Molecular determinants of trade-offs between antibody colloidal stability and non-specificity
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Authors
Gupta, Priyanka
Issue Date
2021-05
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Biochemistry and biophysics
Alternative Title
Abstract
The widespread interest in antibody therapeutics has led to much focus on identifying antibody candidates with favorable developability properties. In particular, there is broad interest in identifying antibody candidates with highly repulsive antibody self-interactions in standard formulation conditions (e.g., low ionic strength buffers at pH 5-6) for high solubility and low viscosity in concentrated antibody formulations. Likewise, there is also broad interest in identifying antibody candidates with low levels of non-specific interactions in physiological conditions (PBS, pH 7.4) to promote favorable pharmacokinetic properties by minimizing non-specific binding to cells and tissues. Here we demonstrate that these two objectives are at natural odds with each other based on our analysis of 42 IgG1 variants with variable fragments (Fv) from four clinical-stage antibodies. Notably, we find that antibodies with the most repulsive self-interactions in standard formulation conditions have the highest levels of non-specific binding in physiological conditions. Conversely, antibodies with the lowest levels of non-specific binding in physiochemical conditions display the highest levels of self-association in standard formulation conditions. These results are largely explained by the fact that the antibody net charges and isoelectric points are most strongly correlated with both types of antibody interactions, as antibodies with increased positive charge displayed decreased antibody self-association in formulation conditions and increased non-specific interactions in physiological conditions. IgG1s with isoelectric points between 8-8.5, and Fv isoelectric points between 7.5-9, generally displayed the best combination of properties, as they generally possessed strongly repulsive self-interactions and low-to-moderate levels of non-specific interactions. We expect these findings will improve the identification and engineering of antibody candidates with drug-like biophysical properties.
Description
May2021
School of Science
School of Science
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY