i-bodies, human single domain antibodies that antagonize chemokine receptor CXCR4

Katherine M Griffiths, Olan Dolezal, Benjamin Cao, Susan K Nilsson, Heng B See, Kevin D G Pfleger, Michael Roche, Paul R Gorry, Andrew Pow, Katerina Viduka, Kevin Lim, Bernadine G. C. Lu, Denison H C Chang, Thomas Murray-Rust, Marc Kvansakul, Matthew A Perugini, Con Dogovski, Marcel Doerflinger, Yuan Zhang, Kathy ParisiJoanne L Casey, Stewart D Nuttall, Michael Foley

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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. 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 (CDR) binding loop, and the isolation and characterisation 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 mobilization of hematopoietic stem cells. Epitope mapping of three CXCR4 i-bodies AM3-114, AM4-272 and AM3-523 revealed binding deep in the binding pocket of the receptor.
Original languageEnglish
Pages (from-to)12641-12657
Number of pages27
JournalJournal of Biological Chemistry
Issue number24
Publication statusPublished - 10 Jun 2016

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