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Antibodies with Weakly Basic Isoelectric Points Minimize Trade-offs between Formulation and Physiological Colloidal
Priyanka Gupta1,2, Emily K Makowski3, Sandeep Kumar2
1Biochemistry and Biophysics Department, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
Molecular Pharmaceutics
|February 2, 2022
Summary
Researchers identified a key factor, the antibody isoelectric point, influencing both self-interactions and non-specific binding. Optimizing this property can improve antibody developability for therapeutics.
Area of Science:
- Biopharmaceutical development
- Protein engineering
- Molecular biophysics
Background:
- Therapeutic antibodies require favorable developability properties, including high solubility, low viscosity, and good pharmacokinetics.
- Identifying antibody candidates with both strong repulsive self-interactions (for solubility/viscosity) and weak non-specific interactions (for pharmacokinetics) is challenging.
- Current methods for predicting these properties are insufficient, potentially hindering drug development.
Purpose of the Study:
- To systematically evaluate repulsive self-interactions and non-specific interactions in antibody variants.
- To understand the relationship between these two critical developability properties.
- To identify strategies for selecting antibody candidates with optimal biophysical characteristics.
Main Methods:
- Assessed self-interaction and non-specific interaction properties of 42 IgG1 variants.
- Utilized variable fragments (Fvs) from four clinical-stage antibodies.
- Incorporated complementarity-determining regions (CDRs) from 10 clinical-stage antibodies.
Main Results:
- A strong inverse correlation was observed: antibodies with high repulsive self-interactions showed high non-specific interactions, and vice versa.
- Antibody isoelectric point (pI) was identified as the primary driver of this behavior.
- Optimal combinations of properties were found in IgG1s with specific pI ranges (8-8.5) and Fv pIs (7.5-9).
Conclusions:
- Antibody isoelectric point is a critical determinant of both colloidal stability and non-specific binding.
- Selecting antibodies with specific pI values can simultaneously enhance repulsive self-interactions and minimize non-specific interactions.
- These findings offer a pathway to improve the identification and engineering of antibody therapeutics with superior drug-like properties.
Keywords:
Fv, chargeIgGcolloidal stabilitydevelopabilityisoelectric pointnon-specificnon-specific interactionoff-target bindingpIpolyreactivityself-associationself-interactionspecificityMore Related Videos
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