title: Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor.
abstract: Biologic tumor necrosis factor (TNF)-α inhibitors do not cross the blood-brain barrier (BBB). A BBB-penetrating TNF-α 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-α 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.
authors.affiliation: Department of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Qing-Hui
authors.initials: QH
authors.lastname: Zhou
authors.forename: Rachita
authors.initials: R
authors.lastname: Sumbria
authors.forename: Eric Ka-Wai
authors.initials: EK
authors.lastname: Hui
authors.forename: Jeff Zhiqiang
authors.initials: JZ
authors.lastname: Lu
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Boado
authors.forename: William M
authors.initials: WM
authors.lastname: Pardridge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000276:immunology / Q000378:metabolism; D016466:CHO Cells; D035061:Control Groups; D003342:Corpus Striatum / Q000187:drug effects; D006224:Cricetinae; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000276:immunology; D051381:Rats; D011990:Receptors, Transferrin / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D013378:Substantia Nigra / Q000187:drug effects; D053319:Tumor Necrosis Factor Decoy Receptors / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D018696:Neuroprotective Agents; D011990:Receptors, Transferrin; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D014446:Tyrosine 3-Monooxygenase; D000068800:Etanercept