Mary Wilson
Well-known member
September 18, 2023
https://doi.org/10.1073/pnas.2303455120
Ruiqi Huang, Gabrielle Warner Jenkins, Yunjeong Kim, +32, and Vaughn V. Smider
Significance
Cows produce antibodies with unusually long CDR H3 regions that form their own unique disulfide bonded “knob” structure that protrudes far from the typical antibody surface. Potently neutralizing ultralong CDR H3 antibodies targeting coronavirus have knobs that can be produced independently of the antibody and maintain their function. These CDR H3-derived knob regions are the smallest antibody fragments with broad applications in biomedicine.
Abstract
Cows produce antibodies with a disulfide-bonded antigen-binding domain embedded within ultralong heavy chain third complementarity determining regions. This “knob” domain is analogous to natural cysteine-rich peptides such as knottins in that it is small and stable but can accommodate diverse loops and disulfide bonding patterns. We immunized cattle with SARS-CoV-2 spike and found ultralong CDR H3 antibodies that could neutralize several viral variants at picomolar IC[SUB]50[/SUB] potencies in vitro and could protect from disease in vivo. The independent CDR H3 peptide knobs were expressed and maintained the properties of the parent antibodies. The knob interaction with SARS-CoV-2 spike was revealed by electron microscopy, X-ray crystallography, NMR spectroscopy, and mass spectrometry and established ultralong CDR H3-derived knobs as the smallest known recombinant independent antigen-binding fragment. Unlike other vertebrate antibody fragments, these knobs are not reliant on the immunoglobulin domain and have potential as a new class of therapeutics.
https://www.pnas.org/doi/10.1073/pnas.2303455120
https://doi.org/10.1073/pnas.2303455120
Ruiqi Huang, Gabrielle Warner Jenkins, Yunjeong Kim, +32, and Vaughn V. Smider
Significance
Cows produce antibodies with unusually long CDR H3 regions that form their own unique disulfide bonded “knob” structure that protrudes far from the typical antibody surface. Potently neutralizing ultralong CDR H3 antibodies targeting coronavirus have knobs that can be produced independently of the antibody and maintain their function. These CDR H3-derived knob regions are the smallest antibody fragments with broad applications in biomedicine.
Abstract
Cows produce antibodies with a disulfide-bonded antigen-binding domain embedded within ultralong heavy chain third complementarity determining regions. This “knob” domain is analogous to natural cysteine-rich peptides such as knottins in that it is small and stable but can accommodate diverse loops and disulfide bonding patterns. We immunized cattle with SARS-CoV-2 spike and found ultralong CDR H3 antibodies that could neutralize several viral variants at picomolar IC[SUB]50[/SUB] potencies in vitro and could protect from disease in vivo. The independent CDR H3 peptide knobs were expressed and maintained the properties of the parent antibodies. The knob interaction with SARS-CoV-2 spike was revealed by electron microscopy, X-ray crystallography, NMR spectroscopy, and mass spectrometry and established ultralong CDR H3-derived knobs as the smallest known recombinant independent antigen-binding fragment. Unlike other vertebrate antibody fragments, these knobs are not reliant on the immunoglobulin domain and have potential as a new class of therapeutics.
https://www.pnas.org/doi/10.1073/pnas.2303455120