On April 30, 2025 Domain Therapeutics ("Domain" or "the Company"), the GPCR experts harnessing deep receptor biology to develop breakthrough treatments for patients, reported new clinical and preclinical data for its key oncology programs DT-9081 and DT-7012, and preclinical insights on its PAR2 biased NAM program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Chicago, USA (Press release, Domain Therapeutics, APR 30, 2025, View Source [SID1234652379]).
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The presentations underscore Domain’s commitment to redefining cancer therapy and the potential of GPCRs to modulate the tumor microenvironment (TME) and enhance anti-tumor immunity. Details on the poster presentations are highlighted below:
Poster presentation #7450 titled "Clinical PK, PD and safety analysis of a phase I clinical trial of DT-9081, an EP4R-antagonist, for RP2D determination in patients with advanced solid tumors", details Phase I clinical trial results for DT-9081, a novel EP4 receptor antagonist. The findings outline DT-9081’s promising potential to inhibit tumor growth and enhance immune response in patients with advanced solid tumors. Administered orally once daily, DT-9081 has demonstrated:
Sustained EP4R target engagement as shown by cytokine release measurements and dose-proportional pharmacokinetics (PK) exposure with the best target coverage profile reported at the dose of 600 mg
An acceptable safety profile with no dose-limiting toxicities (DLT) observed at the highest doses (400 mg and 600 mg). In addition, one-third of patients achieved stable disease after two cycles of treatment
The comprehensive evaluation of safety, tolerability, and PK/pharmacodynamics (PD) profile of DT-9081 allowed to select 600 mg as the RP2D for further clinical development in advanced solid tumors.
Poster presentation #7080 titled "Comprehensive Characterization of DT-7012, a Differentiated CCR8-Depleting Antibody for the Treatment of Solid Tumors", details preclinical and benchmark data highlighting the sophisticated profile of DT-7012, a Treg depleting anti-CCR8 monoclonal antibody. The study highlighted that DT-7012:
Demonstrates a broad pattern of CCR8 binding, high affinity to CCR8, and potent effector functions, enabling effective targeting and selective depletion of CCR8+ Tregs in patient samples
Exhibits high specificity for CCR8, avoiding depletion of circulating immune cells and presenting a favorable safety profile
Maintains functional efficacy, preserving antagonistic activities (ADCC/ADCP) even under high concentrations of the CCR8 ligand CCL1 and effectively blocking CCL1-induced receptor internalization
The highly differentiated and competitive properties of DT-7012 differentiate it from other clinical anti-CCR8 candidates, positioning it as a promising therapeutic solution to overcome immune evasion mechanisms and enhance anti-tumor immune responses in solid tumors. These preclinical findings support the advancement of DT-7012 into Phase I/II trials, anticipated to start in 2025.
Poster presentation #6157, titled "PAR2 inhibitors reduce resistance to immunotherapy against cancer", details the groundbreaking research in collaboration with Prof. John Stagg, demonstrating the promising potential of its PAR2 biased NAM in overcoming resistance to immune checkpoint blockade (ICB) and addressing T cell dysfunction in cancer. The preclinical findings revealed that PAR2 biased NAM:
Synergizes with anti-PD1 therapy, turning macrophage phenotype and cytokine profile toward a pro-inflammatory TME
Promotes antigen-presenting cells and T cells, facilitating robust antitumoral responses
This research provides critical insights into the mechanisms of PAR2 inhibition, positioning Domain’s PAR2 biased NAM program as a transformative therapeutic approach to overcome tumor resistance to ICB and restore effective immune control.
Stephan Schann, Chief Scientific Officer of Domain Therapeutics, said: "The exciting data presented at AACR (Free AACR Whitepaper) 2025 further validates our unique and differentiated drug discovery and development approach, built on our proprietary platform and deep expertise in GPCR biology. These findings underscore the transformative potential of our compounds to address significant unmet medical needs and illustrate our commitment to provide better treatments for patients, a goal that is profoundly important to us."
Prof. John Stagg, Principal Investigator at the Centre Hospitalier de l’Université de Montréal (CHUM), Canada and Member of Domain Therapeutics’ Scientific Advisory Board, commented: "This collaboration with Domain Therapeutics, a unique GPCR company, highlights the importance of tackling challenging targets like PAR2. The comprehensive research presented at AACR (Free AACR Whitepaper) 2025, which explores PAR2’s role in the tumor microenvironment, demonstrates its potential to combat resistance mechanisms and improve treatment efficacy, paving the way for new advancements in immuno-oncology."