In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes

Wyant, Timothy; Yang, Lili; Fedyk, Eric R.

doi:10.4161/mabs.26392

Cited by 52 publications

(40 citation statements)

References 21 publications

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“…In this study, however, the fate of fluorescently labelled vedolizumab was used to deduce the fate of α4β7, whereas we used a non‐competing anti‐β7 antibody to assess the cell surface expression of α4β7 itself. These differences in experimental design could explain why we were able to document the unaltered expression of α4β7 in the presence of vedolizumab, in contrast to the earlier study (Wyant et al, ).…”

Section: Resultscontrasting

confidence: 99%

“…To our surprise, we found vedolizumab to neither reduce the expression of α4β7 nor to affect the expression of integrins α4β1 and αLβ2 (Figure a). Of note, a previous in vitro study focusing on memory T cells, a subpopulation of CD2+ T cells, reported reduced α4β7 surface expression in the presence of vedolizumab (Wyant, Yang, & Fedyk, ). In this study, however, the fate of fluorescently labelled vedolizumab was used to deduce the fate of α4β7, whereas we used a non‐competing anti‐β7 antibody to assess the cell surface expression of α4β7 itself.…”

Section: Resultsmentioning

confidence: 98%

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Anti‐αLβ2 antibodies reveal novel endocytotic cross‐modulatory functionality

Mancuso

Casper

Schmidt³

et al. 2020

British J Pharmacology

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Background and Purpose: Antibodies targeting cell surface receptors are considered to enable highly selective therapeutic interventions for immune disorders and cancer.Their biological profiles are found, generally, to represent the net effects of antibody-target interactions. The former therapeutic anti-integrin αLβ2 antibody efalizumab seems to defeat this paradigm by eliciting, via mechanisms currently unknown, much broader effects than would be predicted based on its target specificity. Experimental Approach:To elucidate the mechanisms behind these broad effects, we investigated in primary human lymphocytes in vitro the effects of anti-αLβ2 antibodies on the expression of αLβ2 as well as unrelated α4 integrins, in comparison to Fab fragments and small-molecule inhibitors. Key Results:We demonstrate that anti-αLβ2 mAbs directly induce the internalization of α4 integrins. The endocytotic phenomenon is a direct consequence of their antibody nature. It is inhibited when monovalent Fab fragments or small-molecule inhibitors are used. It is independent of crosslinking via anti-Fc mAbs and of αLβ2 activation. The cross-modulatory effect is unidirectional and not observed in a similar fashion with the α4 integrin antibody natalizumab. Conclusion and Implications:The present study identifies endocytotic crossmodulation as a hitherto unknown non-canonical functionality of anti-αLβ2 antibodies. This cross-modulation has the potential to fundamentally alter an antibody's benefit risk profile, as evident with efalizumab. The newly described phenomenon may be of relevance to other therapeutic antibodies targeting cluster-forming receptors. Thus, pharmacologists should be cognizant of this action when investigating such antibodies.

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Section: Resultscontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 98%

Anti‐αLβ2 antibodies reveal novel endocytotic cross‐modulatory functionality

Mancuso

Casper

Schmidt³

et al. 2020

British J Pharmacology

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“…When vedolizumab binds to integrin a4b7, the antibody-integrin complex is internalised into the cell within 24 hours, rendering binding to MAdCAM-1 and fibronectin impossible. 86,106 The efficacy of vedolizumab in IBD was demonstrated in several placebo-controlled phase II and III clinical trials of patients with moderately active UC as well as moderately active CD, and it has also been shown to be effective during long-term follow-up. [107][108][109][110] Vedolizumab was licensed for the treatment of CD and UC in 2014.…”

Section: Vedolizumabmentioning

confidence: 99%

Return to sender: Lymphocyte trafficking mechanisms as contributors to primary sclerosing cholangitis

Krijger

Wildenberg

Jonge

et al. 2019

Journal of Hepatology

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Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tree, characterised by stricturing bile duct disease and progression to liver fibrosis. The pathophysiology of PSC is still unknown. The concurrence with inflammatory bowel disease (IBD) in about 70% of cases has led to the hypothesis that gut-homing lymphocytes aberrantly traffic to the liver, contributing to disease pathogenesis in patients with both PSC and IBD (PSC-IBD). The discovery of mutual trafficking pathways of lymphocytes to target tissues, and expression of gut-specific adhesion molecules and chemokines in the liver has pointed in this direction. There is now increasing interest in using drugs that intervene with these trafficking pathways (e.g. vedolizumab, etrolizumab) for the treatment of PSC-IBD. In this review we discuss what is currently known about the immunological interactions between the gut and the liver in concomitant PSC and IBD, as well as potential therapeutic options for intervening in these mechanisms.

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“…cytokine release and cellular activation); however, once vedolizumab is withdrawn, a 4 b 7 is rapidly re-expressed and functional [11]. Moreover, it does not lead to memory T lymphocyteassociated cytotoxicity, lymphocyte activation and cytokine production, and does not affect the suppressive ability of regulatory T lymphocytes.…”

Section: Pharmacodynamic Propertiesmentioning

confidence: 93%

Vedolizumab: A Review of Its Use in Adult Patients with Moderately to Severely Active Ulcerative Colitis or Crohn’s Disease

Garnock-Jones

2014

BioDrugs

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Vedolizumab (Entyvio™) is a humanized monoclonal antibody α4β7 integrin-receptor antagonist indicated for the treatment of adult patients with moderately to severely active ulcerative colitis or Crohn's disease. This article reviews the pharmacological properties of intravenous infusions of vedolizumab and its clinical efficacy in adult patients with these diseases. In phase III clinical trials, patients with ulcerative colitis had significantly higher rates of clinical response and clinical remission when treated with vedolizumab than when receiving placebo at both 6 and 52 weeks. However, outcomes with vedolizumab in patients with Crohn's disease were mixed. In a study that evaluated both clinical remission rate and CDAI-100 response rate as primary endpoints, only the clinical remission rate at 6 weeks was significantly higher with vedolizumab than placebo. In another trial, there was no significant between-group difference in the clinical remission rate in TNF-antagonist failure patients at 6 weeks (primary endpoint), although there was a significant difference at 10 weeks. In the Crohn's disease study that included maintenance treatment, vedolizumab was significantly more effective at 52 weeks than placebo in both endpoints (clinical remission was the only primary endpoint in the maintenance study). Vedolizumab was generally well tolerated in these trials. As vedolizumab is a specific α4β7 integrin antagonist, with gut-specific effects, it is unlikely to be associated with the development of progressive multifocal leukoencephalopathy, a risk observed with the less selective α4β7/α4β1 integrin antagonist natalizumab. Vedolizumab is a useful addition to the treatment options available for patients with moderately to severely active ulcerative colitis and Crohn's disease.

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In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes

Cited by 52 publications

References 21 publications

Anti‐αLβ2 antibodies reveal novel endocytotic cross‐modulatory functionality

Anti‐αLβ2 antibodies reveal novel endocytotic cross‐modulatory functionality

Return to sender: Lymphocyte trafficking mechanisms as contributors to primary sclerosing cholangitis

Vedolizumab: A Review of Its Use in Adult Patients with Moderately to Severely Active Ulcerative Colitis or Crohn’s Disease

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