Low Affinity Blood Brain Barrier Receptor Antibodies and Uses Thereof

Abstract

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

1 .- 29 . (canceled) 
     
     
         30 . A method of making an antibody useful for transporting a compound across the BBB comprising selecting an antibody specific for a transferrin receptor (TfR) with an affinity from about 20 nM to about 10 μM for the TfR and generating a multispecific antibody comprising a first binding site which binds the TfR with an affinity from about 20 nM to about 10 μM and a second antigen binding site which binds a brain antigen. 
     
     
         31 .- 32 . (canceled) 
     
     
         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 .- 55 . (canceled) 
     
     
         56 . The method of  claim 30 , wherein the brain antigen is 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. 
     
     
         57 . The method of  claim 30 , wherein the brain antigen is BACE1. 
     
     
         58 . The method of  claim 30 , wherein the brain antigen is Abeta. 
     
     
         59 . The method of  claim 30 , wherein the antibody binds both TfR and BACE1. 
     
     
         60 . The method of  claim 30 , wherein the antibody binds both TfR and Abeta. 
     
     
         61 . The method of  claim 30 , wherein the antibody has an affinity from about 20 nM to about 1 μM for the TfR. 
     
     
         62 . The method of  claim 30 , wherein the compound is a therapeutic compound which forms one portion of the multispecific antibody. 
     
     
         63 . The method of  claim 30 , wherein the antibody does not inhibit the binding of TfR to transferrin. 
     
     
         64 . The method of  claim 30 , wherein the antibody is a bispecific antibody. 
     
     
         65 . The method of  claim 30 , wherein the antibody is a full-length antibody or an antibody fragment. 
     
     
         66 . A method of making an antibody useful for transporting a compound across the BBB comprising selecting an antibody specific for a TfR with an affinity from 20 nM to 10 for the TfR and coupling the antibody to a therapeutic compound, wherein the antibody comprises at least a portion of an immunoglobulin constant region, wherein the therapeutic compound is a neurological disorder drug. 
     
     
         67 . The method of  claim 66 , wherein the neurological disorder drug is for treating a neurological disorder 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. 
     
     
         68 . The method of  claim 66 , wherein the neurological disorder drug is selected from a narcotic/opioid analgesic, a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, an anti-migraine agent, acetaminophen, a salicylate, an anti-convulsant, an anaesthetic, and a COX-2-inhibitor. 
     
     
         69 . The method of  claim 66 , wherein the neurological disorder drug is selected from an anti-vertigo agent, an anti-nausea agent, a growth hormone and a neurotrophic factor. 
     
     
         70 . The method of  claim 66 , wherein the neurological disorder drug is a chemotherapeutic agent or an anti-cancer immunoglobulin. 
     
     
         71 . The method of  claim 66 , wherein the neurological disorder drug is selected from an anti-angiogenic ophthalmic agent, a carbonic anhydrase inhibitor, an ophthalmic antihistamine, an ocular lubricant, an ophthalmic steroid, an ophthalmic anesthetic, an ophthalmic anti-infective, an ophthalmic anti-inflammatory agent, and an ophthalmic antihistamine or decongestant. 
     
     
         72 . The method of  claim 66 , wherein the neurological disorder drug is selected from an anticonvulsant or an antiepileptic.