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. 2005 Jan 4;102(1):40-4.
doi: 10.1073/pnas.0405797102. Epub 2004 Dec 22.

Antibody buffering of a ligand in vivo

Carol E O'Hear  1 , Jefferson Foote
Affiliations

Antibody buffering of a ligand in vivo

Carol E O'Hear et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Fig. 1.
Fig. 1.
Antibody complexation opposes elimination of Ox. Elimination of Ox administered with the control antibody D1.3 (○, t1/2 = 1.2 ± 0.2 min) occurs much more rapidly than when Ox is administered with NQ11/7.12 (•, t1/2 = 20 ± 2 min). Each point represents data collected from five animals.
Fig. 2.
Fig. 2.
NQ11/7.12 lowers the concentration of free Ox while increasing the plasma half-life of free Ox. The free concentration of Ox is initially lower when Ox is administered with NQ11/7.12 (•) versus D1.3 (○). However, this free concentration with NQ11/7.12 declines more slowly than when Ox is administered without an antibody buffer.
Fig. 3.
Fig. 3.
Antibody Kd determines the half-life of Ox and free Ox concentration. (A) Total Ox vs. time. Antibodies NQ16/113.8 (▪) and NQ22/16.4 (□), which have higher Kd than NQ11/7.12, are able to buffer Ox concentration, but to a lesser degree, than NQ11/7.12 (•). D1.3 (○) is shown for comparison. (B) Free Ox vs. time. The lower-affinity antibodies also reduce the free concentration of Ox in the plasma and are able to prolong the half-life of free Ox, but to a lesser degree than NQ11/7.12.
Fig. 4.
Fig. 4.
NQ11/7.12 retains the ability to buffer Ox days after initial antibody administration. Plasma half-life of total Ox (A) and free Ox (B) is prolonged whether Ox is coadministered with NQ11/7.12 (•) or administered alone 24 h after NQ11/7.12 infusion (▪) or 48 h after NQ11/7.12 infusion (○). Ox administered with a control D1.3 antibody (□) is shown for comparison.
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