Binding symmetry and surface flexibility mediate antibody self-association.

Clicks: 366
ID: 3055
2019
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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 tools generally indicated low reliabilities for predicting the aggregation propensities observed. A structure-aggregation data set is provided here in order to stimulate further improvements of tools for prediction of native aggregation. Incorporation of intermolecular docking, conformational flexibility, and short-range packing interactions may all be necessary features of the ideal algorithm.
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schrag2019bindingmabs Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Schrag, Joseph D;Picard, Marie-Ève;Gaudreault, Francis;Gagnon, Louis-Patrick;Baardsnes, Jason;Manenda, Mahder S;Sheff, Joey;Deprez, Christophe;Baptista, Cassio;Hogues, Hervé;Kelly, John F;Purisima, Enrico O;Shi, Rong;Sulea, Traian;
Journal mabs
Year 2019
DOI
10.1080/19420862.2019.1632114
URL
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