Antibody-Proteolysis Targeting Chimera Conjugate Enables Selective Degradation of Receptor-Interacting Serine/Threonine-Protein Kinase 2 in HER2+ Cell Lines.
Bioconjug Chem
; 34(11): 2049-2054, 2023 11 15.
Article
em En
| MEDLINE
| ID: mdl-37917829
ABSTRACT
Proteolysis targeting chimeras (PROTACs) are a family of heterobifunctional molecules that are now realizing their promise as a therapeutic strategy for targeted protein degradation. However, one limitation of existing designs is the lack of cell-selective targeting of the protein degrading payload. This manuscript reports a cell-targeted approach to degrade receptor-interacting serine/threonine-protein kinase 2 (RIPK2) in HER2+ cell lines. An antibody-PROTAC conjugate is prepared containing a protease-cleavable linkage between the antibody and the corresponding degrader. Potent RIPK2 degradation is observed in HER2+ cell lines, whereas an equivalent anti-IL4 antibody-PROTAC conjugate shows no degradation at therapeutically relevant concentrations. No RIPK2 degradation was observed in HER2- cell lines for both bioconjugates. This work demonstrates the potential for the cell-selective delivery of PROTAC scaffolds by engaging with signature extracellular proteins expressed on the surface of particular cell types.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Imunoconjugados
/
Quimera de Direcionamento de Proteólise
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article