Abstract
Chronic METH use and overdose cause severe medical complications. Treatment with an anti‐METH antibody antagonist could offer significant advantages by reducing drug concentrations in target organs. A smaller version of the IgG could offer opportunities for customized pharmacokinetics for a variety of treatment options (e.g. chronic vs. overdose). Toward this end, we have developed a novel single chain antibody (scFv) against METH. This scFv was engineered from anti‐METH mAb6H4 and was found to have similar immunochemical properties. The anti‐METH scFv (scFv6H4) was cloned and expressed in yeast, and purified to homogeneity as a mixture of dimer (25%) and monomer forms (75%). To test the efficacy of the scFv in vivo, we implanted rats with 3‐day osmotic pumps delivering METH at 3.2 mg/kg/day. After reaching steady state, a dose of scFv6H4 equimolar to the body burden of METH (32 mg/kg) was delivered in a bolus dose with a 3H‐scFv6H4 tracer. Serum pharmacokinetic analysis showed that the introduction of scFv6H4 caused an immediate 65‐fold change in the METH concentration, and a 12‐fold change in the area under the concentration‐time curve. The monomer form was cleared quickly (t½ = 5.5 min), but the dimer form showed a much longer half life (232 min). These data suggest that the dimer was primarily responsible for the in vivo binding of METH in rat serum.
Funded by NIH DA11560, DA14361, and DA018039.