Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Antigen-specific immunological tolerance strategies leverage the natural process of antigen presentation by dendritic cells (DCs) to regulate pathogenic T cells and B cells. We developed a nanoparticulate liposome formulation that encapsulates autoantigenic peptide and NF-kB inhibitor, 1,25 dihydroxycholecalciferol (calcitriol), to target DCs. In mouse models of autoimmune arthritis, multiple doses of liposomes promote disease suppression as well as stable regulation of effector-memory T cells with an increase in the proportion of naive T cells in an antigen-specific manner. We carried out a dose-ranging double-blind placebo-controlled phase I clinical trial of a single dose of liposomes encapsulating 40mg/ml collagen II259-273 (CII) peptide + 400ng/ml calcitriol (DEN-181). The primary objective was assessment of safety and tolerability, and the secondary objectives were assessment of peripheral blood (PB) total and CII-specific naïve, effector and regulatory T cells, clinical response, and calcitriol levels after DEN-181 treatment.
Methods: Vehicle or 3 different dose levels of DEN-181 were administered via single s.c. injection to 17 anti-citrullinated peptide antibody (ACPA)+ HLA-DRB1*0401 or *0101+ RA patients on methotrexate. CII-specific and total CD4+ T cells were evaluated 0, 7 and 28 days post-treatment by flow cytometry using haplotype-specific tetramers. Plasma calcitriol was measured using an ultra-sensitive assay, hourly for 4h post-dose.
Results: Seventeen enrolled patients with a mean age of 50 (range 20-64), methotrexate dose 17.1 (5-25) mg/week, disease duration 4.9 (0.5-18) years, and DAS28CRP 2.66 (1.36-4.65) received vehicle or 3 different dose levels of DEN-181 (6x placebo, 4x 0.3ml, 3x 1ml and 4x 3ml). DEN-181 was generally well tolerated. One treated (1ml) and 1 control patient had AST >1.5x normal. Disease flares requiring steroids occurred in 1 control and 1 treated (3 ml) patient Plasma calcitriol levels were greater than placebo in the 3 ml but not in the 1 or 0.3 ml cohort.. Pre-treatment, CII-specific CD45RO+ memory T cells were identified in PB (range 30-66%). Relative to baseline, the % naïve CII-specific T cells increased and DAS28CRP decreased 7 days after a dose of 0.3ml, while the 3ml dose had the opposite effect (p=0.02 naïve, p=0.06 DAS). Changes in CII-specific naïve T cells differed between dose cohorts over time (p=0.04). After 7 days, reduced DAS28CRP of DEN-181-treated patients was associated with decreases in %CII-specific PD1+ T cells, CII-specific TCR expression, and ACPA IgG/IgA titre.
Conclusion: DEN-181 immunotherapy was safe and modulated antigen-specific T cells in RA patients of appropriate HLA type, where the pharmacodynamic effect of the 0.3ml dose suggests a skew toward immunological tolerance.
To cite this abstract in AMA style:Sonigra A, Nel H, Ramnoruth N, Talekar M, Tesiram J, Stuurman F, Proctor L, Roberts H, Thurmond R, Vecchio P, Gourley I, Rigby M, Felix N, Becart S, Campbell K, Thomas R. A Phase I, Randomized, Double-blind, Placebo-controlled, Single Center, Single-dose Escalation to Investigate the Safety, Tolerability, and Pharmacodynamics of Subcutaneously Administered DEN-181 in Adult Patients with ACPA+ Rheumatoid Arthritis on Stable Methotrexate [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-phase-i-randomized-double-blind-placebo-controlled-single-center-single-dose-escalation-to-investigate-the-safety-tolerability-and-pharmacodynamics-of-subcutaneously-administered-den-181-in-a/. Accessed November 28, 2020.
« Back to 2019 ACR/ARP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-i-randomized-double-blind-placebo-controlled-single-center-single-dose-escalation-to-investigate-the-safety-tolerability-and-pharmacodynamics-of-subcutaneously-administered-den-181-in-a/