Methods for Treating Tau Pathology

Abstract

The present disclosure relates to methods of slowing cognitive decline in mild-to-moderate and moderate Alzheimer's disease, as well as other tau pathologies, using anti-tau antibodies. The present disclosure provides first-in-class immunotherapies for use in attenuating clinical decline in mild-to-moderate AD and moderate AD, and in particular in significantly slowing the rate of cognitive decline to a clinically meaningful extent and significantly preserving memory. The present disclosure also relates to the use of anti-tau antibodies to block the intercellular spread of pathological tau in the brains of patients with AD or related tauopathies.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 238,052, filed August 27, 2021, U.S. Provisional Application No. 63 / 238,737, filed August 30, 2021, U.S. Provisional Application No. 63 / 275,884, filed November 4, 2021, and U.S. Provisional Application No. 63 / 389,269, filed July 14, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to methods of slowing cognitive decline in mild to moderate Alzheimer's disease, as well as other tau pathologies, using anti-tau antibodies.

[0003] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated by reference in its entirety. The XML copy, created on August 26, 2022, is named 000218-0061-WO 1_SL.xml and is 15,329 bytes in size. [Background technology]

[0004] background Alzheimer's disease (AD) is the most common cause of dementia, affecting an estimated 5.7 million people in the United States (Alzheimer's Association 2018). An estimated 46.8 million people have AD or other dementias (Prince et al., World Alzheimer Report 2015: The Global Impact of Dementia, Alzheimer's Disease International, 2015 (available at www.alz.co.uk / research / WorldAlzheimerReport2015.pdf). The disease is pathologically characterized by the accumulation of plaques containing extracellular beta-amyloid (Aβ) peptides and intracellular neurofibrillary tangles containing aggregates of the microtubule-associated protein tau in the brain neocortex. Diagnosis is made by clinical evaluation of the neurological and neuropsychiatric signs and symptoms of AD and the exclusion of other causes of cognitive impairment. AD is generally classified into preclinical, prodromal, mild, moderate, and severe stages according to the presence and severity of clinically relevant functional and / or cognitive decline, as determined by the Clinical Dementia Rating (CDR) scale (Morris, Neurology Diagnosis is often facilitated by global measures such as the Statistical Assessment of Alzheimer's Disease ("Status of Alzheimer's Disease"; Folstein et al. J Psychiatr Res 1975;12:189-98) or the Mini-Mental State Examination ("MMSE"; Folstein et al. J Psychiatr Res 1975;12:189-98). Approved medications that inhibit acetylcholinesterase ("AChE") activity or antagonize N-methyl-D-aspartate receptors in the brain may temporarily ameliorate AD symptoms in some patients but do not modify disease progression (Cummings, N. Engl. J. Med. 2004;351:56-67).

[0005] The deposition of extracellular amyloid plaques and intracellular tau aggregates in the brain is a hallmark pathological finding of AD, first described by Alois Alzheimer in 1906. Intracellular neurofibrillary tangles consist of aggregated, abnormally phosphorylated tau protein. Tau is encoded by the MAPT gene and is expressed in the human brain as six alternatively spliced ​​isoforms ranging in length from 352 to 441 amino acids. The six isoforms contain a combination of three 29-residue near-amino-terminal inserts (0N, 1N, and 2N) and two carboxy-terminal repeat domains (3R and 4R) (Wang and Mandelkow, Nat. Rev. Neurosci. 2016 Jan;17(1):5-21). Although intracellular aggregates are found as neurofibrillary tangles in neuropil threads and as neurofilaments in the dendritic cell compartment, the spread of tau pathology through the brain is thought to be mediated by soluble tau in the extracellular brain environment (Braak et al., Brain 2015;138:2814-33; Wang and Mandelkow, Nat. Rev. Neurosci. 2016 Jan;17(1):5-21).

[0006] The spatial distribution of tau pathology in AD patients correlates with decline in cognitive domains innervated by affected cortical networks (Ossenkoppele et al., Brain 2016;139(Pt 5):1551-67). Knockout of the tau gene in AD transgenic mouse models is protective against cognitive deficits (Roberson et al., Science 2007;316:750-4). Therapies that reduce the spread of tau in the brain are thought to alleviate cognitive impairment and block further synaptic loss, axonal degeneration, and neuronal death.

[0007] Nevertheless, significant failures have marked the development of therapeutic anti-tau antibodies for the treatment of AD and other tauopathies, such as progressive supranuclear palsy (PSP). For example, a phase 2 trial of C2N-8E12, a humanized IgG4 antibody that recognizes aggregated forms of tau, was halted when administration of the drug to patients with PSP failed to demonstrate a therapeutically beneficial effect (ALZFORUM Networking for a Cure, “AbbVie's Tau Antibody Flops in Progressive Supranuclear Palsy,” July 26, 2019, available at https: / / www.alzforum.org / news / research-news / abbvies-Tau-antibody-flops-progressive-supranuclear-palsy), and more recently for use in patients with AD (ALZFORUM Networking for a Cure, Therapeutics, “Tilavonemab,” available at https: / / www.alzforum.org / therapeutics / tilavonemab, updated January 17, 2022). Similarly, a phase 2 trial of goslanemumab, a humanized monoclonal antibody against the N-terminal fragment of tau, was halted when administration to PSP patients failed to demonstrate efficacy in an interim analysis (Sandusky-Beltran, et al., 2020; Neuropharmacology 175:108104).

[0008] Furthermore, in a recent phase 2 trial with gosuranemab for AD, the drug failed to meet its primary efficacy endpoint in patients with mild cognitive impairment (MCI) and mild AD dementia, and no therapeutic benefit was seen across various study endpoints, even though the study reported a reduction in N-terminal tau in patients' cerebrospinal fluid (CSF) (Biogen Inc., “Biogen Announces Topline Results from Phase 2 Study of Gosuranemab, an Anti-Tau Antibody, for Alzheimer's Disease,” June 16, 2021, available at https: / / www.globenewswire.com / news-release / 2021 / 06 / 16 / 2248550 / 0 / en / Biogen-Announces-Topline-Results-From-Phase-2-Study-of-Gosuranemab-an-Anti-Tau-Antibody-for-Alzheimer-s-Disease.html). Similarly, zagotenemab for AD has been discontinued after missing its primary endpoint in a phase 2 clinical trial (ALZFORUM Networking for a Cure, Therapeutics, “Zagotenemab,” available at https: / / www.alzforum.org / therapeutics / zagotenemab, updated October 29, 2021). A phase 2 trial of the anti-tau antibody semorinemab in early (prodromal to mild) AD also failed to meet its primary efficacy and secondary endpoints (AC Immune, “AC Immune Reports Top Line Results from TAURIEL Phase 2 Trial Evaluating Semorinemab in Early Alzheimer's Disease,” September 23, 2020, available at https: / / ir.acimmune.com / news-releases / news-release-details / ac-immune-reports-top-line-results-Tauriel-phase-2-trial).

[0009] It is estimated that one in nine people over the age of 65 has AD, and the total annual costs of health care, long-term care, and hospice care by and on behalf of individuals with AD exceeded $200 billion in 2013 and are estimated to rise to $1.2 trillion by 2050 (Alzheimer's Association, "2013 Alzheimer's Disease Facts and Figures," Alzheimer's and Dementia 9:208-245, 2013). AD is the sixth leading cause of death in the United States as of 2013 (id.).

[0010] Existing treatments for AD provide only modest symptomatic benefit and fail to slow the progression of the underlying neurodegenerative process. There is a significant unmet medical need for disease-modifying therapeutics for patients with AD, particularly mild-to-moderate AD and moderate AD, as well as patients with other tau pathologies. Summary of the Invention

[0011] Disclosure Overview In one aspect, the disclosure provides a method for slowing cognitive decline in a patient diagnosed with mild to moderate Alzheimer's disease (AD), comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0012] In another aspect, the disclosure provides a method of maintaining cognitive performance within 5 points of an Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cogl 1) score in a patient diagnosed with mild to moderate AD, comprising administering a 4500 mg dose of a humanized monoclonal anti-tau antibody to the patient, wherein the patient's ADAS-Cogl 1 score assessed after 12 to 17 doses of the antibody is 2.5 points or less, 3 points or less, 3.5 points or less, 4 points or less, 4.5 points or less, or 5 points or more lower than the patient's ADAS-Cogl 1 score assessed before administration of the antibody. administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, the anti-tau antibody comprising HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO:2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO:3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO:4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO:6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO:7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO:8.

[0013] In another aspect, the disclosure provides a method for slowing cognitive decline in a patient diagnosed with moderate AD, comprising administering to the patient a 4500 mg dose of a human monoclonal anti-tau antibody, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0014] In another aspect, the disclosure provides a method of maintaining cognitive performance within 5 points on the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cogl 1) score in a patient diagnosed with moderate AD, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the patient's ADAS-Cogl 1 score assessed after 12 to 17 doses of the antibody is 2.5 points or less, 3 points or less, 3.5 points or less, 4 points or less, 4.5 points or less, or 5 points or less than the patient's ADAS-Cogl 1 score assessed prior to administration of the antibody. and administering to the patient a high, 4500 mg dose of a humanized monoclonal anti-tau antibody, thereby maintaining memory within 5 points of the patient's ADAS-Cog11 score, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO:2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO:3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO:4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO:6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO:7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO:8.

[0015] In another aspect, the disclosure provides a method for slowing memory decline in a subject diagnosed with mild to moderate AD, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0016] In another aspect, the disclosure provides a method of maintaining memory within 2.5 points of the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cogl 1) memory domain score in a patient diagnosed with mild to moderate AD, comprising administering a 4500 mg dose of a humanized monoclonal anti-tau antibody to the patient, wherein the patient's ADAS-Cogl 1 memory domain score assessed after 12 to 17 doses of the antibody is 1 point or less, 1.5 points or less, 1.7 points or less, 2 points or less, 2.3 points or less, or 2 points or less than the patient's ADAS-Cogl 1 memory domain score assessed before administration of the antibody. and administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, which is no more than 0.5 points higher than the patient's ADAS-Cog11 memory domain score, thereby maintaining memory within 2.5 points of the patient's ADAS-Cog11 memory domain score, wherein the anti-tau antibody comprises HVR-H1 having the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 having the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 having the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 having the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 having the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 having the amino acid sequence set forth in SEQ ID NO: 8.

[0017] In another aspect, the disclosure provides a method of slowing memory decline in a patient diagnosed with moderate AD, comprising administering to the patient a 4500 mg dose of a human monoclonal anti-tau antibody to slow memory decline in the patient, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0018] In another aspect, the disclosure provides a method of maintaining memory within 2.5 points of an Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cogl 1) memory domain score in a patient diagnosed with moderate AD, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the patient's ADAS-Cogl 1 memory domain score assessed after 12 to 17 doses of the antibody is 1 point or less, 1.5 points or less, 1.7 points or less, 2 points or less, 2.3 points or less, or 2.5 points or less than the patient's ADAS-Cogl 1 memory domain score assessed before administration of the antibody. administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, which is less than 2.5 points higher than the patient's ADAS-Cog11 memory domain score, thereby maintaining memory within 2.5 points of the patient's ADAS-Cog11 memory domain score, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0019] In another aspect, the disclosure provides a method for slowing the decline of language ability in a patient diagnosed with mild to moderate AD, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0020] In another aspect, the disclosure provides a method for slowing the decline of language ability in a patient diagnosed with moderate AD, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0021] In another aspect, the disclosure provides a method for slowing the decline of praxis ability in a patient diagnosed with mild to moderate AD, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0022] In another aspect, the disclosure provides a method for slowing the decline in praxis ability in a patient diagnosed with moderate AD, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0023] In another aspect, the disclosure provides a method of treating a patient diagnosed with mild to moderate AD without increasing the risk of adverse events, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody without increasing (or significantly increasing) the risk of treatment-emergent adverse events, optionally with the dose repeated for 12 to 17 doses, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0024] In another aspect, the disclosure provides a method of treating a patient diagnosed with moderate AD without increasing the risk of adverse events, comprising administering to the patient a 4500 mg dose of a humanized monoclonal anti-tau antibody without increasing (or significantly increasing) the risk of treatment-emergent adverse events, optionally with the dose repeated for 12 to 17 doses, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0025] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing cognitive decline in patients diagnosed with mild to moderate AD, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0026] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in maintaining cognitive performance of 5 points or less above the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) score in patients diagnosed with mild to moderate AD after administration of 12 to 17 doses, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0027] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing cognitive decline in patients diagnosed with moderate AD, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0028] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in maintaining cognitive performance of 5 points or less above the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) score in patients diagnosed with moderate AD after administration of 12 to 17 doses, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0029] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing memory decline in patients diagnosed with mild to moderate AD, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0030] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in maintaining memory within 2.5 points of the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) Memory domain score in patients diagnosed with mild to moderate AD after administration of 12 to 17 doses, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0031] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing memory decline in patients diagnosed with moderate AD, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0032] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in maintaining memory within 2.5 points of the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) Memory domain score in patients diagnosed with moderate AD after administration of 12 to 17 doses, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0033] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing the decline of language skills in patients diagnosed with mild to moderate AD, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0034] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing the decline of language skills in patients diagnosed with moderate AD, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0035] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing the decline in praxis ability in patients diagnosed with mild to moderate AD, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0036] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in slowing the decline in praxis ability in patients diagnosed with moderate AD, wherein the anti-tau antibody comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0037] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in treating patients diagnosed with mild to moderate AD without increasing the risk of adverse events, optionally with the dose repeated for 12 to 17 doses, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0038] In another aspect, the disclosure provides a humanized monoclonal anti-tau antibody provided in a dose of 4500 mg for use in treating patients diagnosed with moderate AD without increasing the risk of adverse events, optionally with the dose repeated for 12 to 17 doses, wherein the anti-tau antibody comprises an HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, an HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, an HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and an HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0039] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing cognitive decline in patients diagnosed with mild to moderate AD, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0040] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for maintaining cognitive performance of 5 points or less above the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) score in patients diagnosed with mild to moderate AD following administration of 12 to 17 doses, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0041] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing cognitive decline in patients diagnosed with moderate AD, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0042] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for maintaining cognitive performance of 5 points or less above the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) score in patients diagnosed with moderate AD following administration of 12 to 17 doses, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0043] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing memory decline in patients diagnosed with mild to moderate AD, wherein the antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0044] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for maintaining memory within 2.5 points of the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) Memory domain score in patients diagnosed with mild to moderate AD following administration of 12 to 17 doses, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0045] In another aspect, the disclosure provides the use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing memory decline in patients diagnosed with moderate AD, wherein the antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0046] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for maintaining memory within 2.5 points of the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) Memory domain score in patients diagnosed with moderate AD following administration of 12 to 17 doses, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0047] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing the decline of language ability in patients diagnosed with mild to moderate AD, wherein the antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0048] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing the decline of language ability in patients diagnosed with moderate AD, wherein the antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0049] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing the decline of praxis ability in patients diagnosed with mild to moderate AD, wherein the antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0050] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for slowing the decline of praxis ability in patients diagnosed with moderate AD, wherein the antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0051] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for treating a patient diagnosed with mild to moderate AD without increasing the risk of adverse events, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0052] In another aspect, the disclosure provides use of a humanized monoclonal anti-tau antibody for the manufacture of a medicament for treating a patient diagnosed with moderate AD without increasing the risk of adverse events, wherein the anti-tau antibody is formulated to be provided in a dose of 4500 mg and comprises HVR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 2, HVR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 3, HVR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 4, HVR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 6, HVR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and HVR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0053] In some embodiments, the adverse event of the methods, anti-tau antibodies for uses, or uses of the disclosure is at least one or more selected from the group consisting of infusion-related reactions, neuroimaging abnormalities, immunogenicity; suicidal ideation, headache, cognitive deterioration, altered consciousness, seizures, dizziness, vomiting, falls, urinary tract infection, anxiety, headache, agitation, depression, dizziness, diarrhea, high blood pressure, nasopharyngitis, joint pain, constipation, COVID-19, insomnia, upper respiratory tract infection, abdominal pain, back pain, cough, hematuria, nausea, pain in extremities, anemia, confusion, and hallucinations.

[0054] In some embodiments, the methods, anti-tau antibodies for use, or tau PET tracers for use of the disclosure are administered to the patient before and / or after administration of the antibody and do not increase the risk of adverse events.

[0055] In some embodiments, a patient using a method, anti-tau antibody for use, or use of the disclosure has a Mini-Mental State Examination (MMSE) score of 16 to 19, inclusive, prior to administration of the antibody, and optionally has an MMSE score of 16 to 18, inclusive, prior to administration of the antibody.

[0056] In some embodiments, the patient of the disclosed methods, anti-tau antibodies for use, or uses has a Clinical Dementia Global Scale (CDR-GS) of 1 or 2 prior to administration of the antibody.

[0057] In some embodiments, the dose of the disclosed method, anti-tau antibody for use, or use is repeated at least 5 times, at least 8 times, or at least 10 times, or the dose is repeated for 5 to 17 times, 10 to 17 times, or 12 to 17 doses. In some embodiments, the dose of the disclosed method, anti-tau antibody for use, or use is repeated for 13 to 15 doses, 13 to 14 doses, 14 to 15 doses, or 14 doses. In some embodiments, the dose of the disclosed method, anti-tau antibody for use, or use is repeated for 12 to 16 doses. In some embodiments, the dose of the disclosed method, anti-tau antibody for use, or use is repeated for 14 to 17 doses.

[0058] In some embodiments, the anti-tau antibody for a method, use, or antibody of the disclosure is administered at least once every four weeks (or every month) for at least 24 weeks, optionally. In some embodiments, the anti-tau antibody for a method, use, or antibody of the disclosure is administered at least once every four weeks (or every month) for at least 36 weeks.

[0059] In some embodiments, the anti-tau antibody of the disclosed methods, uses, or uses is administered at least once every four weeks (or every month), optionally for at least 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, or 168 weeks. In some embodiments, the anti-tau antibody of the disclosed methods, uses, or uses is administered at least once every four weeks (or every month), optionally for at least 40, 44, 48, 52, 56, or 60 weeks.

[0060] In some embodiments, the methods, anti-tau antibodies for use, or uses of the disclosure, the antibody is administered at least once every four weeks (or monthly) for at least 48 weeks.

[0061] In some embodiments, the ADAS-Cog11 score of an anti-tau antibody for use or use of the present disclosure is assessed after administration of the antibody to a patient and is no more than 2.5 points, no more than 3 points, no more than 3.5 points, no more than 4 points, no more than 4.5 points, or no more than 5 points higher than the patient's ADAS-Cog11 score assessed before administration of the antibody. In some embodiments, the ADAS-Cog11 score of an anti-tau antibody for use or use of the present disclosure is assessed after administration of the antibody to a patient and is no more than 4 points higher than the patient's ADAS-Cog11 score assessed before administration of the antibody. In some embodiments, the ADAS-Cog11 score of an anti-tau antibody for use or use of the present disclosure is assessed after administration of the antibody to a patient and is 2 to 4 points higher than the patient's ADAS-Cog11 score assessed before administration of the antibody. In some embodiments, the ADAS-Cog11 score of a method, anti-tau antibody for use, or use of the disclosure, assessed after administration of the antibody to the patient, is 3 to 4 points higher than the patient's ADAS-Cog11 score assessed before administration of the antibody.

[0062] In some embodiments, the ADAS-Cog11 memory domain score of an anti-tau antibody for use or use of the present disclosure, assessed after administration of the antibody to a patient, is no more than 1 point, no more than 1.5 points, no more than 1.7 points, no more than 2 points, no more than 2.3 points, or no more than 2.5 points higher than the patient's ADAS-Cog11 memory domain score assessed before administration of the antibody. In some embodiments, the ADAS-Cog11 memory domain score of an anti-tau antibody for use or use of the present disclosure, assessed after administration of the antibody to a patient, is no more than 2 points higher than the patient's ADAS-Cog11 memory domain score assessed before administration of the antibody. In some embodiments, the ADAS-Cog11 memory domain score of an anti-tau antibody for use or use of the present disclosure, assessed after administration of the antibody to a patient, is 1 to 2 points higher than the patient's ADAS-Cog11 memory domain score assessed before administration of the antibody. In some embodiments, the ADAS-Cog11 memory domain score of a method, anti-tau antibody for use, or use of the disclosure, assessed after administration of the antibody to a patient, is 1.5 to 2.5 points higher than the patient's ADAS-Cog11 memory domain score assessed before administration of the antibody.

[0063] In some embodiments, the antibody, anti-tau antibody for use, or use of the disclosed method is administered at least once every four weeks (or monthly) for at least 48 weeks.

[0064] In some embodiments, the ADAS-Cog11 score (of a patient) assessed after administration of a method, anti-tau antibody for use, or the antibody of the present disclosure is reduced by at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to what would be expected without administration of the antibody. In some embodiments, the ADAS-Cog11 score (of a patient) assessed after administration of the antibody to a patient is reduced by at least 40% compared to what would be expected without administration of the antibody. In some embodiments, the ADAS-Cog11 score (of a patient) assessed after administration of the antibody to a patient is reduced by 25-50% compared to what would be expected without administration of the antibody. In some embodiments, the ADAS-Cog11 score (of a patient) assessed after administration of the antibody to a patient is reduced by 40-50% compared to what would be expected without administration of the antibody.

[0065] In some embodiments, the antibody, anti-tau antibody for use, or use of the disclosed method is administered to a patient at least once every four weeks (or monthly) for at least 48 weeks.

[0066] In some embodiments, the disclosed methods, anti-tau antibodies for use, or uses comprise administering the antibody once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the disclosed methods, anti-tau antibodies for use, or uses comprise administering the antibody once every two weeks for one to five doses, then once every four weeks (or once monthly). In some embodiments, the disclosed methods, anti-tau antibodies for use, or uses comprise administering the antibody once every two weeks for three doses, then once every four weeks (or once monthly).

[0067] In some embodiments, the methods, anti-tau antibodies for use, or uses of the present disclosure comprise administering the antibody intravenously.

[0068] In some embodiments, the anti-tau antibody for a method, use, or use of the present disclosure is administered at an infusion rate of 0.5 to 3.0 mL / min. In some embodiments, the anti-tau antibody for a method, use, or use of the present disclosure is administered every 4 weeks (or monthly) at an infusion rate of 0.5 to 3.0 mL / min.

[0069] In some embodiments, the infusion rate of the disclosed methods, anti-tau antibodies for use, or uses is optionally 0.5-1 mL / min for 10-120 minutes of the first infusion, and 3 mL / min thereafter.

[0070] In some embodiments, the anti-tau antibody for use in, or method of the disclosure is an IgG4 antibody.

[0071] In some embodiments, the antibody of the methods, anti-tau antibody for use, or use of the disclosure comprises M252Y, S254T, and T256E mutations according to EU numbering.

[0072] In some embodiments, the antibody of the methods, anti-tau antibody for use, or use of the disclosure comprises a S228P mutation according to EU numbering.

[0073] In some embodiments, an anti-tau antibody for use or method of the disclosure comprises a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 5, and / or a light chain variable region comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 9. In some embodiments, an anti-tau antibody for use or method of the disclosure comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 5 and / or a light chain variable region having the amino acid sequence of SEQ ID NO: 9.

[0074] In some embodiments, the anti-tau antibody for the methods, uses, or antibodies of use of the disclosure is semolinemab.

[0075] In some embodiments, the method, anti-tau antibody for use, or patient for use of the disclosure is Apoε4 positive.

[0076] In some embodiments, the method, anti-tau antibody for use, or patient for use of the disclosure is Apoε4 negative.

[0077] In some embodiments, the patient of the methods, anti-tau antibodies for use, or uses of the disclosure has an MMSE score of 19 to 21 prior to administration of the antibody.

[0078] In some embodiments, a patient of a method, anti-tau antibody for use, or use of the disclosure has an MMSE score of 16 to 19, inclusive, prior to administration of the antibody, and optionally has an MMSE score of 16 to 18, inclusive, prior to administration of the antibody.

