PMID- 16869001
OWN - NLM
STAT- MEDLINE
DCOM- 20060919
LR  - 20220409
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 54
IP  - 8
DP  - 2006 Aug
TI  - A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic 
      protein 1) monoclonal antibody in patients with rheumatoid arthritis.
PG  - 2387-92
AB  - OBJECTIVE: Chemokines such as CCL2/monocyte chemotactic protein 1 (MCP-1) play a 
      key role in leukocyte migration and are potential targets in the treatment of 
      chronic inflammatory disorders. The objective of this study was to evaluate the 
      effects of human anti-CCL2/MCP-1 monoclonal antibody (ABN912) treatment in 
      patients with rheumatoid arthritis (RA). METHODS: Patients with active RA were 
      enrolled in a randomized, placebo-controlled, dose-escalation study of ABN912. 
      Infusions were administered on day 1 and day 15. In the dose-escalation phase, 4 
      cohorts of 8 patients each underwent serial arthroscopic biopsy of synovial 
      tissue. Immunohistochemistry and digital image analysis were used to characterize 
      biomarkers in synovial tissue. Laboratory evaluation included pharmacokinetic 
      analysis and immunotypic studies of peripheral blood mononuclear cells. To assess 
      the clinical effects of treatment with ABN912, an additional 21 patients were 
      treated with the highest dose tolerated. RESULTS: The total study population 
      comprised 45 patients: 33 patients received ABN912, and 12 patients received 
      placebo. ABN912 treatment was well tolerated. Unexpectedly, there was a 
      dose-related increase in ABN912-complexed total CCL2/MCP-1 levels in peripheral 
      blood, up to 2,000-fold. There was no detectable clinical benefit of ABN912 
      compared with placebo, nor did treatment with the study drug result in a 
      significant change in the levels of biomarkers in synovial tissue and peripheral 
      blood. CONCLUSION: ABN912 treatment did not result in clinical or 
      immunohistologic improvement and may have been associated with worsening of RA in 
      patients treated with the highest dose. The results might be related to the 
      greatly increased level of total CCL2/MCP-1 in serum that was observed following 
      treatment with ABN912. This observation may be relevant for a variety of 
      antibody-based therapies.
FAU - Haringman, Jasper J
AU  - Haringman JJ
AD  - Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
FAU - Gerlag, Danielle M
AU  - Gerlag DM
FAU - Smeets, Tom J M
AU  - Smeets TJ
FAU - Baeten, Dominique
AU  - Baeten D
FAU - van den Bosch, Filip
AU  - van den Bosch F
FAU - Bresnihan, Barry
AU  - Bresnihan B
FAU - Breedveld, Ferdinand C
AU  - Breedveld FC
FAU - Dinant, Huib J
AU  - Dinant HJ
FAU - Legay, Francois
AU  - Legay F
FAU - Gram, Hermann
AU  - Gram H
FAU - Loetscher, Pius
AU  - Loetscher P
FAU - Schmouder, Robert
AU  - Schmouder R
FAU - Woodworth, Thasia
AU  - Woodworth T
FAU - Tak, Paul P
AU  - Tak PP
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Biomarkers)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Immunologic Factors)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/pharmacokinetics/*therapeutic use
MH  - Antirheumatic Agents/pharmacokinetics/*therapeutic use
MH  - Arthritis, Rheumatoid/*drug therapy/metabolism/physiopathology
MH  - Biomarkers/metabolism
MH  - Biopsy
MH  - Chemokine CCL2/*immunology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Image Processing, Computer-Assisted
MH  - Immunohistochemistry
MH  - Immunologic Factors/pharmacokinetics/*therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Synovial Membrane/drug effects/metabolism/pathology
MH  - Treatment Outcome
EDAT- 2006/07/27 09:00
MHDA- 2006/09/20 09:00
CRDT- 2006/07/27 09:00
PHST- 2006/07/27 09:00 [pubmed]
PHST- 2006/09/20 09:00 [medline]
PHST- 2006/07/27 09:00 [entrez]
AID - 10.1002/art.21975 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2006 Aug;54(8):2387-92. doi: 10.1002/art.21975.