TY - JOUR
T1 - Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis
AU - Sonigra, Amee
AU - Nel, Hendrik J.
AU - Wehr, Pascale
AU - Ramnoruth, Nishta
AU - Patel, Swati
AU - van Schie, Karin A.
AU - Bladen, Maxwell W.
AU - Mehdi, Ahmed M.
AU - Tesiram, Joanne
AU - Talekar, Meghna
AU - Rossjohn, Jamie
AU - Reid, Hugh H.
AU - Stuurman, Frederik E.
AU - Roberts, Helen
AU - Vecchio, Phillip
AU - Gourley, Ian
AU - Rigby, Mark
AU - Becart, Stephane
AU - Toes, Rene E. M.
AU - Scherer, Hans Ulrich
AU - Cao, Kim-Anh L.
AU - Campbell, Kim
AU - Thomas, Ranjeny
N1 - Funding Information: FUNDING. Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported Funding Information: Trial data analysis in this manuscript is part of a project that received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777357. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations. RT was supported by Arthritis Queensland, a National Health and Medical Research Council (NHMRC) Senior Research Fellowship, and NHMRC grant 2008287. JR is a NHMRC Senior Research Fellow. KALC is an NHMRC Career Development Fellow. Funding Information: by European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287. Funding Information: We thank Translational Research Institute Clinical Trials Unit staff, who carried out clinical assessments; Martin Devereaux, Paul Kubler, and Peter Landsberg, who referred patients; Kylie Loh, Annemarie Dor-jée, and Carolien Koeleman, who provided technical assistance for monomer construction, CCP2 ELISA, and Fc ACPA HPLC, respectively; and Lavinia Proctor, who drafted the investigator’s brochure. Data analysis was carried out at the Translational Research Institute, Woolloongabba, Australia. The Translational Research Institute is supported by a grant from the Australian Government. Publisher Copyright: © 2022, Sonigra et al.
PY - 2022/10/24
Y1 - 2022/10/24
N2 - BACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under “sub-immunogenic” conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol. METHODS. A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71–specific (Cit-Vim–specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate. RESULTS. DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim–specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181–treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim–specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181. CONCLUSION. The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.
AB - BACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under “sub-immunogenic” conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol. METHODS. A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71–specific (Cit-Vim–specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate. RESULTS. DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim–specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181–treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim–specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181. CONCLUSION. The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.
UR - http://www.scopus.com/inward/record.url?scp=85140352127&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/jci.insight.160964
DO - https://doi.org/10.1172/jci.insight.160964
M3 - Article
C2 - 36278483
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 20
M1 - e160964
ER -