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  • Showing results for functional human antibody cdr fusions as long acting therapeutic endocrine agonists. Your search for Functional Human Antibody CDR Fusions as Long-Acting Therpeutic Endocrine Agonists retrieved no results.
Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1356-61. doi: 10.1073/pnas.1423668112. Epub 2015 Jan 20.

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

Author information

1
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
2
California Institute for Biomedical Research, La Jolla, CA 92037.
3
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and California Institute for Biomedical Research, La Jolla, CA 92037 schultz@scripps.edu fwang@calibr.org.
4
California Institute for Biomedical Research, La Jolla, CA 92037 schultz@scripps.edu fwang@calibr.org.

Abstract

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.

KEYWORDS:

antibody; growth hormone; leptin; pharmacology; protein engineering

PMID:
25605877
PMCID:
PMC4321239
DOI:
10.1073/pnas.1423668112
[Indexed for MEDLINE]
Free PMC Article

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