Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice

Abstract

Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood–brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (Aβ) 1–42, soluble-oligomeric Aβ, and microgliosis; however, only TfRMAb-TNFR reduced Aβ peptides, Thioflavin-S-positive Aβ plaques, and insoluble-oligomeric Aβ and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematology- or iron-dysregulation in aged APP/PS1 mice.

Advanced Blood–Brain Barrier Drug Delivery

“…The peptide or MAb acts as a molecular Trojan horse to ferry the biologic agent across the BBB via RMT on the endogenous peptide receptor at the brain endothelium. This Special Issue includes seven articles that describe the use of MAb-based Trojan horses targeting the IR, TfR1, IGF1R, or an orphan receptor [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ], and one article on the use of peptides as a BBB Trojan horse [ 9 ].…”

“…TNFα plays a pro-inflammatory role in AD, but etanercept cannot be used to treat AD because it does not cross the BBB [ 2 ]. However, the human TNFR ECD can be re-engineered for BBB penetration and for the treatment of AD with the genetic engineering and application of an IgG-TNFR fusion protein [ 4 ]. Ou et al [ 4 ] describe the chronic treatment of 1-year-old double transgenic APP/PS1 AD mice with 2–3 mg/kg of either etanercept or the TfRMAb-TNFR fusion protein administered by intra-peritoneal injection three times a week for 10 weeks.…”

“…However, the human TNFR ECD can be re-engineered for BBB penetration and for the treatment of AD with the genetic engineering and application of an IgG-TNFR fusion protein [ 4 ]. Ou et al [ 4 ] describe the chronic treatment of 1-year-old double transgenic APP/PS1 AD mice with 2–3 mg/kg of either etanercept or the TfRMAb-TNFR fusion protein administered by intra-peritoneal injection three times a week for 10 weeks. The TfRMAb-TNFR fusion protein, but not etanercept, reduced the Aβ peptide content, thioflavin-S positive Aβ plaques, and insoluble oligomeric Aβ in the brain, in parallel with an increase in Aβ plaque-associated phagocytic microglia [ 4 ].…”

“…Ou et al [ 4 ] describe the chronic treatment of 1-year-old double transgenic APP/PS1 AD mice with 2–3 mg/kg of either etanercept or the TfRMAb-TNFR fusion protein administered by intra-peritoneal injection three times a week for 10 weeks. The TfRMAb-TNFR fusion protein, but not etanercept, reduced the Aβ peptide content, thioflavin-S positive Aβ plaques, and insoluble oligomeric Aβ in the brain, in parallel with an increase in Aβ plaque-associated phagocytic microglia [ 4 ]. Chronic treatment of the AD mice with the TfRMAb-TNFR fusion protein caused no abnormalities in either hematologic parameters in blood or iron dysregulation in the brain [ 4 ].…”

“…The TfRMAb-TNFR fusion protein, but not etanercept, reduced the Aβ peptide content, thioflavin-S positive Aβ plaques, and insoluble oligomeric Aβ in the brain, in parallel with an increase in Aβ plaque-associated phagocytic microglia [ 4 ]. Chronic treatment of the AD mice with the TfRMAb-TNFR fusion protein caused no abnormalities in either hematologic parameters in blood or iron dysregulation in the brain [ 4 ].…”