Antibody-mediated stripping of CD4 from lymphocyte cell surface in patients with rheumatoid arthritis.
OBJECTIVE
Keliximab studies have provided evidence of the therapeutic potential of a non-depleting CD4 monoclonal antibody (mAb) in the treatment of rheumatoid arthritis (RA). Clenoliximab, an immunoglobulin G4 derivative of keliximab, has substantially reduced potential to deplete CD4 cells. In initial studies of clenoliximab, we investigated the hypothesis that the decrease in cell surface CD4 is the result of antibody-mediated stripping from the cell surface.


METHODS
Patients received single or multiple intravenous infusions of clenoliximab as follows: 0.05, 0.2, 1, 5, 10 or 15 mg/kg (n=3-5/group); 150 or 350 mg weekly x 4; or 350 or 700 mg every other week x 2 (n=12/group). Blood was collected for up to 16 weeks and pharmacokinetic and pharmacodynamic assessments were conducted using immunoassay and flow cytometry.


RESULTS
CD4 count was largely unaffected by clenoliximab treatment. Dose-dependent CD4 coating, down-modulation and stripping were observed. Maximal down-modulation persisted for an increasing period as dose increased, while soluble CD4-clenoliximab complexes accumulated. The amount of CD4 in soluble complex was as much as 20 times the amount of cell-associated CD4. For the same total dose, administration of higher doses, less frequently, resulted in pharmacodynamic profiles similar to those of lower doses administered more frequently.


CONCLUSIONS
Decrease in the density of CD4 on the T-lymphocyte surface is caused by antibody-mediated stripping.
Hepburn
T W
TW
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 709 Swedeland Road, PO Box 1539 (UW2720), King of Prussia, PA 19406, USA. timothy_w_hepburn@gsk.com
Totoritis
M C
MC
Davis
C B
CB
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D015153:Blotting, Western / Q000379:methods; D015704:CD4 Antigens / Q000032:analysis / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007118:Immunoassay; D007262:Infusions, Intravenous; D008297:Male
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; C121870:clenoliximab