Treatment of Ulcerative Colitis with a Humanized Antibody to the α<sub>4</sub>β<sub>7</sub>Integrin

Feagan, Brian G.; Greenberg, Gordon R.; Wild, Gary; Fedorak, Richard N.; Paré, Pierre; McDonald, John W.D.; Dubé, Rejean; Cohen, Albert; Steinhart, A. Hillary; Landau, Steven B.; Aguzzi, Rasha; Fox, Irving H.; Vandervoort, Margaret K.

doi:10.1056/nejmoa042982

Cited by 661 publications

(501 citation statements)

References 29 publications

Supporting

Mentioning

477

Contrasting

Unclassified

Order By: Relevance

“…24 Targeting a4b7 integrin will likely not put patients at risk for this serious complication, as immunologic protection of the central nervous system should remain intact given the specificity of a4b7 integrin for intestinal tissue. A specific MoAb (vedolizumab) has already been developed against a4b7 integrin and is being used in ongoing clinical trials for the treatment of inflammatory bowel disease, 25 and we plan to test this approach for the treatment of intestinal GVHD.…”

Section: Discussionmentioning

confidence: 99%

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

McDonough

Chen

et al. 2012

Bone Marrow Transplant

View full text Add to dashboard Cite

Acute intestinal GVHD remains a major source of morbidity after allogeneic hematopoietic cell transplantation (HCT). a4b7 integrin is a cell surface molecule that mediates lymphocyte trafficking to intestinal tissue. In this analysis, peripheral blood was collected at the time of presentation of symptoms of acute GVHD and before any treatment. In all, 45 samples were collected and divided into three groups on the basis of subsequent evaluation: intestinal GVHD (n ¼ 15), skin GVHD (n ¼ 20) and no GVHD (n ¼ 10). Two patients developed intestinal GVHD after DLI. The no-GVHD group comprised 10 patients who presented with suspicious symptoms, but evaluation yielded other etiologies. Analysis by flow cytometry showed that intestinal GVHD patients had a significantly higher percentage of a4b7 integrin-expressing memory CD8 þ T cells (median 7.69%; lower and upper quartiles, 1.06% and 11.64%, respectively) compared with patients with skin GVHD (1.26%; 0.57% and 2.49%) and no GVHD (0.96%; 0.44% and 1.85%), P ¼ 0.03. No differences were found in a4b7 expression in any CD4 þ T-cell subsets or naive CD8 þ T cells. This study adds to the evidence that a4b7 integrin is involved in lymphocyte trafficking in acute intestinal GVHD.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

McDonough

Chen

et al. 2012

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…The easiest approach to developing a selective antagonist is with complex-specific monoclonal antibodies. A complex-specific α 4 β 7 antibody MLN-02 has shown efficacy in a Phase II trial for ulcerative colitis 157 and specific small-molecule antagonists for α 4 β 7 have been discovered 156 .…”

Section: Role Of Integrin Cytoplasmic Tailsmentioning

confidence: 99%

Integrins as therapeutic targets: lessons and opportunities

Cox

Brennan

Moran

2010

Nat Rev Drug Discov

413

350

View full text Add to dashboard Cite

“…[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] All 20 studies reported a mean age. The composite mean age was 39.2 years with a mean range of 36.2 to 44 years.…”

Section: Biological Agentsmentioning

confidence: 99%

Treatment of Ulcerative Colitis in the Elderly: A Systematic Review

Baggenstos

Hanson²,

Shaukat

2013

Clinical Medicine Insights: Geriatrics

View full text Add to dashboard Cite

Ulcerative colitis (UC) is increasingly recognized as a disease affecting the elderly. Approximately 10%-30% of the UC population is over the age of 60 years. Additionally, younger patients with UC are aging and thus comprise a second group of elderly IBD patients. To date, there have been no clinical trials that have evaluated treatment efficacy of UC in the elderly population. The aim of our study was to conduct a systematic review of all randomized controlled trials (RCTs) addressing treatment outcome in UC; we also sought to identify the elderly population, defined as age 60 years or older, represented in these studies, to see if pooled data would lead to meaningful conclusions regarding treatment efficacy and safety profile in the elderly. A search of the MEDLINE database via PubMed and the EMBASE database via Scopus was performed to identify all RCTs evaluating medical therapy for UC in humans, published within the English language through September 2012. Studies were grouped into three categories: biological agent (BA) therapy; immunosuppressant (IS) therapy; and 5-aminosalicylic acid (5-ASA) therapy. To estimate the number of elderly patients in each study, mean age plus 1 and 2 standard deviations (SD) was calculated to find the closest approximation to age 60. Of 876 studies, 112 RCTs were included in the final analysis-20 studies for BA, 20 for IS, and 72 for 5-ASA agents. While nearly all studies reported either a mean or median age, only 38% additionally reported the SD and age range. The mean composite age was 39.2 years for the BA studies, 38.5 years for the IS studies, and 42.8 years for the 5-ASA studies, consistent with a young middle-aged patient. We estimated that no more than 16% of patients per study would have qualified as elderly, and in most cases a much smaller percentage (,8%). Additionally, there were no BA or IS RCTs that reported results by age subgroup analysis. Four studies in the 5-ASA group report age-specific analyses and showed no difference in treatment efficacy by age. None of the 112 RCTs reported age sub-analyses of safety, tolerability, adverse events, or withdrawal rates. There is insufficient evidence to evaluate efficacy of treatment and adverse events from treatment for UC in the elderly. With the rising number of elderly patients with UC, there is a need for more clinical trials that specifically address UC treatment in this unique population.

show abstract

Treatment of Ulcerative Colitis with a Humanized Antibody to the α₄β₇Integrin

Abstract: In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.

Cited by 661 publications

References 29 publications

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

Integrins as therapeutic targets: lessons and opportunities

Treatment of Ulcerative Colitis in the Elderly: A Systematic Review

Contact Info

Product

Resources

About

Treatment of Ulcerative Colitis with a Humanized Antibody to the α4β7Integrin

Abstract: In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.

Cited by 661 publications

References 29 publications

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

Integrins as therapeutic targets: lessons and opportunities

Treatment of Ulcerative Colitis in the Elderly: A Systematic Review

Contact Info

Product

Resources

About

Treatment of Ulcerative Colitis with a Humanized Antibody to the α₄β₇Integrin