title: Anti-MMP-9 Antibody: A Promising Therapeutic Strategy for Treatment of Inflammatory Bowel Disease Complications with Fibrosis.
abstract: Despite medical treatments or surgical options, more than one-third of patients with Crohn's disease suffer from recurring fistulae. Matrix metalloprotease 9 (MMP-9), a type IV collagenase that cleaves components of the extracellular matrix leading to tissue remodeling, is upregulated in crypt abscesses and around fistulae suggesting an important role for this enzyme in fistula formation. Our aims were (1) to correlate serum levels of MMP-9 degradation products in patients with CD with the presence of fistulae and (2) to investigate the impact of selective MMP-9 inhibition in a mouse model of intestinal fibrosis.
  
  
  
  Serum MMP-9 degradation products were quantified in subjects affected with nonstricturing and nonpenetrating CD (n = 50), stricturing CD (n = 41), penetrating CD (n = 22), CD with perianal fistula (n = 29), and healthy controls (n = 10). Therapeutic efficacy of anti-MMP-9 monoclonal antibodies was assessed in a heterotopic xenograft model of intestinal fibrosis.
  
  
  
  C3M, an MMP-9 degradation product of collagen III, demonstrated the highest serum levels in patients with penetrating CD and differentiated penetrating CD from other CD subgroups and healthy controls, P = 0.0005. Anti-MMP-9 treatments reduced collagen deposition and hydroxyproline content in day-14 intestinal grafts indicating reduced fibrosis.
  
  
  
  The serologic biomarker C3M can discriminate penetrating CD from other CD subgroups and could serve as marker for the development of penetrating CD. Anti-MMP-9 antibody has therapeutic potential to prevent intestinal fibrosis in CD complications.
authors.affiliation: *Calypso Biotech SA, Plan-les-Ouates, Geneva, Switzerland; and †Clinic of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Goffin
authors.forename: Stefania
authors.initials: S
authors.lastname: Fagagnini
authors.forename: Alain
authors.initials: A
authors.lastname: Vicari
authors.forename: Céline
authors.initials: C
authors.lastname: Mamie
authors.forename: Hassan
authors.initials: H
authors.lastname: Melhem
authors.forename: Bruce
authors.initials: B
authors.lastname: Weder
authors.forename: Christian
authors.initials: C
authors.lastname: Lutz
authors.forename: Silvia
authors.initials: S
authors.lastname: Lang
authors.forename: Michael
authors.initials: M
authors.lastname: Scharl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.forename: Yolande
authors.initials: Y
authors.lastname: Chvatchko
authors.forename: Martin
authors.initials: M
authors.lastname: Hausmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D024061:Collagen Type III / Q000097:blood; D003251:Constriction, Pathologic / Q000473:pathology; D003424:Crohn Disease / Q000150:complications* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000188:drug therapy; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011446:Prospective Studies; D012003:Rectal Fistula / Q000473:pathology*; D013557:Switzerland; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D024061:Collagen Type III; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9