Monovalent blood brain barrier shuttle modules

Abstract

Herein is reported a blood brain barrier shuttle module comprising a brain effector entity, a linker and one monovalent binding entity which binds to a blood brain barrier receptor, wherein the linker couples the effector entity to the monovalent binding entity which binds to the blood brain barrier receptor wherein the monovalent binding entity does not comprise the variable domains of the anti-transferrin receptor antibody 8D3 (SEQ ID NO: 01 and SEQ ID NO: 02) or of the variant anti-transferrin receptor antibody 8D3v (SEQ ID NO: 01 and SEQ ID NO: 03).

1 . A blood brain barrier shuttle module comprising a brain effector entity, optionally a linker and exactly one (monovalent) binding entity which binds to a blood brain barrier transferrin receptor (TfR), wherein the linker if present couples the effector entity to the monovalent binding entity, which binds to the blood brain barrier receptor, wherein the (monovalent) binding entity comprises an anti-TfR antibody or fragment thereof comprising (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 117; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 119; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 120; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 121; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122. 
     
     
         2 . A blood brain barrier shuttle module according to  claim 1 , wherein the monovalent binding entity comprises an anti-TfR antibody or fragment thereof comprising a heavy chain variable domain having the amino acid sequence of SEQ ID NO:
 91 and a light chain variable domain having the amino acid sequence of SEQ ID NO: 92.   
     
     
         3 . The blood brain barrier shuttle module according to  claim 1 , wherein the monovalent binding entity, which binds to the blood brain barrier receptor, comprises a molecule selected from the group consisting of a blood brain barrier receptor ligand, a full length antibody, a scFv, an Fv, a scFab, and a VHH. 
     
     
         4 . The blood brain barrier shuttle module according to  claim 1 , wherein the blood brain barrier receptor is selected from the group consisting of transferrin receptor, insulin receptor, insulin-like growth factor receptor, low density lipoprotein receptor-related protein 8, low density lipoprotein receptor-related protein 1 and heparin-binding epidermal growth factor-like growth factor. 
     
     
         5 . The blood brain barrier shuttle module according to  claim 1 , to wherein the monovalent binding entity specifically binds to human transferrin receptor and to cynomolgus transferrin receptor. 
     
     
         6 . The blood brain barrier shuttle module according to  claim 1 , wherein the monovalent binding entity, which binds to the blood brain barrier receptor, comprises one scFab directed to the transferrin receptor. 
     
     
         7 . The blood brain barrier shuttle module according to  claim 1 , wherein the monovalent binding entity, which binds to the blood brain barrier receptor, comprises one scFv directed to the transferrin receptor. 
     
     
         8 . (canceled) 
     
     
         9 . The blood brain barrier shuttle module according to  claim 1 , wherein the brain effector entity is selected from the group consisting of neurological disorder drugs, neurotrophic factors, growth factors, enzymes, cytotoxic agents, antibodies directed to a brain target, monoclonal antibodies directed to a brain target, peptides directed to a brain target. 
     
     
         10 . The blood brain barrier shuttle module according to  claim 9 , wherein the brain target is selected from the group consisting of β-secretase 1, Aβ (Abeta), epidermal growth factor, epidermal growth factor receptor 2, tau, phosphorylated tau, phosphorylated tau(pS422), apolipoprotein E4, alpha synuclein, oligomeric fragments of alpha synuclein, CD20, huntingtin, prion protein, leucine rich repeat kinase 2, parkin, presenilin 2, gamma secretase, death receptor 6, amyloid precursor protein, p75 neurotrophin receptor and caspase 6. 
     
     
         11 . The blood brain barrier shuttle module according to  claim 1 , wherein the monovalent binding entity, which binds to the blood brain receptor, is a polypeptide and the monovalent binding entity is conjugated to the C-terminal end of the brain effector entity either directly or via a linker. 
     
     
         12 . The blood brain barrier shuttle module according to  claim 1 , wherein the brain effector entity comprises a full length antibody directed to a brain target. 
     
     
         13 . A pharmaceutical formulation comprising a blood brain barrier shuttle module according to  claim 1 . 
     
     
         14 . Use of a blood brain barrier shuttle module according to  claim 1  as a medicament. 
     
     
         15 . The use according to  claim 14 , wherein the medicament is for the treatment of a neurological disorder. 
     
     
         16 . The blood brain barrier shuttle module according to  claim 1  for use to transport the brain effector entity across the blood brain barrier.