COMPREHENSIVE PHARMACOKINETICS OF A HUMANIZED ANTIBODY AND ANALYSIS OF RESIDUAL ANTIIDIOTYPIC RESPONSES

A murine antibody to human tumour necrosis factor-alpha (TNF-alpha) (C B0010) was complementarity-determining region (CDR)-grafted using huma n IgG4 heavy and kappa light chain constant regions. In cynomolgus mon keys, the grafted antibody (CDP571) was eliminated with a half-life of 40-90 hr, two to three times longer than CB0010, and immunogenicity w as reduced by > 90%. Responses to the constant regions were almost ent irely eliminated and responses to the CDR loops (anti-idiotype) were l owered. CDP571 was given to 24 human volunteers in doses from 0.1 to 1 0.0 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, whe re by 5 weeks IgG predominated) and was against a conformational epito pe comprising heavy and light chain CDR loops. No antibodies were dete cted against the gamma(4)/kappa domains or frameworks. The response ha d little or no effect on CDP571 binding to TNF-alpha or on plasma clea rance.