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Anti-integrins in IBD

Anti-integrins

Read time: 25 mins
Last updated:18th May 2020

Anti-integrins

A better understanding of the pathological processes involved in IBD has led to the development of new biological agents in ulcerative colitis and Crohn’s disease. Discover how anti-integrins are changing the way inflammatory bowel disease is treated, and why a gut-selective treatment option may offer a promising choice. You can also explore the other emerging anti-integrin treatments that are currently being investigated in clinical trials.

Natalizumab

Natalizumab was first approved in 2004 by the FDA for the treatment of multiple sclerosis (U.S. Food and Drug Administration, 2004) and subsequently received FDA approval in 2008 for both induction of remission and maintenance of remission for moderate-to-severe Crohn's disease (U.S. Food and Drug Administration, 2008).

Natalizumab is an IgG4 recombinant human anti-α4 integrin monoclonal antibody that is not gut-selective. It acts systemically and inhibits both α4β7-integrin/mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction and α4β1/vascular-cell adhesion molecule-1 (VCAM-1) binding. In Crohn’s disease blocking these integrin-receptor-interactions reduces lymphocyte infiltration into the intestinal mucosa and attenuates intestinal inflammation (Guagnozzi & Caprili, 2008).

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Vedolizumab

Vedolizumab is a gut-selective humanised immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin expressed on the surface of leukocytes. It blocks the binding of α4β7 to its ligand mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), expressed on the endothelial surface of venules in lymphoid tissue in the gastrointestinal (GI) tract. The binding of vedolizumab to α4β7 prevents the α4β7-expressing T lymphocytes from entering gut tissue, thereby reducing inflammation (Soler, 2009; Wyant, 2016). 

Vedolizumab was approved in 2014 by both the FDA and EMA, for treating patients with moderately to severely active ulcerative colitis or Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or an anti-tumour necrosis factor alpha (anti-TNFα) therapy (Takeda, 2014a; Takeda, 2014b). Vedolizumab is currently the only gut-specific biological treatment approved for ulcerative colitis or Crohn’s disease (Zwicker et al., 2017).

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Drugs in development

Etrolizumab

Etrolizumab is a humanised monoclonal IgG1 antibody blocking the interaction between α4β7 and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) in the gut, and also the interaction between αEβ7 and E-cadherin in the lamina propria (Fiorino et al., 2016; Park & Jeen, 2018).

In doing so it supresses the migration of lymphocytes into the gut and prevents the accumulation of leukocytes in the intraepithelial compartment of the intestinal mucosa (Park & Jeen, 2018). Etrolizumab has no apparent effect on lymphocyte migration to the central nervous system or non-mucosal tissues (Stefanich et al., 2011). It has not yet been determined if the dual action mechanism of etrolizumab enhances efficacy or improves tolerability.

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