Presentation Title

A brain penetrating biologic TNF-alpha inhibitor for Alzheimer’s disease

Start Date

November 2016

End Date

November 2016

Location

HUB 302-149

Type of Presentation

Poster

Abstract

Tumor necrosis factor alpha (TNFa) is a proinflammatory cytokine thought to play a role in several stages of Alzheimer’s disease (AD) pathogenesis including Ab plaque formation, neuroinflammation, neurodegeneration, and impaired cognition and memory. Neural TNFa can be decreased using TNFa inhibitors (TNFIs). Current TNFIs are biologic drugs, macromolecules that do not cross the blood-brain barrier (BBB) and do not offer protection in acute or chronic models of neurodegeneration. A BBB-penetrating TNFI was engineered by the fusion of a type II human TNF receptor (TNFR) to a genetically engineered chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated cTfRMAb-TNFR. The cTfRMAb domain functions as a molecular Trojan horse, noncompetitively binding to endogenous mouse transferrin receptors and ferrying the drug across the BBB via receptor-mediated transcytosis. The fusion protein was administered by intraperitoneal injection to adult male mutant APP/PS1 mice 3 times/week for 12 weeks to ensure chronic exposure. Etanercept was used as a negative control and saline as a vehicle control. After 12 weeks of treatment, locomotion and spatial memory were assessed, mice were sacrificed and brains were assessed for Ab, plaque burden, and neurodegeneration. The cTfRMAb-TNFR fusion protein treatment caused significant reduction in memory impairment as well as amyloid plaque and Ab burden, whie negative control Etanercept caused a reduction in amyloid plaque but not amyloid beta peptide or memory impairment. Fusion protein cTfRMAb-TNFR is protective against memory impairment, plaque, and Ab burden in a mouse model of Alzheimer’s disease.

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Nov 12th, 1:00 PM Nov 12th, 2:00 PM

A brain penetrating biologic TNF-alpha inhibitor for Alzheimer’s disease

HUB 302-149

Tumor necrosis factor alpha (TNFa) is a proinflammatory cytokine thought to play a role in several stages of Alzheimer’s disease (AD) pathogenesis including Ab plaque formation, neuroinflammation, neurodegeneration, and impaired cognition and memory. Neural TNFa can be decreased using TNFa inhibitors (TNFIs). Current TNFIs are biologic drugs, macromolecules that do not cross the blood-brain barrier (BBB) and do not offer protection in acute or chronic models of neurodegeneration. A BBB-penetrating TNFI was engineered by the fusion of a type II human TNF receptor (TNFR) to a genetically engineered chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated cTfRMAb-TNFR. The cTfRMAb domain functions as a molecular Trojan horse, noncompetitively binding to endogenous mouse transferrin receptors and ferrying the drug across the BBB via receptor-mediated transcytosis. The fusion protein was administered by intraperitoneal injection to adult male mutant APP/PS1 mice 3 times/week for 12 weeks to ensure chronic exposure. Etanercept was used as a negative control and saline as a vehicle control. After 12 weeks of treatment, locomotion and spatial memory were assessed, mice were sacrificed and brains were assessed for Ab, plaque burden, and neurodegeneration. The cTfRMAb-TNFR fusion protein treatment caused significant reduction in memory impairment as well as amyloid plaque and Ab burden, whie negative control Etanercept caused a reduction in amyloid plaque but not amyloid beta peptide or memory impairment. Fusion protein cTfRMAb-TNFR is protective against memory impairment, plaque, and Ab burden in a mouse model of Alzheimer’s disease.