Druggability properties of a L309K mutation in the antibody CH2 domain.

Autor: Li C; Department of Pharmacy, Zhejiang Provincial Hospital of Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310000 Zhejiang China., Yao QQ; Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215000 Jiangsu China., Li J; Department of Pharmacy, Zhejiang Provincial Hospital of Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310000 Zhejiang China.
Jazyk: angličtina
Zdroj: 3 Biotech [3 Biotech] 2024 Jun; Vol. 14 (6), pp. 152. Date of Electronic Publication: 2024 May 11.
DOI: 10.1007/s13205-024-04000-y
Abstrakt: 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.
Competing Interests: Conflicts of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest.
(© King Abdulaziz City for Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
Databáze: MEDLINE
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