posted on 2023-11-21, 18:04authored byMarcus Gutmann, Debora Reinhardt, Christian Seidensticker, Martina Raschig, Lukas Hahn, Alessandra Moscaroli, Martin Behe, Lorenz Meinel, Tessa Lühmann
Attachment of polyethylene glycol (PEG) chains is a common,
well-studied,
and Food and Drug Administration-approved method to address the pharmacokinetic
challenges of therapeutic proteins. Occasionally, PEGylation impairs
the activity of pharmacodynamics (PD). To overcome this problem, disease-relevant
cleavable linkers between the polymer and the therapeutic protein
can unleash full PD by de-PEGylating the protein at its target site.
In this study, we engineered a matrix metalloproteinase (MMP)-responsive
fibroblast growth factor 2 (FGF-2) mutant that was site-specifically
extended with a PEG polymer chain. Using bioinspired strategies, the
bioconjugate was designed to release the native protein at the desired
structure/environment with preservation of the proliferative capacity
in vitro on NIH3T3 cells. In vivo, hepatic exposure was diminished
but not its renal distribution over time compared to unconjugated
FGF-2. By releasing the growth factor from the PEG polymer in response
to MMP cleavage, restored FGF-2 may enter hard-to-reach tissues and
activate cell surface receptors or nuclear targets.