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Differential Scanning Calorimetry — A Method for Assessing the Thermal Stability and Conformation of Protein Antigen
Published on: March 4, 2017
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Framework Mutations of the 10-1074 bnAb Increase Conformational Stability, Manufacturability, and Stability While
Bruce A Kerwin1, Chelsey Bennett2, Yan Brodsky1
1Just Biotherapeutics, Inc., Department of Design, 401 Terry Avenue N., Seattle, Washington 98109.
Journal of Pharmaceutical Sciences
|July 27, 2019
Summary
Engineered antibody 10-1074 shows enhanced stability and reduced aggregation. These modifications improve manufacturability and pharmacokinetics for potential HIV prophylaxis.
Area of Science:
- Immunology
- Protein Engineering
- Biopharmaceutical Development
Background:
- Broadly neutralizing anti-HIV antibody 10-1074 (IgG1) is in development for prophylaxis.
- Identifying and modifying destabilizing residues in the Fv region is crucial for antibody stability.
Purpose of the Study:
- To engineer a more conformationally stable variant of antibody 10-1074.
- To assess the impact of stability enhancements on neutralization activity and manufacturability.
Main Methods:
- Computational algorithms identified potentially destabilizing Fv residues.
- Site-directed mutagenesis introduced specific amino acid substitutions.
- Differential scanning fluorimetry and isothermal chemical unfolding assessed conformational stability.
- Low pH and high-concentration incubations evaluated aggregation and particle formation.
Main Results:
- A variant with 1 light and 3 heavy chain mutations demonstrated significantly increased conformational stability.
- Key stabilization involved replacing heavy chain T108 with R108, forming a salt bridge with D137.
- The variant maintained full neutralization activity.
- Enhanced stability was observed during low pH incubation (no aggregation) and long-term storage (reduced particles).
- Improved pharmacokinetics were noted for the stability-enhanced variant.
Conclusions:
- Increasing the conformational stability of the antibody's Fab region profoundly impacts manufacturability and long-term stability.
- Stability-based design is a viable strategy for developing improved monoclonal antibody therapeutics.
- Engineered antibody 10-1074 exhibits superior stability, supporting its development for HIV prophylaxis.
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