title: Treatment of rheumatoid arthritis with a chimeric CD4 monoclonal antibody (cM-T412): immunopharmacological aspects and mechanisms of action.
abstract: 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.
authors.affiliation: Department of Rheumatology, University Hospital Leiden, The Netherlands.
authors.forename: P A
authors.initials: PA
authors.lastname: van der Lubbe
authors.forename: C
authors.initials: C
authors.lastname: Reiter
authors.forename: A M
authors.initials: AM
authors.lastname: Miltenburg
authors.forename: K
authors.initials: K
authors.lastname: Krüger
authors.forename: A N
authors.initials: AN
authors.lastname: de Ruyter
authors.forename: E P
authors.initials: EP
authors.lastname: Rieber
authors.forename: J A
authors.initials: JA
authors.lastname: Bijl
authors.forename: G
authors.initials: G
authors.lastname: Riethmüller
authors.forename: F C
authors.initials: FC
authors.lastname: Breedveld
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma