Anti-Tau antibodies and methods of use
Inventors
Adolfsson, Oskar • Hotzel, Isidro • Dicara, Danielle
Assignees
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Publication Number
US-11427629-B2
Publication Date
2022-08-30
Expiration Date
Abstract
The invention provides anti-Tau antibodies and methods of using the same.
Core Innovation
The invention relates to anti-Tau antibodies for treatment and diagnosis/detection of tauopathies. The antibody binds to human Tau and is described as pan-Tau binding to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau. The antibody targets an epitope located within mature human Tau residues 2-24 and additionally includes epitope targeting within other specified amino-acid ranges.
The invention further defines high-affinity binding of the anti-Tau antibody to human Tau forms, including binding with dissociation constants (K_D) meeting specified thresholds. Binding is assessed using surface plasmon resonance (Biacore). The antibody is also described as a humanized antibody, including defined humanized antibody variable regions and hypervariable regions (HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3).
The invention includes defined sequence specifications for antibody variable regions using multiple SEQ ID NOs and identity constraints, including variants with at least 95% identity to specified VH/VL sequences. Disease-related applications are described for numerous tauopathies, including Alzheimer’s disease and progressive supranuclear palsy, and the document also describes potential combination use with additional therapies, including anti-amyloid beta, anti-BACE1, and Tau inhibitors.
Claims Coverage
The independent claims recite treatment of a tauopathy by administering an antibody that binds human Tau. Across the independent claims, there are four inventive feature groupings centered on humanized HVR-defined antibodies and defined heavy/light chain sequence combinations.
Humanized anti-Tau antibody with specified HVR sequences
A method of treating a tauopathy by administering to an individual an isolated antibody that binds human Tau, wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 605; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 606; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 607; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 608; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 609; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 610, and wherein the antibody is humanized.
Anti-human Tau antibody with defined paired VH/VL SEQ ID combinations
A method of treating a tauopathy by administering to an individual an antibody that binds to human Tau, wherein the antibody comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 603 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 604; (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 614 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 615; or (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 619 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 620.
Anti-human Tau antibody with defined paired heavy/light sequence options
A method of treating a tauopathy by administering to an individual with a tauopathy an antibody that binds to human Tau, wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 611 or SEQ ID NO: 612 and a light chain comprising the amino acid sequence of SEQ ID NO: 613; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 616 or SEQ ID NO: 617 and a light chain comprising the amino acid sequence of SEQ ID NO: 618; or (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 621 or SEQ ID NO: 622 and a light chain comprising the amino acid sequence of SEQ ID NO: 623.
Anti-human Tau antibody with heavy-chain and light-chain consisting sequences
A method of treating a tauopathy comprising administering to an individual with a tauopathy an antibody that binds to human Tau, wherein the antibody comprises (a) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 611 or SEQ ID NO: 612 and a light chain consisting of the amino acid sequence of SEQ ID NO: 613; (b) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 616 or SEQ ID NO: 617 and a light chain consisting of the amino acid sequence of SEQ ID NO: 618; or (c) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 621 or SEQ ID NO: 622 and a light chain consisting of the amino acid sequence of SEQ ID NO: 623.
The claims collectively cover treatment of tauopathies using anti-human Tau antibodies defined by SEQ ID NO-based humanized HVRs or by specified heavy-chain and light-chain sequence pairings.
Stated Advantages
Pan-Tau binding to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau.
High-affinity binding to human Tau forms with dissociation constants (K_D) meeting specified thresholds.
Targeting of epitopes located within mature human Tau residues 2-24 and additional specified residue ranges.
Defined humanized antibody variable regions and hypervariable regions with specified HVR sequences.
Treatment methods for numerous tauopathies, including Alzheimer’s disease and progressive supranuclear palsy.
Dose-dependent reduction of pTau pathology in Tau P301L-Tg mice.
Neuroprotection in neuron-microglia co-cultures associated with reduced or abrogated effector function variants.
Documented Applications
Treatment of tauopathies by administering an anti-human Tau antibody to an individual with a tauopathy.
Diagnosis/detection of tauopathies using the anti-Tau antibodies for detection in samples including CSF, blood, and brain samples.
Use in combination with additional therapies, including anti-amyloid beta, anti-BACE1, and Tau inhibitors.
Treatment application examples explicitly include Alzheimer’s disease and progressive supranuclear palsy.
Antibody development and characterization tasks include binding screening to full-length Tau, hyperphosphorylated Tau, and oligomeric vs monomeric Tau; epitope mapping using overlapping 15-mer peptides; and affinity measurement by surface plasmon resonance.
In vivo evaluation including pharmacokinetic studies and pharmacodynamic measures (plasma Tau levels) in mice and cynomolgus monkeys, together with transgenic mouse observations in Tau P301L-Tg mice.
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