Physicochemical Rules for Identifying Monoclonal Antibodies with Drug-like Specificity
| Autor: | Seth D. Ludwig, Lilia A. Rabia, Yulei Zhang, Priyanka Gupta, Peter M. Tessier, Matthew D. Smith, Alec A. Desai, Lina Wu |
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| Rok vydání: | 2020 |
| Předmět: |
Drug
medicine.drug_class media_common.quotation_subject Immunoglobulin Variable Region Pharmaceutical Science Bioengineering 02 engineering and technology Computational biology Biology Monoclonal antibody Sensitivity and Specificity 030226 pharmacology & pharmacy Article 03 medical and health sciences 0302 clinical medicine Drug Development Antigen Drug Discovery medicine media_common Viscosity Antibodies Monoclonal High-Throughput Nucleotide Sequencing 021001 nanoscience & nanotechnology Models Chemical Solubility Drug development biology.protein Molecular Medicine Antibody 0210 nano-technology Function (biology) |
| Zdroj: | Mol Pharm |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.0c00257 |
| Popis: | The ability of antibodies to recognize their target antigens with high specificity is fundamental to their natural function. Nevertheless, therapeutic antibodies display variable and difficult-to-predict levels of non-specific and self-interactions that can lead to various drug development challenges, including antibody aggregation, abnormally high viscosity and rapid antibody clearance. Here we report a method for predicting the overall specificity of antibodies in terms of their relative risk for displaying high levels of non-specific and/or self-interactions at physiological conditions. We find that individual and combined sets of chemical rules that limit the maximum and minimum numbers of certain solvent-exposed residues in antibody variable regions are strong predictors of specificity for large panels of preclinical and clinical-stage antibodies. We also demonstrate how the chemical rules can be used to identify sites that mediate non-specific interactions in suboptimal antibodies and guide the design of targeted sub-libraries that yield variants with high antibody specificity. These findings can be readily used to improve the selection and engineering of antibodies with drug-like specificity. |
| Databáze: | OpenAIRE |
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