Treatment of rheumatoid arthritis with a chimeric CD4 monoclonal antibody (cM-T412): immunopharmacological aspects and mechanisms of action.
To investigate the mechanisms of action underlying the therapeutic effect of CD4 monoclonal antibody therapy in rheumatoid arthritis (RA), clinical responses were compared with several laboratory parameters. Twenty-nine RA patients received either 10 mg, 50 mg or 100 mg of cM-T412, a chimeric CD4 MoAb, for 7 days. The CD4 binding sites on circulating lymphocytes were saturated directly with cM-T412 and serum levels of unbound cM-T412 accumulated towards day 7 of treatment only in the patients treated with 50 and 100 mg. The treatment induced an instant and prolonged depression of the number of circulating CD4+ cells, similar for all dosages. Clinical improvement was observed predominantly in the patients treated with 50 or 100 mg cM-T412 daily and did not correlate with changes in counts of circulating leucocyte subsets nor with changes in serum cytokine levels. An antiglobulin response against cM-T412 developed in a majority of the patients. Side effects on the first day of treatment were correlated with an increase of serum IL-6 levels. This study indicates that a favourable clinical effect of cM-T412 administration was associated with the presence of unbound cM-T412 in the circulation of RA patients. Therefore penetration of unbound cM-T412 into the site of inflammation might determine the therapeutic effect in RA.
van der Lubbe
P A
PA
Department of Rheumatology, University Hospital Leiden, The Netherlands.
Reiter
C
C
Miltenburg
A M
AM
Krüger
K
K
de Ruyter
A N
AN
Rieber
E P
EP
Bijl
J A
JA
Riethmüller
G
G
Breedveld
F C
FC
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D015704:CD4 Antigens / Q000276:immunology*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000097:blood; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma