ADME Considerations for the Development of Biopharmaceutical Conjugates Using Cleavable Linkers

Title:ADME Considerations for the Development of Biopharmaceutical Conjugates Using Cleavable Linkers

Volume: 17 Issue: 32

Author(s): L. Nathan Tumey*Sean Han

Affiliation:

• School of Pharmacy and Pharmaceutical Sciences, Binghamton University, PO Box 6000, Binghamton, NY 13902- 6000,United States

Keywords: Brentuximab vedotin, antibody drug conjugates, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, reductive cleavage.

Abstract: The recent approval of trastuzumab emtansine (Kadcyla®) and brentuximab vedotin (Adcetris ®) has spurred tremendous investment in new approaches for the targeted delivery of pharmaceutical agents. Targeted delivery approaches, such as Antibody Drug Conjugates (ADCs), typically rely on an endogenous or exogenous “trigger” that results in the release of the pharmacologically active agent at the intended site of action. Lysosomal and intracellular triggers include proteolytic cleavage, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, and reductive cleavage. Recent work has also illustrated that exogenous triggers and extracellular enzymes can be harnessed to result in linker cleavage at the site of action. As these linker technologies have grown, so also has our understanding of the biophysical parameters that drive exposure and stability. The growth in targeted delivery approaches has also driven advancement in bioanalytical strategies for assessing the distribution, processing, and metabolism of these agents. This review provides a systematic overview of each of these areas, particularly focusing on recent advancements in the field that has the potential to expand the scope of therapeutic areas that ADCs and other targeted delivery approaches can be designed to address.

Cite this article as:

Tumey Nathan L. *, Han Sean, ADME Considerations for the Development of Biopharmaceutical Conjugates Using Cleavable Linkers, Current Topics in Medicinal Chemistry 2017; 17 (32) . https://dx.doi.org/10.2174/1568026618666180118154017