[0079] In some embodiments, the patient of the disclosed methods, anti-tau antibodies for use, or uses is tau positive and / or amyloid beta (Abeta) positive, and optionally the patient is determined to be tau positive by administering to the patient a positron emission tomography (PET) tracer that binds to tau, and optionally the patient is determined to be Abeta positive by administering to the patient a PET tracer that binds Abeta.

[0080] In some embodiments, the level of tau of the methods, anti-tau antibodies for use, or uses of the present disclosure is measured by measuring the standardized uptake value ratio (SUVR) of a scan showing the distribution of the PET tracer in the patient's brain.

[0081] In some embodiments, the patient of the disclosed methods, anti-tau antibodies for use, or uses has high levels of tau, wherein the high levels of tau are (i) median Genentech Tau Probe 1 (GTP1) brain tau levels equal to or greater than the whole cortical gray matter (WCG) (upper-middle division); (ii) a temporal SUVR measurement of 1.325 or greater; and (iii) SUVR measurements from the whole cortical gray matter (WCG) region that are ≥ 1.245 corresponds to one or more of the following:

[0082] In some embodiments, the patient of the disclosed methods, anti-tau antibodies for use, or uses has low levels of tau, wherein the low levels of tau are (i) brain tau levels below the median GTP1 WCG (lower-middle division); (ii) a temporal SUVR measurement that is less than 1.325; and (iii) SUVR measurements from WCG that are less than 1.245 corresponds to one or more of the following:

[0083] In some embodiments, the PET tracer that binds to tau in the method, use or anti-tau antibody for use of the disclosure is 18 F]Genentech Tau Probe 1 ([ 18 The PET tracer that binds to Abeta of the disclosed method, anti-tau antibody for use or use is at least one selected from the group consisting of florbetapir, florbetaben and flutemetamol.

[0084] In some embodiments, tau of the methods, anti-tau antibodies for use, or uses of the present disclosure is measured in a CSF or plasma sample taken from the patient.

[0085] In some embodiments, the patient of the methods, anti-tau antibodies for use, or uses of the disclosure is co-administered one or more additional agents.

[0086] In some embodiments, the one or more additional agents of the methods, anti-tau antibodies for use, or uses of the present disclosure are selected from the group consisting of symptomatic medications, neurological medications, corticosteroids, antibiotics, antiviral medications, additional anti-tau antibodies, tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, BACE1 inhibitors; cholinesterase inhibitors; NMDA receptor antagonists; monoamine depleting agents; ergoloid mesylates; anticholinergic antiparkinsonian agents; dopaminergic antiparkinsonian agents; tetrabenazine; anti-inflammatory agents; hormones; vitamins; dimebolins; homotaurines; serotonin receptor activity modulators; interferons, and glucocorticoids.

[0087] In some embodiments, the anti-tau antibody for use or symptomatic treatment of the disclosed method is selected from the group consisting of a cholinesterase inhibitor, galantamine, rivastigmine, donepezil, an N-methyl-D-aspartate receptor antagonist, memantine, and a dietary supplement (optionally, the dietary supplement is Souvenaid®).

[0088] In some embodiments, the method, anti-tau antibody for use, or anti-amyloid beta antibody for use of the disclosure is aducanumab, lecanemab, or donanemab.

[0089] In some embodiments, the anti-tau antibody for use in the methods, or the anti-amyloid beta antibody for use in the disclosed methods is crenezumab or gantenerumab.

[0090] In some embodiments, the method, anti-tau antibody for use, or additional anti-tau antibody of use of the present disclosure is selected from the group consisting of a different N-terminal binding agent, a mid-domain binding agent, and a fibrillar tau binding agent.

[0091] In some embodiments, the anti-tau antibody for the methods, uses, or additional anti-tau antibody of the disclosed methods is selected from the group consisting of goslanemab, tiravonemab, bepranemab, and zagotenemab.

[0092] In some embodiments, the method, anti-tau antibody for use, or one or more additional agents of use of the disclosure comprises a therapeutic agent that specifically binds to a target selected from the group consisting of beta-secretase, tau, presenilin, amyloid precursor protein or a portion thereof, amyloid beta peptide or oligomers or fibrils thereof, death receptor 6 (DR6), receptor for advanced glycation end products (RAGE), parkin, and huntingtin.

[0093] In some embodiments, the method, anti-tau antibody for use, or monoamine depleting agent of use of the disclosure is tetrabenazine.

[0094] In some embodiments, the anti-tau antibody for use, or anticholinergic anti-Parkinsonian agent of the disclosed methods, uses, or uses is selected from the group consisting of procyclidine, diphenhydramine, trihexylphenidyl, benztropine, biperiden, and trihexyphenidyl.

[0095] In some embodiments, the method, anti-tau antibody for use, or dopaminergic Parkinsonism treatment of use of the disclosure is selected from the group consisting of entacapone, selegiline, pramipexole, bromocriptine, rotigotine, selegiline, ropinirole, rasagiline, apomorphine, carbidopa, levodopa, pergolide, tolcapone, and amantadine.

[0096] In some embodiments, the anti-inflammatory agent of the methods, anti-tau antibodies for use, or uses of the disclosure is selected from the group consisting of nonsteroidal anti-inflammatory drugs and indomethacin.

[0097] In some embodiments, the hormone of the methods, anti-tau antibodies for use, or uses of the present disclosure is selected from the group consisting of estrogen, progesterone, and leuprolide.

[0098] In some embodiments, the method, anti-tau antibody for use, or vitamin for use of the present disclosure is selected from the group consisting of folate and nicotinamide.

[0099] In some embodiments, the homotaurine of a method, anti-tau antibody for use, or use of the disclosure is 3-aminopropanesulfonic acid or 3APS.

[0100] In some embodiments, the serotonin receptor activity modulator of the methods, anti-tau antibodies for the uses or uses of the disclosure is xaliproden.

[0101] In some embodiments, administration of the antibodies, anti-tau antibodies for use, or uses of the disclosed methods does not increase the risk of adverse events.

[0102] In some embodiments, the adverse event of the methods, anti-tau antibodies for uses, or uses of the disclosure is at least one selected from the group consisting of infusion-related reactions, neuroimaging abnormalities, immunogenicity; suicidal ideation, headache, cognitive deterioration, altered consciousness, seizures, dizziness, vomiting, falls, urinary tract infection, anxiety, headache, agitation, depression, dizziness, diarrhea, high blood pressure, nasopharyngitis, joint pain, constipation, COVID-19, insomnia, upper respiratory tract infection, abdominal pain, back pain, cough, hematuria, nausea, pain in extremities, anemia, confusion, and hallucinations.

[0103] In some embodiments, the patient of the disclosed methods, anti-tau antibodies for use, or uses is of Black or Hispanic ethnicity, or of non-European ethnic origin.

[0104] In another aspect, the disclosure provides a method of slowing cognitive decline in a patient diagnosed with mild to moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, and then Q4W thereafter.

[0105] In another aspect, the disclosure provides a method of maintaining cognitive performance within 5 points of the ADAS-Cog11 score in a patient diagnosed with mild to moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0106] In another aspect, the disclosure provides a method of treating a patient diagnosed with mild to moderate AD without increasing the risk of adverse events, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0107] In another aspect, the disclosure provides a method of slowing memory decline in a patient diagnosed with mild to moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0108] In another aspect, the disclosure provides a method of maintaining cognitive performance within 2.5 points of the ADAS-Cog11 score in a patient diagnosed with mild to moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, and then Q4W thereafter.

[0109] In another aspect, the disclosure provides a method of slowing the decline of language ability in a patient diagnosed with mild to moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0110] In another aspect, the disclosure provides a method of slowing the decline in praxis capacity in a patient diagnosed with mild to moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0111] In another aspect, the disclosure provides a method of slowing cognitive decline in a patient diagnosed with moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, and then Q4W thereafter.

[0112] In another aspect, the disclosure provides a method of maintaining cognitive performance within 5 points of the ADAS-Cog11 score in a patient diagnosed with moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses and then Q4W thereafter.

[0113] In another aspect, the disclosure provides a method of treating a patient diagnosed with moderate AD without increasing the risk of adverse events, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0114] In another aspect, the disclosure provides a method of slowing memory decline in a patient diagnosed with moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0115] In another aspect, the disclosure provides a method of maintaining cognitive performance within 2.5 points of the ADAS-Cog11 score in a patient diagnosed with moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses and then Q4W thereafter.

[0116] In another aspect, the disclosure provides a method of slowing the decline of language ability in a patient diagnosed with moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0117] In another aspect, the disclosure provides a method of slowing the decline in praxis capacity in a patient diagnosed with moderate AD, the method comprising intravenously administering a 4500 mg dose of semolinemab to the patient Q2W for three doses, then Q4W thereafter.

[0118] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing cognitive decline in patients diagnosed with mild to moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0119] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in maintaining cognitive performance equal to or less than 5 points above the ADAS-Cog11 score in patients diagnosed with mild to moderate AD, wherein semolinemab is administered intravenously Q2W for three doses and then Q4W thereafter.

[0120] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in treating patients diagnosed with mild to moderate AD without increasing (or significantly increasing) the risk of adverse events, wherein semolinemab is administered intravenously Q2W for three doses and then Q4W thereafter.

[0121] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing memory decline in patients diagnosed with mild to moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0122] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in maintaining cognitive performance equal to or less than 2.5 points above the ADAS-Cog11 score in patients diagnosed with mild to moderate AD, wherein semolinemab is administered intravenously Q2W for three doses and then Q4W thereafter.

[0123] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing the decline of language ability in patients diagnosed with mild to moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0124] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing the decline in praxis capacity in patients diagnosed with mild to moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0125] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing cognitive decline in patients diagnosed with moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0126] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in maintaining cognitive performance of 5 points or less above the ADAS-Cog11 score in patients diagnosed with moderate AD, wherein semolinemab is administered intravenously Q2W for three doses and then Q4W thereafter.

[0127] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in treating patients diagnosed with moderate AD without increasing (or significantly increasing) the risk of adverse events, wherein semolinemab is administered intravenously Q2W for three doses and then Q4W thereafter.

[0128] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing memory decline in patients diagnosed with moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0129] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in maintaining cognitive performance equal to or less than 2.5 points above the ADAS-Cog11 score in patients diagnosed with moderate AD, wherein semolinemab is administered intravenously Q2W for three doses and then Q4W thereafter.

[0130] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing the decline of language ability in patients diagnosed with moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0131] In another aspect, the disclosure provides a 4500 mg dose of semolinemab for use in slowing the decline in praxis capacity in patients diagnosed with moderate AD, wherein semolinemab is administered intravenously Q2W for three doses, then Q4W thereafter.

[0132] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing cognitive decline in patients diagnosed with mild to moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is administered Q2W for three doses, then Q4W thereafter.

[0133] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for maintaining cognitive performance at or below 5 points above the ADAS-Cog11 score in a patient diagnosed with mild to moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, then Q4W thereafter.

[0134] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for treating a patient diagnosed with mild to moderate AD without increasing (or significantly increasing) the risk of adverse events, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, and Q4W thereafter.

[0135] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing memory decline in patients diagnosed with mild to moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, then Q4W thereafter.

[0136] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for maintaining cognitive performance at or below 2.5 points above the ADAS-Cog11 score in a patient diagnosed with mild to moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, and Q4W thereafter.

[0137] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing the decline of language ability in patients diagnosed with mild to moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, and Q4W thereafter.

[0138] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing the decline of praxis capacity in patients diagnosed with mild to moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, and Q4W thereafter.

[0139] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing cognitive decline in patients diagnosed with moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is administered Q2W for three doses, then Q4W thereafter.

[0140] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for maintaining cognitive performance at or below 5 points above the ADAS-Cog11 score in a patient diagnosed with moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, then Q4W thereafter.

[0141] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for treating a patient diagnosed with moderate AD without increasing (or significantly increasing) the risk of adverse events, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, and Q4W thereafter.

[0142] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing memory decline in patients diagnosed with moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, then Q4W thereafter.

[0143] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for maintaining cognitive performance at or below 2.5 points above the ADAS-Cog11 score in a patient diagnosed with moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, then Q4W thereafter.

[0144] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing the decline of language ability in patients diagnosed with moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, and Q4W thereafter.

[0145] In another aspect, the disclosure provides use of semolinemab for the manufacture of a medicament for slowing the decline of praxis capacity in patients diagnosed with moderate AD, wherein the semolinemab is formulated for intravenous administration at a dose of 4500 mg, and the medicament is formulated to be administered Q2W for three doses, and Q4W thereafter.

[0146] In some embodiments, the semolinemab of the method, semolinemab for use, or use of the disclosure is administered Q4W for at least 10 doses. In some embodiments, the semolinemab of the method, semolinemab for use, or use of the disclosure is administered Q4W for at least 13 doses. In some embodiments, the semolinemab of the method, semolinemab for use, or use of the disclosure is administered Q4W for at least 16 doses.

[0147] In some embodiments, semolinemab for the methods, uses, or uses of the disclosure is administered at an infusion rate of 0.5 mL / min to 3.0 mL / min.

[0148] In some embodiments, the infusion rate of semolinemab of the methods, uses, or uses of the disclosure is optionally 0.5 mL / min to 1 mL / min for 10 to 120 minutes of the first infusion, and 3 mL / min thereafter.

[0149] In some embodiments, the methods, semolinemab for use, or uses of the disclosure further comprise administering a 4500 mg dose of semolinemab intravenously to a patient Q4W for 96 weeks. [Brief explanation of the drawings]

[0150] This patent or patent application contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0151] [Figure 1] Figures 1A and 1B provide a schematic diagram depicting the entire study design, including the screening period, double-blind treatment period, optional open-label extension (OLE) period, and safety follow-up period. Due to COVID-19, the blinded period for participants who missed one or more doses of study drug was extended to 60 weeks; if two or more consecutive study drug infusions were missed, participants received a supplemental Q2W dose. Q2W refers to every 2 weeks, and Q4W refers to every 4 weeks. (a) An extension of the 8-week screening period may be granted in some cases by contacting the medical monitor. (b) An extension of the baseline visit period may be granted in some cases by contacting the medical monitor. (c) For Cohorts 2 and 3, if two or more consecutive study drug infusions were missed during the double-blind treatment period, study drug administration resumed with Q2W administration for the next three doses, followed by Q4W administration.

[0152] [Figure 2] Figure 2 shows the study cohort assignments. DBP refers to double-blind period. OLE refers to open-label extension. V3 refers to version 3.

[0153] [Figure 3] Figure 3 is a schematic diagram showing the randomization of study participants.

[0154] [Figure 4] 4A-4B are schematic diagrams showing the dosing and frequency of Cohort 1 (FIG. 4A) and Cohort 2 (FIG. 4B) during the double-blind treatment period.

[0155] [Figure 5] Figure 5A shows the amino acid sequences of the six HVRs of semolinemab; Figure 5B shows the amino acid sequences of the VH and VL domains of semolinemab.

[0156] [Figure 6]Figure 6 shows the adjusted mean change (with 95% CI) in ADAS-Cog11 over time for patients with baseline ADAS-Cog11 and at least one post-baseline value who missed up to one semolinemab dose. The mITT population is defined using the ADAS-Cog11 for all endpoints. Estimates are from a mixed-effects model for repeated measures (MMRM) analysis with an unstructured covariance matrix: change = baseline + age + Apoε + DS result + baseline concomitant medication + analysis visit + treatment + treatment * analysis visit + analysis visit * baseline (repeated values ​​across the analysis baseline correspond to disease worsening). Descriptive statistics at baseline include patients with baseline ADAS-Cog11 and at least one post-baseline value. The mITT population is defined using the ADAS-Cog11 for all endpoints. Estimates are from a mixed-effects model for repeated measures (MMRM) analysis with an unstructured covariance matrix. Change = Baseline + Age + ApoE4 + DS Outcome + Baselineconmed + Analysis Visit + Treatment + Treatment*Analysis Visit + Analysis Visit*Baseline (values ​​repeated across analysis visits). Unadjusted p-values ​​for pairwise comparisons with control group are shown. Increase in endpoint from baseline corresponds to disease worsening. Rave data extraction: August 2, 2021. Clinical data cutoff: July 12, 2021.

[0157] [Figure 7]Figures 7A-7B show the change in ADAS-Cog11 over time in two different populations. An increase in the endpoint from baseline corresponds to disease worsening. Rave data extraction: August 2, 2021. Clinical data cutoff: July 12, 2021. Figure 7A shows the adjusted mean plot (with 95% CI) from a mixed-effects repeated measures model analyzing the change from baseline in ADAS-Cog11 during the double-blind period. Patients were modified intention-to-treat (MITT) with a maximum of one missed dose and completed the Week 49 ADAS-Cog assessment. A maximum of one missed dose, Week 49 completers. Adjusted mean plot (with 95% CI) from a mixed-effects repeated measures model analysis of the change from baseline, ADAS-Cog11, double-blind period, a maximum of one missed dose flag, MITT patients, and Week 49 completers. Figure 7B shows adjusted mean plots (with 95% CI) from a mixed-effects repeated measures model analyzing the change from baseline in ADAS-Cog11 during the double-blind period among modified intention-to-treat (MITT) patients. Adjusted mean plots (with 95% CI) from a mixed-effects repeated measures model analysis of change from baseline, ADAS-Cog11, double-blind period, and MITT patients.

[0158] [Figure 8]Figures 8A-8B show the adjusted mean change (with 95% CI) in ADAS-Cog11 over time in the study cohorts. An increase in the endpoint from baseline corresponds to worsening disease. Rave data extraction: August 2, 2021. Clinical data cutoff: July 12, 2021. Figure 8A shows the adjusted mean plot (with 95% CI) from a mixed-effects repeated measures model analyzing the change from baseline in ADAS-Cog11 during the double-blind period for modified intention-to-treat (MITT) patients assigned to actual study cohort 1. Adjusted mean plot (with 95% CI) from a mixed-effects repeated measures model analysis of change from baseline, ADAS-Cog11, double-blind period, MITT patients, and actual study cohort 1. Figure 8B shows adjusted mean plots (with 95% CI) from a mixed-effects repeated measures model analyzing the change from baseline in ADAS-Cog11 during the double-blind period for modified intention-to-treat (MITT) patients assigned to actual study cohort 2. Adjusted mean plots (with 95% CI) from a mixed-effects repeated measures model analysis of change from baseline, ADAS-Cog11, double-blind period, MITT patients, and actual study cohort 2.

[0159] [Figure 9] Figure 9 shows the cumulative probability of a constant level change from baseline to week 49 on ADAS-Cog11 in the semolinemab and placebo arms for the MITT population.

[0160] [Figure 10]Figures 10A-10B show consistent subgroup differences between semolinemab-treated and placebo-treated patients. Figure 10A shows forest plots illustrating adjusted mean differences from a mixed-effects repeated measures model analyzing the change from baseline to week 49 in ADAS-Cog11 for modified intention-to-treat (MITT) subjects who missed a maximum of one dose. Prespecified subgroups included high or low GTP1 (high GTP1 defined as ≥ median GTP1 WCG, and low GTP1 defined as < median GTP1 WCG); MMSE16-18 or MMSE19-21; and Apoε4 positive or Apoε4 negative. Forest plots from the mixed-effects repeated measures model analysis show the change from baseline for ADAS-Cog11, double-blind period, maximum missed dose flag, and MITT patients. Increases in endpoints from baseline correspond to worsening disease. Rave data extracted: August 2, 2021. Clinical data cutoff: July 12, 2021. Figure 10B further shows forest plots illustrating adjusted mean differences from mixed-effects repeated measures models comparing ADAS-Cog11 results with ADCS-ADL results and analyzing the change from baseline to week 49 in ADAS-Cog11 or ADCS-ADL for MITT subjects who missed up to one dose for different pre-specified subgroups.

[0161] [Figure 11] Figures 11A-11B show the primary endpoint results for the mITT population. Figure 11A shows the adjusted change in ADAS-Cog11 from baseline over time in the placebo (gray circles) and semolinemab (green circles) arms. Figure 11B shows the adjusted change in ADCS-ADL from baseline over time in the placebo (gray circles) and semolinemab (green circles) arms. Graphs are shown as slowing down from baseline values ​​to facilitate comparison.

[0162] [Figure 12]Figures 12A-12C show treatment effects in different cognitive domains (i.e., memory, language, and praxis) within the ADAS-Cog11 (as defined by Verma et al., Alzheimer's Research and Therapy, 2015) for the mITT population over time (weeks after baseline), i.e., ADAS-Cog11 cognitive domain analysis including memory, language, and praxis domains. Results show a primarily memory domain-driven treatment effect in the ADAS-Cog11 for the mITT population over time (weeks after baseline), with a smaller effect in the language domain. Figure 12A shows the unadjusted change from baseline in the ADAS-Cog11 memory domain over time, Figure 12B shows the unadjusted change from baseline in the ADAS-Cog11 language domain over time, and Figure 12C shows the unadjusted change from baseline in the ADAS-Cog11 praxis domain over time.

[0163] [Figure 13]Figures 13A-13D show secondary endpoints of mITT (MMSE and CDR-SB). Figure 13A shows the MMSE-adjusted change from baseline (weeks post-baseline) over time in the placebo arm (gray circles) and semolinemab arm (green circles). Figure 13B shows a forest plot from a mixed-effects repeated-measures model analyzing the change from baseline in MMSE for different pre-specified subgroups: high or low GTP1 (high GTP1 defined as ≥ median GTP1 WCG, and low GTP1 defined as ≤ median GTP1 WCG); MMSE16-18 or MMSE19-21; and Apoε4 positive or Apoε4 negative. Figure 13C shows the CDR-SB (reverse)-adjusted change from baseline (weeks post-baseline) over time in the placebo arm (gray circles) and semolinemab arm (green circles). Figure 13D shows a forest plot from a mixed-effects repeated measures model analyzing the change from baseline in CDR-SB for different pre-specified subgroups: high or low GTP1 (high GTP1 defined as ≥ median GTP1 WCG, low GTP1 defined as ≤ median GTP1 WCG); MMSE16-18 or MMSE19-21; and Apoε4 positive or Apoε4 negative.

[0164] [Figure 14]Figures 14A-14G show no significant effect on tau accumulation in mild to moderate AD and no significant differences in regional analysis. The y-axis is "annualized," so both week 49 and week 61 time points are used. Figure 14A shows the unadjusted annual change from baseline in [18F]GTP1 tau PET signal for the total cortical gray area in the placebo arm (gray) or semolinemab arm (green). Figure 14B shows the total cortical gray matter area in red and indicates the location of the total cortical gray area. Figure 14C shows the unadjusted annual change from baseline in [18F]GTP1 tau PET signal for the frontal region in the placebo arm (gray) or semolinemab arm (green). Figure 14D shows the unadjusted annual change from baseline in [18F]GTP1 tau PET signal for the temporal region in the placebo arm (gray) or semolinemab arm (green). Figure 14E shows the unadjusted annual change from baseline in [18F]GTP1 tau PET signal in the parietal region in the placebo arm (gray) or semolinemab arm (green). Figure 14F shows the unadjusted annual change from baseline in [18F]GTP1 tau PET signal in the occipital region in the placebo arm (gray) or semolinemab arm (green). Figure 14G shows ROIs based on the Hammers template of the anatomical atlas.

[0165] [Figure 15] Figures 15A-15B show serum pharmacokinetics and plasma pharmacodynamics. Figure 15A shows the semolinemab concentration (μg / mL) in serum over time (days), giving CSF / serum ratios consistent with those observed for other monoclonal antibodies. Figure 15B shows the plasma tau concentration (pg / mL) over time (days) in the placebo (gray circles) and semolinemab (green circles) arms, demonstrating support for semolinemab's engagement with tau. Detailed Description of the Invention

[0166] Detailed Description of Disclosure The results of a phase 2 clinical trial in AD patients disclosed herein demonstrate that the N-terminal binding tau antibody semolinemab slows clinical decline and disease progression, particularly cognitive decline, in patients with mild to moderate AD or moderate AD. Furthermore, this effect is seen in patients with tau pathology typical of patients diagnosed with mild to moderate or moderate AD. Furthermore, the results demonstrate that these effects occur without a significant incidence of adverse events, such as neuroimaging abnormalities or suicidal ideation.

