title: Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Haiqun
authors.initials: H
authors.lastname: Jia
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Luo
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Dawna
authors.initials: D
authors.lastname: Caballero
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Jose
authors.initials: J
authors.lastname: Gonzalez
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Lance
authors.initials: L
authors.lastname: Sherwood
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nunez
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Ashley
authors.initials: A
authors.lastname: Woods
authors.affiliation: 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.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037 schultz@scripps.edu fwang@calibr.org.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000276:immunology; D002460:Cell Line; D022801:Complementarity Determining Regions / Q000276:immunology*; D013006:Growth Hormone / Q000819:agonists* / Q000276:immunology; D006801:Humans; D020738:Leptin / Q000819:agonists* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000494:pharmacology; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D022801:Complementarity Determining Regions; D020738:Leptin; D011993:Recombinant Fusion Proteins; D013006:Growth Hormone; D000068878:Trastuzumab
keywords: antibody; growth hormone; leptin; pharmacology; protein engineering