Blood-brain barrier permeable peptide compositions

Abstract

Blood-brain barrier permeable peptide compositions that contain variable antigen binding domains from camelid and/or shark heavy-chain only single-domain antibodies are described. The variable antigen binding domains of the peptide compositions bind to therapeutic and diagnostic biomarkers in the central nervous system, such as the amyloid-beta peptide biomarker for Alzheimer's disease. The peptide compositions contain constant domains from human IgG, camelid IgG, and/or shark IgNAR. The peptide compositions include heavy-chain only single-domain antibodies and compositions with one or more variable antigen binding domain bound to one or more constant domains.

1 .- 96 . (canceled) 
     
     
         97 . A composition comprising:
 a polypeptide comprising the formula R1-L2-R4-Y-R3-X-R5-L1-R2;   wherein R1 comprises a variable antigen-binding domain from a camelid single-domain heavy chain antibody comprising amino acids 1-127 of the amino acid sequence of SEQ ID NO: 11 and R2 is selected from a constant domain CH1, CH2 or CH3 of human IgG, a constant domain CH2 or CH3 of camelid IgG, or constant domain CH1, CH2, CH3, CH4 or CH5 of shark IgNAR;
 wherein L1 and L2 each comprise a hinge region from a camelid single-domain heavy-chain only antibody; 
 wherein X and Y are bifunctional linkers, selected from a maleimido-thiol conjugate and polyethylene glycol; 
 wherein R3 comprises at least one constant domain of human IgG CH2 or CH3 domain; 
   wherein R4 and R5 are selected from proteins that bind to receptors on endothelial cells that form the blood-brain barrier.   
     
     
         98 . The composition of claim  108 , wherein the R4 or R5 is a FC5, FC44, insulin, transferrin, Apo-B, Apo-E, Apo-E4, wherein the polypeptide can cross the blood-brain barrier. 
     
     
         99 . The composition of claim  108 , wherein the R4 or R5 is IL17, IL22. 
     
     
         100 . The composition of claim  108 , wherein the R4 or R5 is a therapeutic agent, protein, peptide, or an enzyme. 
     
     
         101 . The composition of claim  108 , wherein the nanoparticle has a molecular weight of about 70 kDa. 
     
     
         102 . The composition of claim  108 , wherein a hinge region corresponds to the amino acid sequence of SEQ ID NO: 13. 
     
     
         103 . The composition of claim  108 , wherein at least one of L1 and L2 is covalently conjugated to —NH—C(═NH2.HCl)-CH2CH2CH2-S-Maleimide-PEG-CONH—, which in turn is conjugated to a nanoparticle. 
     
     
         104 . A method for introducing a target peptide in the central nervous system of a subject, the method comprising administering to the subject a polypeptide of claim  108 .