Compositions and methods for blood-brain barrier delivery of igg-decoy receptor fusion proteins

Abstract

Provided herein are compositions and related methods for delivering an IgG-decoy receptor to the CNS. The methods include systemic administration of a bifunctional decoy receptor-BBB receptor antibody fusion antibody comprising a receptor extracellular domain (ECD) covalently linked to an antibody to a receptor expressed on the surface of the blood-brain barrier (BBB receptor). In some embodiments, the compositions described herein are administered to treat a subject suffering from a CNS condition.

1 .- 56 . (canceled) 
     
     
         57 . A method for delivering a decoy receptor across the blood brain barrier, comprising systemically administering to a subject a pharmaceutical composition comprising a bifunctional decoy receptor fusion antibody comprising the amino acid sequence of a heavy chain immunoglobulin or a light chain immunoglobulin covalently linked to the amino acid sequence of a receptor extracellular domain, wherein the fusion antibody binds to a receptor expressed on the BBB and the ligand for the receptor extracellular domain. 
     
     
         58 . The method of  claim 57 , wherein the receptor expressed on the BBB is an insulin receptor, a transferrin receptor, an insulin-like growth factor (IGF) receptor, a leptin receptor, or a lipoprotein receptor. 
     
     
         59 . The method of  claim 58 , wherein the receptor expressed on the BBB is the insulin receptor. 
     
     
         60 . The method of  claim 57 , wherein the receptor extracellular domain is from a TNF-α receptor, a TNF-related apoptosis inducing ligand (TRAIL) receptor, a TNF-like weak inducer of apoptosis (TWEAK) receptor, an IL-6 receptor, a vascular endothelial growth factor receptor, or an ephrin receptor. 
     
     
         61 . The method of  claim 57 , wherein the receptor extracellular domain is from a TNF-α receptor. 
     
     
         62 . The method of  claim 61 , wherein the extracellular domain from a TNF-α receptor is covalently linked to the carboxy terminus of the heavy chain immunoglobulin or the light chain immunoglobulin. 
     
     
         63 . The method of  claim 61 , wherein the extracellular domain from a TNF-α receptor is covalently linked to the carboxy terminus of the heavy chain immunoglobulin. 
     
     
         64 . The method of  claim 57 , wherein the systemic administration treats a CNS condition. 
     
     
         65 . The method of  claim 64 , wherein the CNS condition is an acute CNS condition. 
     
     
         66 . The method of  claim 65 , wherein the acute CNS condition is global brain ischemia, local brain ischemia, traumatic brain injury, or spinal cord injury. 
     
     
         67 . The method of  claim 64 , wherein the CNS condition is a chronic CNS condition. 
     
     
         68 . The method of  claim 67 , wherein the chronic CNS condition is a neurodegenerative CNS condition. 
     
     
         69 . The method of  claim 68 , wherein the neurodegenerative condition is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, transverse myelitis, motor neuron disease, Pick's disease, tuberous sclerosis, Canavan's disease, Rett's syndrome, spinocerebellar ataxias, Friedreich's ataxia, optic atrophy, or retinal degeneration.