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 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.
['Liu|Tao|T|', 'Zhang|Yong|Y|', 'Liu|Yan|Y|', 'Wang|Ying|Y|', 'Jia|Haiqun|H|', 'Kang|Mingchao|M|', 'Luo|Xiaozhou|X|', 'Caballero|Dawna|D|', 'Gonzalez|Jose|J|', 'Sherwood|Lance|L|', 'Nunez|Vanessa|V|', 'Wang|Danling|D|', 'Woods|Ashley|A|', 'Schultz|Peter G|PG|', 'Wang|Feng|F|']
D000595:Amino Acid Sequence D000818:Animals D061067:Antibodies, Monoclonal, Humanized D002460:Cell Line D022801:Complementarity Determining Regions D013006:Growth Hormone D006801:Humans D020738:Leptin D051379:Mice D008969:Molecular Sequence Data D016133:Polymerase Chain Reaction D011993:Recombinant Fusion Proteins D000068878:Trastuzumab
antibody pharmacology growth hormone leptin protein engineering