[0167] The study used semolinemab, also referred to herein as MTAU9937A or RO7105705, a pan-tau IgG4 monoclonal antibody designed to bind to and disrupt extracellular isoforms of tau, potentially slowing cell-to-cell spread and propagation of tau pathology throughout cortical and subcortical networks. Semolinemab targets all currently known isoforms of full-length tau, regardless of whether they are post-translationally modified (e.g., phosphorylated).

[0168] The IgG4 backbone of semolinemab has reduced Fc-γ receptor binding affinity compared to the human IgG1 subclass, resulting in reduced immune effector responses. Semolinemab has also been engineered to contain three mutations (M249Y, S251T, and T253E [YTE]) in the fragment-crystallizable (Fc) region of the heavy chain that enhance binding to the neonatal Fc receptor (FcRn), which have been shown to delay peripheral antibody clearance in humans, potentially increasing exposure levels (Robbie et al. Antimicrob Agents Chemother 2013;57:6147-53). In some embodiments, the antibody comprises an IgG4 heavy chain containing S228P, M252Y, S254T, and T256E mutations according to EU numbering and lacking a C-terminal lysine. In some embodiments, the humanized monoclonal anti-tau antibody of the present disclosure is an IgG4 antibody. In some embodiments, a humanized monoclonal anti-tau antibody of the present disclosure comprises an M252Y, S254T, and T256E mutation according to EU numbering. In some embodiments, a humanized monoclonal anti-tau antibody of the present disclosure comprises an S228P mutation according to EU numbering.

[0169] The present disclosure provides methods for treating and monitoring patients diagnosed with mild to moderate or moderate AD, including Apoε4-positive patients, patients with MMSE scores of 16 to 21 (inclusive), and patients with tau pathology typically found in the brains of patients diagnosed with mild to moderate or moderate AD. As exemplified herein, a humanized monoclonal anti-tau antibody has been shown to be effective in significantly reducing cognitive decline in mild to moderate AD without increasing the incidence of adverse events, including neuroimaging abnormalities or suicidal ideation. Results demonstrate a statistically significant and clinically meaningful reduction in the rate of cognitive decline compared to that expected without the antibody for AD patients, including those in the early or mild stages of the disease. The present disclosure also demonstrates that 4500 mg is an effective dose, providing therapeutic benefit after a series of repeated doses.

[0170] Thus, the present disclosure provides therapeutic agents and improved methods of using same for modulating the progression of AD.

[0171] The present disclosure provides methods of treating patients suffering from mild to moderate AD or moderate AD, as well as other related tau pathologies, comprising administering a humanized monoclonal anti-tau antibody or antigen-binding fragment thereof. In some embodiments, the tau pathology is a primary tauopathy. In some embodiments, the tau pathology is a neurodegenerative tauopathy. In some embodiments, the tauopathy is selected from the group consisting of mild to moderate AD, moderate AD, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, drunkard pugilistica, Down syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / Parkinsonism dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcifications, frontotetemporal dementia, frontotetemporal dementia linked to Parkinsonism on chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, and pallidoponto-nigral degeneration. In some embodiments, the tauopathy is selected from progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, the tauopathy is progressive supranuclear palsy. In some embodiments, the tauopathy is mild to moderate AD. In some embodiments, the tauopathy is moderate AD. In some embodiments, the tauopathy is mild to moderate or moderate AD.

[0172] In some embodiments, the antibody or antigen-binding fragment thereof binds to monomeric, oligomeric, unphosphorylated, and phosphorylated forms of tau with a K, e.g., less than 100 nM, less than 75 nM, or less than 50 nM. DIn some embodiments, the antibody binds to an epitope within the N-terminal region of tau, e.g., an epitope within amino acid residues 2-24 of mature human tau (e.g., amino acid residues 2-24 set forth in SEQ ID NO: 1) and / or an epitope within or spanning amino acid residues 6-23 of mature human tau (e.g., amino acid residues 6-23 set forth in SEQ ID NO: 1). In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is an antibody fragment that binds to human tau. In some embodiments, the human tau comprises the sequence of SEQ ID NO: 1. In some embodiments, the antibody binds to cynomolgus monkey tau (SEQ ID NO: 10).

[0173] In some embodiments, the antibody is an IgG4 antibody. In certain embodiments, the antibody or antigen-binding fragment thereof comprises six hypervariable regions (HVRs), wherein HVR-H1 has the amino acid sequence of SEQ ID NO: 2, HVR-H2 has the amino acid sequence of SEQ ID NO: 3, HVR-H3 has the amino acid sequence of SEQ ID NO: 4, HVR-L1 has the amino acid sequence of SEQ ID NO: 6, HVR-L2 has the amino acid sequence of SEQ ID NO: 7, and HVR-L3 has the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 5 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 9. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VL having the amino acid sequence of SEQ ID NO: 9. In some embodiments, the antibody is semolinemab.

[0174] The therapeutic methods provided herein can be applied to patients suffering from AD or other tau pathologies, as further described herein. Suitable patients include patients with mild to moderate AD, patients with moderate AD, Apoε4-positive patients with mild to moderate AD, Apoε4-positive patients with moderate AD, Apoε4-negative patients with mild to moderate AD, Apoε4-negative patients with moderate AD, patients with an MMSE score of 16-21, particularly patients with an MMSE score of 16-19 or 16-18 (e.g., 16-17, 17-18, 17-19, or 18-19), and / or patients with one or two CDR-GS, and tau-positive patients, particularly patients with tau pathophysiology consistent with that seen in patients diagnosed with mild to moderate AD. In some embodiments, the treatment reduces tau burden, particularly aggregated tau, in the extracellular space between neurons in the patient's brain.

[0175] In some aspects, the methods provided herein are methods of alleviating AD decline in patients with mild to moderate AD. In some aspects, the methods provided herein are methods of alleviating AD decline in patients with moderate AD. In some embodiments, the decline is one or more of clinical decline, cognitive decline, and functional decline. In some embodiments, the decline is clinical decline. In some embodiments, the decline is cognitive decline or cognitive decline. Various tests and scales have been developed to measure cognitive performance (including memory) and / or function. In various embodiments, one or more scales are used to measure clinical, functional, or cognitive decline.

[0176] A standard measure of cognitive performance is the Alzheimer's Disease Assessment Scale, Cognitive subscale, e.g., the 11-item version (ADAS-Cog11). Thus, in some embodiments, a reduction or slowing of cognitive decline (or cognitive function decline) in patients treated with an anti-tau antibody is determined using the ADAS-Cog11 scale. An increase in the ADAS-Cog11 score indicates a worsening of the patient's condition.

[0177] A standard measure of functional ability is the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL). Thus, in some embodiments, the ADCS-ADL scale is used to determine the reduction or slowing of functional decline (or decline in functional ability or decline) in patients treated with an anti-tau antibody. A decrease in the ADCS-ADL score indicates a worsening of the patient's condition.

[0178] In some embodiments, the reduction or slowing of cognitive and / or functional decline (or decline in cognitive and / or functional ability) in patients treated with an anti-tau antibody is measured by Clinical Dementia Scale-Total Score (CDR-SOB or CDR-SB) score and / or Mini-Mental State Examination (MMSE). In some embodiments, the reduction or slowing of clinical decline in patients treated with an anti-tau antibody is determined by the Neuropsychiatric Index (NPI) and / or the Alzheimer's Disease Caregiver Global Impression Scale (CaGI-Alz). In some embodiments, reducing or slowing cognitive decline comprises one or more of slowing memory loss, preserving memory capacity, increasing memory capacity, increasing memory function, or increasing cognitive function.

[0179] In some embodiments, one or more types of decline are assessed, and one or more of the aforementioned tests or scales are used to measure delay in disease progression. In some embodiments, the measurements or scores (from one or more tests) are compared to the respective scores at baseline before administration of the antibody. In some embodiments, the slowing of decline is seen at least 13 weeks, at least 24 weeks, at least 25 weeks, at least 37 weeks, at least 49 weeks, at least 61 weeks, at least 69 weeks, or at least 73 weeks after initiation of treatment with the antibody. In some embodiments, the slowing of decline is seen after administration of the antibody for at least 40, 45, 47, 49, 51, 53, 55, 57, or 60 weeks, optionally at least once every four weeks (or monthly). In some embodiments, a slowing of decline occurs after administration of the antibody for at least 40, 45, 47, 49, 51, 53, 55, 57, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, or 168 weeks, optionally at least once every four weeks (or every month).

[0180] In certain embodiments, the disclosure provides methods of maintaining cognitive ability within 5 points (i.e., no more than 5 points higher) of an ADAS-Cog11 score in a patient diagnosed with mild to moderate AD or moderate AD, e.g., when assessing the patient's ADAS-Cog11 score before and after administration of an antibody, e.g., after repeated administration of a number of doses of the antibody. In some embodiments, the patient's ADAS-Cog11 score after administration of the antibody is no more than 2.5 points, no more than 3 points, no more than 3.5 points, no more than 4 points, no more than 4.5 points, or no more than 5 points higher than before administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score after administration of the antibody is 2-4 points, 3-4 points, or 4 points higher than before administration of the antibody. In certain embodiments, the ADAS-Cog11 score is assessed after administration of 5 to 15 doses of the antibody (i.e., 5 to 15 repeated 4500 mg doses), e.g., 10 to 15 doses, 12 to 15 doses, 13 to 15 doses, 13 to 14 doses, 14 to 15 doses, or 14 doses of the antibody. In some embodiments, the antibody is semolinemab. In some embodiments, the antibody is administered at least once every four weeks (or monthly) for at least 49 weeks. In some embodiments, a humanized monoclonal anti-tau antibody is administered at least once every four weeks (or monthly) for at least 48 weeks.

[0181] In some embodiments, the patient's ADAS-Cog11 score after administration of the antibody is reduced by at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to what would be expected without administration of the antibody (e.g., compared to a comparable placebo arm in a clinical study). Typically, a change of 3 points or more is considered clinically meaningful. In certain embodiments, the patient's ADAS-Cog11 score after administration of the antibody is reduced by 25-50%, 40-50%, or 40% compared to what would be expected without administration of the antibody (e.g., compared to a comparable placebo arm in a clinical study). In some embodiments, the antibody is semolinemab. In certain embodiments, the antibody is administered at least once every four weeks (or monthly) for at least 49 weeks. In some embodiments, semolinemab is administered at least once every four weeks (or monthly) for at least 48 weeks.

[0182] In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by at least 25% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by at least 30% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by at least 35% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by at least 40% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by at least 45% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by at least 50% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 25-50% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 40-50% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 25% compared to what would be expected without administration of the antibody.In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 30% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 35% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 40% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 45% compared to what would be expected without administration of the antibody. In some embodiments, the patient's ADAS-Cog11 score assessed after administration of the humanized monoclonal anti-tau antibody is reduced by 50% compared to what would be expected without administration of the antibody.

[0183] The antibodies or antigen-binding fragments thereof of the present disclosure are administered at a dose effective to treat AD or other tau pathologies, as described herein. Suitable doses are described herein and can range from about 200 mg to about 20,000 mg, e.g., about 225 mg, about 675 mg, about 1200 mg, about 1500 mg, about 2100 mg, about 4200 mg, about 4500 mg, about 8100 mg, about 8400 mg, or about 16800 mg. In some embodiments, the dose is 225 mg, 675 mg, 1200 mg, 1500 mg, 2100 mg, 4200 mg, 4500 mg, 8100 mg, 8400 mg, or 16800 mg. In some embodiments, the dose is about 4000 mg to about 5000 mg, about 4000 mg to about 4500 mg, or about 4500 mg to about 5000 mg. In some embodiments, the dose is 4000 mg to 5000 mg, 4000 mg to 4500 mg, or 4500 mg to 5000 mg. In some embodiments, the dose is about 4500 mg. In some embodiments, the dose is 4500 mg. In some embodiments, the dose is 4500 mg administered intravenously at an infusion rate of 0.5 mL / min to 3.0 mL / min, e.g., 0.5 mL / min, 1 mL / min, 1.5 mL / min, or 3 mL / min. In some embodiments, the dose used is 30 mg / kg to 60 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, or 50 mg / kg.

[0184] The methods provided herein contemplate a variety of dosing regimens, including those in which the antibody is administered repeatedly over an extended period of time, e.g., over months to years, e.g., on a weekly or monthly schedule. In some embodiments, the antibody is administered once every 2, 3, 4, 5, 6, 7, or 8 weeks. In some examples, the antibody is administered every 2 weeks for the first 2, 3, or 4 doses, and then every 4 weeks (or monthly) thereafter.

[0185] The humanized monoclonal anti-tau antibodies of the present disclosure offer the additional advantage of not increasing the incidence of adverse events, such as neuroimaging abnormalities or suicidal ideation. As shown herein, there was no statistically significant increase in these adverse events in the treatment arm compared to the placebo arm. Thus, the present disclosure further provides a method of treating patients suffering from mild to moderate or moderate AD without increasing (without significantly increasing) the incidence of adverse events, such as neuroimaging abnormalities, suicidal ideation, headache, cognitive deterioration, altered consciousness, seizures, dizziness, and vomiting.

[0186] The present disclosure further provides pharmaceutical formulations suitable for use in the methods of treatment disclosed herein. The medicaments can be formulated for any convenient route of administration, for example, parenteral or intravenous injection, and typically include, in addition to an anti-tau antibody described herein, one or more acceptable carriers, excipients, and / or diluents appropriate for the desired mode of administration. In some embodiments, the anti-tau antibody may be formulated for intravenous administration. Further embodiments are described herein. The pharmaceutical formulations can be packaged in unit dosage form for ease of use.

[0187] The use of anti-tau antibodies for the treatment of AD or other tau pathologies described herein can be combined with other therapies, including one or more anti-amyloid beta (Abeta) antibodies, or one or more anti-tau antibodies other than semolinemab. Non-limiting examples of other therapies include neurological agents, corticosteroids, antibiotics, antiviral agents, additional anti-tau antibodies, tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE 1 antibodies, BACE1 inhibitors; therapeutic agents that specifically bind to a target; cholinesterase inhibitors; NMDA receptor antagonists; monoamine depleting agents; ergoloid mesylates; anticholinergic antiparkinsonian agents; dopaminergic antiparkinsonian agents; tetrabenazine; anti-inflammatory agents; hormones; vitamins; dimebolins; homotaurines; serotonin receptor modulators; interferons, and glucocorticoids.

[0188] In some embodiments, the patient is being treated with concomitant medication, e.g., a symptomatic medication. In some embodiments, the symptomatic medication is selected from the group consisting of a cholinesterase inhibitor, galantamine, rivastigmine, donepezil, an N-methyl-D-aspartate receptor antagonist, memantine, and a dietary supplement (optionally, the dietary supplement is Souvenaid®). In some embodiments, the symptomatic medication is a cholinesterase inhibitor, such as galantamine, rivastigmine, and / or donepezil. In some embodiments, the symptomatic medication is an N-methyl-D-aspartate receptor antagonist. In some embodiments, the symptomatic medication is memantine. In some embodiments, the symptomatic medication is a dietary supplement, e.g., the dietary supplement Souvenaid®.

[0189] The present disclosure relates, in part, to the surprising finding that anti-tau monoclonal antibodies can reduce the rate of clinical decline in cognition, and in particular memory decline, to a statistically significant degree in patients with mild to moderate AD or moderate AD, as demonstrated by a Phase 2 study. The present disclosure provides a first-in-class immunotherapy for use in reducing clinical decline in cognition, and in particular memory decline, associated with pathological tau in the brains of patients with AD and other tauopathies, such as progressive supranuclear palsy (PSP).

[0190] The clinical trial met its primary endpoint in the first tau antibody Phase 2 trial in mild-to-moderate AD and moderate AD, reducing the rate of clinical decline in cognition from baseline compared to placebo, as measured by ADAS-Cog11, marking the first clinical proof-of-concept for an anti-tau-specific approach in the treatment of AD or related tau pathologies. Furthermore, as shown in the Examples herein, antibodies that bind to the N-terminal region of tau reduce the rate of clinical decline in cognition in patients diagnosed with mild-to-moderate AD or moderate AD, particularly by reducing the rate of loss of memory function.

[0191] The Phase 2 clinical trial disclosed herein was a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial designed to evaluate the clinical efficacy, safety, pharmacokinetics, and pharmacodynamics of semolinemab in patients with mild to moderate AD (MMSE 16-21, CDR-GS 1 or 2). The study included a screening period, a 48-week (Weeks 1-49 for Cohort 1 participants) or 60-week (Weeks 1-61 for Cohort 2 participants) double-blind treatment period, an optional open-label extension (OLE) period, and a safety follow-up period. The ADAS-Cog11 and ADCS-ADL tool were coprimary endpoints, with CDR-SB, MMSE, and safety as secondary endpoints. The study followed 272 participants across 43 research centers worldwide.

[0192] The clinical trials disclosed herein provide the first evidence that tau-targeted therapy reduces the rate of clinical decline in neurodegenerative diseases, including tau pathologies (tauopathies). Topline data from a Phase 2 study showed that semolinemab: ● slowing decline on measures of cognition compared to placebo, meeting one primary endpoint: reducing the rate of cognitive decline from baseline as measured by the ADAS-Cog11-ADAS-Cog11, compared to placebo; and ● It was demonstrated to be safe and well-tolerated, with an acceptable safety profile and no unexpected signals.

[0193] The study also demonstrated an effective dose of an anti-tau antibody in slowing cognitive decline, particularly memory decline, in patients diagnosed with mild to moderate AD. The 4500 mg Q4W dosing regimen in this study took into account the safety profile from a nonclinical toxicology study, the safety and PK profile from a Phase 1 study (GN39058), and results from a target engagement modeling exercise. In the target engagement modeling analysis, simulations were performed to predict the percentage of target (i.e., tau) engagement by semolinemab in brain interstitial fluid. The results demonstrated that high target achievement (i.e., >80%) was possible for the 4500 mg dose under various scenarios (e.g., several plasma:brain distribution ratios and semolinemab binding affinities). Nevertheless, the degree of target engagement required for clinical efficacy was unknown prior to the results of this study.

[0194] The study also surprisingly found clinical responses in patients with AD at a specific stage of the disease, namely mild to moderate severity. Patients in this study met standard research criteria for AD (according to the NIAAA diagnostic criteria and AD guidelines) with mild to moderate disease severity (overall, the population had MMSE scores between 16 and 21, inclusive, and CDRGs of 1 or 2).

[0195] Without being bound by theory, tau pathology appears to continue to increase at this stage of the disease (Jack et al. Lancet Neurol. 2013;12:207-16). Targeting tau proliferation in mild to moderate stages of AD has, in some embodiments, proven more effective than previous interventions that targeted Aβ at this stage of the disease but failed to improve further clinical decline (Doody et al. N Engl J Med 2013; Doody et al. N Engl J Med 2014;370:311-21369:341-5; Salloway et al. N Engl J Med 2014;370:322-33; Egan et al. N Engl J Med 2018;378:1691-1703). Although the majority of Aβ pathology accumulation may already have occurred by the time AD patients reach the moderate stage of disease, tau pathology appears to continue to increase (Jack et al. Lancet Neurol. 2013;12:207-16). Furthermore, at different stages of AD, tau pathology may manifest in different primary configurations, which may play different roles in both the further spread of tau pathology and its relative contribution to clinical decline. While the precise nature of diffusing tau species in AD remains uncertain, both the structure of tau neurofibrillary tangles in the brain parenchyma and the relative abundance of different soluble phospho-tau species in the CSF may evolve with increasing disease severity, and as a result, different anti-tau therapeutics may have different efficacy at different stages of the disease. Nevertheless, for over 30 years, studies have suggested the continued progression of tau pathology in patients with moderate AD, without previously successfully demonstrating the use of anti-tau approaches to slow the rate of clinical decline. For example, consider studies examining tau indicators via neuropathology (Nelson et al. J Neuropathol Exp Neurol. 2012;71:362-81), CSF tau levels (Kanai et al. Ann Neurol 1998;44:17-26), and PET imaging (Ishiki et al. PLoS One 2015;10:e0140311).

[0196] The phase 2 clinical trial disclosed herein also demonstrated that the anti-tau antibody approach treats patients diagnosed with mild to moderate AD or moderate AD without increasing the risk of adverse events. Unlike Aβ, tau is not known to deposit in vasculature, and administration of antibodies against tau may not cause vasogenic edema or microhemorrhages, as seen with some anti-Aβ therapies. Tau pathology occurs primarily intracellularly in the cytoplasm of affected neurons (Braak et al. Acta Neuropathol 2006;112:389-404), while soluble tau from the extracellular space is found in the CSF (Blennow and Zetterberg, J Alzheimers Dis. 2009;18:413-7). Furthermore, semolinemab possesses an IgG4 backbone, which is associated with reduced effector function.

[0197] On the other hand, the occurrence of imaging abnormalities thought to represent cerebral vasogenic edema and microhemorrhages has been reported in association with the investigational use of immunotherapies targeting Aβ peptides, presumably by interacting with intravascular or perivascularly deposited Aβ and inducing an immune response. Symptoms associated with such imaging abnormalities have been reported to include headache, cognitive deterioration, altered consciousness, seizures, dizziness, and vomiting (Salloway et al. Neurology 2009;73:2061-70; Sperling et al. Lancet Neurol. 2012;11:241-9). The present disclosure provides a therapeutic advantage of not inducing such adverse effects. In some embodiments, imaging abnormalities do not occur after administration of an anti-tau antibody. In some embodiments, treatment is achieved without headache, cognitive deterioration, altered consciousness, seizures, dizziness, and / or vomiting.

[0198] General The practice of the methods, and the preparation and use of the compositions disclosed herein will employ, unless otherwise indicated, conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields, which are within the skill of the art and are fully explained in the literature.

[0199] The term "herein" means the entire disclosure.

[0200] It should be understood that any of the embodiments described herein, including those described in different aspects of the disclosure and in different parts of the specification (including embodiments described only in the Examples), can be combined with one or more other embodiments disclosed herein, unless expressly stated to the contrary or inappropriate. Combinations of embodiments are not limited to specific combinations claimed by multiple dependent claims.

[0201] Any publications, patents, and published patent applications mentioned in this disclosure are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0202] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" are synonymous with "including," "containing," or "characterized by," and are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0203] Throughout this specification, when a composition is described as having, including, or comprising certain components (or variations thereof), it is understood that the composition may consist essentially of, or consist of, the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process may consist essentially of, or consist of, the recited process steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein are operable. Moreover, two or more steps or actions may be performed simultaneously.

[0204] The term "consisting of" excludes any element, step, or ingredient not specifically listed.

[0205] The term "consisting essentially of" limits the scope of the disclosure to the specified materials or steps, and those that do not materially affect the basic and novel characteristic(s) of the disclosure.

[0206] The term "eg" or "for example" followed by one or more example(s) is not meant to be exclusive or limiting.

[0207] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an" means one element or more than one element.

[0208] As used herein, the term "about" modifying the quantity of a component, parameter, calculation, or measurement of a composition used in a method of the present disclosure refers to variations in numerical value that may occur, for example, due to common measuring and liquid handling procedures used to make isolated polypeptides or pharmaceutical compositions in the real world; due to inadvertent errors in these procedures; due to differences in the manufacture, source, or purity of components used to make the composition or perform the method; and the like, without substantially affecting the chemical or physical attributes of the composition or method of the present disclosure. Such variations may typically be within 10%, more typically even within 5%, of a given value or range. The term "about" also encompasses amounts that vary due to different equilibrium conditions of a composition resulting from a particular initial mixture. Whether modified by the term "about," a paragraph includes its equivalent. Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments that are directed to the value or parameter itself. For example, a reference to "about X" includes the reference to "X." Numerical ranges include the numbers defining the range.

