Albumin-based drug designs for pharmacokinetic modulation

ABSTRACT

Introduction

A poor pharmacokinetic profile due to inadequate distribution and rapid renal clearance limits site-specific target engagement and drug efficacy. The inherent properties of human serum albumin for broad tissue distribution, prolonged circulation, and ligand transport have been engineered into albumin-based drug designs to modulate the pharmacokinetics to increase efficacy and reduce the frequency of dose.

Areas covered

This review highlights albumin structural features, ligand binding, and molecular interactions key to albumin-drug designs and an overview of the repertoire of albumin-drugs and approaches, with focus on pharmacokinetics of marketed products and clinical trials.

Expert opinion

Comparison, and advantages as well as disadvantages of the endogenous albumin-binding versus recombinant albumin construct approach, and half-life extension and intracellular drug delivery applications. The section addresses current challenges and solutions to the different drug designs, and considerations needed to progress the field such as conjugation chemistries, drug loading, and animal models. The section highlights the need for a paradigm shift in the field from ‘utilizing’ to ‘controlling’ albumin transport with recombinant human albumin variants engineered for tuned affinity to albumin cellular receptors.

KEYWORDS:

• Human serum albumin
• recombinant human albumin
• albumin domains
• albumin fusions
• pharmacokinetics
• neonatal Fc receptor (FcRn)
• half-life extension
• long-acting drugs
• drug conjugation
• drug delivery
• biomolecular assemblies

Article highlights

• Human serum albumin is a natural transport protein with inherent properties of ligand binding, long circulatory half-life, and broad tissue distribution dependent on unique structural features and molecular interactions.

• These features have been engineered into albumin-drugs designed to bind with the endogenous albumin pool or as a recombinant human albumin-drug construct to improve the pharmacokinetic profile of the drug.

• A main application of HSA is half-life extension for long-acting drugs in order to decrease dose requirement (frequency and amount), toxicity, and improve patient compliance.

• Challenges such as conjugation chemistries, drug loading, and relevant animal models need to be addressed.

• Structural analysis of the albumin-binding interface with the neonatal Fc receptor (FcRn) predominately responsible for albumin’s long circulatory half-life, can be used to design recombinant albumin variants engineered with different FcRn affinity for tuning the pharmacokinetics.

• There is a need for a shift from utilizing to controlling the transport properties of albumin for development of more effective next-generation albumin-drugs.

This box summarizes key points contained in the article.

Declaration of interest

KA Howard is a recipient of the Novo Nordisk Foundation Grant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by Novo Nordisk Foundation grant CEMBID Center for Multifunctional Drug Design, Grant Number: [NNF17OC0028070].