Correlation of In Vitro Kinetic Stability to Preclinical In Vivo Pharmacokinetics for a Panel of Anti-PD-1 Monoclonal Antibody Interleukin 21 Mutein Immunocytokines.
Drug Metab Dispos
; 52(3): 228-235, 2024 Feb 14.
Article
de En
| MEDLINE
| ID: mdl-38135505
ABSTRACT
The development of therapeutic fusion protein drugs is often impeded by the unintended consequences that occur from fusing together domains from independent naturally occurring proteins, consequences such as altered biodistribution, tissue uptake, or rapid clearance and potential immunogenicity. For therapeutic fusion proteins containing globular domains, we hypothesized that aberrant in vivo behavior could be related to low kinetic stability of these domains leading to local unfolding and susceptibility to partial proteolysis and/or salvage and uptake. Herein we describe an assay to measure kinetic stability of therapeutic fusion proteins by way of their sensitivity to the protease thermolysin. The results indicate that in vivo pharmacokinetics of a panel of anti-programmed cell death protein 1 monocolonal antibodyinterleukin 21 immunocytokines in both mice and nonhuman primates are highly correlated with their in vitro susceptibility to thermolysin-mediated proteolysis. This assay can be used as a tool to quickly identify in vivo liabilities of globular domains of therapeutic proteins, thus aiding in the optimization and development of new multispecific drug candidates. SIGNIFICANCE STATEMENT This work describes a novel assay utilizing protein kinetic stability to identify preclinical in vivo pharmacokinetic liabilities of multispecific therapeutic fusion proteins. This provides an efficient, inexpensive method to ascertain inherent protein stability in vitro before conducting in vivo studies, which can rapidly increase the speed of preclinical drug development.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Interleukines
/
Anticorps monoclonaux
Limites:
Animals
Langue:
En
Journal:
DMD online
/
Drug Metab Dispos
Sujet du journal:
FARMACOLOGIA
Année:
2024
Type de document:
Article
Pays de publication:
États-Unis d'Amérique