Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists

On the basis of the 3D structure of a bovine antibody with a well-folded, ultralong complementarity-determining region (CDR), we have developed a versatile approach for generating human or humanized antibody agonists with excellent pharmacological properties. Using human growth hormone (hGH) and hum...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-02, Vol.112 (5), p.1356-1361
Main Authors: Liu, Tao, Zhang, Yong, Liu, Yan, Wang, Ying, Jia, Haiqun, Kang, Mingchao, Luo, Xiaozhou, Caballero, Dawna, Gonzalez, Jose, Sherwood, Lance, Nunez, Vanessa, Wang, Danling, Woods, Ashley, Schultz, Peter G., Wang, Feng
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antibodies, Monoclonal, Humanized - chemistry
Antibodies, Monoclonal, Humanized - immunology
Biological Sciences
Cell Line
Cells
Complementarity Determining Regions - immunology
Fusion
Growth Hormone - agonists
Growth Hormone - immunology
Humans
Immunoglobulins
Leptin - agonists
Leptin - immunology
Mice
Molecular Sequence Data
Pharmacology
Plasma
Polymerase Chain Reaction
Proteins
Recombinant Fusion Proteins - immunology
Recombinant Fusion Proteins - pharmacology
Rodents
Trastuzumab
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Summary:On the basis of the 3D structure of a bovine antibody with a well-folded, ultralong complementarity-determining region (CDR), we have developed a versatile approach for generating human or humanized antibody agonists with excellent pharmacological properties. Using human growth hormone (hGH) and human leptin (hLeptin) as model proteins, we have demonstrated that functional human antibody CDR fusions can be efficiently engineered by grafting the native hormones into different CDRs of the humanized antibody Herceptin. The resulting Herceptin CDR fusion proteins were expressed in good yields in mammalian cells and retain comparable in vitro biological activity to the native hormones. Pharmacological studies in rodents indicated a 20-to 100-fold increase in plasma circulating half-life for these antibody agonists and significantly extended in vivo activities in the GH-deficient rat model and leptin-deficient obese mouse model for the hGH and hLeptin antibody fusions, respectively. These results illustrate the utility of antibody CDR fusions as a general and versatile strategy for generating long-acting protein therapeutics.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1423668112