A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics
| Autor: | Micheal A. Batt, Joanne Lin, Andrea Ferrante, Petra Verdino, Anna Maria Russell, Shawn Chang, Stacey Lynn Lee, Rong Fong Huang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
B Cells Computer science Physiology Thermal Stability Biochemistry Biological Factors Epitopes White Blood Cells Database and Informatics Methods Protein Structure Databases 0302 clinical medicine Animal Cells Immune Physiology Medicine and Health Sciences Macromolecular Structure Analysis Amino Acids Enzyme-Linked Immunoassays B-Lymphocytes Multidisciplinary Immune System Proteins biology Organic Compounds Immunogenicity Physics Antigen binding Molecular Docking Simulation Chemistry 030220 oncology & carcinogenesis Physical Sciences Engineering and Technology Thermodynamics Medicine Synthetic Biology Antibody Cellular Types Protein Binding Research Article Antigenicity Protein Structure Proline Immune Cells Science Immunology Context (language use) Computational biology Research and Analysis Methods 03 medical and health sciences Antigen Albumins Antigenic variation Humans Antigens Antibody-Producing Cells Immunoassays Molecular Biology Serum Albumin Blood Cells Organic Chemistry Chemical Compounds Biology and Life Sciences Proteins Cyclic Amino Acids Cell Biology Synthetic Biotherapeutics Single-Domain Antibodies 030104 developmental biology Epitope mapping Biological Databases biology.protein Immunologic Techniques |
| Zdroj: | PLoS ONE, Vol 16, Iss 7, p e0254944 (2021) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Development of biotherapeutics is hampered by the inherent risk of immunogenicity, which requires extensive clinical assessment and possible re-engineering efforts for mitigation. The focus in the pre-clinical phase is to determine the likelihood of developing treatment-emergent anti-drug antibodies (TE-ADA) and presence of pre-existing ADA in drug-naïve individuals as risk-profiling strategies. Pre-existing ADAs are routinely identified during clinical immunogenicity assessment, but their origin and impact on drug safety and efficacy have not been fully elucidated. One specific class of pre-existing ADAs has been described, which targets neoepitopes of antibody fragments, including Fabs, VH, or VHH domains in isolation from their IgG context. With the increasing number of antibody fragments and other small binding scaffolds entering the clinic, a widely applicable method to mitigate pre-existing reactivity against these molecules is desirable. Here is described a structure-based engineering approach to abrogate pre-existing ADA reactivity to the C-terminal neoepitope of VH(H)s. On the basis of 3D structures, small modifications applicable to any VH(H) are devised that would not impact developability or antigen binding. In-silico B cell epitope mapping algorithms were used to rank the modified VHH variants by antigenicity; however, the limited discriminating capacity of the computational methods prompted an experimental evaluation of the engineered molecules. The results identified numerous modifications capable of reducing pre-existing ADA binding. The most efficient consisted of the addition of two proline residues at the VHH C-terminus, which led to no detectable pre-existing ADA reactivity while maintaining favorable developability characteristics. The method described, and the modifications identified thereby, may provide a broadly applicable solution to mitigate immunogenicity risk of antibody-fragments in the clinic and increase safety and efficacy of this promising new class of biotherapeutics. |
| Databáze: | OpenAIRE |
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