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Proceedings of the National Academy of Sciences of the United States of America v.114 no.4, 2017년, pp.E486 - E495   SCI SCIE
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Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding

Koenig, Patrick (Department of Antibody Engineering, Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080 ); Lee, Chingwei V. (Department of Antibody Engineering, Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080 ); Walters, Benjamin T. (Department of Early-Stage Pharmaceutical Development, Pharma Technical Development, Genentech, Inc., South San Francisco, CA 94080 ); Janakiraman, Vasantharajan (Department of Molecular Biology, Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080 ); Stinson, Jeremy (Department of Molecular Biology, Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080 ); Patapoff, Thomas W. (Department of Early-Stage Pharmaceutical Development, Pharma Technical Development, Genentech, Inc., South San Francisco, CA 94080 ); Fuh, Germaine (Department of Antibody Engineering, Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; );
  • 초록  

    Significance On encountering antigens, antibody’s variable domains evolve and mature through multiple rounds of somatic mutation. By surveying the effects of all possible single mutations of an antibody’s variable domains on folding stability and antigen binding, we showed that even for a high-affinity antibody such as the one used in our study, beneficial mutations can be found both near and far from the antigen-binding site. Furthermore, our mutational scan revealed an antigen-distal framework position working as a structural switch whereby a mutation can allow the variable domains to sample different conformational spaces and thus potentially different binding functions. This understanding of the mechanism of somatic mutation in human antibodies illustrates how antibodies efficiently use somatic mutation for evolving diversity in immune recognition. Somatic mutations within the antibody variable domains are critical to the immense capacity of the immune repertoire. Here, via a deep mutational scan, we dissect how mutations at all positions of the variable domains of a high-affinity anti-VEGF antibody G6.31 impact its antigen-binding function. The resulting mutational landscape demonstrates that large portions of antibody variable domain positions are open to mutation, and that beneficial mutations can be found throughout the variable domains. We determine the role of one antigen-distal light chain position 83, demonstrating that mutation at this site optimizes both antigen affinity and thermostability by modulating the interdomain conformational dynamics of the antigen-binding fragment. Furthermore, by analyzing a large number of human antibody sequences and structures, we demonstrate that somatic mutations occur frequently at position 83, with corresponding domain conformations observed for G6.31. Therefore, the modulation of interdomain dynamics represents an important mechanism during antibody maturation in vivo.


  • 주제어

    antibody .   affinity maturation .   immunology .   deep mutational scanning .   conformational dynamics.  

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