SEQUENCE LISTING

This application includes a sequence listing submitted herewith as a text filed named “550543SEQLST.TXT” created on Jul. 10, 2020 and containing 54,374 bytes. The material contained in this text file is incorporated by reference in its entirety for all purposes.

BACKGROUND

Tau is a well-known human protein that can exist in phosphorylated forms (see, e.g., Goedert, Proc. Natl. Acad. Sci. U.S.A. 85:4051-4055(1988); Goedert, EMBO J. 8:393-399(1989); Lee, Neuron 2:1615-1624(1989); Goedert, Neuron 3:519-526(1989); Andreadis, Biochemistry 31:10626-10633(1992). Tau has been reported to have a role in stabilizing microtubules, particularly in the central nervous system. Total tau (t-tau, i.e., phosphorylated and unphosphorylated forms) and phospho-tau (p-tau, i.e., phosphorylated tau) are released by the brain in response to neuronal injury and neurodegeneration and have been reported to occur at increased levels in the CSF of Alzheimer's patients relative to the general population (Jack et al., Lancet Neurol 9: 119-28 (2010)).

Tau is the principal constituent of neurofibrillary tangles, which together with plaques are a hallmark characteristic of Alzheimer's disease. The tangles constitute abnormal fibrils measuring 10 nm in diameter occurring in pairs wound in a helical fashion with a regular periodicity of 80 nm. The tau within neurofibrillary tangles is abnormally phosphorylated (hyperphosphorylated) with phosphate groups attached to specific sites on the molecule. Severe involvement of neurofibrillary tangles is seen in the layer II neurons of the entorhinal cortex, the CA1 and subicular regions of the hippocampus, the amygdala, and the deeper layers (layers III, V, and superficial VI) of the neocortex in Alzheimer's disease. Hyperphosphorylated tau has also been reported to interfere with microtubule assembly, which may promote neuronal network breakdown.

Tau inclusions are part of the defining neuropathology of several neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, progressive supranuclear palsy and Pick's disease.

SUMMARY OF THE CLAIMED INVENTION

The invention provides an antibody comprising a mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:15 and a mature light chain variable region at least 90% identical to SEQ ID NO:22. Optionally, three Kabat CDRs of SEQ ID NO:15 and three Kabat CDRs of SEQ ID NO:22. Optionally, at least one of positions H13, H28, H48 and H91 is occupied by K, P, M and F respectively and at least one of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively. Optionally, positions H13, H28, H48 and H91 are occupied by K, P, M and F respectively and at least two of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively. Optionally, positions H13, H28, H48 and H91 are occupied by K, P, M and F respectively, and at least three of positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively. Optionally, positions H13, H28, H48 and H91 are occupied by K, P, M and F respectively, and positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively. Optionally, the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:15 and a mature light chain variable region at least 95% identical to SEQ ID NO:22. Optionally any differences in CDRs of the mature heavy chain variable region and mature light variable region from SEQ ID NOS: 15 and 22 respectively reside in positions H60-H65. Optionally, the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:15 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:21, 22, or 23. Optionally, the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:15 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:22.

The invention further provides an antibody comprising a mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:35 and a mature light chain variable region at least 90% identical to SEQ ID NO:36 provided position H1 is E and/or position L9 is S. Optionally, the antibody comprises three Kabat CDRs of SEQ ID NO:15 and three Kabat CDRs of SEQ ID NO:22. Optionally, at least one of positions H13, H28, H48 and H91 is occupied by K, P, M and F respectively and at least one of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively. Optionally, positions H13, H28, H48 and H91 are occupied by K, P, M and F respectively and at least two of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively. Optionally, positions H13, H28, H48 and H91 are occupied by K, P, M and F respectively, and at least three of positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively. Optionally, positions H13, H28, H48 and H91 are occupied by K, P, M and F respectively, and positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively. Optionally, positions H13, H28, H48 and H91 are occupied by K, P, M and F respectively, and positions L1, L4, L36 and L43 are occupied by D, L, F and S respectively. Optionally, position H1 is occupied by E. Optionally, position L9 is occupied by S. Optionally, position H1 is E and position L9 is S. Optionally, the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:35 and a mature light chain variable region at least 95% identical to SEQ ID NO:36.

In some antibodies, the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region. Optionally, the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fey receptor relative to the natural human constant region. Optionally, the heavy chain constant region is of IgG1 isotype, optionally SEQ ID NO:29, provided the C-terminal lysine can be missing and the light chain constant region is kappa, preferably SEQ ID NO:32.

Some antibodies are conjugated to a cytotoxic or cytostatic agent. Some antibodies are Fab fragments.

The invention further provides a nucleic acid encoding the heavy and/or light chains of an antibody as described in any of the above antibodies.

The invention further provides a method of treating or effecting prophylaxis of Alzheimer's disease comprising administering an effective regime of any of the above antibodies and thereby treating or effecting prophylaxis of Alzheimer's disease. Optionally, the patient is an ApoE4 carrier.

The invention further provides a method of treating or effecting prophylaxis of a disease associated with tau comprising administering an effective regime of an antibody as defined in any of the above antibodies. Optionally, the disease is a neurological disease.

The invention further provides a method of reducing aberrant transmission of tau comprising administering an effective regime of any of the above antibodies, and thereby reducing transmission of tau.

The invention further provides a method of inducing phagocytosis of tau comprising administering an effective regime of any of the above antibodies and thereby inducing phagocytosis of tau. Optionally, the disease is a neurological disease.

The invention further provides a method of inhibiting tau aggregation or deposition comprising administering an effective regime of any of the above antibodies thereby inhibiting tau aggregation or deposition. Optionally, the disease is a neurological disease.

The invention further provides a method of inhibiting formation of tau tangles comprising administering an effective regime of an antibody of any of the above antibodies. Optionally, the disease is a neurological disease.

The invention further provides a nucleic acid comprising a segment encoding a heavy chain variable region having the sequence of SEQ ID NO: 15 or SEQ ID NO:35. Optionally, the nucleic acid further comprises a segment encoding an IgG1 constant region. Optionally, the IgG1 constant region is a human IgG1 constant region. Optionally, the IgG1 constant region has a sequence of SEQ ID NO: 29 provided the C-terminal lysine can be omitted. Optionally, the segment encoding the IgG1 constant region has a nucleotide sequence of SEQ ID NO: 30. Optionally, the nucleic acid further comprises an intron linking the segments encoding the heavy chain variable region and the IgG1 constant region. Optionally, the segment encoding the IgG1 constant region has a nucleotide sequence of SEQ ID NO: 31. Optionally, the nucleic acid further comprising a segment encoding a kappa constant region. Optionally, the kappa constant region is a human kappa constant region. Optionally, the kappa constant region has the sequence of SEQ ID NO:32. Optionally, the nucleic acid encoding the kappa constant region has the sequence of SEQ ID NO:33. Optionally, the nucleic acid further comprises an intron linking the segment encoding the light chain variable region to the segment encoding the kappa constant region. Optionally, the segment encoding the kappa constant region has the sequence of SEQ ID NO:34.

The invention further provides nucleic acid(s) encoding the heavy chain variable region of SEQ ID NO:15 and/or the light chain variable region of SEQ ID NO:21, 22 or 23.

