Humanized anti-tau(ps422) antibodies and methods of use

Abstract

The invention provides humanized anti-human Tau(pS422) antibodies and methods of using the same.

1 - 20 . (canceled) 
     
     
         21 . A humanized antibody that specifically binds to human Tau(pS422), wherein the antibody
 i) specifically binds to a polypeptide that has the amino acid sequence of SEQ ID NO: 03, and/or   ii) does not bind to full length human Tau (SEQ ID NO: 01) at 1 μg/mL, and/or   iii) specifically binds to full length human Tau phosphorylated at the serine at position 422 (SEQ ID NO: 02), and/or   iv) specifically binds to aggregates of human Tau phosphorylated at the serine at position 422 (SEQ ID NO: 02), and/or   v) specifically binds to human Tau that has the amino acid sequence of SEQ ID NO: 01 and that has the amino acid mutation S422A.   
     
     
         22 . The humanized antibody according to  claim 21 , wherein the antibody has in the heavy chain variable domain at positions 4, 24 and 78 a valine residue. 
     
     
         23 . The humanized antibody according to  claim 22 , wherein the antibody has in the heavy chain variable domain at position 71 an arginine residue. 
     
     
         24 . The humanized antibody according to  claim 23 , wherein the antibody comprises
 a) in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 18 and 10, or   b) in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 09 and 10.   
     
     
         25 . The humanized antibody according to  claim 24 , further comprising
 a) in the light chain variable domain the HVRs of SEQ ID NO: 13, 14 and 15, or   b) in the light chain variable domain the HVRs of SEQ ID NO: 12, 05 and 15.   
     
     
         26 . The humanized antibody according to  claim 23 , comprising
 a) in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 18 and 10, and in the light chain variable domain the HVRs of SEQ ID NO: 13, 14 and 15, or   b) in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 09 and 10, and in the light chain variable domain the HVRs of SEQ ID NO: 12, 05 and 15, or   c) in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 09 and 10, and in the light chain variable domain the HVRs of SEQ ID NO: 13, 14 and 15.   
     
     
         27 . The humanized antibody according to  claims 23 , comprising
 a) a heavy chain variable domain of SEQ ID NO: 20 and a light chain variable domain of SEQ ID NO: 17, or   b) a heavy chain variable domain of SEQ ID NO: 19 and a light chain variable domain of SEQ ID NO: 16, or   c) a heavy chain variable domain of SEQ ID NO: 19 and a light chain variable domain of SEQ ID NO: 17, or   d) a heavy chain variable domain of SEQ ID NO: 21 and a light chain variable domain of SEQ ID NO: 17.   
     
     
         28 . The humanized antibody according to  claim 27 , wherein the antibody is effector function silent. 
     
     
         29 . The humanized antibody according to  claim 21 , wherein the antibody has an EC 50  value for
 a) the human Tau(pS422) fragment that has the amino acid sequence of SEQ ID NO: 03 of 6 ng/mL or less, and/or   b) the full length human Tau(pS422) that has the amino acid sequence of SEQ ID NO: 02 of 4.5 ng/mL or less, and/or   c) aggregates of human Tau (pS422) that has the amino acid sequence of SEQ ID NO: 02 of 30 ng/mL or less, and/or   d) the human Tau that has the amino acid sequence of SEQ ID NO: 01 and that has the amino acid mutation S422A of 125 ng/mL or less.   
     
     
         30 . The humanized antibody according to  claim 29 , wherein the antibody specifically binds to human Tau(pS422) (SEQ ID NO: 02) and does not bind to human Tau (SEQ ID NO: 01). 
     
     
         31 . The humanized antibody according to  claim 27 , wherein the antibody is
 a) a full length antibody of the human subclass IgG1, or   b) a full length antibody of the human subclass IgG4, or   c) a full length antibody of the human subclass IgG1 with the mutations L234A, L235A and P329G,   d) a full length antibody of the human subclass IgG4 with the mutations S228P, L235E and P329G,   e) a full length antibody of the human subclass IgG1 with the mutations L234A, L235A and P329G in both heavy chains and the mutations T366W and S354C in one heavy chain and the mutations T366S, L368A, Y407V and Y349C in the respective other heavy chain, or   f) a full length antibody of the human subclass IgG4 with the mutations S228P, L235E and P329G in both heavy chains and the mutations T366W and S354C in one heavy chain and the mutations T366S, L368A, Y407V and Y349C in the respective other heavy chain.   
     
     
         32 . A pharmaceutical formulation comprising the humanized antibody according to  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         33 . The pharmaceutical formulation according to  claim 32 , further comprising an anti-human alpha-synuclein antibody or an anti-Abeta antibody.