Received for publication June 23, 2005.
Revised February 22, 2006.
Accepted for publication February 22, 2006.

Anti-PCP Monoclonal Antibody Binding Capacity is not the Only Determinant of Effectiveness, Disproving the Concept that Antibody Capacity is easily Surmounted

Abstract

The effectiveness of a high affinity monoclonal antibody (mAb) antagonist against chronic phencyclidine (PCP) use has been demonstrated in rats. In this study, we tested the hypothesis that intravenous doses of PCP in excess of the binding capacity of an anti-PCP mAb cannot easily surmount the beneficial effects of the mAb, even in the presence of a high body burden of the drug. One day after steady-state PCP concentrations were achieved in male rats by continuous s.c. infusion (18 mg/kg/d), a single i.v. dose of saline or the anti-PCP mAb (K_D = 1.3 nM; at one-third the molar dose of the PCP body burden) treatment was administered. In an attempt to further surmount the effects of the mAb, rats were challenged with a single 1.0 mg/kg i.v. bolus PCP dose (along with a [³H]-PCP tracer) three days after the mAb or saline treatment. Total (i.v. bolus + s.c. infusion) PCP concentrations were measured in serum, brain, and testis by RIA before and after the challenge, and [³H]-PCP concentrations were measured by liquid scintillation spectrometry. The anti-PCP mAb protected against adverse health effects, significantly increased the serum total and bolus PCP concentrations (p < 0.05), and significantly decreased brain total and bolus PCP concentrations (p < 0.05) after the i.v. challenge. These results showed the antibody can counteract extreme and potentially fatal PCP challenges and disproved the hypothesis that attempts to surmount the effects of the antibody with extremely high PCP doses would have immediate adverse health effects.

Key words: antibodies, blood-CNS transport, CNS pharmacokinetics, drug distribution, monoclonal antibody

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