Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis
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 (ACP...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.160964 |
| _version_ | 1827768006599507968 |
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| author | Amee Sonigra Hendrik J. Nel Pascale Wehr Nishta Ramnoruth Swati Patel Karin A. van Schie Maxwell W. Bladen Ahmed M. Mehdi Joanne Tesiram Meghna Talekar Jamie Rossjohn Hugh H. Reid Frederik E. Stuurman Helen Roberts Phillip Vecchio Ian Gourley Mark Rigby Stephane Becart Rene E.M. Toes Hans Ulrich Scherer Kim-Anh Lê Cao Kim Campbell Ranjeny Thomas |
| author_facet | Amee Sonigra Hendrik J. Nel Pascale Wehr Nishta Ramnoruth Swati Patel Karin A. van Schie Maxwell W. Bladen Ahmed M. Mehdi Joanne Tesiram Meghna Talekar Jamie Rossjohn Hugh H. Reid Frederik E. Stuurman Helen Roberts Phillip Vecchio Ian Gourley Mark Rigby Stephane Becart Rene E.M. Toes Hans Ulrich Scherer Kim-Anh Lê Cao Kim Campbell Ranjeny Thomas |
| author_sort | Amee Sonigra |
| collection | DOAJ |
| description | 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.TRIAL REGISTRATION Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDING Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported 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. |
| first_indexed | 2024-03-11T12:06:23Z |
| format | Article |
| id | doaj.art-25d3db325866461e8778f8d46b427806 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:23Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-25d3db325866461e8778f8d46b4278062023-11-07T16:24:42ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-10-01720Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritisAmee SonigraHendrik J. NelPascale WehrNishta RamnoruthSwati PatelKarin A. van SchieMaxwell W. BladenAhmed M. MehdiJoanne TesiramMeghna TalekarJamie RossjohnHugh H. ReidFrederik E. StuurmanHelen RobertsPhillip VecchioIan GourleyMark RigbyStephane BecartRene E.M. ToesHans Ulrich SchererKim-Anh Lê CaoKim CampbellRanjeny ThomasBACKGROUND 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.TRIAL REGISTRATION Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDING Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported 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.https://doi.org/10.1172/jci.insight.160964AutoimmunityClinical trials |
| spellingShingle | Amee Sonigra Hendrik J. Nel Pascale Wehr Nishta Ramnoruth Swati Patel Karin A. van Schie Maxwell W. Bladen Ahmed M. Mehdi Joanne Tesiram Meghna Talekar Jamie Rossjohn Hugh H. Reid Frederik E. Stuurman Helen Roberts Phillip Vecchio Ian Gourley Mark Rigby Stephane Becart Rene E.M. Toes Hans Ulrich Scherer Kim-Anh Lê Cao Kim Campbell Ranjeny Thomas Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis JCI Insight Autoimmunity Clinical trials |
| title | Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis |
| title_full | Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis |
| title_fullStr | Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis |
| title_full_unstemmed | Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis |
| title_short | Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis |
| title_sort | randomized phase i trial of antigen specific tolerizing immunotherapy with peptide calcitriol liposomes in acpa rheumatoid arthritis |
| topic | Autoimmunity Clinical trials |
| url | https://doi.org/10.1172/jci.insight.160964 |
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