Background
Neutralizing antibodies targeting HLA-DQ2.5 are considered a target for treatment of celiac disease (CeD) by blocking gluten peptide presentation to CD4+ T-cells. However, systemic HLA blockade poses safety risks (e.g., infection, impaired thymic selection) and is limited by rapid target-mediated drug clearance. To overcome these limitations, we developed DONQ52, a humanized multi-specific monoclonal antibody that selectively binds to HLA-DQ2.5–gluten peptide complexes, thereby preventing gluten-induced T-cell activation without systemic HLA disruption. This first-in-human Phase 1 study (DQB101US; NCT05425446) evaluated the safety, tolerability, and pharmacokinetics (PK) of DONQ52.
Methods
Patients with biopsy-proven CeD and HLA-DQ2.5 were randomized to receive either subcutaneous DONQ52 or placebo. The study consisted of a single ascending dose part (SAD; 0.2, 0.67, 2, or 4 mg/kg) and a multiple ascending dose part (MAD; 0.67, 2, or 4 mg/kg weekly for 2 weeks followed by every 2 weeks for 10 weeks).
Results
The SAD and MAD parts enrolled 32 and 24 patients, respectively. DONQ52 exposure increased in a dose-dependent manner in both parts. Mean half-life values were 7.69, 11.7, 10.5, and 15.7 days for the 0.2, 0.67, 2, and 4 mg/kg groups in the SAD part, respectively, and 22.2, 28.9, and 39.5 days for the 0.67, 2, and 4 mg/kg groups in the MAD part, respectively, suggesting PK nonlinearity due to target-mediated clearance. Treatment-emergent adverse events (TEAEs) occurred in 68.3% (28/41) of the DONQ52 group and 80.0% (12/15) of the placebo group; no serious adverse events were reported. The most common adverse drug reactions were injection-site reactions, which were generally mild and occurred at similar rates in the active-treatment and placebo groups.
Conclusion
The bispecific antibody DONQ52 targets complexes formed by HLA-DQ2.5 and gluten peptides has favorable safety, tolerability, and PK profiles in patients with treated CeD, supporting further clinical development of DONQ52 for CeD.