Brain protection from stroke with intravenous TNFα decoy receptor-Trojan horse fusion protein.
Tumor necrosis factor (TNF)-α is produced in brain in response to acute cerebral ischemia, and promotes neuronal apoptosis. Biologic TNF inhibitors (TNFIs), such as the etanercept, cannot be developed as new stroke treatments because these large molecule drugs do not cross the blood-brain barrier (BBB). A BBB-penetrating biologic TNFI was engineered by fusion of the type II human TNF receptor (TNFR) to each heavy chain of a genetically engineered chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated as cTfRMAb-TNFR fusion protein. The cTfRMAb domain of the fusion protein acts as a molecular Trojan horse to deliver the fused TNFR across the BBB. Etanercept or the cTfRMAb-TNFR fusion protein (1 mg/kg) was administered intravenously in adult mice subjected to 1-hour reversible middle cerebral artery occlusion up to 90 minutes after the occlusion. Neuroprotection was assessed at 24 hours or 7 days after occlusion. The cTfRMAb-TNFR fusion protein treatment caused a significant 45%, 48%, 42%, and 54% reduction in hemispheric, cortical, and subcortical stroke volumes, and neural deficit, respectively. Intravenous etanercept had no therapeutic effect. Biologic TNFIs can be reengineered for BBB penetration, and the IgG-TNFR fusion protein is therapeutic after delayed intravenous administration in experimental stroke.
Department of Medicine, UCLA, Los Angeles, California 90024, USA.
Rachita K
RK
Sumbria
Ruben J
RJ
Boado
William M
WM
Pardridge
D061605:Administration, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D011990:Receptors, Transferrin / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D007142:Immunoglobulin gamma-Chains; D018696:Neuroprotective Agents; D011990:Receptors, Transferrin; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C099374:Ro 45-2081