4.7 Article

Approach for Half-Life Extension of Small Antibody Fragments That Does Not Affect Tissue Uptake

Journal

BIOCONJUGATE CHEMISTRY
Volume 27, Issue 10, Pages 2534-2539

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.6b00469

Keywords

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Funding

  1. NSF [1429972]
  2. Directorate For Engineering [1429972] Funding Source: National Science Foundation
  3. Div Of Industrial Innovation & Partnersh [1429972] Funding Source: National Science Foundation

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The utility of antigen-binding antibody fragments is often limited by their short half-lives. Half-life extension of such fragments is usually accomplished by attachment or binding to high-molecular-weight carriers that reduce the renal elimination rate. However, the higher hydrodynamic radius results in greater confinement in the vascular compartment and, thus, lower tissue distribution. We have developed a chemically controlled drug delivery system in which the drug is covalently attached to hydrogel microspheres by a self-cleaving beta-eliminative linker; upon subcutaneous injection, the t(1/2,beta) of the released drug acquires the tin of linker cleavage. In the present work, we compared the pharmacokinetics of an anti-TNF alpha scFv, the same scFv attached to 40 kDa PEG by a stable linker, and the scFv attached to hydrogel microspheres by a self-cleaving linker. We also developed a general approach for the selective attachment of beta-eliminative linkers to the N-termini of proteins. In rats, the scFv had a t(1/2,beta) of 4 h and a high volume of distribution at steady state (V-d,V-SS), suggesting extensive tissue distribution. The PEG-scFv conjugate had an increased t(1/2,beta) of about 2 days but showed a reduced Vd,ss that was similar to the plasma volume. In contrast, the tissue-penetrable scFv released from the hydrogel system had a t(1/2,beta) of about 2 weeks. Thus, the cleavable microsphere-scFv conjugate releases its protein cargo with a prolonged half-life comparable to that of most full-length mAbs and in a form that has the high tissue distribution characteristic of smaller mAb fragments. Other antigen-binding antibody fragments should be amenable to the half-life extension approach described here.

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