i-bodies, Human Single Domain Antibodies That Antagonize Chemokine Receptor CXCR4

被引：47

作者：

Griffiths, Katherine ^{[1
]}

Dolezal, Olan ^{[2
]}

Cao, Benjamin ^{[3
,4
]}

Nilsson, Susan K. ^{[3
,4
]}

See, Heng B. ^{[5
,6
]}

Pfleger, Kevin D. G. ^{[5
,6
,7
]}

Roche, Michael ^{[8
,9
]}

Gorry, Paul R. ^{[10
]}

Pow, Andrew ^{[1
,13
]}

Viduka, Katerina ^{[1
,14
]}

Lim, Kevin ^{[1
,15
]}

Lu, Bernadine G. C. ^{[1
,16
]}

Chang, Denison H. C. ^{[1
,17
]}

Murray-Rust, Thomas ^{[1
]}

Kvansakul, Marc ^{[11
]}

Perugini, Matthew A. ^{[11
]}

Dogovski, Con ^{[11
,18
]}

Doerflinger, Marcel ^{[1
,19
]}

Zhang, Yuan ^{[12
]}

Parisi, Kathy ^{[1
,11
]}

Casey, Joanne L. ^{[1
,19
]}

Nuttall, Stewart D. ^{[2
]}

Foley, Michael ^{[1
,11
]}

机构：

[1] AdAlta Pty Ltd, 15-2 Pk Dr, Bundoora, Vic 3083, Australia

[2] CSIRO Mfg, Biomed Mfg, 343 Royal Parade, Parkville, Vic 3052, Australia

[3] Monash Univ, Australian Regenerat Med Inst, Wellington Rd, Clayton, Vic 3800, Australia

[4] CSIRO Mfg, Biomed Mfg, Bayview Ave, Clayton, Vic 3168, Australia

[5] Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia

[6] Univ Western Australia, Ctr Med Res, Crawley, WA 6009, Australia

[7] Dimerix Biosci Ltd, Nedlands, WA 6009, Australia

[8] Univ Melbourne, Doherty Inst Infect & Immun, 792 Elizabeth St, Melbourne, Vic 3000, Australia

[9] Burnet Inst, 85 Commercial Rd, Melbourne, Vic 3004, Australia

[10] RMIT Univ, Coll Sci Engn & Hlth, Sch Hlth & Biomed Sci, Melbourne, Vic 3001, Australia

[11] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem & Genet, Melbourne, Vic 3086, Australia

[12] Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic 3065, Australia

[13] Compugen Ltd, 260 East Grand Ave, San Francisco, CA 94080 USA

[14] AgriBio Ctr, Dept Econ Dev Jobs Transport & Resources, 5 Ring Rd, Bundoora, Vic 3083, Australia

[15] Imunexus, 343 Royal Parade, Parkville, Vic 3052, Australia

[16] CSL Ltd, 45 Poplar Rd, Parkville, Vic 3052, Australia

[17] Virbac, Milperra, NSW 2214, Australia

[18] Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic 3010, Australia

[19] Nexvet, 21-31 Wright St, Clayton, Vic 3168, Australia

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2016年 / 291卷 / 24期

关键词：

HUMAN-IMMUNODEFICIENCY-VIRUS; HEMATOPOIETIC STEM; MONOCLONAL-ANTIBODIES; RAPID MOBILIZATION; CRYSTAL-STRUCTURE; ANTIGEN RECEPTOR; PROGENITOR CELLS; AMD3100; HIV-1; FRAGMENTS;

D O I：

10.1074/jbc.M116.721050

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：12641 / 12657

页数：17

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