| Clearance results in a 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 co-administered. 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 re-equilibration from the antibody-drug complex, giving a long effective lifetime. Here antibody buffering is explored experimentally using two model compounds: lysozyme, a protein, and 2-phenyl-oxazol-5-one-gamma-amino butyrate (Ox), a small hapten. Lysozyme was significantly buffered in the plasma of the rat, and the amount of buffering obtained could be altered by changing the relative amounts of lysozyme and antibody administered. In addition to being able to buffer the concentration of a protein in the plasma, an antibody buffer can extend by an order of magnitude the plasma lifetime of a small molecule hapten, Ox, in rats. By employing a panel of anti-Ox antibodies, it was shown that the steady-state free Ox level depends on the molecular properties of the antibody used to buffer the Ox. Ox can also be buffered by an anti-Ox antibody within the cerebrospinal fluid compartment. In addition, the 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. |
