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Interaction of a Macrocycle with an Aggregation-Prone Region of a Monoclonal Antibody.
Martinez Morales, Marcello; Zalar, Matja; Sonzini, Silvia; Golovanov, Alexander P; van der Walle, Christopher F; Derrick, Jeremy P.
Afiliação
  • Martinez Morales M; School of Biological Sciences, Manchester Academic Health Science Centre , The University of Manchester , Manchester M13 9PL , U.K.
  • Zalar M; Manchester Institute of Biotechnology and School of Chemistry , The University of Manchester , Manchester M1 7DN , U.K.
  • Golovanov AP; Manchester Institute of Biotechnology and School of Chemistry , The University of Manchester , Manchester M1 7DN , U.K.
  • Derrick JP; School of Biological Sciences, Manchester Academic Health Science Centre , The University of Manchester , Manchester M13 9PL , U.K.
Mol Pharm ; 16(7): 3100-3108, 2019 07 01.
Article em En | MEDLINE | ID: mdl-31088082
ABSTRACT
Colloidal stability is among the key challenges the pharmaceutical industry faces during the production and manufacturing of protein therapeutics. Self-association and aggregation processes can not only impair therapeutic efficacy but also induce immunogenic responses in patients. Aggregation-prone regions (APRs) consisting of hydrophobic patches are commonly identified as the source for colloidal instability, and rational strategies to mitigate aggregation propensity often require genetic engineering to eliminate hydrophobic amino acid residues. Here, we investigate cucurbit[7]uril (CB[7]), a water-soluble macrocycle able to form host-guest complexes with aromatic amino acid residues, as a potential excipient to mitigate protein aggregation propensity. Two monoclonal antibodies (mAbs), one harboring an APR and one lacking an APR, were first assessed for their colloidal stability (measured as the translational diffusion coefficient) in the presence and absence of CB[7] using dynamic light scattering. Due to the presence of a tryptophan residue within the APR, we were able to monitor changes in intrinsic fluorescence in response to increasing concentrations of CB[7]. Isothermal titration calorimetry and NMR spectroscopy were then used to characterize the putative host-guest interaction. Our results suggest a stabilizing effect of CB[7] on the aggregation-prone mAb, due to the specific interaction of CB[7] with aromatic amino acid residues located within the APR. This provides a starting point for exploring CB[7] as a candidate excipient for the formulation of aggregation-prone mAbs.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos Macrocíclicos / Excipientes / Anticorpos Monoclonais Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos Macrocíclicos / Excipientes / Anticorpos Monoclonais Idioma: En Ano de publicação: 2019 Tipo de documento: Article