Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses.
A murine antibody to human tumour necrosis factor-alpha (TNF-alpha) (CB0010) was complementarity-determining region (CDR)-grafted using human IgG4 heavy and kappa light chain constant regions. In cynomolgus monkeys, the grafted antibody (CDP571) was eliminated with a half-life of 40-90 hr, two to three times longer than CB0010, and immunogenicity was reduced by > 90%. Responses to the constant regions were almost entirely eliminated and responses to the CDR loop (anti-idiotype) were lowered. CDP571 was given to 24 human volunteers in doses from 0.1 to 10.0 mg/kg. It was well tolerated, with a half-life of approximately 13 days. Anti-CDP571 antibodies were low or undetectable at higher doses. At lower doses, anti-CDP571 peaked at 2 weeks and then declined. The response was primarily IgM (in contrast to the cynomolgus monkey, where by 5 weeks IgG predominated) and was against a conformational epitope comprising heavy and light chain CDR loops. No antibodies were detected against the gamma 4/kappa domains or frameworks. The response had little or no effect on CDP571 binding to TNF-alpha or on plasma clearance.
Stephens
S
S
Celltech Therapeutics Ltd, Slough, Berkshire, UK.
Emtage
S
S
Vetterlein
O
O
Chaplin
L
L
Bebbington
C
C
Nesbitt
A
A
Sopwith
M
M
Athwal
D
D
Novak
C
C
Bodmer
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D000939:Epitopes / Q000276:immunology; D006207:Half-Life; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D007147:Immunoglobulin Light Chains / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D008969:Molecular Sequence Data; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007130:Immunoglobulin Idiotypes; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D014409:Tumor Necrosis Factor-alpha