[0209] As used herein, the term "or" should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0210] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein should be understood to encompass all subranges subsumed therein. For example, a range stated as "1 to 10" should be considered to include all subranges between the minimum value of 1 and the maximum value of 10, inclusive; i.e., all subranges beginning with a minimum value of 1 or greater, e.g., 1 to 6.1, and all subranges ending with a maximum value of 10 or less, e.g., 5.5 to 10. The disclosure of a range should also be considered a disclosure of the endpoints of that range.

[0211] Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0212] Specific Definitions and Abbreviations Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, NY 1992) provide those skilled in the art with a general guide to many of the terms used in this disclosure.

[0213] For purposes of interpreting this specification, the following definitions shall apply, and where appropriate, in the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth below shall control.

[0214] Ranges provided in this specification and the appended claims include both endpoints and all points between those endpoints, so for example, a range of 2.0 to 3.0 includes 2.0, 3.0, and all points between 2.0 and 3.0.

[0215] The following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0216] "Administering" a substance, compound, or agent to a subject or "administration of" a substance, compound, or agent to a subject refers to contacting the substance, compound, or agent with the subject or the subject's cells, tissues, organs, or bodily fluids. For example, a compound or agent can be administered intravenously or subcutaneously. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods of time. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a subject to self-administer a drug or to have another person administer a drug and / or provides a subject with a prescription for a drug is administering a drug to a subject. The terms "administering," "administration of," and "administered" are used interchangeably with "provided" and its variants.

[0217] As used herein, the phrases "substantially similar" or "substantially the same" refer to a sufficiently high degree of similarity between two numerical values ​​that one of skill in the art would consider the difference between the two values ​​to be of little or no biological and / or statistical significance in the context of the biological attribute measured by the values ​​(e.g., Kd values), where the difference between the two values ​​is less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% as a function of value.

[0218] The terms "antibody" and "immunoglobulin" ("Ig") are used interchangeably in the broadest sense and refer to an immunoglobulin molecule (e.g., a complete antibody, an antibody fragment, or a modified antibody) that can recognize and bind to a specific target or antigen, such as a carbohydrate, polynucleotide, lipid, or polypeptide, via at least one antigen recognition site located in the variable region of the immunoglobulin molecule. The term includes, but is not limited to, monoclonal antibodies (e.g., full-length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies (e.g., bispecific antibodies), antibodies with polyepitopic specificity, single-chain antibodies, multispecific antibodies (e.g., bispecific antibodies, trispecific antibodies, tetraspecific antibodies), and antibody fragments, provided that they exhibit the desired biological activity. Such antibodies may be chimeric, humanized, human, synthetic, and / or affinity matured. In some embodiments, "antibody" and / or "immunoglobulin" (Ig) refer to a polypeptide comprising at least two heavy (H) chains (approximately 50-70 kDa) and two light (L) chains (approximately 25 kDa), optionally interconnected by disulfide bonds. There are two types of light chains: lambda and kappa. In humans, lambda and kappa light chains are similar, but only one type is present in each antibody. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, which define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)), incorporated by reference in its entirety. The methods, uses, and compositions for use disclosed herein utilize IgG antibodies.

[0219] As used herein, the terms "amyloid beta," "amyloid β," "Abeta," and "Abeta" are used interchangeably and refer to a peptide of 36-43 amino acid residues that is the major component of amyloid plaques found in the brains of people with Alzheimer's disease.

[0220] As used herein, the terms "additional anti-tau antibody" and "different anti-tau antibody" are used interchangeably and refer to anti-tau antibodies that do not have the same six CDRs of semolinemab.

[0221] As used herein, the term "antigen-binding fragment" refers to a portion (or fragment) of an antibody that retains its antigen-binding specificity. Thus, as used herein, an antigen-binding fragment retains the six CDRs of the reference antibody.

[0222] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein and refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0223] An "antibody fragment" preferably comprises only a portion of an intact antibody, which portion retains at least one, and typically most or all, of the functions normally associated with that portion when present in an intact antibody. In some embodiments, an antibody fragment comprises the antigen-binding site of an intact antibody and thus retains the ability to bind to antigen. In some embodiments, an antibody fragment, e.g., an antibody fragment comprising an Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half-life regulation, ADCC function, and complement fixation. In some embodiments, an antibody fragment is a monovalent antibody that has an in vivo half-life substantially similar to that of an intact antibody. For example, such an antibody fragment may contain an antigen-binding arm attached to the Fc sequence, which may confer in vivo stability to the fragment. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab'), diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0224] As used herein, the terms "Fc," "Fc region," or "Fc domain" are used interchangeably herein and refer to the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In some embodiments, a human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues within an Fc region or constant region is according to EU numbering, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. Those skilled in the art will recognize that EU numbering may differ from the residue numbering of the sequences disclosed herein. For example, one skilled in the art will recognize that the S225P, M249Y, S251T, and T253E mutations based on the residue numbering in SEQ ID NO: 11 are S228P, M252Y, S254T, and T256E mutations according to EU numbering. In the case of IgG, the Fc domain comprises immunoglobulin domains Cγ2 and Cγ3 and the lower hinge region between Cγ1 and Cγ2.

[0225] As used herein, the term "Fc variant" or "variant Fc" refers to a protein comprising an amino acid modification in the Fc domain.

[0226] As used herein, the terms "Fc gamma receptor," "Fc-gamma receptor," "FcγR," and "Fc gamma R" are used interchangeably and refer to any member of a family of proteins that bind to the Fc region of an IgG antibody and are encoded by the FcγR gene. The FcγR may be from any organism. In some embodiments, the FcγR is a human FcγR. In humans, this family includes, but is not limited to, FcγRI (CD64), which includes the isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), which includes the isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; FcγRIII (CD16), which includes the isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIb-NA1 and FcγRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65 (incorporated by reference in its entirety)), and any unidentified human FcγR or FcγR isoform or allotype.

[0227] As used herein, the term "FcRn" or "neonatal Fc receptor" refers to a protein that binds to the Fc region of an IgG antibody and is at least partially encoded by the FcRn gene. The FcRn may be derived from any organism. In some embodiments, the FcRn is human. As known in the art, a functional FcRn protein often comprises two polypeptides, referred to as a heavy chain and a light chain. The light chain is beta2 microglobulin, and the heavy chain is encoded by the FcRn gene. Unless otherwise specified herein, FcRn or FcRn protein refers to the complex of the FcRn heavy chain and beta2 microglobulin. Various FcRn variants can be used to increase binding to the FcRn receptor and, in some cases, increase serum half-life. Generally, unless otherwise specified, the Fc monomers disclosed herein retain binding to the FcRn receptor (and can include amino acid variants that increase binding to the FcRn receptor, as described below).

[0228] As used herein, the term "effector function" refers to a biological activity attributable to the Fc region of an antibody that varies depending on the antibody isotype and results from the interaction of the antibody Fc region with an Fc receptor or another effector molecule (e.g., Fc receptor-like (FcRL) molecule, complement component C1q, and tripartite motif-containing protein 21 (TRIM21)). Examples of antibody effector functions include: Clq binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors); and B cell activation. It is known in the art that wild-type IgG4 antibodies have fewer effector functions than wild-type IgG1 antibodies. Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). As used herein, the term "ADCC" or "antibody-dependent cell-mediated cytotoxicity" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibody on target cells, subsequently causing lysis of the target cells. ADCC correlates with binding to FcγRIIIa, and increased binding to FcγRIIIa results in increased ADCC activity. As discussed herein, many embodiments of the present disclosure completely ablate ADCC activity. As used herein, the term "ADCP" or "antibody-dependent cell-mediated phagocytosis" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibody on target cells, subsequently causing phagocytosis of the target cells. As used herein, the term "CDC" or "complement-dependent cytotoxicity" refers to the effector function that results in activation of the classical complement pathway, which is triggered by antibody binding to an antigen on a target cell and activates a series of cascades involving complement-related proteins in the blood.

[0229] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competitive assay; conversely, the reference antibody blocks the binding of the antibody to its antigen by 50% or more in a competitive assay.

[0230] As used herein, the term "affinity" or "binding affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., between the binding arm of an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein, any of which can be used for purposes of the present disclosure. The Kd binding affinity constant can be measured by surface plasmon resonance, for example, using the BIACORE® system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). See also Jonsson et al., Ann. Biol. Clin. 51:19 26 (1993); Jonsson et al., Biotechniques 11:620 627 (1991); Jonsson et al., J. Mol. Recognit. 8:125 131 (1995); Johnsson et al., Anal. Biochem. 198:268 277 (1991); Hearty S et al., Methods Mol Biol. 907:411-42 (2012), each of which is specifically incorporated herein by reference. KD may be measured using the KinExA® system (Sapidyne Instruments, Hanover, Germany and Boise, ID).

[0231] As used herein, the terms "amino acid" and "amino acid identity" refer to one of the 20 naturally occurring amino acids encoded by DNA and RNA.

[0232] As used herein, the term "amino acid substitution" or "substitution" refers to the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid. Notably, in some embodiments, the substitution is for an amino acid that does not naturally occur at the particular position and does not naturally occur in the organism or any organism. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which glutamic acid at position 272 has been replaced with tyrosine. For clarity, a protein that has been engineered to alter the nucleic acid coding sequence but not change the starting amino acid (e.g., exchanging CGG (which encodes arginine) for CGA (which still encodes arginine) to increase expression levels in the host organism) is not an "amino acid substitution." That is, if a new gene encoding the same protein is generated, but the protein has the same amino acid at a particular position that is the starting position, it is not considered an amino acid substitution.

[0233] As used herein, the terms "amino acid insertion," "amino acid addition," or "addition" or "insertion" refer to the addition of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, -233E, _233E, or 233E indicates the insertion of glutamic acid after position 233 and before position 234. Furthermore, -233ADE, _233ADE, or 233ADE indicates the insertion of AlaAspGlu after position 233 and before position 234.

[0234] As used herein, "amino acid deletion" or "deletion" refers to the removal of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, E233- or E233#, E233(), E233_ or E233del refers to the deletion of glutamic acid at position 233. Additionally, EDA233-, EDA233_ or EDA233# indicates the deletion of the sequence GluAspAla beginning at position 233.

[0235] As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably to refer to a polymer of amino acid residues.

[0236] An "affinity matured" antibody has one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess those alterations, which alterations result in an improvement in the affinity of the antibody for antigen.

[0237] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0238] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, and is hereby registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California), or can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0239] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or comprising a particular % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction (X / Y) where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​as used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0240] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope except for possible naturally occurring mutations, or antibodies that may be present in minor amounts during production of a monoclonal antibody preparation. Monoclonal antibodies are highly specific for a single antigen. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.

[0241] As used herein, monoclonal antibodies specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)).

[0242] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into "subclasses" (or "isotypes"), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0243] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. A "humanized antibody" refers to a chimeric antibody containing amino acid residues from non-human HVRs and human FRs. In most cases, humanized antibodies are antibodies in which hypervariable region residues of a human immunoglobulin (recipient antibody) are replaced by residues from a hypervariable region of a non-human species (donor antibody), such as mouse, rat, rabbit, or non-human primate, possessing the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient or donor antibody. These modifications are made to further refine antibody performance. Generally, humanized antibodies comprise substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin and all or substantially all of the FRs being those of a human immunoglobulin sequence. The humanized antibody optionally also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the following review articles and the references cited therein: Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994).

[0244] A "human antibody" is one that contains an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, and / or is derived from a non-human source that utilizes the human antibody repertoire or other human antibody coding sequences, e.g., made using any of the techniques for making human antibodies disclosed herein. Such techniques include, but are not limited to, screening human-derived combinatorial libraries, such as phage display libraries (see, e.g., Marks et al., J. Mol. Biol., 222:581-597 (1991) and Hoogenboom et al., Nucl. Acids Res., 19:4133-4137 (1991)); production of human monoclonal antibodies using human myeloma and mouse-human heteromyeloma cell lines (see, e.g., Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 55-93 (Marcel Dekker, Inc., New York, 1987); and Boerner et al. al., J. Immunol., 147:86 (1991); as well as generating monoclonal antibodies in transgenic animals (e.g., mice) that are capable of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255 (1993); Bruggermann et al., Year in Immunol, 7:33 (1993)). This definition of a human antibody specifically excludes humanized antibodies containing antigen-binding residues from non-human animals.

[0245] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of natural antibodies generally have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, for example, Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain is sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen may be isolated by using the VH or VL domain of an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively (see, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0246] The terms "hypervariable region," "HVR," or "HV," as used herein, refer to the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops and / or contain antigen-contacting residues ("antigen contacts"). Generally, antibodies contain six hypervariable regions: three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). Several hypervariable region descriptive methods are in use and are encompassed herein. The Kabat complementarity-determining region (CDR) is based on sequence variability and is the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia, instead, refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The AbM hypervariable regions are a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "contact" hypervariable regions are based on an analysis of available complex crystal structures. Exemplary HVRs herein include the following: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) A combination of (a), (b) and / or (c) comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3). Unless otherwise specified, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0247] "Framework" or "FR" residues are those variable domain residues other than the hypervariable region residues as herein defined. The FR of a variable domain generally comprises four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0248] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0249] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup similar to Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In some embodiments, for VL, the subgroup is subgroup kappa I. In some embodiments, for VH, the subgroup is subgroup III as in Kabat et al.

[0250] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecule(s), including but not limited to an additional therapy (additional therapeutic agent).

[0251] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., an additional therapeutic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0252] An "isolated" antibody is one that has been identified and separated and / or recovered from components of its natural environment. Contaminant components of its natural environment are substances that would interfere with diagnostic and therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, antibodies are purified to greater than 95% or greater than 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0253] The terms "nucleic acid," "polynucleotide," and "oligonucleotide" are used interchangeably and refer to deoxyribonucleotide or ribonucleotide polymers in linear or circular conformation, and in single- or double-stranded form. For purposes of this disclosure, these terms are not to be construed as limiting the length of the polymer.

[0254] As used herein, the term "position" refers to a location within a protein or polynucleotide sequence. Positions may be numbered consecutively or according to established formats, such as the EU index for antibody numbering. Positions may be defined relative to a reference sequence. In such cases, the reference sequence is provided for comparison purposes.

[0255] As used herein, the term "residue" refers to a position in a protein and its associated amino acid identity. For example, asparagine 297 (also called Asn297 or N297) is the residue at position 297 in a particular protein.

[0256] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably herein and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny without regard to the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0257] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acid includes a nucleic acid molecule that is contained in cells that ordinarily contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0258] An "isolated nucleic acid encoding an anti-tau antibody" refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present in one or more locations within a host cell.

[0259] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures as well as vectors that are integrated into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of a nucleic acid to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0260] As used herein, the term "target," unless otherwise indicated, refers to any naturally occurring molecule from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length" unprocessed targets, as well as any form of target that results from processing within a cell. The term also encompasses naturally occurring variants of a target, such as splice variants or allelic variants.

[0261] The terms "anti-target antibody" or "antibody that binds to a target" refer to an antibody that can bind to a target with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent when targeted to the target. In some embodiments, the extent of binding of the anti-target antibody to an unrelated, non-target protein is less than about 10% of the binding of the antibody to the target, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the anti-target antibody binds to an epitope of the target that is conserved across different species.

[0262] As used herein, the term "tau," unless otherwise indicated, refers to any native tau protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed tau, as well as any form of tau resulting from processing within a cell. The term also encompasses naturally occurring variants of tau, such as splice variants or allelic variants. Tau is known to exist in different forms. The structure and sequence of tau are well known to those skilled in the art, as are methods for producing such peptides or extracting them from brain and other tissues. Tau and tau peptides are commercially available in various forms.

[0263] As used herein, the term "pTau" refers to tau that is phosphorylated by a protein kinase on a serine, threonine, or tyrosine residue by the addition of a covalently attached phosphate group. In some embodiments, pTau is phosphorylated on a serine or threonine residue. In some embodiments, pTau is phosphorylated on serine 409 and / or serine 404. Additional phosphorylation sites on tau include, but are not limited to, Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser235, Ser422, and Thr534.

[0264] As used herein, the term "soluble tau" or "soluble tau protein" refers to solubilized tau protein / peptide monomers, tau-like peptides / proteins, modified or truncated tau peptides / proteins, and / or other derivatives of tau peptide / protein monomers, any of which are soluble, substantially soluble, or completely soluble. "Soluble tau" also refers to tau protein oligomers that are soluble, substantially soluble, or completely soluble. Conversely, "soluble tau" excludes neurofibrillary tangles (NFTs).

[0265] As used herein, the term "insoluble tau" refers to multiple aggregated monomers of tau peptides or proteins, tau-like peptides / proteins, modified or truncated tau peptides / proteins, and / or other derivatives of tau peptides / proteins, any of which are insoluble in the mammalian or human body, more specifically in the brain. Insoluble tau generally forms insoluble oligomeric or polymeric structures in aqueous media both in vitro and in vivo in the mammalian or human body, more specifically in the brain. "Insoluble tau" specifically includes neurofibrillary tangles (NFTs).

[0266] As used herein, the terms "monomeric tau," "tau monomer," and "monomeric form of tau" refer to fully (or substantially) solubilized tau protein that is free of aggregated complexes in aqueous media.

[0267] As used herein, the terms "aggregated tau," "oligomeric tau," "tau oligomer," and "oligomeric forms of tau" refer to multiple aggregated monomers of tau peptides or proteins, tau-like peptides / proteins, modified or truncated tau peptides / proteins, and / or other derivatives of tau peptides / proteins that form oligomeric or polymeric structures that are insoluble in the mammalian or human body, particularly the brain. Generally, aggregated tau is insoluble (completely insoluble or substantially insoluble) both in vitro and in vivo in aqueous media in the mammalian or human body, more particularly the brain.

[0268] As used herein, the terms "p-tau PHF," "PHF," and "paired helical filament" refer to pairs of helically wound filaments with a periodicity of 160 nm visible by electron microscopy. Their width varies between 10 and 22 nm. PHFs are the predominant structure in AD neurofibrillary tangles and neuropil threads. PHFs may also be found in some, but not all, degenerating neurites associated with senile plaques. The primary component of PHFs is a hyperphosphorylated form of the microtubule-associated protein tau. PHFs may be composed, in part, of disulfide-linked antiparallel hyperphosphorylated tau proteins. PHF-forming tau can be cleaved at 20 amino acid residues from its C-terminus. Although the mechanism underlying PHF formation is unclear, hyperphosphorylation of tau may release it from microtubules and increase the soluble pool of tau from which PHFs can form within neurons.

[0269] The terms "tau pathology," "tauopathy," "tau protein-associated disease," or "tau-associated disease" are used interchangeably herein and refer to a group of diseases and disorders caused by or associated with tau aggregates in the extracellular space of a patient's brain, including those caused by or associated with the formation of neurofibrils or neuropil threads. Such diseases include, but are not limited to, neurological disorders such as AD, and diseases or conditions characterized by loss of cognitive ability. Non-limiting examples of tau pathologies include amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, pugilistically impaired persons, Down's syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / Parkinsonism dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcifications, frontotetemporal dementia, frontotetemporal dementia linked to Parkinsonism on chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, and pallidoponto-nigral degeneration. degeneration), Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, the tauopathy is progressive supranuclear palsy. In some embodiments, the tau pathology is characterized by tau pathology in the extracellular space of the patient's brain that is substantially similar to that seen in mild to moderate AD, and such tau pathology is referred to herein as tau pathology associated with mild to moderate AD or "associated tau pathology." In some embodiments, the tau pathology is AD. In some embodiments, the tau pathology is mild to moderate AD. In some embodiments, the tau pathology is moderate AD. In some embodiments, the tau pathology is mild to moderate or moderate AD.

[0270] A "tau positive" individual is a patient with brain tau isoforms and / or levels typical of tau pathology, e.g., a positive tau positron emission tomography (PET) scan (e.g., a positive [ 18 F]GTP1 scan) and / or have tau serum or plasma detection characteristic of a tauopathy; and / or have tau CSF detection characteristic of a tauopathy. In some embodiments, the tau burden is consistent with that seen in patients diagnosed with mild to moderate AD. Current tau PET tracers only reliably detect AD tau deposits and do not consistently label / detect PSP, FTD, or CTE tau deposits. As a result, elevated pTau181, pTau217, and pTau231 are relatively specific to AD and are not commonly elevated in other tauopathies.

[0271] Alzheimer's disease ("AD") is generally diagnosed based on medical history, clinical examination, and established imaging modalities.

[0272] Abeta positivity can be used to diagnose AD. In some embodiments, AD patients are determined to be amyloid positive (McKhann et al. Alzheimer's Dement 2011;7:263-9; Dubois et al. Lancet Neurol. 2014;13:614-29). Biomarker evidence of Abeta deposition can be assessed by reduced CSF Abeta 1-42 levels (e.g., using a pre-specified cutoff point and the Roche Diagnostics Elecsys® βAmyloid[1-42] immunoassay (lower cutoff; 1,000 pg / mL or less)) and / or focused visual assessment of the brain with amyloid PET imaging. Both approaches have been shown to correlate with the "gold standard" of Abeta pathology at autopsy (Shaw et al. Ann Neurol. 2009:65;403-13; Clark et al. JAMA 2011;305:275-83; Le Bastard et al. J Alzheimer's Dis 2013;33:117-31) (see Example 1, which uses this approach for enrollment in a clinical study).

[0273] This approach is consistent with emerging evidence demonstrating consistency between amyloid PET imaging and CSF biomarkers: low CSF Aβ1-42 shows an inverse relationship with in vivo Aβ cortical burden measured by Pittsburgh Compound B amyloid PET imaging (Fagan et al. Ann Neurol. 2006;59:512-9; Forsberg et al. Neurobiol Aging 2008;29:1456-65; Tolboom et al. J Nucl Med 2009;50:1464-70). Information obtained via amyloid PET imaging and low CSF Aβ1-42 is consistent across a wide range of populations spanning the spectrum of AD severity (mild to moderate AD predementia; Jagust et al. Neurology 2009;73:1193-9; Fagan et al. Arch Neurol. 2011;68:1137-44; Landau et al. Ann Neurol. 2013;74:826-36; Zwan et al. J Alzheimer's Dis 2014;41:801-7).

[0274] Furthermore, both the National Institute of Advanced Industrial Science and Technology (NIA) AA diagnostic criteria and guidelines for AD and the European Committee for Medicinal Products for Human Use (ECRM) qualified opinion encourage the use of CSF biomarkers and / or PET amyloid imaging to enhance testing in mild-to-moderate AD dementia (2012), and the U.S. Food and Drug Administration (FDA) draft guidance does the same for early AD (2018). While the FDA guidance refers to the early stage of AD, in which individuals exhibit mild cognitive impairment, biomarkers of amyloid pathology are also expected to add value to patient selection in moderate AD. Further details for diagnosing AD are provided in Table 1 below. [Table 1] AD = Alzheimer's disease; CSF = cerebrospinal fluid; NIA-AA = National Institute on Aging / Alzheimer's Association; PET = positron emission tomography.

[0275] As used herein, the term "early Alzheimer's disease" or "early AD" (e.g., "a patient diagnosed with early AD" or "a patient suffering from early AD") includes prodromal to mild AD severity.

[0276] AD patients can be identified as having one or more AD biomarkers, such as amyloid-positive patients or patients with a positive tau PET scan. One or more commercially available amyloid tracers, such as florbetapir, florbetaben, flutemetamol, etc., can be used. One or more tau PET tracers can be used, for example, the tau tracer [F]Genentech tau probe 1 ([F]GTP1), as described in U.S. Pat. No. 10,076,581. In some embodiments, other tau probes can be used. Examples of such tracer molecules include, but are not limited to, RO-948 (F. Hoffmann-La Roche AG); AV-1451 ("Flortaucipir", Avid, Inc.); PI-2014 and PI-2620 (AC Immune); MK-6240 (Merck Sharp & Dohme); and T-808 (Eli Lilly & Co.). Methods for quantifying tau distribution in a patient's brain based on imaging of a radiolabeled tracer include the "standardized uptake value ratio" (SUVR) (see, e.g., J. Nucl. Med., S. Sanabria Bohorquez et al., 58(1), (2017), incorporated herein by reference).

