title: Biologic TNFα-inhibitors that cross the human blood-brain barrier.
abstract: Tumor necrosis factor (TNF)α inhibitors (TNFI) are a major class of biologic therapeutics, and include decoy receptor and monoclonal antibody (MAb) therapeutics that block TNFα action. TNFα is a pro-inflammatory cytokine in brain disease, such as stroke, brain or spinal cord injury, or Alzheimer disease. However, the biologic TNFIs cannot be developed for the brain, because these large molecules do not cross the blood-brain barrier (BBB). Brain penetrating forms of TNFα decoy receptors or anti-TNFα antibody therapeutics can be re-engineered as IgG fusion proteins with a BBB molecular Trojan horse, such as the mAb against the human insulin receptor (HIR). The HIRMAb undergoes receptor-mediated transport across the BBB via the endogenous insulin receptor, and carries into brain the fused biologic TNFI. A fusion protein of the HIRMAb and the type II TNF receptor (TNFR) extracellular domain, designated the HIRMAb-TNFR fusion protein, has been engineered and expressed in stably transfected Chinese hamster ovary (CHO) cells. The HIRMAb-TNFR fusion protein binds both the HIR and TNFα with low nM affinity. The HIRMAb cross reacts with the Rhesus monkey insulin receptor, and the HIRMAb-TNFR is rapidly, and selectively, taken up by primate brain at concentrations that inhibit TNFα. In addition, a fusion protein of the HIRMAb and a therapeutic single chain Fv (ScFv) antibody has been engineered and also expressed in stably transfected CHO cells. The BBB molecular Trojan horse platform technology allows for the engineering of brain-penetrating recombinant proteins as new biologic therapeutics for the human brain.
authors.affiliation: University of California, Los Angeles, Los Angeles, CA, USA. wpardridge@mednet. ucla.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Pardridge
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D006801:Humans; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C435941:INSR protein, human; D011972:Receptor, Insulin