ALBUMIN-BINDING FUSION PROTEINS IN THE DEVELOPMENT OF NOVEL LONG-ACTING THERAPEUTICS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 174

11

ALBUMIN-BINDING FUSION PROTEINS IN THE
DEVELOPMENT OF NOVEL LONG-ACTING
THERAPEUTICS

A DAM W ALKER , 1 G RAINNE D UNLEVY , 1 AND P ETER T OPLEY 2
1 Biopharm R&D, Domantis Ltd., Cambridge, UK
2 Biopharm R&D, GlaxoSmithKline Medicines Research Centre, Stevenage, UK

11.1 Introduction
11.2 Clinically validated half-life extension technologies—an
overview
11.3 Interferon- a fused to human serum albumin or AlbudAb—a
direct comparison of HSA and AlbudAb fusion technologies
11.4 Nanobodies in the development of alternative half-life
extension technologies based on single immunoglobulin
variable domains
11.5 Novel half-life extension technologies—alternative
approaches to single immunoglobulin variable domains
11.6 Conclusions
References

therapeutic molecules, predominantly by reducing the clear-
ance rate by renal filtration and preventing trafficking to
degradative pathways, for example, lysosomal breakdown.
Rates of excretion and clearance can be reduced by increas-
ing the size of the therapeutic molecule above the threshold
for renal clearance, whereas prevention of enzymatic deg-
radation can be achieved by engaging recycling mechanisms
to limit proteolytic cleavage following endocytosis of ther-
apeutics which act as ligands for cell surface receptors and
would ordinarily be internalized and targeted for destruction
in the lysosome.
Covalent attachment of branched or linear polymers of
polyethylene glycol (PEG) to recombinant proteins and pep-
tides can result in a significant improvement in their pharma-
cokinetic profile owing to the increased molecular radius of
these PEGylated molecules. Similarly, chemical conjugation
or genetic fusion of therapeutic molecules to large carrier
proteins such as human serum albumin (HSA) can also be
used as a method of half-life extension due to the increased
molecular size and may result in additional improvements in
pharmacokinetic properties in comparison to PEGylated
molecules due to FcRn-mediated recycling of HSA.
Neither of these half-life extension technologies is with-
out significant development challenges with regard to bio-
pharmaceutical production, and to this end, alternative half-
life extension technologies such as serum albumin-binding
antibodies (AlbudAbs) have been developed with a view to
addressing some of the development issues faced by PEGy-
lation and serum albumin fusion technologies. Alternative
half-life extension technologies besides AlbudAbs are also

11.1 INTRODUCTION

Recombinant proteins and peptides are potentially of huge
benefit in the treatment of a wide variety of human diseases.
Unfortunately, the majority of such molecules are hampered
in their use as therapeutic agents as they are rapidly excreted
and degraded following subcutaneous or intravenous admin-
istration. In order to maintain a therapeutically active dose,
protein- and peptide-based therapeutics must therefore be
administered at frequent intervals in many cases, which can
have a negative impact on their safety and tolerability
profile, clinical efficacy, and associated cost of goods.
This has led to the development of a number of technologies
aimed at improving the pharmacokinetic profiles of