[0277] In some embodiments, AD patients are identified using a PET tracer. In some embodiments, the PET tracer binds to tau. In some embodiments, the PET tracer binds to Abeta. In some embodiments, the PET tracer binds to tau or Abeta. In some embodiments, the PET tracer that binds to tau is 18 F]Genentech Tau Probe 1 ([ 18In some embodiments, the PET tracer that binds to tau is at least one selected from the group consisting of [F]GTP1), RO-948, AV-1451 (flortaucipir), PI-2014, PI-2620, MK-6240, and T-808, and the PET tracer that binds to Abeta is at least one selected from the group consisting of florbetapir, florbetaben, and flutemetamol. 18 F]Genentech Tau Probe 1 ([ 18 In some embodiments, the PET tracer that binds to Abeta is at least one selected from the group consisting of [F]GTP1), RO-948, AV-1451 (flortaucipir), PI-2014, PI-2620, MK-6240, and T-808. In some embodiments, the PET tracer that binds to Abeta is at least one selected from the group consisting of florbetapir, florbetaben, and flutemetamol. In some embodiments, the PET tracer is 18 F]Genentech Tau Probe 1 ([ 18 F]GTP1). In some embodiments, the PET tracer is RO-948. In some embodiments, the PET tracer is AV-1451 (flortaucipir). In some embodiments, the PET tracer is PI-2014. In some embodiments, the PET tracer is PI-2620. In some embodiments, the PET tracer is MK-6240. In some embodiments, the PET tracer is T-808. In some embodiments, the PET tracer is florbetapir. In some embodiments, the PET tracer is florbetaben. In some embodiments, the PET tracer is flutemetamol.

[0278] In some embodiments, prodromal AD refers to AD characterized by a CDR score of 0.5. AD disease progresses from prodromal to mild, mild to moderate, and moderate to severe.

[0279] In some embodiments, the term "mild Alzheimer's disease" or "mild AD" can refer to AD characterized by an MMSE score of 20 to 26. In some embodiments, mild AD refers to AD characterized by a CDR score of 1.

[0280] As used herein, the term "mild-to-moderate Alzheimer's disease" or "mild-to-moderate AD" encompasses both mild and moderate AD. As used herein, mild-to-moderate AD is characterized by an MMSE score of 16 to 21. Among the group of patients with a score of 16 to 21, patients with an MMSE score of 18 or less may be considered to have moderate AD, and patients with a score of 19 or greater may be considered to have mild AD.

[0281] As used herein, the terms "moderate Alzheimer's disease" or "moderate AD" (e.g., "a patient diagnosed with moderate AD") generally refer to a stage of AD characterized by a lower MMSE score, such as an MMSE score of 10 to 19. In some embodiments, moderate AD refers to AD characterized by a CDR score of 2. Patients with moderate AD can be distinguished from patients with the mild cognitive impairment or mild dementia stage of the disease.

[0282] Mild to moderate AD can be assessed by one or more of the following: (1) Mini-Mental State Examination; (2) Clinical Dementia Scale; (3) Clinical Dementia Assessment-Total Score; (4) Alzheimer's Disease Assessment Scale-Cognitive Subscale; (5) ADAS-Cog12; (6) ADAS-Cog11; (7) Alzheimer's Disease Cooperative Study Group-Activities of Daily Living Inventory or Alzheimer's Disease Cooperative Study Group-Activities of Daily Living Scale; (8) Neuropsychiatric Symptom Assessment; (9) Alzheimer's Disease Caregiver Global Impression Scale; (10) Instrumental Activities of Daily Living Scale; and (11) Amsterdam Instrumental Daily Living Questionnaire.

[0283] (1) Mini-Mental State Examination The Mini-Mental State Examination ("MMSE") is a brief clinical cognitive test commonly used to screen for dementia and other cognitive deficits (Folstein et al. J Psychiatr Res 1975;12:189-98). The MMSE provides a total score of 0 to 30. A score of 26 or less is generally considered to indicate a deficit. The lower the numerical score on the MMSE, the greater the deficit or impairment in the tested patient compared to another individual with a higher score. An increase in the MMSE score may indicate an improvement in the patient's condition, while a decrease in the MMSE score may indicate a worsening of the patient's condition. In some embodiments, a stable MMSE score may indicate a delay, slowing, or halt in the progression of AD, or a lack of the emergence of new clinical, functional, or cognitive symptoms or impairments, or an overall stabilization of the disease.

[0284] (2)Clinical dementia scale The Clinical Dementia Scale ("CDR") (Morris Neurology 1993;43:2412-4) is a semi-structured interview that yields five degrees of impairment of performance in each of six categories of cognitive-based function: memory, orientation, judgment and problem-solving, social problems, home and hobbies, and personal care. The CDR was initially designed with a global score: 0 - no dementia, 0.5 - probable dementia, 1 - mild dementia, 2 - moderate dementia, 3 - severe dementia.

[0285] (3) Clinical Dementia Assessment - Total Score The complete CDR-SB score is based on the sum of the scores across all six boxes. Subscores can also be obtained for each box or component individually, e.g., CDR / Memory or CDR / Judgment and Problem Solving. As used herein, a "deterioration in CDR-SB performance" or an "increase in CDR-SB score" indicates a worsening of the patient's symptoms and may reflect the progression of AD.

[0286] The term "CDR-SB" refers to the Clinical Dementia Rating-SB Score, which provides a score between 0 and 18 (O'Bryant et al., 2008, Arch Neurol 65:1091-1095). The CDR-SB score is based on semi-structured interviews with patient and caregiver informants and yields five levels of impairment in performance for each of six categories of cognitive-based functioning: memory, orientation, judgment / problem-solving, community issues, home and hobbies, and personal care. The test is administered to both the patient and caregiver, and each component (or "box") is scored on a scale of 0 to 3 (0: no impairment, 0.5: suspected impairment, 1: mild impairment, 2: moderate impairment, 3: severe impairment). The sum of the scores across the six categories is the CDR-SB score. A decrease in the CDR-SB score may indicate an improvement in the patient's symptoms, whereas an increase in the CDR-SB score may indicate a worsening of the patient's symptoms. In some embodiments, a stable CDR-SB score may indicate a slowing, delay, or halt in the progression of AD, or a lack of emergence of new clinical, functional, or cognitive symptoms or impairments, or an overall stabilization of the disease.

[0287] (4) Alzheimer's Disease Assessment Scale-Cognitive Subscale The Alzheimer's Disease Assessment Scale-Cognitive Subscale ("ADAS-Cog") is a frequently used measure to assess cognition in clinical trials for mild to moderate AD (Rozzini et al. Int J Geriatr Psychiatry 2007;22:1217-22; Connor and Sabbagh, J Alzheimers Dis. 2008;15:461-4; Ihl et al. Int J Geriatr Psychiatry 2012;27:15-21). The ADAS-Cog is an examiner-administered battery that assesses multiple cognitive domains, including memory, comprehension, praxis, orientation, and spontaneous speech (Rosen et al. 1984, Am J Psychiatr 141:1356-64; Mohs et al. 1997, Alzheimer Dis Assoc Disord 11(S2):S13-S21). The ADAS-Cog is the standard primary endpoint in AD treatment trials (Mani 2004, Stat Med 23:305-14). The higher the numerical score on the ADAS-Cog, the greater the deficit or impairment in the tested patient compared to another individual with a lower score. The ADAS-Cog can be used to assess whether a treatment for AD is therapeutically effective. An increase in the ADAS-Cog score indicates a worsening of the patient's symptoms, while a decrease in the ADAS-Cog score indicates an improvement in the patient's symptoms. In some embodiments, a stable ADAS-Cog score can indicate a delay, slowing, or halt in the progression of AD, or a lack of emergence of new clinical or cognitive symptoms or impairments, or an overall stabilization of the disease.

[0288] (5) ADAS-Cog12 The ADAS-Cog12 is a 70-point version of the ADAS-Cog with the addition of a 10-point delayed word recall item that assesses recall of a trained word list. The ADAS-Cog11 is another version with a range of 0 to 70. Other ADAS-Cog scales include the ADAS-Cog13 and ADAS-Cog14.

[0289] (6) ADAS-Cog11 A decrease in the ADAS-Cog11 score may indicate an improvement in the patient's condition, while an increase in the ADAS-Cog11 score may indicate a worsening of the patient's condition. In some embodiments, a stable ADAS-Cog11 score may indicate a slowing, delay, or halt in the progression of AD, or a reduction in the progression of clinical or cognitive decline, or a lack of the appearance of new clinical or cognitive symptoms or impairments, or an overall stabilization of the disease.

[0290] The component subtests of the ADAS-Cog11 can be grouped into three cognitive domains: memory, language, and praxis (Verma et al. Alzheimer's Research & Therapy 2015). This "breakdown" can improve sensitivity in measuring cognitive decline, for example, when focusing on mild to moderate stages of AD (Verma, 2015). Therefore, the ADAS-Cog11 score can be analyzed for changes in each of the three cognitive domains: memory, language, and praxis. The memory domain value of the ADAS-Cog11 score may be referred to herein as the "ADAS-Cog11 memory domain score" or simply the "memory domain." Slowing memory decline may refer to a reduction in the rate of decline in memory capacity and / or function, memory retention, and / or reduced memory loss. Slowing memory decline can be evidenced, for example, by a smaller (or less negative) score on the ADAS-Cog11 memory domain (see, e.g., Table 12).

[0291] Similarly, the language domain value of the ADAS-Cog11 score may be referred to herein as the "ADAS-Cog11 language domain score" or simply the "language domain score," and the praxis domain value of the ADAS-Cog11 score may be referred to herein as the "ADAS-Cog11 praxis domain score" or simply the "praxis domain." Praxis can refer to the planning and / or execution of simple tasks, and / or prax can refer to the ability to conceptualize, plan, and execute complex sequences of motor movements, as well as copy drawings or three-dimensional structures and following commands.

[0292] The memory domain score is further divided into components, including scores reflecting the subject's ability to recognize and / or recall words, thereby assessing "vocabulary recognition" or "vocabulary retrieval" abilities. The word recognition assessment of the ADAS-Cog11 memory domain score may be referred to herein as the "ADAS-Cog11 vocabulary recognition score" or simply the "vocabulary recognition score." For example, equivalent alternative forms of the vocabulary retrieval and vocabulary recognition subtests may be used in sequential testing administrations for a given patient. In some embodiments, slowing memory decline may refer specifically to slowing the decline in vocabulary recognition ability, e.g., reducing the rate of vocabulary recognition loss, retaining memory for recognizing words, and / or reducing memory loss when recalling a list of words. A slowing of memory decline may be evidenced, for example, by a smaller (or less negative) score on the vocabulary recognition component of the ADAS-Cog11 memory domain.

[0293] (7) Alzheimer's Disease Cooperative Study Group Activities of Daily Living Inventory or Alzheimer's Disease Cooperative Study Group Activities of Daily Living Scale The Alzheimer's Disease Cooperative Study Group-Activities of Daily Living Inventory or Alzheimer's Disease Cooperative Study Group-Activities of Daily Living Scale ("ADCS-ADL;" Galasko et al. Alzheimer Dis Assoc Disord 1997;11(Suppl 2):S33-9) is the most widely used measure for assessing functional outcome in patients with AD (Vellas et al. Lancet Neurol. 2008;7:436-50). Scores range from 0 to 78, with higher scores indicating better ADL function. The ADCS-ADL is administered to caregivers and covers both basic ADLs (e.g., eating and toileting) and more complex or instrumental ADLs (e.g., using the telephone, managing finances, and preparing meals) (Galasko et al. Alzheimer Disease and Associated Disorders, 1997 11(Suppl 2),S33-S39).

[0294] (8) Neuropsychiatric symptom assessment The Neuropsychiatric Index ("NPI") (Cummings et al. Neurology 1994;44:2308-14) is a widely used scale that assesses the behavioral symptoms of AD, including their frequency, severity, and associated distress. Individual symptom scores range from 0 to 12, and the total NPI score ranges from 0 to 144. The NPI is administered to caregivers and refers to the patient's behavior over the past month.

[0295] (9) Alzheimer's Disease Caregiver Global Impression Scale The Alzheimer's Disease Caregiver Global Impression Scale ("CaGI-Alz") is a novel scale used in the clinical trials described herein and consists of four items to assess caregivers' perceptions of changes in a patient's disease severity. All items are rated on a 7-point Likert-type scale ranging from 1 (much improved since treatment initiation / previous CaGI-Alz assessment) to 7 (much worse since treatment initiation / previous CaGI-Alz assessment).

[0296] (10) Instrumental activities of daily living scale The term "iADL" refers to the Instrumental Activities of Daily Living Scale (Lawton, MP, and Brody, EM, 1969, Gerontologist 9:179-186). This scale measures the ability to perform typical daily activities such as housework, laundry, using the telephone, shopping, and preparing meals. The lower the score, the more impaired the individual is in performing activities of daily living.

[0297] (11) Amsterdam Instrumental Activities of Daily Living Questionnaire Another measure that may be used is the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q).

[0298] In some embodiments, "mild to moderate AD" refers to moderate AD dementia defined by a screening MMSE score of 16-21 points (inclusive) and a CDR GS of 1 or 2, where AD is diagnosed based on standard research criteria according to the National Institute on Aging-Alzheimer's Disease Association (NIA AA) diagnostic criteria and AD guidelines outlined above in Table 1. In Example 1, for example, these scores together provide evidence of mild to moderate AD (e.g., mild AD correlated with an MMSE score of 19-21 and / or a CDR GS of 1; moderate AD correlated with an MMSE score of 16-18 and / or a CDR GS of 2).

[0299] "Amyloidosis" refers to a group of diseases and disorders associated with amyloid or amyloid-like proteins, such as the amyloid-beta protein involved in AD.

[0300] The terms "anti-tau immunoglobulin," "anti-tau antibody," and "antibody that binds to tau" are used interchangeably herein and refer to an antibody that can bind to tau (e.g., human tau) with sufficient affinity so as to be useful as a diagnostic and / or therapeutic agent in targeting tau. In some embodiments, the extent to which an anti-tau antibody binds to an unrelated, non-tau protein is less than about 10% of the binding of the antibody to tau, as measured, for example, by radioimmunoassay (RIA). In some embodiments, an antibody that binds to tau has an affinity of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g. 10 -8 ~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D ). In some embodiments, the anti-tau antibody binds to an epitope of tau that is conserved among tau from different species. In some cases, the antibody binds to monomeric tau, oligomeric tau, and / or phosphorylated tau. In some embodiments, the anti-tau antibody binds to monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau with comparable affinities in vitro, such as affinities that differ by no more than 50-fold. In some embodiments, antibodies that bind to monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau are referred to as "pan-tau antibodies." A non-limiting example of an anti-tau antibody is semolinemab.

[0301] An "N-terminally binding anti-tau antibody" or "N-terminal binding agent" refers to an antibody that binds to tau towards its N-terminus, e.g., binds to an epitope within amino acids 2-24 of mature human tau, e.g., in some embodiments, binds within / spanning amino acids 6-23 of mature human tau.

[0302] The terms "semolinemab," "MTAU9937A," and "RO7105705" are used interchangeably herein to refer to a specific anti-tau antibody that binds to monomeric, oligomeric, unphosphorylated, and phosphorylated forms of tau. In some embodiments, the anti-tau antibody binds to an epitope within the N-terminal region of tau, e.g., residues 2-24, e.g., residues 6-23. In some embodiments, the anti-tau antibody comprises the HVR sequences shown in Figure 5A. In some embodiments, the anti-tau antibody comprises: an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO:2; an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO:3; an HVR-H3 sequence comprising the amino acid sequence of SEQ ID NO:4; an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO:6; an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO:7; and an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the specific anti-tau antibody comprises VH and VL domains having the amino acid sequences shown in Figure 5B. In some embodiments, the anti-tau antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-tau antibody is an IgG4 antibody. In some embodiments, the IgG4 antibody comprises one or more mutations selected from M252Y, S254T, and T256E, according to EU numbering. In some embodiments, the IgG4 antibody comprises M252Y, S254T, and T256E mutations, according to EU numbering. In some embodiments, the antibody comprises a S228P mutation, according to EU numbering.

[0303] The term "therapeutic agent" refers to any agent used to treat a disease, including but not limited to, an agent that treats a symptom of the disease or slows the progression of the disease.

[0304] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention that attempts to alter the natural course of a condition in the individual being treated, and can be performed either for prevention or during the course of the condition.

[0305] Desirable effects of treatment include, but are not limited to, prevention of disease onset or recurrence, alleviation or amelioration of one or more symptoms, reduction or delay of direct or indirect pathological consequences of the disease, halting or delaying the worsening of any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, amelioration or palliation of the disease state, remission, and / or improved prognosis. In some embodiments, the anti-tau antibodies described herein are used to delay disease onset or slow disease progression, for example, to slow clinical decline in mild to moderate AD or related tauopathy (e.g., slowing cognitive decline by slowing loss of memory function). In some particular embodiments, anti-tau antibodies are used to disrupt, prevent, or slow the spread of extracellular forms of tau to disrupt, prevent, or slow the intercellular spread of tau and / or the propagation of tau toxicity and pathology throughout the cortical and subcortical networks of the brain of patients with mild to moderate AD or related tauopathy.

[0306] As used herein, the term "therapeutic regimen" refers to a combination of dosage, mode of administration, frequency of administration, and / or duration of treatment, with or without the addition of another therapy, e.g., a concomitant drug treatment.

[0307] As used herein, the term "effective therapeutic regimen" refers to a therapeutic regimen that provides a beneficial effect to the patient receiving the treatment.

[0308] As used herein, the term "modifying treatment" refers to a change in the treatment regimen, including a change in dosage, mode of administration, frequency of administration, or duration of treatment, and / or the addition or elimination of additional therapies.

[0309] As used herein, the term "treatment-emergent" refers to an event that occurs after the first dose of a therapeutic agent is administered. For example, a "treatment-emergent adverse event" is an event that is identified during or after the first administration of a treatment in a clinical study.

[0310] An "adverse event" is any untoward medical occurrence in a patient administered a medicinal product, regardless of causal attribution. Thus, an adverse event can be any of the following: Any untoward and unintended signs (including abnormal laboratory findings), symptoms or diseases temporally associated with the use of the medicinal product, whether or not considered related to the product. New disease or exacerbation of an existing disease (worsening of the character, frequency, or severity of known symptoms) Recurrence of intermittent medical symptoms (e.g., headaches) not present at baseline Symptoms related or associated with investigational drugs (e.g., semolinemab, 18 F]GTP1 radioligand, or amyloid radioligand) resulting in a decline in laboratory values ​​or other clinical tests (e.g., ECG, X-ray) resulting in a change in study treatment or concomitant treatment or discontinuation Adverse events related to protocol-specified interventions, such as those occurring before assignment of study treatment (e.g., screening invasive procedures such as biopsy). For example, adverse events may include one or more of abnormal laboratory values ​​(e.g., hyperkalemia, elevated potassium), abnormal vital signs (e.g., hypertension), abnormal liver function tests, more frequent headaches, and hospitalization.

[0311] A "serious adverse event" is an adverse event that meets any of the following criteria: is fatal (i.e., the adverse event actually causes or leads to death); is life-threatening (i.e., the adverse event places the patient at immediate risk of death, in the investigator's opinion) (but does not include adverse events that may have caused death if they occurred in a more severe form or were allowed to continue); requires or prolongs inpatient hospitalization; results in persistent or significant disability / incapacity (i.e., the adverse event results in substantial disruption of the patient's ability to perform normal life functions); or is associated with a significant adverse event associated with the study drug (e.g., 18F]GTP1 radioligand or amyloid radioligand); or a serious medical event in the investigator's judgment (e.g., potentially endangering the patient or requiring medical / surgical intervention to prevent one of the outcomes listed above).

[0312] The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of the adverse event (e.g., rated as mild, moderate, or severe, or rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events), and the event itself may be relatively medically insignificant (e.g., a severe headache with no further findings).

[0313] As used herein, "adverse events of special concern" include cases of potential drug-induced liver injury, including ALT or AST elevation combined with either bilirubin elevation or clinical jaundice, as defined by Hy's rule; any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic, including those caused by the study drug or 18 suspected transmission of an infectious agent by a [F]GTP1 radioligand; treatment-emergent clinically significant MRI abnormalities; and / or severe (grade 3 or greater) infusion-related reactions.

[0314] A "persistent adverse event" is one that continues unabated between patient evaluation time points.

[0315] A "recurrent adverse event" is one that resolves between patient evaluation times and then recurs.

[0316] As used herein, the term "baseline" refers to the time point at which a patient is assessed prior to administration of the first dose of an anti-tau antibody in the treatment methods herein. A "baseline score" or "baseline assessment" refers to a score assessed prior to treatment, prior to the first / first dose of antibody. In some embodiments, the baseline assessment is performed during a pre-treatment screening period.

[0317] As used herein, the "lifespan" of a patient refers to the remaining time a patient has left life after treatment begins.

[0318] As used herein, the term "progression" refers to the worsening of a disease over time. The "rate of progression" or "progression rate" of a disease refers to how fast or slow the disease develops over time in patients diagnosed with the disease. The rate of disease progression can be represented by measurable changes in specific characteristics of the disease over time. A patient with a particular genetic trait is said to have or is likely to have an "increased rate of progression" if their condition progresses more rapidly than patients without that genetic trait. On the other hand, a patient who responds to treatment is said to have or is likely to have a "decreased rate of progression" if their disease progression slows after administration of the treatment compared to their disease state before treatment or other patients who have not received the treatment.

[0319] "Slowing clinical decline," "slowing clinical decline," "reducing cognitive decline," and other grammatical variants refer to, for example, a reduction in the rate of progression of a given disease following treatment. In some embodiments, clinical decline is compared to patients diagnosed with the same disease at a similar stage (e.g., mild to moderate AD) but who were administered a placebo rather than an anti-tau antibody as described herein. A comparison to placebo (e.g., to an equivalent placebo arm of a clinical study) may represent a comparison to disease progression expected without administration of the anti-tau antibody. Slowing clinical decline may be measured, for example, by a reduction in functional and / or cognitive decline, e.g., as described herein, or in a specific cognitive domain, e.g., memory.

[0320] As used herein, the terms "sample" and "test sample" are used interchangeably herein and refer to a composition obtained or derived from a subject of interest containing cellular and / or other molecular elements to be characterized and / or identified based on, for example, physical, biochemical, chemical, and / or physiological characteristics. In some embodiments, the definition encompasses blood and other liquid samples of biological origin, as well as tissue samples such as biopsy specimens or tissue cultures or cells derived therefrom. Sources of tissue samples can be fresh, frozen, and / or preserved organ or tissue samples, or solid tissue from biopsies or aspirates; blood or any blood components; body fluids; and cells from any stage in a subject's pregnancy or development, or plasma.

[0321] As used herein, the term "biological sample" includes, but is not limited to, whole blood, blood-derived cells, serum, plasma, sputum, tissue biopsies (e.g., lung samples), nasal samples including nasal swabs or nasal polyps, lymphatic fluid, synovial fluid, cell extracts, and combinations thereof. In some embodiments, the sample is a clinical sample. In some embodiments, the sample is used in a diagnostic assay. In some embodiments, the sample is a CSF sample or a plasma sample, e.g., a CSF or plasma sample used to assess tau levels in a patient. In some embodiments, the sample is a CSF sample taken from a patient suffering from a tau pathology, such as AD. In some embodiments, the sample is a plasma sample taken from a patient suffering from a tau pathology, such as AD.

[0322] The term "biological sample" may also include biological samples that have been manipulated in some way after their procurement, such as by treatment with reagents, solubilization or enrichment of particular components such as proteins or polynucleotides, or embedding in a semi-solid or solid matrix for sectioning purposes. For purposes herein, a "section" of a tissue sample means a single portion or piece of a tissue sample, e.g., a thin slice of tissue or cells cut from a tissue sample. In some embodiments, the sample is obtained from a subject or patient prior to treatment with an anti-tau antibody. In some embodiments, the sample is obtained from a subject or patient after at least one treatment with an anti-tau antibody.

