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- Title
Rational Design of a Humanized Glucagon-Like Peptide-1 Receptor Agonist Antibody.
- Authors
Zhang, Yong; Zou, Huafei; Wang, Ying; Caballero, Dawna; Gonzalez, Jose; Chao, Elizabeth; Welzel, Gus; Shen, Weijun; Wang, Danling; Schultz, Peter G.; Wang, Feng
- Abstract
Bovine antibody BLV1H12 possesses a unique 'stalk-knob' architecture in its ultralong heavy chain CDR3, allowing substitutions of the 'knob' domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon-like peptide-1 (GLP-1) receptor agonist antibody by first introducing a coiled-coil 'stalk' into CDR3H of the antibody herceptin. Exendin-4 (Ex-4), a GLP-1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex-4 to allow release of the N-terminus of the fused peptide. The resulting clipped herceptin-Ex-4 fusion protein is more potent in vitro in activating GLP-1 receptors than the Ex-4 peptide. The clipped herceptin-Ex-4 has an extended plasma half-life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics.
- Subjects
IMMUNOGLOBULINS; PEPTIDES; PHARMACOLOGY; PROTEIN engineering; GLUCAGON
- Publication
Angewandte Chemie International Edition, 2015, Vol 54, Issue 7, p2126
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201410049