Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Angew Chem Int Ed Engl. 2015 Feb 9;54(7):2126-30. doi: 10.1002/anie.201410049. Epub 2014 Dec 29.

Rational design of a humanized glucagon-like peptide-1 receptor agonist antibody.

Author information

1
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA 92037 (USA).

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.

KEYWORDS:

antibodies; peptide; pharmacology; protein engineering; receptors

PMID:
25556336
DOI:
10.1002/anie.201410049
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center