PMID- 26170138
OWN - NLM
STAT- MEDLINE
DCOM- 20160407
LR  - 20220129
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 149
IP  - 6
DP  - 2015 Nov
TI  - Proteolytic cleavage and loss of function of biologic agents that neutralize 
      tumor necrosis factor in the mucosa of patients with inflammatory bowel disease.
PG  - 1564-1574.e3
LID - S0016-5085(15)00937-3 [pii]
LID - 10.1053/j.gastro.2015.07.002 [doi]
AB  - BACKGROUND & AIMS: Many patients with inflammatory bowel disease (IBD) fail to 
      respond to anti-tumor necrosis factor (TNF) agents such as infliximab and 
      adalimumab, and etanercept is not effective for treatment of Crohn's disease. 
      Activated matrix metalloproteinase 3 (MMP3) and MMP12, which are increased in 
      inflamed mucosa of patients with IBD, have a wide range of substrates, including 
      IgG1. TNF-neutralizing agents act in inflamed tissues; we investigated the 
      effects of MMP3, MMP12, and mucosal proteins from IBD patients on these drugs. 
      METHODS: Biopsy specimens from inflamed colon of 8 patients with Crohn's disease 
      and 8 patients with ulcerative colitis, and from normal colon of 8 healthy 
      individuals (controls), were analyzed histologically, or homogenized and proteins 
      were extracted. We also analyzed sera from 29 patients with active Crohn's 
      disease and 33 patients with active ulcerative colitis who were candidates to 
      receive infliximab treatment. Infliximab, adalimumab, and etanercept were 
      incubated with mucosal homogenates from patients with IBD or activated 
      recombinant human MMP3 or MMP12 and analyzed on immunoblots or in luciferase 
      reporter assays designed to measure TNF activity. IgG cleaved by MMP3 or MMP12 
      and antihinge autoantibodies against neo-epitopes on cleaved IgG were measured in 
      sera from IBD patients who subsequently responded (clinical remission and 
      complete mucosal healing) or did not respond to infliximab. RESULTS: MMP3 and 
      MMP12 cleaved infliximab, adalimumab, and etanercept, releasing a 32-kilodalton 
      Fc monomer. After MMP degradation, infliximab and adalimumab functioned as 
      F(ab')2 fragments, whereas cleaved etanercept lost its ability to neutralize TNF. 
      Proteins from the mucosa of patients with IBD reduced the integrity and function 
      of infliximab, adalimumab, and etanercept. TNF-neutralizing function was restored 
      after incubation of the drugs with MMP inhibitors. Serum levels of endogenous IgG 
      cleaved by MMP3 and MMP12, and antihinge autoantibodies against neo-epitopes of 
      cleaved IgG, were higher in patients who did not respond to treatment vs 
      responders. CONCLUSIONS: Proteolytic degradation may contribute to the 
      nonresponsiveness of patients with IBD to anti-TNF agents.
CI  - Copyright (c) 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Biancheri, Paolo
AU  - Biancheri P
AD  - Centre for Immunobiology, Blizard Institute, Barts and The London School of 
      Medicine and Dentistry, London, United Kingdom; Department of Internal Medicine, 
      S. Matteo Hospital, University of Pavia, Pavia, Italy.
FAU - Brezski, Randall J
AU  - Brezski RJ
AD  - Biologics Research, Janssen Research and Development, LLC, Spring House, 
      Pennsylvania.
FAU - Di Sabatino, Antonio
AU  - Di Sabatino A
AD  - Department of Internal Medicine, S. Matteo Hospital, University of Pavia, Pavia, 
      Italy.
FAU - Greenplate, Allison R
AU  - Greenplate AR
AD  - Biologics Research, Janssen Research and Development, LLC, Spring House, 
      Pennsylvania.
FAU - Soring, Keri L
AU  - Soring KL
AD  - Biologics Research, Janssen Research and Development, LLC, Spring House, 
      Pennsylvania.
FAU - Corazza, Gino R
AU  - Corazza GR
AD  - Department of Internal Medicine, S. Matteo Hospital, University of Pavia, Pavia, 
      Italy.
