Rational Design of a Humanized Glucagon‐Like Peptide‐1 Receptor Agonist Antibody |
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| Authors: | Dr Yong Zhang Dr Huafei Zou Dr Ying Wang Dawna Caballero Jose Gonzalez Elizabeth Chao Gus Welzel Dr Weijun Shen Dr Danling Wang Dr Peter G Schultz Dr Feng Wang |
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| Affiliation: | California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA 92037 (USA) |
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| 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. |
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| Keywords: | antibodies peptide pharmacology protein engineering receptors |
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