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Chemometrics in Protein Formulation : Stability Governed by Repulsion and Protein Unfolding

Kulakova, Alina ; Augustijn, Dillen ; El Bialy, Inas ; Gentiluomo, Lorenzo ; Greco, Maria Laura ; Hervø-Hansen, Stefan LU ; Indrakumar, Sowmya ; Mahapatra, Sujata ; Martinez Morales, Marcello and Pohl, Christin LU , et al. (2023) In Molecular Pharmaceutics 20(6). p.2951-2965
Abstract

Therapeutic proteins can be challenging to develop due to their complexity and the requirement of an acceptable formulation to ensure patient safety and efficacy. To date, there is no universal formulation development strategy that can identify optimal formulation conditions for all types of proteins in a fast and reliable manner. In this work, high-throughput characterization, employing a toolbox of five techniques, was performed on 14 structurally different proteins formulated in 6 different buffer conditions and in the presence of 4 different excipients. Multivariate data analysis and chemometrics were used to analyze the data in an unbiased way. First, observed changes in stability were primarily determined by the individual... (More)

Therapeutic proteins can be challenging to develop due to their complexity and the requirement of an acceptable formulation to ensure patient safety and efficacy. To date, there is no universal formulation development strategy that can identify optimal formulation conditions for all types of proteins in a fast and reliable manner. In this work, high-throughput characterization, employing a toolbox of five techniques, was performed on 14 structurally different proteins formulated in 6 different buffer conditions and in the presence of 4 different excipients. Multivariate data analysis and chemometrics were used to analyze the data in an unbiased way. First, observed changes in stability were primarily determined by the individual protein. Second, pH and ionic strength are the two most important factors determining the physical stability of proteins, where there exists a significant statistical interaction between protein and pH/ionic strength. Additionally, we developed prediction methods by partial least-squares regression. Colloidal stability indicators are important for prediction of real-time stability, while conformational stability indicators are important for prediction of stability under accelerated stress conditions at 40 °C. In order to predict real-time storage stability, protein-protein repulsion and the initial monomer fraction are the most important properties to monitor.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
colloidal and conformational stability, multivariate data analysis, protein characterization, protein formulation, therapeutic proteins
in
Molecular Pharmaceutics
volume
20
issue
6
pages
15 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:37146162
  • scopus:85163321275
ISSN
1543-8384
DOI
10.1021/acs.molpharmaceut.3c00013
language
English
LU publication?
yes
id
ae1c75e7-16df-4e94-96e2-8624f2eaf90b
date added to LUP
2023-09-15 11:57:50
date last changed
2024-04-26 02:21:24
@article{ae1c75e7-16df-4e94-96e2-8624f2eaf90b,
  abstract     = {{<p>Therapeutic proteins can be challenging to develop due to their complexity and the requirement of an acceptable formulation to ensure patient safety and efficacy. To date, there is no universal formulation development strategy that can identify optimal formulation conditions for all types of proteins in a fast and reliable manner. In this work, high-throughput characterization, employing a toolbox of five techniques, was performed on 14 structurally different proteins formulated in 6 different buffer conditions and in the presence of 4 different excipients. Multivariate data analysis and chemometrics were used to analyze the data in an unbiased way. First, observed changes in stability were primarily determined by the individual protein. Second, pH and ionic strength are the two most important factors determining the physical stability of proteins, where there exists a significant statistical interaction between protein and pH/ionic strength. Additionally, we developed prediction methods by partial least-squares regression. Colloidal stability indicators are important for prediction of real-time stability, while conformational stability indicators are important for prediction of stability under accelerated stress conditions at 40 °C. In order to predict real-time storage stability, protein-protein repulsion and the initial monomer fraction are the most important properties to monitor.</p>}},
  author       = {{Kulakova, Alina and Augustijn, Dillen and El Bialy, Inas and Gentiluomo, Lorenzo and Greco, Maria Laura and Hervø-Hansen, Stefan and Indrakumar, Sowmya and Mahapatra, Sujata and Martinez Morales, Marcello and Pohl, Christin and Polimeni, Marco and Roche, Aisling and Svilenov, Hristo L. and Tosstorff, Andreas and Zalar, Matja and Curtis, Robin and Derrick, Jeremy P. and Frieß, Wolfgang and Golovanov, Alexander P. and Lund, Mikael and Nørgaard, Allan and Khan, Tarik A. and Peters, Günther H.J. and Pluen, Alain and Roessner, Dierk and Streicher, Werner W. and van der Walle, Christopher F. and Warwicker, Jim and Uddin, Shahid and Winter, Gerhard and Bukrinski, Jens Thostrup and Rinnan, Åsmund and Harris, Pernille}},
  issn         = {{1543-8384}},
  keywords     = {{colloidal and conformational stability; multivariate data analysis; protein characterization; protein formulation; therapeutic proteins}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{2951--2965}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Molecular Pharmaceutics}},
  title        = {{Chemometrics in Protein Formulation : Stability Governed by Repulsion and Protein Unfolding}},
  url          = {{http://dx.doi.org/10.1021/acs.molpharmaceut.3c00013}},
  doi          = {{10.1021/acs.molpharmaceut.3c00013}},
  volume       = {{20}},
  year         = {{2023}},
}