RGD Reference Report - Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor. - Rat Genome Database

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Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor.

Authors: Zhou, QH  Sumbria, R  Hui, EK  Lu, JZ  Boado, RJ  Pardridge, WM 
Citation: Zhou QH, etal., J Pharmacol Exp Ther. 2011 Nov;339(2):618-23. doi: 10.1124/jpet.111.185876. Epub 2011 Aug 10.
RGD ID: 7247422
Pubmed: PMID:21831964   (View Abstract at PubMed)
PMCID: PMC3199996   (View Article at PubMed Central)
DOI: DOI:10.1124/jpet.111.185876   (Journal Full-text)

Biologic tumor necrosis factor (TNF)-alpha inhibitors do not cross the blood-brain barrier (BBB). A BBB-penetrating TNF-alpha inhibitor was engineered by fusion of the extracellular domain of the type II human TNF receptor (TNFR) to the carboxyl terminus of the heavy chain of a mouse/rat chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb-TNFR fusion protein and etanercept bound human TNF-alpha with high affinity and K(D) values of 374 +/- 77 and 280 +/- 80 pM, respectively. Neuroprotection in brain in vivo after intravenous administration of the fusion protein was examined in a mouse model of Parkinson's disease. Mice were also treated with saline or a non-BBB-penetrating TNF decoy receptor, etanercept. After intracerebral injection of the nigral-striatal toxin, 6-hydroxydopamine, mice were treated every other day for 3 weeks. Treatment with the cTfRMAb-TNFR fusion protein caused an 83% decrease in apomorphine-induced rotation, a 67% decrease in amphetamine-induced rotation, a 82% increase in vibrissae-elicited forelimb placing, and a 130% increase in striatal tyrosine hydroxylase (TH) enzyme activity. In contrast, chronic treatment with etanercept, which does not cross the BBB, had no effect on neurobehavior or striatal TH enzyme activity. A bridging enzyme-linked immunosorbent assay specific for the cTfRMAb-TNFR fusion protein showed that the immune response generated in the mice was low titer. In conclusion, a biologic TNF inhibitor is neuroprotective after intravenous administration in a mouse model of neurodegeneration, providing that the TNF decoy receptor is reengineered to cross the BBB.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinsonism treatmentISOTnf (Mus musculus)7247422; 7247422 RGD 
Parkinsonism treatmentIDA 7247422; 7247422 RGD 
Parkinsonism treatmentISOTNFRSF1B (Homo sapiens)7247422; 7247422 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Tnf  (tumor necrosis factor)
Tnfrsf1b  (TNF receptor superfamily member 1B)

Genes (Mus musculus)
Tnf  (tumor necrosis factor)
Tnfrsf1b  (tumor necrosis factor receptor superfamily, member 1b)

Genes (Homo sapiens)
TNF  (tumor necrosis factor)
TNFRSF1B  (TNF receptor superfamily member 1B)


Additional Information