Abstract
After 20 years of successful targeting of pro-inflammatory cytokines for the treatment of IBD, an alternative therapeutic strategy has emerged, based on several decades of advances in understanding the pathogenesis of IBD. The targeting of molecules involved in leukocyte traffic has recently become a safe and effective alternative. With 2 currently approved drugs (ie, natalizumab, vedolizumab) and several others in phase 3 trials (eg, etrolizumab, ozanimod, anti-MAdCAM-1), the blockade of trafficking molecules has firmly emerged as a new therapeutic era for IBD. We discuss the targets that have been explored in clinical trials: chemokines and its receptors (eg, IP10, CCR9), integrins (eg, natalizumab, AJM300, vedolizumab, and etrolizumab), and its endothelial ligands (MAdCAM-1, ICAM-1). We also discuss a distinct strategy that interferes with lymphocyte recirculation by blocking lymphocyte egress from lymph nodes (small molecule sphingosine-phosphate receptor [S1PR] agonists: fingolimod, ozanimod, etrasimod, amiselimod). Strategies on the horizon include additional small molecules, allosteric inhibitors that specifically bind to the active integrin form and nanovectors that allow for the use of RNA interference in the quest to modulate pro-inflammatory leukocyte trafficking in IBD.
Original language | English (US) |
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Pages (from-to) | 270-282 |
Number of pages | 13 |
Journal | Inflammatory bowel diseases |
Volume | 25 |
Issue number | 2 |
DOIs | |
State | Published - Jan 10 2019 |
Funding
From the *Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA; †VA San Diego Healthcare System, San Diego, CA, USA; ‡Hospital San Borja Arriarán, Santiago, Chile; §Universidad Católica de Chile, Santiago, Chile; ¶GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece Conflicts of interest: TPJ, CJT, JDB, TK, GB, DP, and JRN have no disclosures or potential conflicts of interest. PSD has received research support, travel support, and honorarium from Takeda, research support from Pfizer, and support from a training grant through the National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007202). BSB has received research support from Takeda, and support from CCFA career development award, and UCSD KL2 (1KL2TR001444). WJS has received personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, personal fees from Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, University of Western Ontario (owner of Robarts Clinical Trials), grants and personal fees from Prometheus Laboratories, AbbVie, Gilead Sciences, Boehringer Ingelheim, Amgen, Takeda, Atlantic Pharmaceuticals, Bristol-Myers Squibb Genentech, GlaxoSmithKline, Pfizer, Nutrition Science Partners, Receptos, Amgen, grants, personal fees, and nonfinancial support from Janssen, grants from Broad Foundation, American College of Gastroenterology, and Exact Sciences. DRP has been a speaker bureau ABBVIE. Supported by: This work is funded by grants from the National Institutes of Health (DK108670) and VA Merit grant BLRD-I01 BX003436.
Keywords
- Crohn's
- MAdCAM-1
- colitis
- gut homing
- sphingosine-1-phosphate
- ulcerative colitis
- α4β7 Integrin
ASJC Scopus subject areas
- Gastroenterology
- Immunology and Allergy