Intrinsic physicochemical profile of marketed antibody-based biotherapeutics.
Proc Natl Acad Sci U S A
; 118(37)2021 09 14.
Article
em En
| MEDLINE
| ID: mdl-34504010
ABSTRACT
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 â¼29% of the Fv regions in human antibodies and â¼27% 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Engenharia de Proteínas
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Regiões Determinantes de Complementaridade
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Descoberta de Drogas
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Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article