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 - 55 . (canceled) 
     
     
         56 . A multispecific antibody comprising a first antigen binding site and a second antigen binding site, wherein the first antigen binding site binds to a transferrin receptor (TfR) with low affinity from about 20 nM to about 10 μM, and wherein the second antigen binding site binds to a brain antigen. 
     
     
         57 . The multispecific antibody of  claim 56 , wherein the affinity of the antibody for the TfR is from about 30 nM to about 10 μM. 
     
     
         58 . The multispecific antibody of  claim 56 , wherein the affinity of the antibody for the TfR is from about 100 nM to about 10 μM. 
     
     
         59 . The multispecific antibody of  claim 56 , wherein the affinity of the antibody for the TfR is from about 20 nM to about 1 μM. 
     
     
         60 . The multispecific antibody of  claim 56  wherein the TfR is a human TfR. 
     
     
         61 . The multispecific antibody of  claim 56  wherein the brain antigen is selected from 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. 
     
     
         62 . The multispecific antibody of  claim 61 , wherein the brain antigen is BACE1. 
     
     
         63 . The multispecific antibody of  claim 61 , wherein the brain antigen is Abeta. 
     
     
         64 . The multispecific antibody of  claim 56 , wherein the antibody does not inhibit the binding of TfR to transferrin. 
     
     
         65 . The multispecific antibody of  claim 56 , which is an antibody fragment with a first antigen binding site that binds the TfR and a second antigen binding site that binds a brain antigen. 
     
     
         66 . The multispecific antibody of  claim 65 , wherein the affinity of the antibody for the TfR is from about 30 nM to about 10 μM. 
     
     
         67 . The multispecific antibody of  claim 65 , wherein the affinity of the antibody for the TfR is from about 100 nM to about 10 μM. 
     
     
         68 . The multispecific antibody of  claim 65 , wherein the affinity of the antibody for the TfR is from about 20 nM to about 1 μM. 
     
     
         69 . The multispecific antibody of  claim 65 , which is a F(ab′)2 fragment. 
     
     
         70 . The multispecific antibody of  claim 65 , wherein the brain antigen is selected from 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. 
     
     
         71 . The multispecific antibody of  claim 65 , wherein the antibody does not inhibit the binding of TfR to transferrin. 
     
     
         72 . A pharmaceutical formulation comprising the multispecific antibody of  claim 56  and a pharmaceutically acceptable carrier. 
     
     
         73 . A pharmaceutical formulation comprising the multispecific antibody of  claim 57  and a pharmaceutically acceptable carrier. 
     
     
         74 . A pharmaceutical formulation comprising the multispecific antibody of  claim 58  and a pharmaceutically acceptable carrier. 
     
     
         75 . A pharmaceutical formulation comprising the multispecific antibody of  claim 59  and a pharmaceutically acceptable carrier.