Antibody molecules are enormously important as therapeutic and diagnostic molecules. More recently, unique scaffolds like the VHH of camelids, or even non-antibody frameworks like "knottins" have become important in biomedicine. Antibody diversity and antigen binding in mammals is often restricted to the CDR loops of the immunoglobulin fold. In experiments challenging this paradigm, we have recently solved the crystal structures of two bovine antibodies containing ultralong CDR H3s (56 and 61 amino acids) and also deep sequenced the ultralong repertoire. Our data reveal that these CDR H3s form a very unusual architecture composed of a long b-strand "stalk" which supports a disulfide rich "knob" that protrudes far from the immunoglobulin surface. Interestingly, the two different antibodies contain different patterns of disulfides, which result in different knob structures. Deep sequencing reveals extensive diversity in the ultralong CDR H3s where a multitude of different disulfides could potentially form within the knob. Thus, the bovine antibody system can produce an unprecedented repertoire of mega CDR H3s that may result in an impressive diversity of minifolds containing combinations of somatically generated disulfides. Thus, antibody diversity is located in a new minifold supported by the immunoglobulin domain. We will perform structural, functional, and engineering studies to investigate the properties of this new antibody class, as well as to lead the way to developing this unique structure into therapeutics.

Public Health Relevance

Understanding the structure and function of antibodies is enormously important in several medical fields. Antibody drugs are now a large therapeutic class, therefore detailed knowledge underlying antibody diversity, physical properties, affinity and engineering is critically important to drug development. Our research on the structure of a unique class of bovine antibodies with ultralong CDR3s will further develop our understanding of and ability to engineer the antibody molecule.

National Institute of Health (NIH)
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Macromolecular Structure and Function B Study Section (MSFB)
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Smith, Ward
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Scripps Research Institute
La Jolla
United States
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