Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond

Karnell, Jodi L.; Rieder, Sadiye Amcaoglu; Ettinger, Rachel; Kolbeck, Roland

doi:10.1016/j.addr.2018.12.005

Cited by 205 publications

(188 citation statements)

References 169 publications

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“…Although CD40 is also expressed by B cells (Fig. 3C) and known to be crucial for B cell activation as a costimulatory protein (18), the eQTL effect at this locus was not observed in B cells in our study. 1 0 The biological role of the CD40-CD40L pathway in SFs has been discussed previously (19,20).…”

Section: Stimulatory Conditions Specific To the Function Of Ra Geneticontrasting

confidence: 78%

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Tsuchiya

Sumitomo

et al. 2019

Preprint

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One Sentence Summary: SFs under synergistic inflammation is associated with RA heritability, and MTF1 and RUNX1 could be crucial for the pathogenic chromatin rearrangement. Abstract:In rheumatoid arthritis (RA), synovial fibroblasts (SFs) produce a variety of pathogenic molecules in the inflamed synovium. Despite their potential importance, comprehensive genetic network of SFs under inflammatory conditions remains elusive. Here, to elucidate the actions of SFs and their contributions to RA pathogenesis, SFs, stimulated with 8 proinflammatory cytokines, were analyzed using genomic, epigenomic and transcriptomic approaches. SFs exposed to synergistically acting cytokines produced markedly higher levels of pathogenic molecules, including CD40 whose expression was significantly affected by a RA risk SNP (rs6074022). Upon chromatin remodeling in 2 7

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Section: Stimulatory Conditions Specific To the Function Of Ra Geneticontrasting

confidence: 78%

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Tsuchiya

Sumitomo

et al. 2019

Preprint

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“…B cells from dLNs of female CIA rats "enjoy" greater CD4+ T-cell help. Given that GC formation and the production of class-switched antibodies is reliant on the activation of antigen-specific B cells by CD4+ T cells capable of recognizing epitopes of the same antigenic complex, and that CD40:CD40L (CD154) contact is critical in this interaction 43 , the expression of CD40 and CD40L was investigated on CD45RA+ and CD4+ cells recovered from dLNs, respectively. The frequency of CD40+ cells among B cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

Dimitrijević

Arsenović-Ranin

Kosec

et al. 2020

Sci Rep

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The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki- 67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higherTfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-γ/IL-4 production ratio was shifted towards IFN-γ. Consistently, the serum IgG2a(b)/ IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.Rheumatoid arthritis (RA) is a chronic autoimmune systemic inflammatory disease characterized by synovial inflammation and the progressive destruction of joint cartilage and bones significantly reducing health-related quality of life 1 . The prevalence of RA is approximately threefold higher in women than in men, and the disease in women exhibits a more severe course 2 . Thus, research focused on sex as a determinant of disease severity could be important for further personalized management of patients with this autoimmune disease 3 .Collagen-induced arthritis (CIA) is a well-established experimental model mimicking many aspects of RA immunopathogenesis 4 . Differently from most of the mouse models of experimentally induced arthritis 5,6 , in several studies, female rats exhibited greater susceptibility to CIA compared with their male counterparts 7-10 . Thus, these rat CIA models seem to be suitable for research aimed to elucidate cellular and molecular mechanisms underlying sex differences in pathogenesis and clinical outcome of RA, as a base for designing efficient sex-specific therapies.Sex differences in susceptibility to autoimmune diseases have been related to sex-based differences in immunopathogenesis and susceptibility of the target tissue to damage caused by autoimmune or inflammatory burden 11,12 . These differences most likely arise from intricate interactions between circulating sex steroids, microbiota, genetic and environmental factors 11,13 .CIA is shown to be T helper (Th)1/Th17 mediated disease 14 . The main function of Th cells is to activate macrophages and fibroblasts and transform them into tissue-destructive cells 15 . Our previous studies in Dark Agouti (DA) rat CIA mo...

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“…22 Iscalimab is a blocking, nondepleting anti-CD40 mAb currently in development for prevention of allograft rejection, 13 and primary SS. 22 Iscalimab is a blocking, nondepleting anti-CD40 mAb currently in development for prevention of allograft rejection, 13 and primary SS.…”

Section: Discussionmentioning

confidence: 99%

“…Blockade of CD40-CD154 interactions prolongs allograft survival and ameliorates disease activity in various autoimmune diseases, providing rationale for development of therapies targeting this signaling pathway. 22 Iscalimab is a blocking, nondepleting anti-CD40 mAb currently in development for prevention of allograft rejection, 13 and primary SS. 14 In this FIH study, we evaluated single doses of iscalimab ranging from 0.03 to 30 mg/kg IV and 3 mg/kg SC in HS and RA patients.…”

Section: Discussionmentioning

confidence: 99%

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Espié

Koo

et al. 2020

American Journal of Transplantation

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Pascal Espié and YanLing He are co-first authors who have contributed equally to the work. James S. Rush and Peter Gergely have contributed equally to the work.Clinical Trial Registration Number: NCT02089087.Abbreviations: AEs, adverse events; AUC last , area under the plasma concentration-time curve from time zero to the last quantifiable concentration; BLQ, below limit of quantification;Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases. K E Y W O R D S clinical research/practice, clinical trial, immunosuppressant -fusion proteins and monoclonal antibodies: B cell specific, immunosuppression/immune modulation, translational research/ science S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Espié P, He Y, Koo P, et al. First-inhuman clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am J Transplant. 2020;20: 463-473. https ://doi.

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Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond

Cited by 205 publications

References 169 publications

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

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