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Druggability properties of a L309K mutation in the antibody CH2 domain.
- Source :
-
3 Biotech . 5/11/2024, Vol. 14 Issue 6, p1-11. 11p. - Publication Year :
- 2024
-
Abstract
- In the early stages of antibody drug development, it is imperative to conduct a comprehensive assessment and enhancement of the druggability attributes of potential molecules by considering their fundamental physicochemical properties. This study specifically concentrates on the surface-exposed hydrophobic region of the candidate antibody aPDL1-WT and explores the effectiveness of the L309K mutation strategy. The resulting aPDL1-LK variant demonstrates a notable enhancement over the original antibody in addressing the issue of aggregation and formation of large molecular impurities under accelerated high-temperature conditions. The mutated molecule, aPDL1-LK, exhibits excellent physicochemical properties such as hydrophilicity, conformational stability, charge variant stability, post-translational modifications, and serum stability. In terms of biological function, aPDL1-LK maintains the same glycosylation pattern as the original antibody and shows no significant difference in affinity for antigen hPDL1 protein, CD16a-F158, CD64, CD32a-H131, and complement C1q, compared to aPDL1-WT. The L309K mutation results in an approximately twofold reduction in its affinity for CD16a-V158 and CD32a-R131. In vitro biological assays, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), reveal that the L309K mutation may decrease CD16a-V158-mediated ADCC activity due to the mutation-induced decrease in ligand affinity, while not affect CD32a-R131-mediated ADCP activity. In conclusion, the L309K mutation offers a promising strategy to enhance the druggability properties of candidate antibodies. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 2190572X
- Volume :
- 14
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- 3 Biotech
- Publication Type :
- Academic Journal
- Accession number :
- 177190442
- Full Text :
- https://doi.org/10.1007/s13205-024-04000-y