Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

Vedolizumab is a humanized monoclonal antibody that targets the ␣ 4 ␤ 7 integrin exclusively, and modulates inflammation in the gastrointestinal tract without inducing the systemic immunosuppression that characterizes anti-␣ 4 chain monoclonal antibodies, such as natalizumab. This unique pharmacologic profile is largely attributable to four determinants. The first determinant is the restriction of the expression of the ␣ 4 ␤ 7 integrin to subsets of leukocytes. Vedolizumab does not bind to the majority of memory CD4 ϩ T lymphocytes (60%), neutrophils, and most monocytes. The highest level of vedolizumab binding is to a subset (ϳ25%) of human peripheral blood memory CD4 ϩ T lymphocytes that include gut-homing interleukin 17 T-helper lymphocytes. Vedolizumab also binds to eosinophils at high levels, and to naive T-helper lymphocytes, naive and memory cytotoxic T lymphocytes, B lymphocytes, natural killer cells, and basophils at lower levels; vedolizumab binds to memory CD4 ϩ T and B lymphocytes with subnanomolar potency (EC 50 ϭ 0.3-0.4 nM). The second determinant is binding specificity; vedolizumab binds exclusively to the ␣ 4 ␤ 7 integrin, and not to the ␣ 4 ␤ 1 and ␣ E ␤ 7 integrins. The third determinant is selective antagonism; vedolizumab selectively inhibits adhesion of ␣ 4 ␤ 7 -expressing cells to mucosal addressin cell adhesion molecule 1 (median inhibition concentration [IC 50 ] ϭ 0.02-0.06 g/ml) and fibronectin (IC 50 ϭ 0.02 g/ml), but not vascular cell adhesion molecule 1. The fourth determinant is the gastrointestinal-specific tropism of the ␣ 4 ␤ 7 integrin function. These pharmacologic properties of vedolizumab, in conjunction with the gastrointestinal tropism of ␣ 4 ␤ 7 integrin function, may ultimately confer an improved risk-to-benefit profile for patients with inflammatory bowel diseases.

Vedolizumab demonstrated dose-proportional pharmacokinetics and maximally saturated α(4) β(7) receptors over the tested dose range. Multiple dosing up to 10 mg/kg was well tolerated. Over the course of follow-up a greater proportion of patients treated with vedolizumab were in clinical response than those who were assigned to placebo.

Vedolizumab is a novel therapeutic monoclonal antibody recently approved for the treatment of moderately to severely active ulcerative colitis and Crohn's disease in adults who have failed at least one conventional therapy. An integrin antagonist, vedolizumab binds to the αβ integrin which is expressed specifically by a subset of gastrointestinal-homing T lymphocytes. The binding of αβ integrin to mucosal addressin cell adhesion molecule-1 expressed on the surface of mucosal endothelial cells is a crucial component of the gut-selective homing mechanism for lymphocytes.In contrast, other monoclonal antibodies approved for the treatment of inflammatory bowel diseases, such as tumour necrosis factor α antagonists and the integrin antagonist natalizumab, act systemically or on multiple targets to reduce inflammation.The unique gut selectivity of vedolizumab may contribute to the favourable benefit-risk profile observed in vedolizumab clinical trials. In this review, we summarise data from the preclinical development of vedolizumab and describe the current understanding of the mechanism of action as it relates to other biological therapies for inflammatory bowel disease.

Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4β7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations. At therapeutic concentrations, vedolizumab primarily undergoes linear elimination. From population pharmacokinetic modeling, the vedolizumab terminal elimination half-life (t ½ β) was estimated to be 25.5 days; linear clearance (CLL) was similar for patients with UC (0.159 L/day) and CD (0.155 L/day). Extreme low albumin concentrations and extreme high body weight values were potentially clinically important predictors of vedolizumab CLL. Other factors, including concomitant therapy use (methotrexate, azathioprine, mercaptopurine, or aminosalicylates) or prior tumor necrosis factor-α (TNF-α) antagonist use, had no clinically relevant effects on CLL. A positive exposure–efficacy relationship for clinical remission and clinical response was apparent for vedolizumab induction therapy in patients with UC or CD. On average, patients with higher albumin, lower fecal calprotectin (UC only), lower C-reactive protein (CD only), and no prior TNF-α antagonist use had a higher probability of remission. Off drug, 10% of patients with UC or CD were positive for anti-drug antibodies. This article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, exposure–efficacy relationships, and immunogenicity of vedolizumab.