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I-bodies: human single domain antibodies that antagonize chemokine receptor CXCR4.

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Griffiths K, Dolezal O, Cao B, Nilsson SK, See HB, Pfleger KD, Roche M, Gorry PR, Pow A, Viduka K, Lim K, Lu BG, Chang DH, Murray-Rust TA, Kvansakul M, Perugini MA, Dogovski C, Doerflinger M, Zhang Y, Parisi K, Casey JL, Nuttall SD, Foley M,


Griffiths K, Dolezal O, Cao B, Nilsson SK, See HB, Pfleger KD, Roche M, Gorry PR, Pow A, Viduka K, Lim K, Lu BG, Chang DH, Murray-Rust TA, Kvansakul M, Perugini MA, Dogovski C, Doerflinger M, Zhang Y, Parisi K, Casey JL, Nuttall SD, Foley M, (click to view)

Griffiths K, Dolezal O, Cao B, Nilsson SK, See HB, Pfleger KD, Roche M, Gorry PR, Pow A, Viduka K, Lim K, Lu BG, Chang DH, Murray-Rust TA, Kvansakul M, Perugini MA, Dogovski C, Doerflinger M, Zhang Y, Parisi K, Casey JL, Nuttall SD, Foley M,

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The Journal of biological chemistry 2016 4 1() pii

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. 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.

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