ArticlemAbs2019
Binding symmetry and surface flexibility mediate antibody self-association.
Article in mAbs, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Article
- Article
- Exploring rigid-backbone protein docking in biologics discovery: a test using the DARPin scaffold.Frontiers in molecular biosciences · 2023Article
- Structure-based dual affinity optimization of a SARS-CoV-1/2 cross-reactive single-domain antibody.PloS one · 2022Article
- Redesigning an antibody H3 loop by virtual screening of a small library of human germline-derived sequences.Scientific reports · 2021Article
- Characterization and Modeling of Reversible Antibody Self-Association Provide Insights into Behavior, Prediction, and Correction.Antibodies (Basel, Switzerland) · 2021Article
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Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Solution stability is an important factor in the optimization of engineered biotherapeutic candidates such as monoclonal antibodies because of its possible effects on manufacturability, pharmacology, efficacy and safety. A detailed atomic understanding of the mechanisms governing self-association of natively folded protein monomers is required to devise predictive tools to guide screening and re-engineering along the drug development pipeline. We investigated pairs of affinity-matured full-size antibodies and observed drastically different propensities to aggregate from variants differing by a single amino-acid. Biophysical testing showed that antigen-binding fragments (Fabs) from the aggregating antibodies also reversibly associated with equilibrium dissociation constants in the low-micromolar range. Crystal structures (PDB accession codes 6MXR, 6MXS, 6MY4, 6MY5) and bottom-up hydrogen-exchange mass spectrometry revealed that Fab self-association occurs in a symmetric mode that involves the antigen complementarity-determining regions. Subtle local conformational changes incurred upon point mutation of monomeric variants foster formation of complementary polar interactions and hydrophobic contacts to generate a dimeric Fab interface. Testing of popular
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