Pharmacokinetics and brain uptake in the rhesus monkey of a fusion protein of arylsulfatase a and a monoclonal antibody against the human insulin receptor

被引:49
作者
Boado, Ruben J. [1 ,2 ]
Lu, Jeff Zhiqiang [1 ]
Hui, Eric K. -W. [1 ]
Sumbria, Rachita K. [2 ]
Pardridge, William M. [2 ]
机构
[1] ArmaGen Technol Inc, Santa Monica, CA 90401 USA
[2] Univ Calif Los Angeles, Los Angeles, CA 90024 USA
关键词
arylsulfatase A; monoclonal antibody; drug delivery; insulin receptor; bloodbrain barrier; MULTIPLE SULFATASE DEFICIENCY; NERVOUS-SYSTEM PATHOLOGY; METACHROMATIC LEUKODYSTROPHY; TARGETED DELIVERY; TROJAN HORSE; MOUSE MODEL; BARRIER; EXPRESSION; MICE; ACCUMULATION;
D O I
10.1002/bit.24795
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, and acts as a molecular Trojan horse to ferry the ASA into brain from blood. The HIRMAb-ASA is expressed in stably transfected Chinese hamster ovary cells grown in serum free medium, and purified by protein A affinity chromatography. The fusion protein retains high affinity binding to the HIR, EC50=0.34 +/- 0.11nM, and retains high ASA enzyme activity, 20 +/- 1units/mg. The HIRMAb-ASA fusion protein is endocytosed and triaged to the lysosomal compartment in MLD fibroblasts. The fusion protein was radio-labeled with the BoltonHunter reagent, and the [125I]-HIRMAb-ASA rapidly penetrates the brain in the Rhesus monkey following intravenous administration. Film and emulsion autoradiography of primate brain shows global distribution of the fusion protein throughout the monkey brain. These studies describe a new biological entity that is designed to treat the brain of humans with MLD following non-invasive, intravenous infusion of an IgG-ASA fusion protein. Biotechnol. Bioeng. 2013; 110: 14561465. (c) 2012 Wiley Periodicals, Inc.
引用
收藏
页码:1456 / 1465
页数:10
相关论文
共 30 条
[1]   THE ASSAY OF ARYLSULPHATASE-A AND ARYLSULPHATASE-B IN HUMAN URINE [J].
BAUM, H ;
DODGSON, KS ;
SPENCER, B .
CLINICA CHIMICA ACTA, 1959, 4 (03) :453-455
[2]   Accumulation of lysosulfatide in the brain of arylsulfatase A-deficient mice [J].
Blomqvist, Maria ;
Gieselmann, Volkmar ;
Mansson, Jan-Eric .
LIPIDS IN HEALTH AND DISEASE, 2011, 10
[3]   Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood-brain barrier [J].
Boado, Ruben J. ;
Zhang, Yun ;
Zhang, Yufeng ;
Xia, Chun-fang ;
Wang, Yuntao ;
Pardridge, William M. .
BIOTECHNOLOGY AND BIOENGINEERING, 2008, 99 (02) :475-484
[4]   Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier [J].
Boado, Ruben J. ;
Zhang, Yufeng ;
Zhang, Yun ;
Pardridge, William M. .
BIOTECHNOLOGY AND BIOENGINEERING, 2007, 97 (06) :1376-1386
[5]   Reversal of Lysosomal Storage in Brain of Adult MPS-I Mice with Intravenous Trojan Horse-Iduronidase Fusion Protein [J].
Boado, Ruben J. ;
Hui, Eric Ka-Wai ;
Lu, Jeff Zhiqiang ;
Zhou, Qing-Hui ;
Pardridge, William M. .
MOLECULAR PHARMACEUTICS, 2011, 8 (04) :1342-1350
[6]   Comparison of Blood-Brain Barrier Transport of Glial-Derived Neurotrophic Factor (GDNF) and an IgG-GDNF Fusion Protein in the Rhesus Monkey [J].
Boado, Ruben J. ;
Pardridge, William M. .
DRUG METABOLISM AND DISPOSITION, 2009, 37 (12) :2299-2304
[7]  
Bourne GH, 1975, RHESUS MONKEY, P6
[8]   The distribution of D2/D3 receptor binding in the adolescent rhesus monkey using small animal PET imaging [J].
Christian, Bradley T. ;
Vandehey, Nicholas T. ;
Fox, Andrew S. ;
Murali, Dhanabalan ;
Oakes, Terrence R. ;
Converse, Alex K. ;
Nickles, Robert J. ;
Shelton, Steve E. ;
Davidson, Richard J. ;
Kalin, Ned H. .
NEUROIMAGE, 2009, 44 (04) :1334-1344
[9]   The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases [J].
Cosma, MP ;
Pepe, S ;
Annunziata, I ;
Newbold, RF ;
Grompe, M ;
Parenti, G ;
Ballabio, A .
CELL, 2003, 113 (04) :445-456
[10]  
Dali C, 2009, AM COLL MED GEN ANN