PMID- 17286273
OWN - NLM
STAT- MEDLINE
DCOM- 20070918
LR  - 20071203
IS  - 0006-3592 (Print)
IS  - 0006-3592 (Linking)
VI  - 97
IP  - 6
DP  - 2007 Aug 15
TI  - 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.
PG  - 1376-86
AB  - Neurotrophins, such as brain derived neurotrophic factor (BDNF), do not cross the 
      blood-brain barrier (BBB). Certain monoclonal antibodies (MAb) to the human 
      insulin receptor (HIR) do cross the BBB via receptor-mediated transport, and can 
      act as a molecular Trojan horse to ferry across the BBB an attached drug. A 
      genetically engineered fusion protein was produced whereby the amino terminus of 
      human BDNF is fused to the carboxyl terminus of the heavy chain of a chimeric 
      HIRMAb. The HIRMAb-BDNF fusion protein reacted equally with antibodies to human 
      IgG and BDNF. The bi-functionality of the fusion protein was retained as the 
      affinity of the fusion protein for the HIR was identical to that of the chimeric 
      HIRMAb, and the affinity of the fusion protein for the trkB receptor was 
      identical to that of BDNF. The fusion protein was equi-potent with BDNF in a 
      neuroprotection assay in human neural cells. The pharmacokinetics (PK) of the 
      fusion protein was examined in the adult Rhesus monkey. The mean residence time 
      (MRT) of the fusion protein in blood was >100-fold longer than the MRT of BDNF. 
      Therapeutic levels of BDNF were produced in primate brain following the 
      intravenous administration of the fusion protein. A fusion protein tandem vector 
      was engineered that allowed for isolation of a CHO cell line that produced the 
      fusion protein at high levels in serum free medium. Neurotrophins, such as BDNF, 
      can be re-formulated to enable these molecules to cross the human BBB, and such 
      fusion proteins represent a new class of human neurotherapeutics.
CI  - (c) 2007 Wiley Periodicals, Inc.
FAU - Boado, Ruben J
AU  - Boado RJ
AD  - ArmaGen Technologies Inc., Santa Monica, California, USA.
FAU - Zhang, Yufeng
AU  - Zhang Y
FAU - Zhang, Yun
AU  - Zhang Y
FAU - Pardridge, William M
AU  - Pardridge WM
LA  - eng
GR  - R44-NS-044654/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Biotechnol Bioeng
JT  - Biotechnology and bioengineering
JID - 7502021
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Recombinant Fusion Proteins)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/genetics/*pharmacokinetics
MH  - Blood-Brain Barrier/*metabolism
MH  - Brain-Derived Neurotrophic Factor/*metabolism/*pharmacokinetics
MH  - Drug Delivery Systems/*methods
MH  - Female
MH  - Haplorhini
MH  - Humans
MH  - Macaca mulatta
MH  - Metabolic Clearance Rate
MH  - Protein Engineering/*methods
MH  - Recombinant Fusion Proteins/pharmacokinetics
EDAT- 2007/02/09 09:00
MHDA- 2007/09/19 09:00
CRDT- 2007/02/09 09:00
PHST- 2007/02/09 09:00 [pubmed]
PHST- 2007/09/19 09:00 [medline]
PHST- 2007/02/09 09:00 [entrez]
AID - 10.1002/bit.21369 [doi]
PST - ppublish
SO  - Biotechnol Bioeng. 2007 Aug 15;97(6):1376-86. doi: 10.1002/bit.21369.