Low affinity blood brain barrier receptor antibodies and uses therefor

Abstract

The present invention relates to antibodies that bind blood brain barrier receptors (BBB-R) and methods of using the same.

1 . A method of transporting a compound across the blood-brain barrier comprising exposing an antibody which binds with low affinity to a blood-brain barrier receptor (BBB-R) coupled to a compound to the blood-brain barrier such that the antibody transports the compound coupled thereto across the blood-brain barrier 
     
     
         2 . A method of increasing exposure of the CNS to a compound, wherein the compound is coupled to an antibody which binds with low affinity to a BBB-R, thereby increasing the exposure of the CNS to the compound. 
     
     
         3 . A method of decreasing clearance of a compound administered to a subject, wherein the compound is coupled to an antibody which binds with low affinity to a BBB-R, such that the clearance of the compound is decreased. 
     
     
         4 . A method of increasing retention in the CNS of a compound administered to a subject, wherein the compound is coupled to an antibody which binds with low affinity to a BBB-R, such that the retention in the CNS of the compound is increased. 
     
     
         5 . A method of optimizing the pharmcokinetics and/or pharmacodynamics of a compound to be efficacious in the CNS in a subject, wherein the compound is coupled to an antibody which binds with low affinity to a BBB-R, and the antibody is selected such that its affinity for the BBB-R after coupling to the compound results in an amount of transport of the antibody conjugated to the compound across the BBB that optimizes the pharmacokinetics and/or pharmacodynamics of the compound in the CNS. 
     
     
         6 . A method of treating a neurological disorder in a mammal comprising treating the mammal with an antibody that binds a BBB-R and is coupled to a compound, wherein the antibody has been selected to have a low affinity for the BBB-R and thereby improves CNS uptake of the antibody and coupled compound. 
     
     
         7 . The method of  claim 1 , wherein the compound is a neurological disorder drug or an imaging agent. 
     
     
         8 . The method of  claim 2 , wherein the increase is measured relative to a typical antibody not having lowered affinity for the BBB-R. 
     
     
         9 . The method of  claim 1 , wherein the antibody does not impair the binding of the BBB-R to one or more of its native ligands. 
     
     
         10 . The method of  claim 1 , wherein the blood-brain barrier is in a mammal 
     
     
         11 . The method of  claim 10 , wherein the mammal has a neurological disorder 
     
     
         12 . The method of  claim 11 , wherein the neurological disorder is selected from the group consisting of Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman's syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, and traumatic brain injury 
     
     
         13 . The method of  claim 10  wherein the mammal is a human. 
     
     
         14 . The method of  claim 1 , wherein the antibody has an IC50 for the BBB-R from about 1 nM to about 100 μM. 
     
     
         15 . The method of  claim 8 , wherein the IC50 is from about 5 nM to about 100 μM. 
     
     
         16 . The method of  claim 8 , wherein the IC50 is from about 50 nM to about 100 μM. 
     
     
         17 . The method of  claim 8 , wherein the IC50 is from about 100 nM to about 100 μM. 
     
     
         18 . The method of  claim 1 , wherein the antibody has an affinity for the BBB-R from about 5 nM to about 10 μM. 
     
     
         19 . The method of  claim 1 , wherein the antibody coupled to the compound has an affinity for the BBB-R from about 30 nM to about 1 μM. 
     
     
         20 . The method of  claim 1 , wherein the BBB-R is selected from the group consisting of transferrin receptor (TfR), insulin receptor, insulin-like growth factor receptor (IGF receptor), low density lipoprotein receptor-related protein 8 (LRP8), low density lipoprotein receptor-related protein 1 (LRP1), and heparin-binding epidermal growth factor-like growth factor (HB-EGF). 
     
     
         21 . The method of  claim 20 , wherein the BBB-R is transferrin receptor 
     
     
         22 . The method of  claim 21 , wherein the antibody does not inhibit the binding of TfR to transferrin. 
     
     
         23 . The method of  claim 1 , wherein the antibody coupled to the compound is administered at a therapeutic dose. 
     
     
         24 . The method of  claim 23 , wherein the therapeutic dose is BBB-R-saturating. 
     