FAU - Kok, Klaartje B
AU  - Kok KB
AD  - Centre for Immunobiology, Blizard Institute, Barts and The London School of 
      Medicine and Dentistry, London, United Kingdom.
FAU - Rovedatti, Laura
AU  - Rovedatti L
AD  - Department of Internal Medicine, S. Matteo Hospital, University of Pavia, Pavia, 
      Italy.
FAU - Vossenkamper, Anna
AU  - Vossenkamper A
AD  - Centre for Immunobiology, Blizard Institute, Barts and The London School of 
      Medicine and Dentistry, London, United Kingdom.
FAU - Ahmad, Nadja
AU  - Ahmad N
AD  - Centre for Immunobiology, Blizard Institute, Barts and The London School of 
      Medicine and Dentistry, London, United Kingdom.
FAU - Snoek, Susanne A
AU  - Snoek SA
AD  - Centre for Immunobiology, Blizard Institute, Barts and The London School of 
      Medicine and Dentistry, London, United Kingdom.
FAU - Vermeire, Severine
AU  - Vermeire S
AD  - Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, 
      Belgium.
FAU - Rutgeerts, Paul
AU  - Rutgeerts P
AD  - Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, 
      Belgium.
FAU - Jordan, Robert E
AU  - Jordan RE
AD  - Biologics Research, Janssen Research and Development, LLC, Spring House, 
      Pennsylvania.
FAU - MacDonald, Thomas T
AU  - MacDonald TT
AD  - Centre for Immunobiology, Blizard Institute, Barts and The London School of 
      Medicine and Dentistry, London, United Kingdom. Electronic address: 
      t.t.macdonald@qmul.ac.uk.
LA  - eng
GR  - G0800746/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150711
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Biological Factors)
RN  - 0 (Epitopes)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - B72HH48FLU (Infliximab)
RN  - EC 3.4.24.17 (MMP3 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.65 (MMP12 protein, human)
RN  - EC 3.4.24.65 (Matrix Metalloproteinase 12)
RN  - FYS6T7F842 (Adalimumab)
RN  - OP401G7OJC (Etanercept)
SB  - IM
MH  - Adalimumab/metabolism
MH  - Antibodies, Monoclonal, Humanized/metabolism
MH  - Biological Factors/*metabolism/pharmacology
MH  - Biopsy
MH  - Case-Control Studies
MH  - Colitis, Ulcerative/drug therapy/immunology/metabolism
MH  - Colon/immunology/metabolism/pathology
MH  - Crohn Disease/drug therapy/immunology/metabolism
MH  - Epitopes/metabolism
MH  - Etanercept/metabolism
MH  - Female
MH  - Humans
MH  - Immunoblotting/methods
MH  - Immunoglobulin G/*metabolism
MH  - Inflammatory Bowel Diseases/drug therapy/immunology/*metabolism
MH  - Infliximab/metabolism
MH  - Intestinal Mucosa/drug effects/immunology/*metabolism
MH  - Male
MH  - Matrix Metalloproteinase 12/metabolism
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Middle Aged
MH  - Proteolysis/*drug effects
MH  - Tumor Necrosis Factor-alpha/*metabolism
OTO - NOTNLM
OT  - CD
OT  - Inflammation
OT  - Therapy
OT  - UC
EDAT- 2015/07/15 06:00
MHDA- 2016/04/08 06:00
CRDT- 2015/07/15 06:00
PHST- 2015/02/13 00:00 [received]
PHST- 2015/07/01 00:00 [revised]
PHST- 2015/07/02 00:00 [accepted]
PHST- 2015/07/15 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2016/04/08 06:00 [medline]
AID - S0016-5085(15)00937-3 [pii]
AID - 10.1053/j.gastro.2015.07.002 [doi]
PST - ppublish
SO  - Gastroenterology. 2015 Nov;149(6):1564-1574.e3. doi: 
      10.1053/j.gastro.2015.07.002. Epub 2015 Jul 11.