Anti–Interleukin-12 Antibody for Active Crohn's Disease

Mannon, Peter J.; Fuss, Ivan J.; Mayer, Lloyd; Elson, Charles O.; Sandborn, William J.; Present, Daniel H.; Dolin, Ben J.; Goodman, Nancy; Groden, Catherine; Hornung, Ronald L.; Quezado, Martha; Salfeld, Jochen; Veldman, Geertruida M.; Schwertschlag, Ullrich; Strober, Warren

doi:10.1056/nejmoa033402

Cited by 800 publications

(503 citation statements)

References 20 publications

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“…Furthermore, monoclonal antibodies targeting the p40 subunit of IL-12 and IL-23 were effective in treating patients with CD in preliminary studies. 42 We conclude that MST1 is the most likely IBD/PSC-associated gene defined by the rs3197999 association and rs3197999 itself is the genetic variant causing disease association. The gain of function caused by rs3197999 has at least two effects, which would be expected to promote local inflammation: (1) increased attraction of macrophages to chemotactic agents and (2) increased macrophage proliferation.…”

Section: Analysis Of Msp Clonesmentioning

confidence: 74%

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease

et al. 2012

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Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg 689 (MSP wt ) and Cys 689 (MSP mut )) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSP mut significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro-inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC.

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Section: Analysis Of Msp Clonesmentioning

confidence: 74%

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease

et al. 2012

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“…Subsequently, various antibodies against IL 12-IL 23 p40 and IL 23 p19 subunits were developed for clinical trials (such as ABT 874, ustekinumab, risanki zumab, LY 2525623, AMG139/MEDI2079 and guselku mab) [105][106][107] . Studies with ABT 874 and ustekinumab as p40 blockers demonstrated higher response rates in patients with Crohn's disease than placebo.…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

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512

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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“…Understanding the complex, pleiotropic action of IL-23R and the specific variants that give rise to each of these autoimmune traits will undoubtedly increase progress in our understanding of the molecular pathophysiology underlying these chronic autoinflammatory conditions. Moreover, coupled with the recent advances in autoinflammatory biology, the IL23R variants described herein may lead to a deeper understanding of molecular action of targeted therapeutics such as the efficacious IL-12/IL-23 monoclonal antibodies [44][45][46] and prove useful in autoinflammatory pharmacogenetics.…”

Section: Discussionmentioning

confidence: 98%

“…37,38 (2) (5) clinical studies have shown dramatic efficacy of IL-12p40 antibodies in reducing symptoms in a high percentage of psoriatic subjects 44,45 and those with active Crohn's disease. 46 These diverse studies have conspired to highlight the central function of the IL-23/T H -17 axis in mediating chronic inflammatory disease pathogenesis, downplaying the role of IL-12. Hence, full genetic description of both IL12B and IL23R, genes encoding for critical proteins in the IL-23/T H -17 response, is necessary to delineate specific variants predisposing and protective of disease and to further our understanding of the molecular pathobiology of autoinflammatory phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

García¹,

Chang²,

Brandon³

et al. 2008

Genes Immun

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Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (42800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR common ¼ 0.67; P comb ¼ 4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P Het ¼ 0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.

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Anti–Interleukin-12 Antibody for Active Crohn's Disease

Abstract: Treatment with a monoclonal antibody against interleukin-12 may induce clinical responses and remissions in patients with active Crohn's disease. This treatment is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.

Cited by 800 publications

References 20 publications

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease

Current and emerging therapeutic targets for IBD

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

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