A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes.

Autor:	Marwaha AK; Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada., Chow S; Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada., Pesenacker AM; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada., Cook L; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Sun A; Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada., Long SA; Benaroya Research Institute at Virginia Mason, Translational Research Program, Seattle, WA, USA., Yang JHM; Department of Immunobiology, King's College London, London, UK., Ward-Hartstonge KA; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada., Williams E; Department of Immunobiology, King's College London, London, UK., Domingo-Vila C; Department of Immunobiology, King's College London, London, UK., Halani K; Emmes Canada, Burnaby, British Columbia, Canada., Harris KM; Immune Tolerance Network, Bethesda, MD, USA., Tree TIM; Department of Immunobiology, King's College London, London, UK., Levings MK; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada., Elliott T; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; BCDiabetes, Vancouver, British Columbia, Canada., Tan R; Department of Pathology, Sidra Medicine and Weill Cornell Medicine, Doha, Qatar.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Dutz JP; Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Jazyk:	angličtina
Zdroj:	Immunotherapy advances [Immunother Adv] 2021 Nov 13; Vol. 2 (1), pp. ltab022. Date of Electronic Publication: 2021 Nov 13 (Print Publication: 2022).
DOI:	10.1093/immadv/ltab022
Abstrakt:	Objectives: We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia. Methods: We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses. Results: Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A. Conclusion: Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response. (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology.)
Databáze:	MEDLINE
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