Antibodies specific for hyperphosphorylated tau and methods of use thereof
The present invention relates to a novel class of monoclonal antibody that specifically binds the phosphorylated serine 396 residue on pathological hyperphosphorylated (PHF) tau (pS396), as well as to methods of using these molecules and their tau binding fragments in the treatment of Alzheimer's disease and tauopathies.
1. An immunoglobulin molecule comprising
(a) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:17;
(b) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:18;
(c) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:19;
(d) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:20;
(e) a Heavy Chain CDR2 having the amino acid sequence of SEQ ID NO:21; and
(f) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:22.
2. The immunoglobulin molecule according to claim 1 , wherein said immunoglobulin molecule is a monoclonal antibody or a bispecific antibody having an Fc domain.
3. The immunoglobulin molecule according to claim 1 , wherein said immunoglobulin molecule is an epitope-binding fragment of a monoclonal antibody that is selected from the group consisting of: an Fv fragment, an Fv fragment fused to an Fc domain, a Fab fragment, a Fab′ fragment, a F(ab) 2 fragment, a single V H variable domain and a single V L variable domain.
4. The immunoglobulin molecule according to claim 1 , wherein said immunoglobulin molecule is a humanized antibody.
5. The immunoglobulin molecule according to claim 1 , comprising the heavy chain of SEQ ID NO:24 and/or the light chain of SEQ ID NO:23.
6. A pharmaceutical composition comprising immunoglobulin molecule according to claim 1 , and a pharmaceutical acceptable carrier.
7. A nucleic acid encoding the immunoglobulin molecule according to claim 1 .
8. A method of treating Alzheimer's disease or other tauopathy in a subject in need thereof, said method comprising administering to said subject an effective amount of the immunoglobulin molecule of claim 1 .
9. A method of diagnosing or imaging Alzheimer's disease or other tauopathy in a subject in need thereof, wherein said method comprises administering to said subject an amount of the immunoglobulin molecule of claim 1 sufficient to detect or measure the presence or amount of said hyperphosphorylated variant of human tau in the brain of said subject.
10. A method of treating Alzheimer's Disease in a subject in need thereof, wherein said method comprises administering to said subject an amount of the immunoglobulin molecule of claim 1 sufficient to reduce or attenuate the accumulation of pathological tau protein in said patient.
11. The immunoglobulin molecule of claim 1 , wherein the immunoglobulin molecule is capable of immunospecifically binding to the phosphorylated residue 396 of human tau (SEQ ID NO:33).