Biological Therapies for Inflammatory Bowel Diseases

doi:10.1053/j.gastro.2009.02.001

Gastroenterology

Volume 136, Issue 4, April 2009, Pages 1182-1197

https://doi.org/10.1053/j.gastro.2009.02.001 Get rights and content

Crohn's disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs). Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified and biological therapies that target key molecules have been designed. Infliximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody to tumor necrosis factor, dramatically improved treatment of patients with Crohn's disease and ulcerative colitis. Infliximab has achieved treatment goals such as mucosal healing and decreasing the need for hospitalizations and surgeries. Although several anti–tumor necrosis factor therapies have been developed, there is a great need for drugs that target other pathways. Natalizumab, an antibody against the integrin α4 subunit, blocks leukocyte adhesion and has reached the clinic in the United States but has not been approved in the European Union; other anti-adhesion molecules currently are under development. Additional approaches under clinical development include therapeutics that target cytokines, such as interleukin-12/23, as well as those that block T-cell signaling. The use of recombinant human proteins, including immunoregulatory cytokines and growth factors, has not been successful so far. The efficacy of each therapy must be shown in carefully designed clinical programs. Biological therapies carry a definite safety risk, so their place in treatment algorithms must be defined carefully.

Section snippets

Anti–Tumor Necrosis Factor Strategies

Tumor necrosis factor (TNF) (also known as TNF-α) is a proinflammatory cytokine that induces cell proliferation and differentiation; its signaling pathways regulate gene expression and up-regulate adhesion molecules. TNF promotes the inflammatory response in various diseases including rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and ulcerative colitis, and psoriasis. Symptoms of these disorders improve upon therapy with TNF inhibitors. Three anti-TNF molecules are used

Anti–Interleukin-12/Interleukin-23 p40 and Anti–IFN-γ Antibodies

Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of Crohn's disease. Naive CD4⁺ T cells differentiate into several functional lineages characterized mainly by their dependent cytokines. CD4+ T-cell phenotypes include T-helper 1 (Th1), Th2, Th17, and CD4+ T-regulatory cells. Their differentiation and survival depends on the relative abundance of key regulatory cytokines produced mainly by macrophages and dendritic cells. In the presence of IL-12, a heterodimer of p40 and

Recombinant Human Cytokines

Systemic administration of both recombinant human IL-10 and recombinant human IL-11 have been investigated as treatments for Crohn's disease and ulcerative colitis but both programs have been discontinued because of a lack of efficacy in controlled trials. Animal studies showed that local administration of IL-10 to the colon via genetically engineered Lactococcus lactis bacteria that are administered orally allows for the achievement of high colonic mucosal concentrations of IL-10, resulting

Small Molecules That Target Immune Pathways

Small molecules already are used widely in the treatment of IBD. Examples are mesalamine, azathioprine/6-mercaptopurine, and methotrexate. The mechanism of action of these drugs is poorly understood. Recently, a large number of small molecules that target specific immune pathways were studied for the treatment of IBD. There are a number of important problems associated with the use of these drugs. In contrast with monoclonal antibodies, small molecules rarely completely are specific for one

The Future of Biological Therapies

Anti-TNF agents allow a more profound control of the bowel inflammation that results in mucosal healing, compared with conventional therapies, which could translate into improvement of long-term outcome of the disease course. There already are preliminary data showing that infliximab therapy decreases the need for hospitalizations and surgery in patients with luminal or fistulizing Crohn's disease17, 18; similar data are available for adalimumab.⁷⁴ This has led to the concept that the

