A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis.
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.


CONCLUSIONS
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.
Haringman
Jasper J
JJ
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Gerlag
Danielle M
DM
Smeets
Tom J M
TJ
Baeten
Dominique
D
van den Bosch
Filip
F
Bresnihan
Barry
B
Breedveld
Ferdinand C
FC
Dinant
Huib J
HJ
Legay
Francois
F
Gram
Hermann
H
Loetscher
Pius
P
Schmouder
Robert
R
Woodworth
Thasia
T
Tak
Paul P
PP
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D018932:Chemokine CCL2 / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D007155:Immunologic Factors