期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：37
DOI：10.1073/pnas.2020577118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Successful biologic drug discovery and development involves finding functional as well as developable candidates. Once a candidate has been demonstrated to be functional, the next step is to determine whether it can be translated into a drug product. This requires that the candidate can withstand stresses encountered during manufacturing, shipping, and storage. Additionally, it must be safe, efficacious, and possess good pharmacology. In silico analyses of the variable regions of 77 marketed antibody-based biotherapeutics have revealed five nonredundant physicochemical descriptors. Distributions of these descriptors, observed for marketed biotherapeutics, can help prioritize a drug candidate for experimental testing at early discovery stages, guide engineering efforts to further optimize it, and help increase the productivity of biologic drug discovery and development.
Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable regions (Fv) found in 77 marketed antibody-based biotherapeutics. Fv regions of these biotherapeutics demonstrate significant diversities in their germlines, complementarity determining region loop lengths, hydrophobicity, and charge distributions. Furthermore, an analysis of 24 physicochemical descriptors, calculated using homology-based molecular models, has yielded five nonredundant descriptors whose distributions represent stability, isoelectric point, and molecular surface characteristics of their Fv regions. Fv regions of candidates from our internal discovery campaigns, human next-generation sequencing repertoires, and those in clinical-stages (CST) were assessed for similarity with the physicochemical profile derived here. The Fv regions in 33% of CST antibodies show physicochemical properties that are dissimilar to currently marketed biotherapeutics. In comparison, physicochemical characteristics of ∼29% of the Fv regions in human antibodies and ∼27% of our internal hits deviated significantly from those of marketed biotherapeutics. The early availability of this information can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. Insights from this work can also help support portfolio risk assessment, in-licensing, and biopharma collaborations.