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Biologic or small-molecule therapies are highly effective for the treatment of inflammatory bowel disease (IBD), and approval by the FDA has significantly increased both their clinical use and the development of novel regimens. However, the identification and management of their associated toxicities poses challenges for clinicians and researchers.
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This study offers a comprehensive summary of toxic side effects of IBD treatments and a useful reference for both patients and clinicians.
Solidification and oral delivery of biologics to the colon- A review
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The oral delivery of biologics such as therapeutic proteins, peptides and oligonucleotides for the treatment of colon related diseases has been the focus of increasing attention over the last years. However, the major disadvantage of these macromolecules is their degradation propensity in liquid state which can lead to the undesirable and complete loss of function. Therefore, to increase the stability of the biologic and reduce their degradation propensity, formulation techniques such as solidification can be performed to obtain a stable solid dosage form for oral administration. Due to their fragility, stress exerted on the biologic during solidification has to be reduced with the incorporation of stabilizing excipients into the formulation. This review focuses on the state-of-the-art solidification techniques required to obtain a solid dosage form for the oral delivery of biologics to the colon and the use of suitable excipients for adequate stabilization upon solidification. The solidifying processes discussed within this review are spray drying, freeze drying, bead coating and also other techniques such as spray freeze drying, electro spraying, vacuum- and supercritical fluid drying. Further, the colon as site of absorption in both healthy and diseased state is critically reviewed and possible oral delivery systems for biologics are discussed.
Armillariella tabescens methanol extract ameliorates ulcerative colitis via inhibiting TLR4/NF-κB and NLRP3 activation and mediating intestinal barrier integrity
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Armillariella tabescens is a traditional Chinese medicinal and edible fungus which holds importance for treatment of gastrointestinal disorders. This study was aimed to evaluate the effect of methanol extract of A. tabescens (AME) in dextran sulfate sodium (DSS) induced ulcerative colitis (UC). The results showed that AME significantly attenuated UC symptoms, suppressed the activity of myeloperoxidase (MPO), decreased the levels of LPS, TNF-α, IL-1β, IL-18, and increased the level of IL-10 in serum. Besides, AME could improve the expression of tight junction proteins ZO-1, occludin and claudin-1. Moreover, AME inhibited the activation of TLR4/NF-κB and NLRP3 signaling pathways in colon tissue. In addition, eight compounds were identification in AME by high performance liquid chromatography (HPLC)-high resolution mass spectroscopy (HRMS). Therefore, this study indicated that AME was potential to be further developed into a suitable functional food additive or promising therapeutic agent for UC treatment.
Gα12 and endoplasmic reticulum stress-mediated pyroptosis in a single cycle of dextran sulfate-induced mouse colitis
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Active nanoparticle targeting of MUC5AC ameliorates therapeutic outcome in experimental colitis
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: Conflicts of interest The authors disclose no conflicts.

: Funding Professor Rutgeerts consults, has received research support, and has lectured for Centocor, Schering Plough, Union Chimique Belge Brussels Belgium, and Abbott; and consulted for Elan-Biogen, PDL, Avidia, Bristol Myers Squibb, Millenium Pharmaceuticals, Genetech, Novimmune, and Cheocentrix. Dr Van Assche has received research support from Abbott; honoraria or speaking fees from UCB, Schering-Plough, and Abbott; and consulted for Novartis, Centocor, and Schering-Plough. Dr Vermeire has received research support from UCB (Chair); and honoraria/speaking fees from UCB, Abbott, and Schering-Plough.

View full text

Reviews in Basic and Clinical GastroenterologyBiological Therapies for Inflammatory Bowel Diseases

Section snippets

Anti–Tumor Necrosis Factor Strategies

Anti–Interleukin-12/Interleukin-23 p40 and Anti–IFN-γ Antibodies

Recombinant Human Cytokines

Small Molecules That Target Immune Pathways

The Future of Biological Therapies

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Dig Liver Dis

Clin Gastroenterol Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Lancet

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Am J Gastroenterol

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Frequency of glucocorticoid resistance and dependency in Crohn's disease

Gut

Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis

Gut

Methotrexate for the treatment of Crohn's disease

N Engl J Med

A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease

N Engl J Med

Cyclosporine in severe ulcerative colitis refractory to steroid therapy

N Engl J Med

Reviews in Basic and Clinical Gastroenterology
Biological Therapies for Inflammatory Bowel Diseases