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Selectivity Conversion of Protease Inhibitory Antibodies
Tyler Lopez1, Aaron Ramirez1, Chris Benitez1
1Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA.
Antibody Therapeutics
|November 9, 2018
Summary
Researchers developed a novel antibody engineering method to convert matrix metalloproteinase (MMP)-14 inhibitors into highly selective MMP-9 inhibitors. This approach enhances protease drug development by creating specific inhibitory antibodies for targeted therapies.
Area of Science:
- Biochemistry
- Immunology
- Drug Discovery
Background:
- Proteases are crucial pharmaceutical targets, but their homologous nature complicates selective inhibition.
- Dysregulation of proteases is linked to various diseases, necessitating specific therapeutic strategies.
Purpose of the Study:
- To develop a novel method for generating protease-specific inhibitory antibodies.
- To convert a matrix metalloproteinase (MMP)-14 inhibitor into highly selective MMP-9 inhibitory antibodies.
Main Methods:
- Generated an error-prone single-chain variable fragment (scFv) library from an MMP-14 inhibitor.
- Employed dual-color competitive fluorescence-activated cell sorting (FACS) for simultaneous selection and counter-selection.
- Performed extensive biochemical characterization of isolated MMP-9 specific scFvs.
Main Results:
- Achieved dramatic selectivity shifts (690-4,500-fold) from MMP-14 to MMP-9 specificity.
- Isolated scFvs demonstrated nanomolar potency against MMP-9 with high selectivity over related MMPs.
- Characterization revealed competitive inhibition via CDR-H3 interactions near the MMP-9 active site.
Conclusions:
- A novel antibody engineering approach successfully converted protease inhibitor selectivity.
- This methodology is applicable for developing specific inhibitory antibodies against various proteases of biomedical importance.
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