Volume 127, Issue 7 pp. 2154-2158

Zuschrift

Rational Design of a Humanized Glucagon-Like Peptide-1 Receptor Agonist Antibody

Dr. Yong Zhang,

Dr. Yong Zhang

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

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Dr. Huafei Zou,

Dr. Huafei Zou

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

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Dr. Ying Wang,

Dr. Ying Wang

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

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Dawna Caballero,

Dawna Caballero

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

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Jose Gonzalez,

Jose Gonzalez

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

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Elizabeth Chao,

Elizabeth Chao

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

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Gus Welzel,

Gus Welzel

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

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Dr. Weijun Shen,

Dr. Weijun Shen

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

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Dr. Danling Wang,

Dr. Danling Wang

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

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Dr. Peter G. Schultz,

Corresponding Author

Dr. Peter G. Schultz

[email protected]

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

California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA 92037 (USA)Search for more papers by this author

Dr. Feng Wang,

Corresponding Author

Dr. Feng Wang

[email protected]

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

California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA 92037 (USA)Search for more papers by this author

Dr. Yong Zhang,

Dr. Yong Zhang

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

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Dr. Huafei Zou,

Dr. Huafei Zou

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

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Dr. Ying Wang,

Dr. Ying Wang

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

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Dawna Caballero,

Dawna Caballero

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

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Jose Gonzalez,

Jose Gonzalez

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

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Elizabeth Chao,

Elizabeth Chao

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

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Gus Welzel,

Gus Welzel

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

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Dr. Weijun Shen,

Dr. Weijun Shen

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

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Dr. Danling Wang,

Dr. Danling Wang

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

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Dr. Peter G. Schultz,

Corresponding Author

Dr. Peter G. Schultz

[email protected]

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

California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA 92037 (USA)Search for more papers by this author

Dr. Feng Wang,

Corresponding Author

Dr. Feng Wang

[email protected]

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

California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA 92037 (USA)Search for more papers by this author

First published: 29 December 2014

https://doi.org/10.1002/ange.201410049

Citations: 4

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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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Volume127, Issue7

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Rational Design of a Humanized Glucagon-Like Peptide-1 Receptor Agonist Antibody

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Rational Design of a Humanized Glucagon-Like Peptide-1 Receptor Agonist Antibody

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