Author
Gupta, Priyanka
Other Contributors
Cramer, Steven, M; Tessier, Peter, M; Cramer, Steven, M; Tessier, Peter, M; Karande, Pankaj; Koffas, Mattheos; Scheer, Justin, M;
Date Issued
2021-05
Subject
Biochemistry and biophysics
Degree
PhD;
Terms of Use
This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute (RPI), Troy, NY. Copyright of original work retained by author.;
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
Department
Biochemistry and Biophysics Program;
Publisher
Rensselaer Polytechnic Institute, Troy, NY
Relationships
Rensselaer Theses and Dissertations Online Collection;
Access
Restricted to current Rensselaer faculty, staff and students in accordance with the
Rensselaer Standard license. Access inquiries may be directed to the Rensselaer Libraries.;