Infliximab-Tumor Necrosis Factor Complexes Elicit Formation of Anti-Drug Antibodies.
Animals
Antibodies
/ blood
Case-Control Studies
Endocytosis
Female
Humans
Immunity, Innate
Immunoglobulin Fab Fragments
/ administration & dosage
Inflammatory Bowel Diseases
/ blood
Infliximab
/ administration & dosage
Injections, Intravenous
Interleukin-1beta
/ immunology
Intestines
/ immunology
Leukocytes, Mononuclear
/ immunology
Macrophages
/ immunology
Mice, Inbred C57BL
THP-1 Cells
Tumor Necrosis Factor Inhibitors
/ administration & dosage
Tumor Necrosis Factor-alpha
/ administration & dosage
Biologic Therapy
IBD Treatment Complication
Side Effect
mAb
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
18
04
2019
revised:
25
07
2019
accepted:
01
08
2019
pubmed:
12
8
2019
medline:
20
12
2019
entrez:
12
8
2019
Statut:
ppublish
Résumé
Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation. C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab') Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1β (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone. In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.
Sections du résumé
BACKGROUND & AIMS
Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation.
METHODS
C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab')
RESULTS
Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1β (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone.
CONCLUSIONS
In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.
Identifiants
pubmed: 31401142
pii: S0016-5085(19)41201-8
doi: 10.1053/j.gastro.2019.08.009
pii:
doi:
Substances chimiques
Antibodies
0
IL1B protein, human
0
Immunoglobulin Fab Fragments
0
Interleukin-1beta
0
TNF protein, human
0
Tumor Necrosis Factor Inhibitors
0
Tumor Necrosis Factor-alpha
0
Infliximab
B72HH48FLU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1338-1351.e8Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.