Diversity selection, screening and quantitative structure-activity relationships of osmolyte-like additive effects on the thermal stability of a monoclonal antibody.
Eur J Pharm Sci
; 97: 151-157, 2017 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-27866015
ABSTRACT
Solvents used for therapeutic proteins in downstream processing and in formulations often contain stabilizing additives that inhibit denaturation and aggregation. Such additives are mostly selected based on their positive effect on thermal stability of the protein, and are often derived from naturally occuring osmolytes. To better understand the structural basis underlying the effect of additives, we selected a diverse library of compounds comprising 79 compounds of the polyol, amino acid and methylamine chemical classes and determined the effect of each compound on thermal stability of a monoclonal antibody as a function of compound concentration. Thermal stabilization of the antibody was influenced by solution pH. Quantitative structure-activity relationships (QSAR) were derived by partial least squares regression for individual compound classes and globally. The global model suggests that ligands with a phenyl ring will decrease the Tm, while highly soluble, polar compounds with at least two hydrogen bond donors will increase the Tm. This approach may be beneficial for further studies on the influence of other solution conditions like ionic strength and buffer species on additive-mediated protein stabilization.
Palabras clave
1,4-Anhydroerythritol (PubChem CID: 641,773); Differential scanning fluorimetry; Diversity selection; Glutamine (PubChem CID: 5961); Mannitol (PubChem CID: 6251); Monoclonal antibody; Osmolyte; Protein stabilization; QSAR; Sarcosine ethyl ester hydrochloride (PubChem CID: 171,173); Thermal stability; Tricine (PubChem CID: 79,784); l-Phenylalanine methyl ester hydrochloride (PubChem CID: 75,736)
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Recombinantes
/
Relación Estructura-Actividad Cuantitativa
/
Calor
/
Anticuerpos Monoclonales
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Pharm Sci
Asunto de la revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Año:
2017
Tipo del documento:
Article