Antibody buffering of a ligand in vivo.

Abstract

Clearance is the practical limit on drug action. Here we propose a means of slowing clearance, thereby extending drug lifetime in vivo by "antibody buffering." In this process, a drug and an anti-drug antibody are coadministered. Most of the drug is bound to the antibody, preventing the drug from acting, but also preventing its elimination. A dynamic free drug pool is established by reversible dissociation from the antibody. The free drug is active and can be eliminated, but the free pool is constantly replenished by reequilibration from the antibody-drug complex, giving a long effective lifetime. Here we explore antibody buffering experimentally by using a model compound, 2-phenyloxazol-5-one-gamma-aminobutyrate (Ox), as a drug proxy. We show that antibody buffering can extend by an order of magnitude the plasma lifetime of Ox in rats, and that the steady-state Ox level depends on the molecular properties of the antibody used to buffer the Ox. In addition, the anti-Ox antibody can be recharged with drug in vivo to extend Ox lifetime without additional antibody administration, making this technique even more suitable for possible clinical application.