posted on 2021-07-27, 19:20authored byCaitlin
L. Maikawa, Andrea I. d’Aquino, Eric T. Vuong, Bo Su, Lei Zou, Peyton C. Chen, Leslee T. Nguyen, Anton A. A. Autzen, Joseph L. Mann, Matthew J. Webber, Eric A. Appel
Proteins
are an impactful class of therapeutics but can exhibit
suboptimal therapeutic performance, arising from poor control over
the timescale of clearance. Covalent PEGylation is one established
strategy to extend circulation time but often at the cost of reduced
activity and increased immunogenicity. Supramolecular PEGylation may
afford similar benefits without necessitating that the protein be
permanently modified with a polymer. Here, we show that insulin pharmacokinetics
can be modulated by tuning the affinity-directed dynamics of a host–guest
motif used to non-covalently endow insulin with a poly(ethylene glycol)
(PEG) chain. When administered subcutaneously, supramolecular PEGylation
with higher binding affinities extends the time of total insulin exposure
systemically. Pharmacokinetic modeling reveals that the extension
in the duration of exposure arises specifically from decreased absorption
from the subcutaneous depot governed directly by the affinity and
dynamics of host–guest exchange. The lifetime of the supramolecular
interaction thus dictates the rate of absorption, with negligible
impact attributed to association of the PEG upon rapid dilution of
the supramolecular complex in circulation. This modular approach to
supramolecular PEGylation offers a powerful tool to tune protein pharmacokinetics
in response to the needs of different disease applications.