ALBUMIN-BINDING FUSION PROTEINS IN THE DEVELOPMENT OF NOVEL LONG-ACTING THERAPEUTICS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 184

limited choice of expression host required to produce a large
and complex molecule such as serum albumin.
Alternative single domain antibodies based on camelid
V HH domains (nanobodies) can also be used as a means of
half-life extension in much the same way as AlbudAbs.
Nanobodies have been shown to possess desirable bio-
physical properties with little or no further engineering
required. However, in contrast to dAbs, which are based
on fully human immunglobulin variable domain scaffolds,
nanobodies are based on the camelid V HH scaffold, and it
therefore remains to be seen whether the presence of non-
human epitopes will limit their clinical efficacy due to their
potential for immunogenic responses in patients.
Serum albumin binding technologies based on alternative
formats besides immunoglobulin variable domains are also
in development, for example, albumin-binding peptides and
small molecules which have both been shown to extend the
circulating half-lives of Fab fragments. It is unclear at this
stage what benefit these alternative formats of albumin-
binding molecule will bring to the development of thera-
peutics with improved pharmacokinetics. No reports of
either technology in comparison to serum albumin fusion,
AlbudAb, or nanobody technology have so far been pub-
lished; therefore, it is difficult to predict how the half-life,
potency, or efficacy of therapeutics developed using this
technology will differ in comparison to those using alterna-
tive half-life extension strategies. Some of the potential
disadvantages associated with the use of nonnatural peptides
as a means of half-life extension include immunogenicity,
whereas small molecule conjugates require further down-
stream processing in order to couple them to therapeutic
proteins, which is also likely to impact negatively on
production costs associated with development of such
molecules.
Strategies to incorporate hydrophilic polymers into ther-
apeutic proteins by recombinant means during expression,
rather than via chemical coupling to purified molecules,
have also been described, and this may address such “cost of
goods” issues. However, many of these technologies are in
early stage development; therefore, the likely improvements
in pharmacokinetic profiles of therapeutic proteins devel-
oped using such technologies compared to other half-life
extension strategies are currently undetermined. In contrast,
our studies have demonstrated conclusively that AlbudAbs
fused to human IFN- a can be used to develop a molecule
which is class leading in terms of pharmacokinetics and
efficacy in preclinical models when compared directly with
current clinically validated half-life extension strategies.

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