Safety, PK, and PD of recombinant anti-interleukin-21 monoclonal antibody in a first-in-human trial

Ignatenko, Stanislav; Skrumsager, Birte K.; Mouritzen, Ulrik

doi:10.5414/cp202474

Cited by 37 publications

(22 citation statements)

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“…IL-21 has been implicated in the pathogenesis of RA and therefore is an emerging therapeutic target [ 24 ]. In fact, clinical trials targeting IL-21 for the treatment of RA are ongoing [ 36 ]. Our data suggest that targeting IL-21 might reduce autoimmune pathology induced by autoantibodies, while preserving T-cell responses for host defense against pathogens.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice

et al. 2016

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BackgroundInterleukin-21 (IL-21) is a T-cell-derived cytokine whose receptor is expressed on a variety of cells and therefore might have pleiotropic roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated the involvement of IL-21 signaling in the development of collagen-induced arthritis (CIA), an animal model of RA, using IL-21 receptor knockout (Il21r KO) mice.MethodsIl21r KO mice or wild-type (WT) C57BL/6 mice were immunized with chicken type II collagen (CII) emulsified in complete Freund adjuvant on day 0 and were given a boost injection on day 21. The production of anti-CII antibody, development of T-cell and B-cell subsets, and T-cell responses to CII were analyzed. CIA was induced in Rag2 KO mice to which combinations of WT or Il21r KO CD4 T cells and WT or Il21r KO B cells had been transferred, in order to examine the role of IL-21 signaling in each cell subset.ResultsIl21r KO mice were resistant to the development of CIA. CII-specific IgG but not IgM production was impaired in Il21r KO mice. This is consistent with a reduction of germinal center B cells in the draining lymph nodes. In contrast, CII-specific Th1 and Th17 responses were unaffected in Il21r KO mice. There was also no difference in the number of CII-specific follicular helper T cells between WT and Il21r KO mice. By analyzing the development of CIA in T-cell and B-cell mixed transfer experiments, we confirmed that IL-21 receptor expression on B cells, but not on T cells, was essential for the development of CIA.ConclusionIL-21 signaling in B cells, but not in T cells, plays essential roles in the production of pathogenic autoantibodies that induce CIA development.

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Section: Discussionmentioning

confidence: 99%

Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice

et al. 2016

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“…159 IL-21 is also implicated in the immunopathogenesis of RA and therefore treatment with a monoclonal antibody binding to IL-21, NNC0114-0005, is currently being tested in these patients. 160 When safety and efficacy is proven in RA, this treatment could be translated into other inflammatory disorders such as Crohn's disease. However, caution should be taken because genetic defects in IL-21 gene were recently reported to cause a severe CVID-like disorder 161 that manifests with early-onset inflammatory bowel disease.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Immunopathogenesis of granulomas in chronic autoinflammatory diseases

et al. 2016

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Granulomas are clusters of immune cells. These structures can be formed in reaction to infection and display signs of necrosis, such as in tuberculosis. Alternatively, in several immune disorders, such as sarcoidosis, Crohn's disease and common variable immunodeficiency, non-caseating granulomas are formed without an obvious infectious trigger. Despite advances in our understanding of the human immune system, the pathogenesis underlying these non-caseating granulomas in chronic inflammatory diseases is still poorly understood. Here, we review the current knowledge about the immunopathogenesis of granulomas, and we discuss how the involved immune cells can be targeted with novel therapeutics.

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“…NNC01140006 is also an mAb targeting IL‐21 for which early clinical development has been conducted in both healthy subjects and specific patient populations (rheumatoid arthritis, SLE, and diabetes mellitus) . Results from healthy subjects and patients with rheumatoid arthritis (126 subjects dosed) did not reflect significant untoward safety risks or significant changes in laboratory safety parameters …”

Section: Discussionmentioning

confidence: 96%

“…16 Results from healthy subjects and patients with rheumatoid arthritis (126 subjects dosed) did not reflect significant untoward safety risks or significant changes in laboratory safety parameters. 17 The multifunctional effects of IL-21 on the immune system make it an attractive therapeutic target for SLE and other autoimmune diseases, such as rheumatoid arthritis. 18 In this phase I clinical trial, the anti-IL-21 mAb BOS161721 seemed to be well-tolerated in healthy subjects after single-dose i.v.…”

Section: Double-blind Phase 1 Sad Study Of Bos161721mentioning

confidence: 99%

A Double‐Blind, Phase I, Single Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BOS161721 in Healthy Subjects

Hussaini

Mukherjee

Berdieva³

et al. 2019

Clinical Translational Sci

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The purpose of this study was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BOS161721, a humanized immunoglobulin G1 triple mutation (M252Y/S254T/T256E) monoclonal antibody that inhibits interleukin‐21 (IL‐21) bioactivity. This randomized, single‐center, double‐blind, placebo‐controlled study randomized healthy volunteers 3:1 to single ascending intravenous and subcutaneous doses of BOS161721 (range 1–240 mg) or placebo. BOS161721 and placebo groups had similar rates of adverse events, mostly mild; none led to study discontinuation. There were no clinically significant findings in physical examination, vital signs, or laboratory assessment. In the pooled BOS161721 population, four subjects (8.5%) tested antidrug antibody‐positive predose, and seven (14.9%) postdose. Absolute CD4+ lymphocyte count remained normal throughout follow‐up. BOS161721 administered subcutaneously was absorbed slowly, with a median time to maximum concentration (Tmax) of 144 hours across doses (range 1–15 days) and a mean apparent terminal elimination half‐life of 80–87 days for doses ≥ 30 mg. Area under the concentration‐time curve from time zero to infinity (AUC0‐inf) and maximum observed concentration (Cmax) were linear across doses > 10 mg. Subcutaneous bioavailability was 64%. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) decreased dose‐dependently with threshold characteristics at doses of ≥ 10 mg. Downregulation in BATF, IL6, LAG3, and SOCS3 genes caused by IL‐21 stimulation was reversed dose‐dependently. BOS161721 was well‐tolerated across doses, suppressed IL‐21‐induced pSTAT3 dose‐dependently, and reversed downregulation of genes critical to tolerance induction and T‐cell exhaustion induced by IL‐21. Further clinical studies are ongoing in patients with systemic lupus erythematosus, in which IL‐21 has a pathogenetic role.

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Safety, PK, and PD of recombinant anti-interleukin-21 monoclonal antibody in a first-in-human trial

Cited by 37 publications

References 0 publications

Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice

Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice

Immunopathogenesis of granulomas in chronic autoinflammatory diseases

A Double‐Blind, Phase I, Single Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BOS161721 in Healthy Subjects

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