| Literature DB >> 27036939 |
Katherine Griffiths1, Olan Dolezal2, Benjamin Cao3, Susan K Nilsson3, Heng B See4, Kevin D G Pfleger5, Michael Roche6, Paul R Gorry7, Andrew Pow1, Katerina Viduka1, Kevin Lim1, Bernadine G C Lu1, Denison H C Chang1, Thomas Murray-Rust1, Marc Kvansakul8, Matthew A Perugini8, Con Dogovski8, Marcel Doerflinger1, Yuan Zhang9, Kathy Parisi10, Joanne L Casey1, Stewart D Nuttall2, Michael Foley11.
Abstract
CXCR4 is a G protein-coupled receptor with excellent potential as a therapeutic target for a range of clinical conditions, including stem cell mobilization, cancer prognosis and treatment, fibrosis therapy, and HIV infection. We report here the development of a fully human single-domain antibody-like scaffold termed an "i-body," the engineering of which produces an i-body library possessing a long complementarity determining region binding loop, and the isolation and characterization of a panel of i-bodies with activity against human CXCR4. The CXCR4-specific i-bodies show antagonistic activity in a range of in vitro and in vivo assays, including inhibition of HIV infection, cell migration, and leukocyte recruitment but, importantly, not the mobilization of hematopoietic stem cells. Epitope mapping of the three CXCR4 i-bodies AM3-114, AM4-272, and AM3-523 revealed binding deep in the binding pocket of the receptor.Entities:
Keywords: CXC chemokine receptor type 4 (CXCR-4); G protein-coupled receptor (GPCR); antibody engineering; hematopoietic stem cells; protein structure; single-domain antibody (sdAb, nanobody)
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Year: 2016 PMID： 27036939 PMCID： PMC4933451 DOI： 10.1074/jbc.M116.721050
Source DB: PubMed Journal: J Biol Chem ISSN： 0021-9258 Impact factor: 5.157