Methods in antibody discovery



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Antibodies are an essential part of adaptive immunity and can be raised against almost any molecule. The ability to bind a wide variety of molecules with exquisite specificity, causes antibodies to be highly desirable tools for research and in medicine. Beginning with the discovery of antibodies in 1890 by Behring and Kitasato, the scientific community was aware of the enormous therapeutic potential of molecules that can be induced to bind any disease-causing factor. However, the realization of this potential was stifled by the lack of techniques to isolate and produce antibodies of defined specificity. Since then, versatile antibody discovery methods have been developed, however, initial antibody isolation and characterization remain a bottleneck in the antibody discovery process. The work presented here improves upon existing methods of antibody discovery. Development of a novel yeast surface display strain reduces selection times by half and expedites downstream development by use of a native antibody format that translates effortlessly into full-length antibodies. The combination of antibody yeast surface display and mass-spectrometry based protein sequencing of serum antibodies successfully isolates SARS-CoV-2 binders from infected donors. Additionally, examination of the role of antibody light chains leads to insights into repertoire diversity and sparks an innovative approach to antibody heavy and light chain pairing. Cumulatively, the synergistic use of these antibody discovery methods yields 49 SARS-CoV-2 neutralizing antibodies against a variety of spike protein epitopes. Four antibodies and their binding mode were structurally characterized, revealing overlap with known antigenic supersites of the spike protein, and a unique quaternary binding mode at the receptor binding domain.



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