Biologic TNFα-inhibitors that cross the human blood-brain barrier

Pardridge, William M.

doi:10.4161/bbug.1.4.12105

Cited by 34 publications

(27 citation statements)

References 23 publications

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“…TNF-α and IL-1β are known to be upregulated in senile plaques and dystrophic neurites in AD (59) and in an AD mouse model (49). TNF-α is thought to amplify brain inflammation and cognitive impairment in both AD patients and AD models (60)(61)(62)(63)(64). Dysregulated apoptosis has been implicated in several neurodegenerative disorders, including AD.…”

Section: Animals Cxcr3-deficient (Cxcr3mentioning

confidence: 99%

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

Krauthausen¹,

Kummer²,

Zimmermann³

et al. 2014

J. Clin. Invest.

118

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Section: Animals Cxcr3-deficient (Cxcr3mentioning

confidence: 99%

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

Krauthausen¹,

Kummer²,

Zimmermann³

et al. 2014

J. Clin. Invest.

118

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“…One group is developing what it refers to as a molecular Trojan horse decoy receptor system to get a similar anti-TNF fusion molecule into the brain (Pardridge, 2010;Zhou et al, 2011). Others (http://www.neurokine.…”

Section: A Specific Inhibition Of Tumor Necrosis Factormentioning

confidence: 99%

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

et al. 2012

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“…Biologic TNFIs could also prove to be important new treatments for brain disorders (Pardridge, 2010b), because TNF␣ plays a proinflammatory role in both acute disorders of the brain [such as traumatic brain injury, spinal cord injury, and stroke (Nawashiro et al, 1997;Knoblach et al, 1999;Marchand et al, 2009)] as well as chronic brain diseases [such as Parkinson's disease or Alzheimer's disease (McCoy et al, 2006;McAlpine et al, 2009)]. However, biologic TNFIs cannot be developed for the brain, because these large molecule drugs do not cross the BBB, as recently demonstrated for the TNFR in the primate (Boado et al, 2010a).…”

Section: Zhou Et Almentioning

confidence: 99%

Brain-Penetrating Tumor Necrosis Factor Decoy Receptor in the Mouse

et al. 2010

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ABSTRACT:Biologic tumor necrosis factor inhibitors (TNFIs) include TNF decoy receptors (TNFRs). TNF␣ plays a pathologic role in both acute and chronic brain disease. However, biologic TNFIs cannot be developed as brain therapeutics because these large molecule drugs do not cross the blood-brain barrier (BBB). To enable penetration of the brain via receptor-mediated transport, the human TNFR type II was re-engineered as an IgG fusion protein, where the IgG part is a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb part of the fusion protein acts as a molecular Trojan horse to ferry the TNFR across the BBB via transport on the endogenous BBB TfR. cTfRMAb-TNFR was expressed by stably transfected Chinese hamster ovary cells and purified by affinity chromatography to homogeneity on electrophoretic gels. The fusion protein reacted with antibodies to both mouse IgG and the human TNFR and bound TNF␣ with high affinity (K d ‫؍‬ 96 ؎ 34 pM). cTfRMAb-TNFR was rapidly transported into mouse brain in vivo after intravenous administration, and the brain uptake of the fusion protein was 2.8 ؎ 0.5% of injected dose per gram of brain, which is >45-fold higher than the brain uptake of an IgG that does not recognize the mouse TfR. This new IgG-TNFR fusion protein can be tested in mouse models of brain diseases in which TNF␣ plays a pathologic role.

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Biologic TNFα-inhibitors that cross the human blood-brain barrier

Cited by 34 publications

References 23 publications

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

Brain-Penetrating Tumor Necrosis Factor Decoy Receptor in the Mouse

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