[0323] As used herein, a "reference sample" refers to any sample, standard, or level used for comparison purposes. In some embodiments, a reference sample is obtained from a patient prior to the initiation of treatment with an anti-tau antibody, as described herein, e.g., to provide a baseline. In some embodiments, a reference sample is obtained from a healthy and / or non-diseased part (e.g., tissue or cells) of the body of the same subject or patient. In some embodiments, a reference sample is obtained from untreated tissue and / or cells of the body of the same subject or individual. In some embodiments, a reference sample is obtained from a healthy and / or non-diseased part (e.g., tissue or cells) of the body of an individual who is not the subject or patient. In some embodiments, a reference sample is obtained from an untreated tissue and / or cell part of the body of an individual who is not the subject or patient.

[0324] In certain embodiments, the reference sample is a single sample or a combination of multiple samples from the same subject or patient, which are obtained at one or more different time points from the time point from which the test sample is obtained.For example, the reference sample can be obtained from the same subject or patient at an earlier time point than the time point from which the test sample is obtained.In certain embodiments, the reference sample is obtained from one or more individuals who are not the subject or patient and have tau pathology, such as AD.

[0325] In certain embodiments, the reference sample is a combination of multiple samples from one or more healthy individuals who are not the subject or patient. In certain embodiments, the reference sample is combined with multiple samples from one or more individuals who are not the subject or patient and have a disease or disorder (e.g., a tauopathy, such as AD or mild to moderate AD). In certain embodiments, the reference sample is pooled CSF, pooled plasma, or serum samples from one or more individuals who are not the subject or patient.

[0326] As used herein, the terms "patient," "subject," and "individual" are used interchangeably herein and refer to any single subject for whom treatment is desired. In certain embodiments, the patient is a human. The subject is typically a human. In certain embodiments, the subject is a non-human mammal. Exemplary non-human mammals include laboratory animals, farm animals, pet animals, sport animals, and livestock animals, such as mice, cats, dogs, horses, and cows. Typically, the subject is eligible for treatment, e.g., exhibits one or more signs of disease. Generally, such a subject or patient is eligible for treatment of a tau pathology, e.g., mild to moderate AD. In some embodiments, such an eligible subject or patient is a subject who is experiencing or has experienced one or more signs, symptoms, or other indicators of mild to moderate AD, as described above, or who has been diagnosed with mild to moderate AD. In some embodiments, an eligible subject or patient is a subject who is experiencing or has experienced one or more signs, symptoms, or other indicators of moderate AD, as described above, or who has been diagnosed with moderate AD.

[0327] The subjects intended to be included are individuals involved in clinical research trials or epidemiological studies, or subjects used as controls. The subjects may have been previously treated with an anti-Abeta or anti-tau antibody, or an antigen-binding fragment thereof, or another drug, or may not have been so treated. The subjects may be naive to the additional drug(s) used when the treatment herein is initiated, i.e., the subjects may not have been previously treated with a treatment other than an anti-tau antibody, for example, at "baseline." Such "naive" subjects are generally considered to be candidates for treatment with such additional drug(s).

[0328] Patients include people of different ethnic origins. For example, in some embodiments, the patient is of non-European descent, e.g., Black, Hispanic, and / or Asian descent. In some embodiments, the patient is Black or Hispanic, or has a non-European ethnic origin. In some embodiments, the patient is Black. In some embodiments, the patient is Hispanic. In some embodiments, the patient is Asian. In some embodiments, the patient is of non-European descent.

[0329] As used herein, the term "more likely to respond" refers to patients who are most likely to show beneficial effects after administration of an anti-tau antibody, including slowing, delaying, or halting disease progression and / or slowing, delaying, or halting the intercellular spread of tau toxicity and pathology throughout cortical / subcortical networks in the patient's brain. With respect to mild to moderate AD, "more likely to respond" also refers to patients who are more likely to show reduced functional or cognitive loss after anti-tau antibody treatment. The phrase "responsive to," in the context of the present disclosure, indicates that a patient suffering from or diagnosed with a disorder described herein will show a response to anti-tau antibody treatment.

[0330] The terms "apolipoprotein ε4 carrier" or "Apoε4 carrier" are used interchangeably herein with "apolipoprotein ε4 positive" or "Apoε4 positive" and refer to individuals who have at least one apolipoprotein ε4 (or "Apoε4") allele. Individuals who have zero Apoε4 alleles are referred to herein as "Apoε4 negative" or "Apoε4 non-carriers" (Prekumar, et al., 1996, Am. J Pathol. 148:2083-95).

[0331] The terms "pharmaceutical formulation" or "pharmaceutical composition" are used interchangeably herein and refer to a preparation that is in a form such that the biological activity of the active ingredient contained therein is effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0332] The terms "therapeutically effective amount," "effective amount," and "effective dose" of an agent, e.g., an anti-tau antibody, in a pharmaceutical composition are used interchangeably herein and refer to an amount effective for a period of time necessary to achieve a desired therapeutic or preventative result. For example, a therapeutically effective amount is an amount effective for a period of time necessary to treat the indicated disease, clinical condition, or symptom, such as to modify the progression of AD, particularly mild to moderate AD, and / or to alleviate and / or prevent one or more symptoms of AD. In certain embodiments, an effective amount is used to reduce the rate of memory decline.

[0333] A "fixed" or "flat" dose of a therapeutic agent refers to a dose administered to a human patient without regard to the patient's body weight (WT) or body surface area (BSA). Thus, this fixed or flat dose may be expressed as a mg / kg dose or a mg / m 2 It is not defined as a dose, but rather as an absolute amount of therapeutic agent or active ingredient.

[0334] A "pharmaceutically acceptable carrier" refers to an ingredient of a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0335] The terms "wild-type" or "WT" are used interchangeably herein and refer to an amino acid sequence or nucleotide sequence found in nature, including allelic variants. A WT protein has an amino acid sequence that has not been intentionally modified, or is encoded by a nucleotide sequence that has not been intentionally modified.

[0336] The sequences referenced herein are set forth in Table 3 below. It is known in the art that during processing and expression of Fc-containing proteins, the C-terminal lysine may be cleaved (also known in the art as C-terminal lysine clipping). Thus, for each sequence disclosed herein that includes a C-terminal lysine, the corresponding sequence that does not include the C-terminal lysine (i.e., a C-terminal lysine cleavage product) is also contemplated. In some embodiments, the first monomer includes a C-terminal lysine. In some embodiments, the monomer includes a C-terminal lysine. In some embodiments, the monomer lacks a C-terminal lysine. In some embodiments, the heavy chain of the anti-tau antibody includes a C-terminal lysine. In some embodiments, the heavy chain of the anti-tau antibody lacks a C-terminal lysine.

[0337] It is also known in the art that the C-terminal cleavage process is imprecise and may result in additional C-terminal residues being cleaved. Thus, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the two C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the three C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the four C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the five C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the six C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the seven C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the eight C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the nine C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the 10 C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the 11 C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the 12 C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the 13 C-terminal residue is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the 14 C-terminal residue is also contemplated. In some embodiments, for each sequence disclosed herein that includes a C-terminal lysine, a corresponding sequence that does not include the 15 C-terminal residue is also contemplated.In some embodiments, the missing C-terminal residues are the result of manipulation (eg, expressing a polynucleotide that lacks a nucleotide sequence encoding one or more C-terminal residues).

[0338] An "imaging agent" is a compound that has one or more properties that allow for its presence and / or location to be detected, either directly or indirectly. Examples of imaging agents include proteins and small molecule compounds that incorporate a label moiety that allows for detection.

[0339] The term "small molecule" refers to an organic molecule having a molecular weight between 50 and 2500 daltons.

[0340] A "label" is a marker attached to a molecule used for detection or imaging. Examples of such labels include radiolabels, fluorophores, chromophores, or affinity tags. In some embodiments, the label is a radiolabel used in medical imaging, e.g., Tc 99 or 123 I, or spin labels for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, iodine-131, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, iron, etc.

[0341] The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications, and / or warnings for the use of such therapeutic products. The term "package insert" is also used to refer to instructions typically included in commercial packaging of diagnostic products that contain information about the intended use, test principle, reagent preparation and handling, specimen collection and preparation, calibration of the assay and assay procedure, performance and accuracy data such as assay sensitivity and specificity.

[0342] Compositions and Methods The present disclosure provides compositions and methods for treating, prognosing, selecting, and / or identifying patients for treatment with anti-tau antibodies. In one aspect, the present disclosure is based in part on improved methods for treating tau pathologies, particularly mild-to-moderate or moderate AD. A. Exemplary Antibodies

[0343] Methods of treating tauopathies using antibodies that bind to tau are provided. In some embodiments, the antibodies bind to monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau. In some embodiments, the antibodies bind to an epitope within amino acids 2-24 of mature human tau. In some embodiments, the antibodies bind to an epitope within tau at amino acids 2-24 and bind to monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau. In some embodiments, the antibodies bind to an epitope within or spanning amino acids 6-23 of mature human tau. In some embodiments, the antibodies bind to an epitope within or spanning amino acids 6-23 of tau and bind to monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau. In some embodiments, the antibodies bind to an epitope of human tau having or consisting of the sequence AEPRQEFEVMEDHAGTYGLGDRK (SEQ ID NO: 1). In some embodiments, the antibody binds to an epitope of cynomolgus monkey tau having or consisting of the sequence AEPRQEFDVMEDHAGTYGLGDRK (SEQ ID NO: 10).

[0344] In some embodiments, a humanized monoclonal anti-tau antibody of the present disclosure binds within residues 2 and 24, or within residues 6 and 23, of human tau (SEQ ID NO: 1) in monomeric, oligomeric, unphosphorylated, and phosphorylated tau. In some embodiments, a humanized monoclonal anti-tau antibody of the present disclosure binds within residues 2 and 24 of human tau (SEQ ID NO: 1) in monomeric, oligomeric, unphosphorylated, and phosphorylated tau. In some embodiments, a humanized monoclonal anti-tau antibody of the present disclosure binds within residues 6 and 23 of human tau (SEQ ID NO: 1) in monomeric, oligomeric, unphosphorylated, and phosphorylated tau.

[0345] In some embodiments, the humanized monoclonal anti-tau antibodies of the present disclosure have a K of less than 100 nM, less than 75 nM, or less than 50 nM for each of monomeric tau, phosphorylated tau, unphosphorylated tau, and oligomeric tau. D In some embodiments, the humanized monoclonal anti-tau antibodies of the present disclosure bind to each of monomeric tau, phosphorylated tau, unphosphorylated tau, and oligomeric tau with a K of less than 100 nM. D In some embodiments, the humanized monoclonal anti-tau antibodies of the present disclosure bind to each of monomeric tau, phosphorylated tau, unphosphorylated tau, and oligomeric tau with a K of less than 75 nM. D In some embodiments, the humanized monoclonal anti-tau antibodies of the present disclosure bind to each of monomeric tau, phosphorylated tau, unphosphorylated tau, and oligomeric tau with a K of less than 50 nM. D Combine with.

[0346] In some embodiments, the humanized monoclonal anti-tau antibodies of the present disclosure bind to cynomolgus monkey tau (SEQ ID NO: 10).

[0347] In some embodiments, the anti-tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0348] In some embodiments, the anti-tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0349] In some embodiments, the anti-tau antibody is humanized. In some embodiments, the anti-tau antibody comprises, e.g., the HVRs described above, and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework.

[0350] In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the antibody comprises a VH and a VL comprising the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 9, respectively, including post-translational modifications of these sequences, if any.

[0351] In some embodiments, an anti-tau antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 95% identical to the sequence of SEQ ID NO: 5. In some embodiments, an anti-tau antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 95% identical to the sequence of SEQ ID NO: 9. In some embodiments, an anti-tau antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 95% identical to the sequence of SEQ ID NO: 5, and a VL comprising an amino acid sequence at least 95% identical to the sequence of SEQ ID NO: 9. In some embodiments, an anti-tau antibody of the present disclosure comprises a VH having the amino acid sequence of SEQ ID NO: 5 and a VL having the amino acid sequence of SEQ ID NO: 9.

[0352] In some embodiments, the antibody is an IgG4 antibody. In some embodiments, the IgG4 antibody comprises one or more mutations selected from M252Y, S254T, and T256E, according to EU numbering. In some embodiments, the IgG4 antibody comprises M252Y, S254T, and T256E mutations, according to EU numbering. In some embodiments, the antibody comprises a S228P mutation, according to EU numbering.

[0353] In some embodiments, the anti-tau antibody comprises a heavy chain comprising an amino acid sequence at least 95% identical to the sequence of SEQ ID NO: 11. In some embodiments, the anti-tau antibody comprises a heavy chain comprising an amino acid sequence at least 95% identical to the sequence of SEQ ID NO: 12. In some embodiments, the anti-tau antibody comprises a light chain comprising an amino acid sequence at least 95% identical to the sequence of SEQ ID NO: 13. In some embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-tau antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 12 and a light chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-tau antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 12 and a light chain consisting of the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and a light chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and a light chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 13.

[0354] Other N-terminally linked anti-tau antibodies may be used in the disclosed methods described herein. Examples of such antibodies include, but are not limited to, the N-terminally linked anti-tau antibodies disclosed in PCT / US2016 / 035409 and / or PCT / US2018 / 024300.

[0355] In some embodiments, the anti-tau antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In some embodiments, the anti-tau antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In some embodiments, the antibody is a full-length antibody, such as an intact IgG1 or IgG4 antibody, or other antibody class or isotype as defined herein. In some embodiments, the anti-tau antibody is semolinemab. In some embodiments, the anti-tau antibody according to any of the above embodiments can incorporate any of the features, alone or in combination, as described in Sections 1-5 below.

[0356] 1. Antibody affinity In certain embodiments, the antibodies provided herein have a cytotoxicity of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D )

[0357] In some embodiments, K D is measured by radiolabeled antigen binding assay (RIA). In some embodiments, an RIA is performed on a Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of a Fab for an antigen is measured by measuring the binding affinity of the Fab to the antigen at the lowest concentration ( 125I) Fab is equilibrated with labeled antigen, followed by capturing the bound antigen on a plate coated with an anti-Fab antibody (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish assay conditions, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 μg / mL of capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), then blocked with 2% (w / v) bovine serum albumin in PBS for 2 to 5 hours at room temperature (approximately 23°C). In non-adsorbent plates (Nunc No. 269620), 100 pM or 26 pM [ 125 [I]-antigen is mixed with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight, although this incubation can be continued for a longer period (e.g., approximately 65 hours) to ensure equilibrium is reached. The mixture is then transferred to a capture plate for incubation at room temperature (e.g., 1 hour). The solution is then removed, and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plate has dried, 150 μl / well of scintillant (MICROSCINT-20™; Packard) is added, and the plate is counted for 10 minutes in a TOPCOUNT™ gamma counter (Packard). The concentration of each Fab that results in 20% or less of maximum binding is selected for use in the competitive binding assay.

[0358] According to another embodiment, K Dis measured using a BIACORE® surface plasmon resonance assay. For example, assays using a BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) are performed at 25°C using approximately 10 response units (RU) of immobilized antigen CM5 chips. In some embodiments, a carboxymethylated dextran biosensor chip (CM5, BIAcore, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / mL (approximately 0.2 μM) with 10 mM sodium acetate (pH 4.8) and then injected at a flow rate of 5 μL / min, yielding approximately 10 resonance units (RU) of coupled protein. After antigen injection, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) were incubated in 0.05% polysorbate 20 (TWEEN-20 TM ) in PBS containing surfactant (PBST) at 25°C and a flow rate of approximately 25 μl / min. on ) and dissociation rate (k off ) using a simple one-to-one Langmuir binding model (BIACORE (登録商標) Calculate the equilibrium dissociation constant (K) by simultaneously fitting the association and dissociation sensorgrams using the evaluation software version 3.2. D ) is the ratio k off / k on (Chen et al., J. Mol. Biol. 293:865-881 (1999)). The on-rate was calculated as 10 6 M -1 s -1If the on-rate exceeds , the on-rate can be determined by using a fluorescence quenching technique to measure the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab form) in PBS (pH 7.2) at 25°C in the presence of increasing concentrations of antigen as measured with a spectrophotometer such as a stopped-flow equipped spectrophotometer (Aviv Instruments) or an 8000 series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

[0359] 2. Antibody fragment In certain embodiments, the antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, Fab'-SH fragments, F(ab')2 fragments, Fv fragments, and scFv fragments, as well as other fragments described below. For a review of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994). See also WO 93 / 16185 and U.S. Pat. Nos. 5,571,894 and 5,587,458. See US Pat. No. 5,869,046 for a description of Fab and F(ab')2 fragments that contain salvage receptor binding epitope residues and have increased in vivo half-lives.

[0360] Diabodies are antibody fragments with two bivalent or bispecific antigen-binding sites. See, e.g., EP 404,097, WO 1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003). Single-domain antibodies are antibody fragments that contain all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, single-domain antibodies are human single-domain antibodies (Domantis, Inc., Waltham, Massachusetts; see, e.g., U.S. Pat. No. 6,248,516 B1).

[0361] Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies, as well as production by recombinant host cells (e.g., E. coli or phage) as described herein.

[0362] 3. Chimeric and humanized antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0363] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Usually, a humanized antibody contains one or more variable domains in which the HVRs, e.g., CDRs (or portions thereof), are derived from a non-human antibody, and the FRs (or portions thereof) are derived from human antibody sequences. Optionally, a humanized antibody also contains at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0364] Humanized antibodies and methods for producing them are reviewed, e.g., by Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are also described, e.g., by Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing grafting of specificity-determining regions (SDRs)); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a "guided selection" approach to FR shuffling).

[0365] Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from human antibody consensus sequences of particular subtypes of heavy or light chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al. al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996).

[0366] 4. Multispecific antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, e.g., bispecific antibodies. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for tau and the other is for any other antigen. In certain embodiments, one of the binding specificities is for tau and the other is for amyloid beta. In certain embodiments, the bispecific antibody can bind to two different epitopes of tau. Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing tau. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0367] Techniques for producing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305:537 (1983); WO 93 / 08829; and Traunecker et al., EMBO J. 10:3655 (1991)), and "knob-into-hole" engineering (see, e.g., U.S. Pat. No. 5,731,168). Multispecific antibodies can also be produced by manipulating electrostatic steering effects to create antibody Fc heterodimeric molecules (WO 2009 / 089004 A1); cross-linking two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980, and Brennan et al., Science, 229:81 (1985)); using leucine zippers to create bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using "diabody" technology to create bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 148(5):1547-1553 (1992)). al., J. Immunol., 152:5368 (1994)); and, for example, by the preparation of trispecific antibodies as described in Tutt et al. J. Immunol. 147:60 (1991).

[0368] Also included herein are engineered antibodies with three or more functional antigen-binding sites, including "Octopus antibodies" (see, e.g., U.S. Patent Application Publication No. 2006 / 0025576A1). Antibodies or fragments herein also include "Dual Acting FAbs" or "DAFs" that contain antigen-binding sites that bind to tau and another distinct antigen (see, e.g., U.S. Patent Application Publication No. 2008 / 0069820).

[0369] 5. Antibody Variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of, residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to arrive at the final construct, provided that the final construct possesses the desired properties, e.g., antigen binding.

[0370] Substitution, insertion, and deletion variants In certain embodiments, antibody variants with one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include HVRs and FRs. Conservative substitutions are shown in Table 2 under the heading of "Preferred Substitutions." More substantial changes are provided in Table 2 under the heading of "Exemplary Substitutions," and are further described below with respect to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the products screened for a desired activity, such as retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 2]

[0371] Amino acids can be grouped according to the following common side chain properties: (1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0372] Non-conservative substitutions entail exchanging a member of one of these classes for a member of another class.

[0373] Certain substitutional variants involve substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have a modification (e.g., an improvement) in a particular biological property (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and / or will have substantially retained a particular biological property of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which can be conveniently generated using, for example, phage-display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated, and the variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0374] Modifications (e.g., substitutions) can be made to HVRs, for example, to improve antibody affinity. Such modifications can be made within HVR "hot spots," i.e., residues encoded by codons that undergo frequent mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or residues that contact the antigen, and the resulting variant VH or VL are tested for binding affinity. Affinity maturation by construction and reselection from secondary libraries is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then generated. This library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity involves an HVR-directed approach, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 are often targeted in particular.

[0375] In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, so long as such modifications do not substantially reduce the ability of the antibody to bind to the antigen. For example, conservative modifications (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in the HVRs. Such modifications may, for example, be outside of antigen-contacting residues within the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is either unchanged or contains no more than one, two, or three amino acid substitutions.

[0376] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues, e.g., Arg, Asp, His, Lys, and Glu) is identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. Further substitutions may be introduced at amino acid positions that demonstrate functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of the antigen-antibody complex may be used to identify contact points between the antibody and antigen. Such contact and adjacent residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they possess desired properties.

[0377] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion includes an antibody with an N-terminal methionyl residue. Other insertional variants of antibody molecules include the N- or C-terminal fusion of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0378] In some embodiments, the antibody is an IgG4 antibody. IgG4 antibodies are known to have reduced effector function. IgG4 antibodies are dynamic molecules that can undergo a process known as Fab-arm exchange. Certain amino acid substitutions, such as S228P, can prevent Fab-arm exchange in IgG4 antibodies. In some embodiments, the IgG4 antibody contains an S228P substitution.

[0379] B glycosylation variants In certain embodiments, the antibodies provided herein are modified to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0380] If the antibody contains an Fc region, the carbohydrate attached thereto can be modified. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides, commonly attached to Asn297 in the CH2 domain of the Fc region by an N-linkage (Wright et al., TIBTECH 15:26-32 (1997)). The oligosaccharides can contain various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the bisecting oligosaccharide structure. In some embodiments, oligosaccharide modifications in the antibodies of the present disclosure can be performed to generate antibody variants with improved certain properties.

[0381] In some embodiments, antibody variants are provided that have carbohydrate structures lacking fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such antibodies can be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan at Asn297 relative to the sum of all glycans (e.g., complex, hybrid, and high-mannose structures) attached to Asn297, as measured, for example, by MALDI-TOF mass spectrometry as described in WO 2008 / 077546. Asn297 refers to the asparagine residue located at approximately position 297 (Eu numbering of Fc region residues) in the Fc region; however, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function (see, e.g., U.S. Patent Application Publication No. 2003 / 0157108 (Presta, L.); U.S. Patent Application Publication No. 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.)). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include: U.S. Patent Application Publication No. 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; U.S. Patent Application Publication No. 2003 / 0115614; WO 2002 / 0164328; WO 2004 / 0093621; WO 2004 / 0093622; 132140; 2004 / 0110704; 2004 / 0110282; 2004 / 0109865; WO 2003 / 085119; 2003 / 084570; 2005 / 035586; 2005 / 035778; 2005 / 053742; 2002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application Publication No. 2003 / 0157108 A1, Presta, L; and WO 2004 / 056312 A1, Adams et al., especially Example 11), and knockout cell lines, such as α-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO 2003 / 085107).

[0382] Further provided are antibody variants having bisected oligosaccharides, for example, biantennary oligosaccharides attached to the Fc region of the antibody, bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); and U.S. Patent Application Publication No. 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997 / 30087 (Patel et al.), WO 1998 / 58964 (Raju, S.), and WO 1999 / 22764 (Raju, S.).

[0383] c. Fc region variants In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby creating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., a substitution) at one or more amino acid positions.

