating that inhibition of CD73 augments adaptive immunity early in the neoplastic microenvironment.

P1/2, N=227, Active, not recruiting, Arcus Biosciences, Inc. | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jul 2024 --> Oct 2024

Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge, presenting a new paradigm for ICD treatment combined with adenosine metabolism.

CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response.

P1, N=195, Recruiting, Arcus Biosciences, Inc. | Active, not recruiting --> Recruiting

P2, N=23, Recruiting, Catherine Spina | Trial primary completion date: Apr 2024 --> Dec 2025

P1, N=165, Active, not recruiting, Arcus Biosciences, Inc. | Trial completion date: Jun 2024 --> May 2027 | Trial primary completion date: Jun 2024 --> May 2027

P2, N=360, Recruiting, Arcus Biosciences, Inc. | N=200 --> 360 | Trial completion date: Nov 2025 --> Jun 2027 | Trial primary completion date: Sep 2025 --> Sep 2026

P2, N=60, Recruiting, Gulam Manji | Initiation date: Oct 2023 --> Jun 2024

P1/2, N=56, Suspended, Jonsson Comprehensive Cancer Center | Recruiting --> Suspended

P1/2, N=173, Active, not recruiting, Arcus Biosciences, Inc. | Phase classification: P1b/2 --> P1/2 | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

P1/2, N=227, Active, not recruiting, Arcus Biosciences, Inc. | Phase classification: P1b/2 --> P1/2 | Trial completion date: Jan 2024 --> Jul 2024 | Trial primary completion date: Jan 2024 --> Jul 2024

P2, N=39, Recruiting, Nataliya Uboha | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Jun 2024 --> Jan 2025

P2, N=39, Recruiting, Nataliya Uboha | Not yet recruiting --> Recruiting

Results from ARC-8 demonstrate the addition of Q 100 mg ± Z to G/nP was safe and tolerable, with no significant added toxicity to GnP. Modulation of eADO with Q may confer benefit beyond radiographic measures of disease. The OS is promising and supports further development of Q in mPDAC.

AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.

P1, N=165, Active, not recruiting, Arcus Biosciences, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jan 2024 --> Jun 2024 | Trial primary completion date: Jan 2024 --> Jun 2024

P1b/2, N=227, Active, not recruiting, Arcus Biosciences, Inc. | Trial primary completion date: Sep 2023 --> Jan 2024

Quemliclustat (quemli) is a potent, selective, small molecule inhibitor of CD73...Domvanalimab (dom) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks T cell Immunoglobulin and ITIM domain (TIGIT), reducing immunosuppression of T/natural killer (NK) cells and promoting antitumor activity. Zimberelimab (zim) is a mAb that binds PD-1 on T/NK cells, preventing PD-L1-mediated immunosuppressive effects and resulting in increased immune-mediated tumor cell death...In substudy C, patients with metastatic NSCLC who have progressed after prior platinum-based chemotherapy and anti-PD-L1 therapy will receive docetaxel (75 mg/m2 IV Q3W) in combination with either quemli (300 mg IV Q3W) or dom (1200 mg IV Q3W) in combination with zim (360 mg IV Q3W)...Other endpoints include disease control rate, progression-free survival, duration of response, overall survival, and pharmacokinetics. EDGE-Lung is currently enrolling patients in Asia-Pacific, Europe, and North America.

P2, N=23, Recruiting, Catherine Spina | Not yet recruiting --> Recruiting

P2, N=23, Not yet recruiting, Catherine Spina

Inhibiting CD73 restructures TME and reduces PanIN incidence and progression to PDAC. CD73 inhibition may be a candidate immunoprevention strategy in pancreatic cancer.

P2, N=200, Recruiting, Arcus Biosciences, Inc. | N=120 --> 200 | Trial completion date: May 2024 --> Nov 2025 | Trial primary completion date: Mar 2024 --> Sep 2025

CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Moreover, cGAS expression in mouse KPC tumor cells was required for anti-tumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.

In this study, we demonstrated that a novel combination therapy of AB680 and palbociclib may be advantageous for the treatment of CRC.

P1b/2, N=342, Recruiting, Arcus Biosciences, Inc. | N=165 --> 342 | Trial completion date: Oct 2023 --> Dec 2025

CD73 inhibitor Adenosine 5'-(α,β-methylene)diphosphate also abrogated PMN suppressor function while using a different inhibitor (AB-680) had no effect...Together, these studies point to eATP as a modulator of PMN suppressor function in the TME and the potential to abrogate suppression by targeting CD39. Future studies will address the specific signaling functions of eATP on PMN in the TME that drive suppressor function.

We conclude oral gavage delivery of CD73 inhibitor AB680 at 10mg/kg (6x/week) reduces tumor growth in KPC syngeneic tumor bearing mice. Treatment with AB680 at 10mg/kg 3x/week significantly increases tumor doubling time, significantly alters intratumoral immune cell populations, and results in a significant decrease in intratumoral adenosine levels. In addition, we observed a significant increase in infiltration of activated CD8-positive T cells indicating oral gavage delivery using AB680 reverses immunosuppression in vivo.

Macrophage-derived exosome-mimetic nanovesicles (EMVs) were designed and validated as a nanoplatform for coloading and delivery of the CD73 inhibitor (AB680) and the monoclonal antibody to programmed cell death ligand 1 (aPDL1)...Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted the activation and infiltration of cytotoxic T-lymphocytes, which helped to optimally suppress tumor growth and extend median survival in vivo. Therefore, using EMVs to deliver a combination of aPDL1 and the CD73 inhibitor may be a useful combined immunotherapy strategy for treating bladder cancer.

The intratumoral immunomodulation of CD73 inhibition is distinct from PD-1 inhibition and exhibits potential as a novel anticancer immunotherapy for CRC, possibly through a synergistic effect when combined with PD-1 blocker treatments. This study may contribute to the ongoing development of anticancer immunotherapies targeting refractory CRC.

Treatment arms will independently evaluate AB928 + zimberelimab (AB122; anti-PD-1 antibody) alone or in combination with an SOC backbone (enzalutamide or docetaxel) in earlier-line pts or AB928 + AB680 (CD73 inhibitor) +/- zimberelimab in later-line pts. Funding: Arcus Biosciences. Clinical trial identification: NCT04381832.

We found AB680 to be a reversible, slow-onset competitive inhibitor of human CD73 with a K of 5 pM. Clinical candidates of this potency are uncommon and deserve special consideration during lead optimization.

Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences. Research Funding: Arcus Biosciences.

Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences. Research Funding: Arcus Biosciences.