Skip to main content
U.S. flag

An official website of the United States government

Blood−brain barrier penetrating biologic TNF‑α inhibitor for Alzheimer’s disease


Year of Publication:
Contact PI Name:
Rachita K. Sumbria
Contact PI Affiliation:
Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, Claremont, California, USA
Rudy Chang, Jillian Knox, Jae Chang, Aram Derbedrossian, Vitaly Vasilevko, David Cribbs, Ruben J. Boado, William M. Pardridge
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
Study Goal and Principal Findings:

Tumor necrosis factor alpha (TNF-α) driven processes are involved at multiple stages of Alzheimer’s disease (AD) pathophysiology and disease progression. Biologic TNF-α inhibitors (TNFIs) are the most potent class of TNFIs but cannot be developed for AD since these macromolecules do not cross the blood−brain barrier (BBB). A BBB-penetrating TNFI was engineered by the fusion of the extracellular domain of the type II human TNF receptor (TNFR) to a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), designated as the cTfRMAb-TNFR fusion protein. The cTfRMAb domain functions as a molecular Trojan horse, binding to the mouse TfR and ferrying the biologic TNFI across the BBB via receptor-mediated transcytosis. The aim of the study was to examine the effect of this BBB-penetrating biologic TNFI in a mouse model of AD. Six-month-old APPswe, PSEN 1dE9 (APP/PS1) transgenic mice were treated with saline (n = 13), the cTfRMAb-TNFR fusion protein (n = 12), or etanercept (non-BBB-penetrating biologic TNFI; n = 11) 3 days per week intraperitoneally. After 12 weeks of treatment, recognition memory was assessed using the novel object recognition task, mice were sacrificed, and brains were assessed for amyloid beta (Aβ) load, neuroinflammation, BBB damage, and cerebral microhemorrhages. The cTfRMAb-TNFR fusion protein caused a significant reduction in brain Aβ burden (both Aβ peptide and plaque), neuroinflammatory marker ICAM-1, and a BBB disruption marker, parenchymal IgG, and improved recognition memory in the APP/PS1 mice. Fusion protein treatment resulted in low antidrug-antibody formation with no signs of either immune reaction or cerebral microhemorrhage development with chronic 12-week treatment. Chronic treatment with the cTfRMAb-TNFR fusion protein, a BBB-penetrating biologic TNFI, offers therapeutic benefits by targeting Aβ pathology, neuroinflammation, and BBB-disruption, overall improving recognition memory in a transgenic mouse model of AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Peptide
Therapeutic Agent:
Therapeutic Target:
Tumor Necrosis Factor alpha (TNF alpha)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Novel Object Recognition Test (NORT)
Dense-core/Compact Plaques
Activated Microglia
beta Amyloid Load
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Deposits
Inflammation-Inducible Protein Intercellular Adhesion Molecule 1 (ICAM1)
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Blood Brain Barrier Disruption
Plaque Characteristics
Drug Concentration-Plasma
Body Weight
Motor Function