[0384] In certain embodiments, the present disclosure contemplates antibody variants that retain some, but not all, effector functions, making them desirable candidates for applications in which in vivo antibody half-life is important but certain effector functions (e.g., complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduced / absent CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and thus potentially lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. Expression of FcRs on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest include those described in U.S. Pat. No. 5,500,362 (e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985)); U.S. Pat. No. 5,821,337 (Bruggemann, M. et al. al., J. Exp. Med. 166:1351-1361 (1987). Alternatively, non-radioactive assay methods may be used (e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA) and CytoTox96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells.Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be performed to confirm that the antibody is unable to bind C1q and therefore lacks CDC activity. See, e.g., C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Determination of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0385] Antibodies with reduced effector function include those with substitutions at one or more of residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (U.S. Patent No. 6,737,056). Such Fc variants include Fc variants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant with substitutions of residues 265 and 297 to alanine (U.S. Patent No. 7,332,581).

[0386] Certain antibody variants have been described with improved or diminished binding to FcRs (e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312; Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).

[0387] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, e.g., substitutions at Fc region positions 298, 333, and / or 334 (EU numbering of residues). In some embodiments, modifications are made within the Fc region that result in altered (i.e., either improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0388] Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for transferring maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976); Kim et al., J. Immunol. 24:249 (1994)), are described in U.S. Patent Application Publication No. 2005 / 0014934 A1 (Hinton et al.). These antibodies comprise an Fc region with one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include substitutions at one or more of Fc region residues: 238, 252, 254, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, e.g., substitution at Fc region residue 434 (e.g., U.S. Pat. No. 7,371,826). For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988), U.S. Pat. No. 5,648,260, U.S. Pat. No. 5,624,821, and WO 94 / 29351. In some embodiments, the antibody is an IgG4 antibody. In some embodiments, the IgG4 antibody comprises one or more mutations selected from M252Y, S254T, and T256E, according to EU numbering. In some embodiments, the IgG4 antibody comprises M252Y, S254T, and T256E mutations, according to EU numbering.

[0389] d. Cysteine ​​Engineered Antibody Variants In certain embodiments, it may be desirable to generate cysteine-engineered antibodies, e.g., "thioMAbs," in which one or more residues of an antibody are substituted with a cysteine ​​residue. In certain embodiments, the substituted residues are located at accessible sites of the antibody. By replacing these residues with cysteine, reactive thiol groups are thereby placed at accessible sites on the antibody, which can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to generate immunoconjugates, as further described herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain, A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of the heavy chain Fc region. Cysteine-engineered antibodies may be generated, for example, as described in U.S. Pat. No. 7,521,541.

[0390] e. Antibody derivative In certain embodiments, the antibodies provided herein may be further modified to contain additional nonproteinaceous moieties known in the art and readily available. Suitable sites for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone), polyethylene glycol, polypropylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous during manufacturing due to its stability in water. Polymers may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary, and when more than one polymer is attached, the polymers can be the same or different molecules. Generally, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular property or function of the antibody to be improved, whether the antibody derivative will be used therapeutically under defined conditions, etc.

[0391] In some embodiments, conjugates of antibodies and non-proteinaceous moieties are provided that can be selectively heated by exposure to radiation. In some embodiments, the non-protective moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation can be of any wavelength that is not harmful to normal cells, including, but not limited to, wavelengths that heat the non-protective moiety to temperatures that kill cells proximal to the antibody-non-protective moiety.

[0392] A. Recombinant Methods and Compositions Antibodies can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. In some embodiments, isolated nucleic acids encoding the anti-tau antibodies described herein are provided. Such nucleic acids may encode an amino acid sequence comprising the VL of the antibody and / or an amino acid sequence comprising the VH of the antibody (e.g., the light chain and / or heavy chain of the antibody). In further embodiments, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In further embodiments, host cells comprising nucleic acids are provided. In some embodiments, the host cell comprises (e.g., transformed): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In some embodiments, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., a Y0, NS0, or Sp20 cell). In some embodiments, methods are provided for making an anti-tau antibody, comprising culturing a host cell comprising nucleic acid encoding an antibody as provided above under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0393] For recombinant production of an anti-tau antibody, nucleic acid encoding the antibody, such as those described above, is isolated and inserted into one or more vectors for further cloning and / or expression in a host cell. Such nucleic acid can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of binding specifically to genes encoding the heavy and light chains of the antibody).

[0394] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly if glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523 (see Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli). Following expression, antibodies of the invention can be isolated from bacterial cell paste as a soluble fraction and further purified.

[0395] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized," resulting in the production of antibodies with partial or fully human glycosylation patterns (Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006)).

[0396] Suitable host cells for the expression of glycosylated antibodies can also be obtained from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Numerous baculovirus strains have been identified that can be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0397] Plant cell cultures can also be used as hosts (see, e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429, which describe PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0398] Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to grow in suspension can be useful. Other examples of useful mammalian host cell lines include the SV40 (COS-7) transformed monkey kidney CV1 line; human embryonic kidney lines (e.g., 293 or 293 cells described in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells described in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK); buffalo rat liver cells (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor (MMT060562); see, e.g., Mather et al., Annals Other useful mammalian host cell lines include TRI cells, described in NYAcad. Sci. 383:44-68 (1982); MRC5 cells; and FS4 cells. - Examples include Chinese hamster ovary (CHO) cells, including CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)), and myeloma cell lines such as Y0, NS0, and Sp2 / 0. For a review of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Mol. Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0399] B. Assay The anti-tau antibodies provided herein may be identified, screened, or characterized for their physical / chemical properties and / or biological activity by various assays known in the art.

[0400] 1. Binding Assays and Other Assays Antibodies of the present disclosure can be tested for their antigen binding activity by known methods, such as, for example, ELISA, Western blot, and the like.

[0401] Competition assays can be used to identify antibodies that compete with the antibodies described herein for binding to tau. In certain embodiments, such competing antibodies bind to the same epitope (e.g., a linear or conformational epitope) as that bound by semolinemab. Detailed exemplary methods for mapping antibody-binding epitopes are provided in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology, vol. 66 (Humana Press, Totowa, NJ).

[0402] In an exemplary competitive assay, immobilized tau (such as monomeric tau) is incubated in a solution containing a first labeled antibody that binds to tau (e.g., any antibody described herein, e.g., semolinemab) and a second unlabeled antibody being tested for its ability to compete with the first antibody for binding to tau. The second antibody may be present in hybridoma supernatant. As a control, immobilized tau is incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to tau, excess unbound antibody is removed and the amount of label associated with immobilized tau is measured. If the amount of label associated with immobilized tau is substantially reduced in the test sample compared to the control sample, this indicates that the second antibody competes with the first antibody for binding to tau (Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY)).

[0403] 2. Activity Assay The present disclosure also provides assays for identifying anti-tau (e.g., pan-tau) antibodies thereof having biological activity. Biological activity can include, for example, binding of such antibodies to multiple forms of tau (e.g., monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau) and reducing levels of tau protein (e.g., total soluble tau, soluble unphosphorylated tau, soluble phosphorylated tau, total insoluble tau, insoluble unphosphorylated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical fibrils containing hyperphosphorylated tau in the brain, e.g., in the cerebral cortex and / or hippocampus). Antibodies having such biological activity in vivo and / or in vitro are also provided.

[0404] In certain embodiments, antibodies of the present disclosure are tested for such biological activity. For example, animal models of tauopathy, such as tau transgenic mice (e.g., P301L), can be used to detect binding of anti-tau antibodies to brain sections, e.g., to neurofibrillary tangles in the brains of transgenic mice. Furthermore, animal models of tauopathy, such as tau transgenic mice (e.g., P301L), can be treated with anti-tau antibodies, and experimental techniques known in the art can be used to evaluate whether such treatment reduces the levels of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, soluble non-phosphorylated tau, total insoluble tau, insoluble phosphorylated tau, insoluble non-phosphorylated tau, hyperphosphorylated tau, or paired helical fibrils containing hyperphosphorylated tau) in the mouse brain (e.g., in the cerebral cortex and / or hippocampus).

[0405] 3. Diagnostic and Detection Assays In certain embodiments, any of the anti-tau antibodies provided herein are useful for detecting the presence of tau in a biological sample. As used herein, the term "detecting" encompasses quantitative or qualitative detection. In certain embodiments, a biological sample includes a tissue or cell sample obtained from an organism, such as cells or tissues, such as serum, plasma, nasal swab, sputum, cerebrospinal fluid, aqueous humor of the eye, or a sample containing neural or brain tissue.

[0406] In some embodiments, anti-tau antibodies are provided for use in diagnostic or detection methods. In a further aspect, methods for detecting the presence of tau in a biological sample are provided. In certain embodiments, the methods comprise contacting the biological sample with an anti-tau antibody described herein under conditions that allow binding of the anti-tau antibody to tau, and detecting whether a complex is formed between the anti-tau antibody and tau. Such methods may be in vitro or in vivo methods.

[0407] Exemplary disorders that may be diagnosed using the antibodies described herein are those characterized by tau pathology, particularly aggregated tau in the brain, or tau burden in the extracellular space substantially similar to that seen in mild to moderate AD. Non-limiting examples of disorders for diagnosis using the antibodies described herein include mild to moderate or moderate AD, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, pugilistically impaired persons, Down's syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / parkinsonism dementia syndrome, and non-Guam motor neuron disease with neurofibrillary tangles. In some embodiments, the tauopathy is progressive supranuclear palsy, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, postencephalitic parkinsonism, and myotonic dystrophy.

[0408] In certain embodiments, labeled anti-tau antibodies are provided. Labels include, but are not limited to, labels or moieties that are directly detected (such as fluorescent, chromophore, electron-dense, chemiluminescent, and radioactive labels) and moieties, such as enzymes or ligands, that are indirectly detected, for example, via enzymatic reactions or molecular interactions. Exemplary labels include radioisotopes. 33 P, 14 C. 125 I, 3Examples of suitable oxidases include, but are not limited to, H and 131I, rare earth chelates or fluorophores such as fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luciferases such as firefly luciferase and bacterial luciferase (U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, sugar oxidases such as glucose oxidase, galactose oxidase, glucose-6-phosphate dehydrogenase, heterocyclic oxidases such as uricase and xanthine oxidase conjugated to enzymes that use hydrogen peroxide to oxidize dye precursors, such as HRP, lactoperoxidase, or microperoxidase, biotin / avidin, spin labels, bacteriophage labels, stable free radicals, and the like.

[0409] 4. Immunoconjugates In some embodiments, any of the anti-tau antibodies provided herein are useful to form immunoconjugates comprising an anti-tau antibody conjugated to one or more other therapeutic agents or radioisotopes.

[0410] In some embodiments, the immunoconjugate comprises an antibody described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioisotopes are available for the production of radioconjugates. Examples include At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 When a radioactive substance is used for detection, it can be a radioactive atom, such as 99mTc for scintigraphy studies, or a radioisotope of 99mTc or 123I, or spin labels for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

[0411] Antibody conjugates can be made using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotides to antibodies (WO 94 / 11026). The linker may be a "cleavable linker" that facilitates the release of the cytotoxic drug within the cell. For example, an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Pat. No. 5,208,020) can be used.

[0412] The immunoconjugates or ADCs herein expressly contemplate such conjugates prepared with crosslinker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate), which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL, USA).

[0413] C. Pharmaceutical Preparations In a further aspect, the present disclosure provides pharmaceutical formulations comprising any of the anti-tau antibodies provided herein, e.g., for use in any of the described methods of treatment. In some embodiments, the pharmaceutical formulation comprises an anti-tau antibody and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical formulation further comprises at least one additional therapeutic agent, e.g., as described herein.

[0414] Pharmaceutical formulations of the anti-tau antibodies described herein are prepared in the form of lyophilized formulations or aqueous solutions by mixing such antibodies having the desired degree of purity with one or more optional pharmaceutically acceptable carriers, diluents, and / or excipients (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Exemplary lyophilized antibody formulations are described, for example, in U.S. Pat. No. 6,267,958. Aqueous antibody formulations include those described in U.S. Pat. No. 6,171,586 and WO 2006 / 044908, the latter formulations containing a histidine-acetate buffer.

[0415] Pharmaceutically acceptable carriers, diluents, and excipients are generally non-toxic to recipients at the dosages and concentrations employed, and include, but are not limited to, sterile water, buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight ( Examples of suitable pharmaceutically acceptable carriers include polypeptides of less than about 10 residues; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include intercalating drug dispersing agents, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), e.g., human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Application Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one embodiment, a sHASEGP is combined with one or more additional glycosaminoglycanases (e.g., chondroitinases).

[0416] In any of the above embodiments and aspects, the antibody may be semolinemab.

[0417] The formulations herein may also contain more than one therapeutic active ingredient as necessary for the particular indication being treated, preferably with complementary activities that do not adversely affect each other. For example, it may be desirable to additionally provide one or more compounds for preventing or treating the symptoms of AD. Such active ingredients are suitably present in combination in amounts effective for the intended purpose.

[0418] The active ingredient may be encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0419] Sustained-release preparations may also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.

[0420] Formulations to be used for in vivo administration are generally sterile. Sterilization may be readily accomplished, for example, by filtration through sterile filtration membranes.

[0421] Methods of treatment and compositions for use therein As described above, the present disclosure provides the first clinical data demonstrating a slowdown in clinical decline and a reduction in disease progression in mild-to-moderate and moderate AD using an anti-tau approach. Specifically, patients with mild-to-moderate or moderate AD showed a reduced rate of cognitive decline when treated with semolinemab compared to placebo. Furthermore, the dose used did not increase the incidence of adverse events. Thus, in one aspect, the present disclosure provides the use of any of the anti-tau antibodies in the treatment of mild-to-moderate or moderate AD and related tauopathies. Such anti-tau antibodies are provided for use as medicines. In some embodiments, the anti-tau antibody is for the treatment of mild-to-moderate AD. In some embodiments, the anti-tau antibody is for the treatment of moderate AD.

[0422] In some embodiments, the tauopathy is a neurodegenerative tauopathy. In some embodiments, the tau pathology is characterized by tau pathology in the extracellular space of the patient's brain that is substantially similar to that seen in mild to moderate AD. Exemplary tau pathologies that can be treated with the anti-tau antibodies disclosed herein include, but are not limited to, mild to moderate AD, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, pugilistically impaired persons, Down's syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / parkinsonism dementia syndrome, and non-Guam motor neuron syndrome with neurofibrillary tangles. Examples of tau-related disorders include Alzheimer's disease, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, an anti-tau antibody is provided for use in the treatment of mild to moderate AD. In some embodiments, an anti-tau antibody is provided for use in the treatment of progressive supranuclear palsy. In some embodiments, an anti-tau antibody is provided for use in the treatment of tau pathology characterized by tau pathology in the extracellular space of the patient's brain substantially similar to that seen in mild to moderate AD.

[0423] Additionally, tau pathologies that can be treated with anti-tau antibodies include diseases or disorders manifesting as impairment or loss of cognitive function, such as reasoning, situational awareness, memory capacity, learning, and / or specialized navigation. In certain embodiments, the present disclosure provides an anti-tau antibody for use in a method of treating an individual having any one of the above tau pathologies, the method comprising administering to the individual an effective amount of an anti-tau antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., a concomitant symptomatic drug.

[0424] In any of the foregoing embodiments and aspects, the antibody of the disclosure can be semolinemab.

[0425] Patients are typically first evaluated for the presence of one or more tauopathies before determining suitability for treatment. As one non-limiting example, mild to moderate AD can be diagnosed in patients using the NINCDS-ADRDA (Neurological and Communicative Disorders and Stroke-Alzheimer's Disease Related Disorders Assessment) criteria (McKhann, et al., 1984, Neurology 34:939-44). Patients who may be administered one or more antibodies described herein may be tested for the presence or absence of one or more genetic markers that predispose the patient to either (i) being more or less likely to experience one or more tauopathies, (ii) being more or less likely to benefit from treatment, or (iii) being more or less likely to experience one or more adverse events or side effects during the course of antibody administration. As one non-limiting example, it is known that patients with the Apoε4 allele have a substantially higher risk of developing AD than patients lacking the allele (Saunders et al, Neurology 1993;43:1467-72; Prekumar et al., Am. J. Pathol. 1996;148:2083-95).

[0426] In some embodiments, the antibodies disclosed herein are used to treat mild to moderate AD in a patient. The patient can be Apoε4 positive or Apoε4 negative. In some embodiments, the antibodies are used to treat Apoε4 positive patients with mild to moderate AD. In some embodiments, the antibodies are used to treat Apoε4 positive patients with moderate AD. In some embodiments, the patient is Apoε4 positive. In some embodiments, the patient is Apoε4 negative.

[0427] In some embodiments, the antibodies disclosed herein are used to treat patients with an MMSE score between 16 and 21, between 16 and 18, or between 19 and 21. In some embodiments, the antibodies are used to treat patients with 1 or 2 CDR GS.

[0428] In some embodiments, the antibodies disclosed herein are used to treat patients with an MMSE score between 16 and 20, between 16 and 19, between 16 and 18, between 16 and 17, between 17 and 21, between 17 and 20, between 17 and 19, between 17 and 18, between 18 and 21, between 18 and 20, between 18 and 19, between 19 and 21, or between 19 and 20. As used herein, an MMSE score between two numbers includes both ends of the range. For example, an MMSE score between 16 and 21 includes MMSE scores of 16 and 21.

[0429] In some embodiments, a patient of the present disclosure has an MMSE score of 16 to 19, inclusive, prior to administration of a humanized monoclonal anti-tau antibody, and optionally has an MMSE score of 16 to 18, inclusive, prior to administration of the antibody. In some embodiments, a patient of the present disclosure has an MMSE score of 16 to 19, inclusive, prior to administration of a humanized monoclonal anti-tau antibody. In some embodiments, a patient of the present disclosure has an MMSE score of 16 to 18, inclusive, prior to administration of a humanized monoclonal anti-tau antibody.

[0430] In some embodiments, the antibodies disclosed herein are used to treat patients who are tau positive. In certain embodiments, the antibodies are used to treat patients who have a tau burden or tau pathology typical of that seen in patients diagnosed with mild to moderate AD. In certain embodiments, the antibodies are used to treat patients who have a tau burden or tau pathology typical of that seen in patients diagnosed with moderate AD.

[0431] In some embodiments, the patient of the present disclosure is tau positive and / or amyloid beta (Abeta) positive. In some embodiments, the patient is determined to be tau positive by administering to the patient a positron emission tomography (PET) tracer that binds to tau. In some embodiments, the patient is determined to be Abeta positive by administering to the patient a PET tracer that binds Abeta. In some embodiments, the patient of the present disclosure is tau positive, and optionally, the patient is determined to be tau positive by administering to the patient a positron emission tomography (PET) tracer that binds to tau. In some embodiments, the patient of the present disclosure is Abeta positive, and optionally, the patient is determined to be Abeta positive by administering to the patient a positron emission tomography (PET) tracer that binds Abeta. In some embodiments, the patient of the present disclosure is tau positive and / or Abeta positive. In some embodiments, the patient of the present disclosure is tau positive. In some embodiments, the patient of the present disclosure is Abeta positive. In some embodiments, the patient is determined to be tau positive by administering to the patient a positron emission tomography (PET) tracer that binds tau. In some embodiments, the patient is determined to be Abeta positive by administering to the patient a positron emission tomography (PET) tracer that binds to Abeta.

[0432] In further embodiments, the present disclosure provides anti-tau antibodies for use in slowing tau accumulation (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau) in a patient. For example, the antibodies can be used to slow tau aggregation in the extracellular space between neurons in the patient's brain. In some embodiments, the present disclosure provides anti-tau antibodies for use in slowing the accumulation of tau protein in a patient as measured by a tau PET scan. For example, such slow accumulation can occur in the brain (e.g., in the cerebral cortex and / or hippocampus). In some embodiments, the present disclosure provides anti-tau antibodies for use in slowing the accumulation of phosphorylated tau, including soluble phosphorylated tau. In some embodiments, the present disclosure provides anti-tau antibodies for use in slowing the accumulation of aggregated tau. In some embodiments, the present disclosure provides anti-tau antibodies for use in slowing the accumulation of insoluble tau (e.g., insoluble phosphorylated tau). In some embodiments, the present disclosure provides anti-tau antibodies for use in slowing the accumulation of hyperphosphorylated tau. In some embodiments, the present disclosure provides anti-tau antibodies for use in slowing the accumulation of paired helical filaments (e.g., paired helical filaments containing hyperphosphorylated tau) in brain tissue (e.g., in the brain cortex and / or hippocampus). In certain embodiments, the disclosure provides an anti-tau antibody for use in a method for slowing the accumulation of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau) in the brain (e.g., in the cerebral cortex and / or hippocampus) of a patient, comprising administering to the patient an effective amount (e.g., 4500 mg) of the anti-tau antibody to slow tau accumulation. In some embodiments, the antibody binds to an epitope within the N-terminal region of tau (N-terminal-binding anti-tau antibody), e.g., an epitope within amino acid residues 2-24 of mature human tau, e.g., an epitope within amino acid residues 6-23 / spanning amino acid residues of mature human tau. In some embodiments, the antibody is semolinemab.Without being limited to any hypothesis or theory, the anti-tau antibodies described herein can be used to disrupt tau extracellularly, preventing the seeding / spread of further tau deposits to previously unaffected neurons.

[0433] In further embodiments, the present disclosure provides methods of slowing tau accumulation (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau) by administering a therapeutically effective amount of an anti-tau antibody to a patient. For example, the antibody can be used to slow tau aggregation in the extracellular space between neurons in the patient's brain. In some embodiments, the present disclosure provides methods of slowing the accumulation of tau protein in a patient as measured by a tau PET scan by administering a therapeutically effective amount of an anti-tau antibody to the patient. For example, such slow accumulation can occur in the brain (e.g., in the cerebral cortex and / or hippocampus). In some embodiments, the present disclosure provides methods of slowing the accumulation of phosphorylated tau, including soluble phosphorylated tau, by administering a therapeutically effective amount of an anti-tau antibody to a subject. In some embodiments, the present disclosure provides methods of slowing the accumulation of aggregated tau by administering a therapeutically effective amount of an anti-tau antibody to a subject. In some embodiments, the present disclosure provides methods of slowing the accumulation of insoluble tau (e.g., insoluble phosphorylated tau) by administering a therapeutically effective amount of an anti-tau antibody to a subject. In some embodiments, the present disclosure provides methods of slowing the accumulation of hyperphosphorylated tau by administering a therapeutically effective amount of an anti-tau antibody to a subject. In some embodiments, the present disclosure provides methods of slowing the accumulation of paired helical filaments (e.g., paired helical filaments containing hyperphosphorylated tau) in brain tissue (e.g., in the brain cortex and / or hippocampus) by administering a therapeutically effective amount of an anti-tau antibody to a subject. In certain embodiments, the present disclosure provides methods for slowing the accumulation of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau) in the brain (e.g., in the cerebral cortex and / or hippocampus) of a patient, comprising administering to the patient a therapeutically effective amount (e.g., 4500 mg) of an anti-tau antibody to slow the accumulation of tau.In some embodiments, the antibody binds to an epitope within the N-terminal region of tau (N-terminal binding anti-tau antibody), e.g., an epitope within amino acid residues 2-24 of mature human tau, e.g., an epitope within amino acid residues 6-23 / spanning amino acid residues of mature human tau. In some embodiments, the antibody is semolinemab.

[0434] In some embodiments, the reduction in tau levels is determined by measuring the density and / or extent of tau pathology and / or aggregated tau. Thus, a reduction in the density or extent of tau pathology and / or aggregated tau (e.g., measured by positron emission tomography imaging) is considered to indicate a reduction in tau levels. The levels of tau, non-phosphorylated tau, phosphorylated tau, or hyperphosphorylated tau can be measured by positron emission tomography (PET) or by analysis of cerebrospinal fluid, such as cerebrospinal fluid obtained via lumbar puncture. In some embodiments, the reduction in tau protein levels is determined by measuring the levels of tau fragments.

