ArticleProceedings of the National Academy of Sciences of the United States of America2012
General strategy for the generation of human antibody variable domains with increased aggregation resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers.
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Who cites it
112 citing papers in PubMed.
- Hypervariable loop profiling decodes sequence determinants of antibody stability.Nature structural & molecular biology · 2026Article
- Reliable repurposing of the antibody interactome inside the cell.Nature communications · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- Structure-Guided Engineering of High-Affinity Antibodies Against Zika Virus Using Deep Learning and Molecular Dynamics.Chemistry & biodiversity · 2026Article
- Investigating Local Sequence-Structural Attributes of Amyloidogenic Light Chain Variable Domains.Proteins · 2025Article
- Monoclonal Antibodies Against Myeloid Leukemia Cells: Current Knowledge and Future Directions.International journal of molecular sciences · 2025Review
- Antibody-Nanoparticle Conjugates in Therapy: Combining the Best of Two Worlds.Small (Weinheim an der Bergstrasse, Germany) · 2025Review
- A Practical Guide to Computational Tools for Engineering Biocatalytic Properties.International journal of molecular sciences · 2025Review
- Improving the production and stability of nanobodies.Protein engineering, design & selection : PEDS · 2025Article
- Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody-drug conjugates.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural trends in antibody-antigen binding interfaces: a computational analysis of 1833 experimentally determined 3D structures.Computational and structural biotechnology journal · 2024Article
- The process using a synthetic library that generates multiple diverse human single domain antibodies.Antibody therapeutics · 2024Article
- A single-domain antibody library based on a stability-engineered human VH3 scaffold.Scientific reports · 2024Article
- Genetic barrier to resistance: a critical parameter for efficacy of neutralizing monoclonal antibodies against SARS-CoV-2 in a nonhuman primate model.Journal of virology · 2024Article
- Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain.International journal of molecular sciences · 2024Article
- Computational optimization of antibody humanness and stability by systematic energy-based ranking.Nature biomedical engineering · 2024Article
- Serum immunoglobulin or albumin binding single-domain antibodies that enable tailored half-life extension of biologics in multiple animal species.Frontiers in immunology · 2024Article
- Characterization of an HNA aptamer suggests a non-canonical G-quadruplex motif.Nucleic acids research · 2023Article
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8 authors.
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Abstract
The availability of stable human antibody reagents would be of considerable advantage for research, diagnostic, and therapeutic applications. Unfortunately, antibody variable heavy and light domains (V(H) and V(L)) that mediate the interaction with antigen have the propensity to aggregate. Increasing their aggregation resistance in a general manner has proven to be a difficult and persistent problem, due to the high level of sequence diversity observed in human variable domains and the requirement to maintain antigen binding. Here we outline such an approach. By using phage display we identified specific positions that clustered in the antigen binding site (28, 30-33, 35 in V(H) and 24, 49-53, 56 in V(L)). Introduction of aspartate or glutamate at these positions endowed superior biophysical properties (non-aggregating, well-expressed, and heat-refoldable) onto domains derived from common human germline families (V(H)3 and V(κ)1). The effects of the mutations were highly positional and independent of sequence diversity at other positions. Moreover, crystal structures of mutant V(H) and V(L) domains revealed a surprising degree of structural conservation, indicating compatibility with V(H)/V(L) pairing and antigen binding. This allowed the retrofitting of existing binders, as highlighted by the development of robust high affinity antibody fragments derived from the breast cancer therapeutic Herceptin. Our results provide a general strategy for the generation of human antibody variable domains with increased aggregation resistance.
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