     
         25 . The method of  claim 1 , wherein the antibody is a multispecific antibody and the compound optionally forms one portion of the multispecific antibody 
     
     
         26 . The method of  claim 25  wherein the multispecific antibody comprises a first antigen binding site which binds the BBB-R and a second antigen binding site which binds a brain antigen. 
     
     
         27 . The method of  claim 26 , wherein the brain antigen is selected from the group consisting of beta-secretase 1 (BACE1), Abeta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), Tau, apolipoprotein E4 (ApoE4), alpha-synuclein, CD20, huntingtin, prion protein (PrP), leucine rich repeat kinase 2 (LRRK2), parkin, presenilin 1, presenilin 2, gamma secretase, death receptor 6 (DR6), amyloid precursor protein (APP), p75 neurotrophin receptor (p75NTR), and caspase 6 
     
     
         28 . The method of  claim 26 , wherein the multispecific antibody binds both TfR and BACE1 
     
     
         29 . The method of  claim 26 , wherein the multispecific antibody binds both TfR and Abeta. 
     
     
         30 . A method of making an antibody useful for transporting a compound across the BBB comprising selecting an antibody specific for a blood-brain barrier receptor (BBB-R) because it has a desirably low affinity for the BBB-R. 
     
     
         31 . The method of  claim 30 , wherein the affinity for the BBB-R is from about 5 nM to about 10 μM 
     
     
         32 . The method of  claim 30 , wherein the antibody has an IC50 of from about 1 nM to about 100 μM. 
     
     
         33 . The method of  claim 30  wherein the antibody is selected from a panel of antibodies based upon the affinity of the selected antibody 
     
     
         34 . The method of  claim 30  wherein the antibody is engineered to have the affinity 
     
     
         35 . The method of  claim 30  comprising coupling the antibody with a therapeutic compound. 
     
     
         36 . The method of  claim 35  wherein the therapeutic compound is a neurological disorder drug. 
     
     
         37 . The method of  claim 30  comprising making a multispecific antibody which comprises a first antigen binding site which binds the BBB-R and a second antigen binding site which binds a brain antigen. 
     
     
         38 . An antibody which binds to a BBB-R, wherein the affinity of the antibody for the BBB-R is from about 5 nM to about 10 μM. 
     
     
         39 . The antibody of  claim 38  wherein the affinity is from about 20 nM to about 1 μM 
     
     
         40 . The antibody of  claim 38  wherein the BBB-R is selected from the group consisting of transferrin receptor (TfR), insulin receptor, insulin-like growth factor receptor (IGF receptor), low density lipoprotein receptor-related protein 8 (LRP8), low density lipoprotein receptor-related protein 1 (LRP1), and heparin-binding epidermal growth factor-like growth factor (HB-EGF). 
     
     
         41 . The antibody of  claim 40  wherein the BBB-R is transferrin receptor (TfR). 
     
     
         42 . The antibody of  claim 40  wherein the BBB-R is insulin receptor 
     
     
         43 . The antibody of  claim 38  wherein the BBB-R is a human BBB-R. 
     
     
         44 . The antibody of  claim 38  which is coupled with a neurological disorder drug. 
     
     
         45 . The antibody of  claim 44  which is a multispecific antibody which comprises a first antigen binding site which binds the BBB-R and a second antigen binding site which binds a brain antigen. 
     
     
         46 . The antibody of  claim 45  wherein the brain antigen is selected from the group consisting of beta-secretase 1 (BACE1), Abeta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), Tau, apolipoprotein E4 (ApoE4), alpha-synuclein, CD20, huntingtin, prion protein (PrP), leucine rich repeat kinase 2 (LRRK2), parkin, presenilin 1, presenilin 2, gamma secretase, death receptor 6 (DR6), amyloid precursor protein (APP), p75 neurotrophin receptor (p75NTR), and caspase 6. 
     
     
         47 . The antibody of  claim 46  wherein the brain antigen is BACE1 
     
     
         48 . The antibody of  claim 46  wherein the brain antigen is Abeta. 
     
     
         49 . The antibody of  claim 38  which is an antibody fragment with an antigen binding region that binds the BBB-R. 
     
     
         50 . The antibody fragment of  claim 49  which is a Fab fragment. 
     
     
         51 . The multispecific antibody of  claim 45  which is a full-length antibody or an antibody fragment. 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled)