Background: Celiac disease is an autoimmune disorder in which dietary gluten activates gluten-specific CD4+ T cells, leading to gastrointestinal symptoms and enteropathy. The only established treatment is lifelong adherence to a gluten-free diet, and no drug therapy is approved. EVQ-001 is an investigational subcutaneous NanoDisc therapy incorporating three gluten-derived peptides that contain five immunodominant HLA-DQ2.5-restricted T-cell epitopes. EVQ-001 is designed to treat celiac disease by promoting tolerogenic antigen presentation and antigen-specific immune regulation.
Methods: EVQ-001 was evaluated in complementary translational systems. Human whole blood and peripheral blood mononuclear cells from 20 adult HLA-DQ2.5+ celiac disease patients were assessed before and after gluten challenge for cytokine release, T-cell proliferation, and antigen-specific T-cell phenotypes. In vivo pharmacology was evaluated using an EVQ-001 surrogate in transgenic mice. A first-in-human clinical study was designed to evaluate safety, tolerability, and pharmacodynamic activity in celiac disease patients.
Results: In patient whole blood, EVQ-001 elicited IL-2 release consistent with engagement of gluten-reactive T cells and an emerging IL-10 signal consistent with regulatory immune activity. In PBMC culture, EVQ-001 induced gluten-specific CD4+ T-cell proliferation and increased antigen-responsive CD4+ T cells expressing activation/inhibitory receptors, including PD-1 and TIM-3, as well as Tr1-like CD49b+LAG3+ phenotypes. In transgenic mice, repeated subcutaneous administration of an EVQ-001 surrogate produced dose-dependent suppression of antigen-specific splenocyte recall responses, reducing IFN-γ and IL-2 toward background levels. The planned first-in-human study is a two-part single- and multiple-ascending-dose study in HLA-DQ2.5+ celiac disease patients on a gluten-free diet, incorporating blood-based cytokine and immune-cell profiling pharmacodynamic endpoints and gluten challenge in the multiple-dose portion.
Conclusions: EVQ-001 demonstrates antigen-specific immune engagement and induction of regulatory/inhibitor phenotypes in human ex vivo assays, with concordant suppression of antigen-specific recall responses in vivo. These data support clinical evaluation of EVQ-001 as a disease-targeted immune tolerance therapy for celiac disease.