[0435] In some embodiments, tau levels are measured by normalized uptake value ratio (SUVR) measurements of scans showing the distribution of PET tracers in the brain of patients of the present disclosure. In some embodiments, patients of the present disclosure have high levels of tau, where high levels of tau correspond to one or more of the following: (i) brain tau levels equal to or greater than the median Genentech Tau Probe 1 (GTP1) whole cortical gray matter (WCG) (upper-middle division); (ii) a SUVR measurement from the temporal region equal to or greater than 1.325; and (iii) a SUVR measurement from the whole cortical gray matter (WCG) region equal to or greater than 1.245. In some embodiments, patients of the present disclosure have high levels of tau, where high levels of tau correspond to brain tau levels equal to or greater than the median Genentech Tau Probe 1 (GTP1) whole cortical gray matter (WCG) (upper-middle division). In some embodiments, patients of the present disclosure have high levels of tau, where high levels of tau correspond to a SUVR measurement from the temporal region equal to or greater than 1.325. In some embodiments, a patient of the present disclosure has a high level of tau, where the high level of tau corresponds to a SUVR measurement from the whole cortical gray matter (WCG) region that is greater than or equal to 1.245. In some embodiments, the patient has a low level of tau, where the low level of tau corresponds to one or more of the following: (i) brain tau levels below the median GTP1 WCG (inferior-middle division); (ii) a SUVR measurement from the temporal region that is less than 1.325; and (iii) a SUVR measurement from the WCG that is less than 1.245. In some embodiments, the patient has a low level of tau, where the low level of tau corresponds to a brain tau level below the median GTP1 WCG (inferior-middle division). In some embodiments, the patient has a low level of tau, where the low level of tau corresponds to a SUVR measurement from the temporal region that is less than 1.325. In some embodiments, the patient has a low level of tau, where the low level of tau corresponds to a SUVR measurement from the WCG that is less than 1.245.

[0436] In some embodiments, the disclosure provides anti-tau antibodies for use in modulating tau load (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau), e.g., in a patient's brain (e.g., in the cerebral cortex and / or hippocampus). In some embodiments, the disclosure provides methods of modulating tau load (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau), e.g., in a patient's brain (e.g., in the cerebral cortex and / or hippocampus), by administering a therapeutically effective amount of an anti-tau antibody to the patient. In some embodiments, the antibody is semolinemab. In some embodiments, the dose is 4500 mg of semolinemab.

[0437] In a further aspect, the disclosure provides use of an anti-tau antibody in the manufacture or preparation of a medicament. The medicament can be for the treatment of any of the tau pathologies described above. In some embodiments, the medicament is for the treatment of mild to moderate or moderate AD. In some embodiments, the medicament is for the treatment of mild to moderate AD. In some embodiments, the medicament is for the treatment of moderate AD. In some embodiments, the medicament is for reducing tau pathology (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau) in the brain of a patient.

[0438] In some aspects, the present disclosure provides methods of alleviating one or more symptoms of tau pathology, or provides anti-tau antibodies, or medicaments comprising anti-tau antibodies, for alleviating one or more symptoms of tau pathology (e.g., any of the diseases or disorders described herein, e.g., mild-to-moderate AD or moderate AD). In some aspects, the present disclosure provides methods of reducing the number of symptoms or the severity of one or more symptoms of tau pathology, or provides anti-tau antibodies, or medicaments comprising anti-tau antibodies, for reducing the number or severity of symptoms of tau pathology (e.g., any of the diseases or disorders described herein, e.g., AD). In certain embodiments, the symptom of tau pathology is impaired cognitive ability or cognitive decline, e.g., a progressive decline in cognitive ability. In some embodiments, the symptom of tau pathology is impaired praxis, such as a progressive decline in praxis. In some embodiments, the symptom of tau pathology is a learning impairment, such as a progressive decline in learning. In some embodiments, a symptom of tau pathology is impairment of memory, such as a progressive decline in memory ability. In some embodiments, a symptom of tau pathology is long-term memory loss. In certain embodiments, a symptom of tau pathology is dementia. In some embodiments, a symptom of tau pathology is confusion, irritability, aggression, mood swings, or language impairment. In some embodiments, a symptom of tau pathology is impairment or loss of one or more cognitive functions, such as reasoning, judgment, memory capacity, praxis, and / or learning. In an additional aspect, the present disclosure provides methods of treating mild-to-moderate or moderate AD and related tauopathies in a subject in need thereof by administering a therapeutically effective amount of an anti-tau antibody to the subject. In some embodiments, the method is a method of treating mild-to-moderate AD. In some embodiments, the method is a method of treating moderate AD. The methods provided herein include administering to a patient (e.g., a person exhibiting one or more symptoms of tau pathology) an amount (e.g., a therapeutically effective amount such as 4500 mg) of an anti-tau antibody. In certain embodiments, the antibody is semolinemab.

[0439] In certain aspects, the present disclosure provides methods for preserving or increasing memory capacity, memory function, or cognitive function, or for delaying memory loss or cognitive loss associated with tau pathology. Accordingly, in some aspects, the present disclosure provides anti-tau antibodies, or medicaments comprising anti-tau antibodies, for preserving or increasing memory capacity, memory function, or cognitive function, or for delaying memory loss or cognitive loss associated with tau pathology (e.g., any disease or disorder described herein, such as AD, mild-to-moderate AD, or moderate AD (memory loss is generally a central feature of disease progression)). Memory can be assessed, for example, as one of the three domains comprising the ADAS-Cog11 score, e.g., as described herein (ADAS-Cog11 Memory Domain Score). In certain embodiments, memory is assessed for word recognition and / or vocabulary recall, e.g., as assessed using the ADAS-Cog11 test. The methods provided herein include administering to a patient (e.g., a person exhibiting one or more symptoms of memory loss or reduced memory capacity) an amount (e.g., a therapeutically effective amount such as 4500 mg) of an anti-tau antibody. In certain embodiments, the antibody is semolinemab.

[0440] In certain aspects, the present disclosure provides methods for slowing the decline in vocabulary recognition ability associated with tau pathology. Accordingly, in some aspects, the present disclosure provides an anti-tau antibody, or a medicament comprising an anti-tau antibody, for slowing the loss of vocabulary recognition and / or vocabulary recall associated with tau pathology (e.g., any of the diseases or disorders described herein, e.g., mild-to-moderate AD or moderate AD). Vocabulary recognition / recall can be assessed, for example, as described herein, as a component of the memory domain that makes up the ADAS-Cog11 score (ADAS-Cog11 vocabulary recognition score). The methods provided herein include administering an amount (e.g., a therapeutically effective amount, such as 4500 mg) of an anti-tau antibody to a patient (e.g., a person exhibiting one or more symptoms of decline in vocabulary recognition ability). In certain embodiments, the antibody is semolinemab.

[0441] In some aspects, the present disclosure provides methods for slowing the decline in language and / or praxis associated with tau pathology. Accordingly, in some aspects, the present disclosure provides anti-tau antibodies, or medicaments comprising anti-tau antibodies, for slowing the loss of language and / or praxis associated with tau pathology (e.g., any of the diseases or disorders described herein, e.g., mild-to-moderate AD or moderate AD). Language and praxis can be assessed, for example, as domains comprising the ADAS-Cog11 score, e.g., as described herein (ADAS-Cog11 Language Domain Score or ADAS-Cog11 Praxis Domain Score). The methods provided herein include administering an amount (e.g., a therapeutically effective amount, such as 4500 mg) of an anti-tau antibody to a patient (e.g., a person exhibiting one or more symptoms of decline in language and / or praxis). In certain embodiments, the antibody is semolinemab.

[0442] In some aspects, the present disclosure provides methods of reducing the rate of progression of tau pathology, or provides anti-tau antibodies, or medicaments comprising anti-tau antibodies, for reducing the rate of progression of tau pathology (e.g., any of the diseases or disorders described herein, e.g., mild-to-moderate AD or moderate AD). The methods provided herein include administering an amount (e.g., a therapeutically effective amount, such as 4500 mg) of an anti-tau antibody to a patient (e.g., one exhibiting one or more symptoms of tau pathology). In certain embodiments, the antibody is semolinemab.

[0443] Furthermore, the antibodies of the present disclosure are useful for treating mild to moderate AD or moderate AD without increasing the incidence of adverse events. In some embodiments, the patient is Apoε4 positive. In some embodiments, the patient has an MMSE score of 16-18 or an MMSE score of 16-19.

[0444] The anti-tau antibodies are formulated, administered, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual subject, the cause of the disease, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to medical practitioners. C. Route of Administration

[0445] The antibodies described herein (and any additional therapeutic agents) can be administered by any suitable means, including parenterally. In some embodiments, the antibodies are administered intravenously or subcutaneously, and in some embodiments, the antibodies are administered intravenously. In some embodiments, the antibodies are administered subcutaneously.

[0446] Dosing can be by any suitable route, for example, injection, such as intravenous injection, depending in part on whether the administration is brief or chronic. In some embodiments, the antibody is injected subcutaneously. In some embodiments, the antibody is injected intravenously. In some embodiments, semolinemab is administered subcutaneously. In some embodiments, semolinemab is administered intravenously. In some embodiments, the antibody is administered using a syringe (e.g., pre-filled or not) or an autoinjector. Various dosing schedules are contemplated herein, including, but not limited to, a single dose or multiple doses over various time points, a bolus dose, or pulse infusion.

[0447] In certain embodiments, the antibody is administered intravenously by infusion. In some embodiments, the infusion rate is 0.1-5.0 mL / min, e.g., 0.2 mL / min, 0.3 mL / min, 0.4 mL / min, 0.5 mL / min, 0.6 mL / min, 0.7 mL / min, 0.8 mL / min, 1.0 mL / min, 1.5 mL / min, 2.0 mL / min, 2.5 mL / min, 2.8 mL / min, 3.0 mL / min, 3.2 mL / min, 3.5 mL / min, 4.0 mL / min, or 4.5 mL / min. In some embodiments, the infusion rate is 0.5-3.0 mL / min. The infusion rate may be constant throughout administration or may be increased after an initial period or after the first infusion for a patient receiving treatment. In some embodiments, the infusion rate is 0.5-1 mL / min for 10-120 minutes of the first infusion, then 2-4 mL / min, then 2.8-3.2 mL / min, or 3 mL / min thereafter. In some embodiments, the infusion rate is 0.5-1 mL / min for 30-60 minutes of the first infusion, then 2-4 mL / min, then 2.8-3.2 mL / min, or 3 mL / min thereafter. In some embodiments, the infusion rate is 0.5 for the first 30 minutes of the first infusion, 1 mL / min for the next 30 minutes, and 3 mL / min during the subsequent infusions and optionally during subsequent infusions.

[0448] In some embodiments, the humanized monoclonal anti-tau antibody is administered at an infusion rate of 0.5 mL / min to 3.0 mL / min. In some embodiments, the humanized monoclonal anti-tau antibody is administered every four weeks (or monthly) at an infusion rate of 0.5 mL / min to 3.0 mL / min. In some embodiments, the humanized monoclonal anti-tau antibody is administered at an infusion rate of 0.5 mL / min to 1 mL / min, optionally for 10-120 minutes of the first infusion, and 3 mL / min thereafter. In some embodiments, the humanized monoclonal anti-tau antibody is administered at an infusion rate of 0.5 mL / min to 1.0 mL / min.

[0449] In some embodiments, semolinemab is administered at an infusion rate of 0.5 mL / min to 3.0 mL / min. In some embodiments, the semolinemab anti-tau antibody of the present disclosure is administered every four weeks (or monthly) at an infusion rate of 0.5 mL / min to 3.0 mL / min. In some embodiments, semolinemab is administered at an infusion rate of 0.5 mL / min to 1 mL / min, optionally for 10-120 minutes of the first infusion, and then 3 mL / min thereafter. In some embodiments, semolinemab is administered at an infusion rate of 0.5 mL / min to 1 mL / min.

[0450] In some embodiments, the methods, antibodies for use and uses of the disclosure further comprise administering a 4500 mg dose of semolinemab intravenously to the patient Q4W for 96 weeks. 1. Dosage and frequency ...

Claims

1. A pharmaceutical comprising a human monoclonal anti-tau antibody for use in a method for slowing cognitive decline in patients diagnosed with mild to moderate Alzheimer's disease (AD) characterized by a Mini-Mental State Examination (MMSE) score of 16 to 21, inclusive, comprising: the method comprising administering to the patient a 4500 mg dose of an anti-tau antibody; The pharmaceutical composition comprises an anti-tau antibody comprising HVR-H1 having the amino acid sequence shown in SEQ ID NO: 2, HVR-H2 having the amino acid sequence shown in SEQ ID NO: 3, HVR-H3 having the amino acid sequence shown in SEQ ID NO: 4, HVR-L1 having the amino acid sequence shown in SEQ ID NO: 6, HVR-L2 having the amino acid sequence shown in SEQ ID NO: 7, and HVR-L3 having the amino acid sequence shown in SEQ ID NO:

8.

2. A pharmaceutical comprising a human monoclonal anti-tau antibody for use in a method for maintaining cognitive performance within 5 points on the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-item version (ADAS-Cog11) score in patients diagnosed with mild to moderate AD characterized by an MMSE score of 16 to 21, inclusive, comprising: The method comprises: administering a 4500 mg dose of an anti-tau antibody to the patient, wherein the patient's ADAS-Cog11 score assessed after 12 to 17 doses of the antibody is no more than 2.5 points, no more than 3 points, no more than 3.5 points, no more than 4 points, no more than 4.5 points, or no more than 5 points higher than the patient's ADAS-Cog11 score assessed before administration of the antibody; Thereby, maintaining the patient's cognitive ability within 5 points of the ADAS-Cog11 score. Including, The pharmaceutical composition comprises an anti-tau antibody comprising HVR-H1 having the amino acid sequence shown in SEQ ID NO: 2, HVR-H2 having the amino acid sequence shown in SEQ ID NO: 3, HVR-H3 having the amino acid sequence shown in SEQ ID NO: 4, HVR-L1 having the amino acid sequence shown in SEQ ID NO: 6, HVR-L2 having the amino acid sequence shown in SEQ ID NO: 7, and HVR-L3 having the amino acid sequence shown in SEQ ID NO:

8.

3. A pharmaceutical comprising a human monoclonal anti-tau antibody for use in a method for maintaining memory within 2.5 points on the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-item version (ADAS-Cog11) Memory Domain score in patients diagnosed with mild to moderate AD characterized by an MMSE score of 16 to 21, inclusive, comprising: The method comprises: administering a 4500 mg dose of an anti-tau antibody to the patient, wherein the patient's ADAS-Cog11 memory domain score assessed after 12 to 17 doses of the antibody is no more than 1 point, no more than 1.5 points, no more than 1.7 points, no more than 2 points, no more than 2.3 points, or no more than 2.5 points higher than the patient's ADAS-Cog11 memory domain score assessed before administration of the antibody; This maintains the patient's ADAS-Cog11 memory domain score within 2.5 points. Including, The pharmaceutical composition comprises an anti-tau antibody comprising HVR-H1 having the amino acid sequence shown in SEQ ID NO: 2, HVR-H2 having the amino acid sequence shown in SEQ ID NO: 3, HVR-H3 having the amino acid sequence shown in SEQ ID NO: 4, HVR-L1 having the amino acid sequence shown in SEQ ID NO: 6, HVR-L2 having the amino acid sequence shown in SEQ ID NO: 7, and HVR-L3 having the amino acid sequence shown in SEQ ID NO:

8.

4. A pharmaceutical comprising a human monoclonal anti-tau antibody provided at a dose of 4500 mg for use in slowing cognitive decline in patients diagnosed with mild to moderate AD characterized by an MMSE score of 16 to 21, inclusive, The pharmaceutical composition comprises an anti-tau antibody comprising HVR-H1 having the amino acid sequence shown in SEQ ID NO: 2, HVR-H2 having the amino acid sequence shown in SEQ ID NO: 3, HVR-H3 having the amino acid sequence shown in SEQ ID NO: 4, HVR-L1 having the amino acid sequence shown in SEQ ID NO: 6, HVR-L2 having the amino acid sequence shown in SEQ ID NO: 7, and HVR-L3 having the amino acid sequence shown in SEQ ID NO:

8.

5. 1. A pharmaceutical comprising a human monoclonal anti-tau antibody provided in a dose of 4500 mg for use in maintaining cognitive performance of 5 points or less above the Alzheimer's Disease Assessment Scale, Cognitive subscale, 11-item version (ADAS-Cog11) score in patients diagnosed with mild to moderate AD characterized by an MMSE score of 16 to 21, inclusive, after administration of 12 to 17 doses, The pharmaceutical composition comprises an anti-tau antibody comprising HVR-H1 having the amino acid sequence shown in SEQ ID NO: 2, HVR-H2 having the amino acid sequence shown in SEQ ID NO: 3, HVR-H3 having the amino acid sequence shown in SEQ ID NO: 4, HVR-L1 having the amino acid sequence shown in SEQ ID NO: 6, HVR-L2 having the amino acid sequence shown in SEQ ID NO: 7, and HVR-L3 having the amino acid sequence shown in SEQ ID NO:

8.

6. 1. A pharmaceutical comprising a human monoclonal anti-tau antibody provided at a dose of 4500 mg for use in maintaining memory within 2.5 points of the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-item version (ADAS-Cog11) Memory Domain score in patients diagnosed with mild to moderate AD characterized by an MMSE score of 16 to 21, inclusive, after administration of 12 to 17 doses, The pharmaceutical composition comprises an anti-tau antibody comprising HVR-H1 having the amino acid sequence shown in SEQ ID NO: 2, HVR-H2 having the amino acid sequence shown in SEQ ID NO: 3, HVR-H3 having the amino acid sequence shown in SEQ ID NO: 4, HVR-L1 having the amino acid sequence shown in SEQ ID NO: 6, HVR-L2 having the amino acid sequence shown in SEQ ID NO: 7, and HVR-L3 having the amino acid sequence shown in SEQ ID NO:

8.

7. The medicament of any one of claims 1 to 6, wherein the patient has a Mini-Mental State Examination (MMSE) score of 16 to 19, inclusive, before administration of the antibody, and optionally has an MMSE score of 16 to 18, inclusive, before administration of the antibody.

8. The pharmaceutical agent according to any one of claims 1 to 6, wherein the patient has a Clinical Dementia Global Scale (CDR-GS) of 1 or 2 before administration of the antibody.

9. the dosing is repeated at least 5 times, at least 8 times, or at least 10 times, or the dosing is repeated for 5 to 17 doses, 10 to 17 doses, or 12 to 17 doses; Optionally, (i) whether the dose is repeated for 13 to 15 doses, 13 to 14 doses, 14 to 15 doses, or 14 doses; (ii) the dose is repeated for 12 to 16 doses; or (iii) the dose is repeated for 14 to 17 doses; The pharmaceutical composition according to any one of claims 1 to 6. (i) the antibody is administered at least once every four weeks (or monthly), optionally for at least 24 weeks; (ii) the antibody is administered at least once every four weeks (or monthly), optionally for at least 36 weeks; (iii) the antibody is administered at least once every four weeks (or every month) for at least 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, or 168 weeks; (iv) the antibody is administered at least once every four weeks (or monthly) for at least 40, 44, 48, 52, 56, or 60 weeks; or (v) the antibody is administered at least once every four weeks (or monthly) for at least 48 weeks. The pharmaceutical composition according to any one of claims 1 to 6.

11. the patient's ADAS-Cog11 score assessed after administration of the antibody is: (i) the patient's ADAS-Cog11 score assessed prior to administration of the antibody is 2.5 points or less, 3 points or less, 3.5 points or less, 4 points or less, 4.5 points or less, or 5 points or less, preferably 4 points or less, higher; (ii) the patient's ADAS-Cog11 score is 4 points or less higher than the patient's ADAS-Cog11 score assessed prior to administration of the antibody; (iii) an ADAS-Cog11 score that is 2 to 4 points higher than the patient's ADAS-Cog11 score assessed prior to administration of the antibody; or (iv) an ADAS-Cog11 score of 3 to 4 points higher than the patient's ADAS-Cog11 score assessed prior to administration of the antibody; The pharmaceutical composition according to claim 1 or 4.

12. The pharmaceutical according to any one of claims 1 to 6, wherein the antibody comprises the mutations M252Y, S254T, T256E, and S228P according to EU numbering. (i) the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO:5, and / or a light chain variable region comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO:9; (ii) the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 5 and / or a light chain variable region having the amino acid sequence of SEQ ID NO: 9; or (iii) the antibody is semolinemab; The pharmaceutical composition according to any one of claims 1 to 6.

14. the patient is tau positive and / or amyloid beta (Abeta) positive, optionally the patient is determined to be tau positive by administering to the patient a positron emission tomography (PET) tracer that binds to tau, and optionally the patient is determined to be Abeta positive by administering to the patient a PET tracer that binds Abeta; Further optionally, (a) tau levels are measured by standardized uptake value ratio (SUVR) measurements of scans showing the distribution of said PET tracer in the brain of said patient; and optionally (1) The patient has a high level of tau, and the high level of tau is (i) median Genentech Tau Probe 1 (GTP1) brain tau levels equal to or greater than the whole cortical gray matter (WCG) (upper middle division); (ii) a temporal SUVR measurement of 1.325 or greater; and (iii) an SUVR measurement from the whole cortical gray matter (WCG) region that is greater than or equal to 1.245; corresponds to one or more of: (2) the patient has a low level of tau, and the low level of tau is (i) brain tau levels below the median GTP1 WCG (lower-middle division); (ii) an SUVR measurement from the temporal region that is less than 1.325; and (iii) an SUVR measurement from the WCG that is less than 1.245; corresponds to one or more of (b) the PET tracer that binds to the tau is at least one selected from the group consisting of [ 18 F]Genentech Tau Probe 1 ([ 18 F]GTP1), RO-948, AV-1451 (flortaucipir), PI-2014, PI-2620, MK-6240, and T-808, and the PET tracer that binds to Abeta is at least one selected from the group consisting of florbetapir, florbetaben, and flutemetamol; and / or (c) the tau is measured in a CSF or plasma sample taken from the patient. The pharmaceutical composition according to any one of claims 1 to 6.

15. one or more additional agents are co-administered to the patient; Optionally, (a) the one or more additional agents are selected from the group consisting of symptomatic medications, neurological agents, corticosteroids, antibiotics, antiviral agents, additional anti-tau antibodies, tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, BACE1 inhibitors; cholinesterase inhibitors; NMDA receptor antagonists; monoamine depleting agents; ergoloid mesylates; anticholinergic antiparkinsonian agents; dopaminergic antiparkinsonian agents; tetrabenazine; anti-inflammatory agents; hormones; vitamins; dimebolins; homotaurines; serotonin receptor modulators; interferons, and glucocorticoids; or (b) the one or more additional agents comprise a therapeutic agent that specifically binds to a target selected from the group consisting of beta-secretase, tau, presenilin, amyloid precursor protein or a portion thereof, amyloid beta peptide or oligomers or fibrils thereof, death receptor 6 (DR6), receptor for advanced glycation end products (RAGE), parkin, and huntingtin, and optionally, (i) the symptomatic medication is selected from the group consisting of a cholinesterase inhibitor, galantamine, rivastigmine, donepezil, an N-methyl-D-aspartate receptor antagonist, memantine, and a dietary supplement (optionally, the dietary supplement is Souvenaid®); (ii) the anti-amyloid beta antibody is aducanumab, lecanemab, or donanemab; (iii) the anti-amyloid beta antibody is crenezumab or gantenerumab; (iv) the additional anti-tau antibody is selected from the group consisting of a different N-terminal binding agent, a mid-domain binding agent, and a fibrillar tau binding agent; (v) the additional anti-tau antibody is selected from the group consisting of goslanemab, tiravonemab, bepranemab, and zagotenemab; (vi) the monoamine depletor is tetrabenazine; (vii) the anticholinergic anti-Parkinsonian drug is selected from the group consisting of procyclidine, diphenhydramine, trihexylphenidyl, benztropine, biperiden and trihexyphenidyl; (viii) the dopaminergic anti-Parkinsonian drug is selected from the group consisting of entacapone, selegiline, pramipexole, bromocriptine, rotigotine, selegiline, ropinirole, rasagiline, apomorphine, carbidopa, levodopa, pergolide, tolcapone and amantadine; (ix) the anti-inflammatory agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs and indomethacin; (x) the hormone is selected from the group consisting of estrogen, progesterone, and leuprolide; (xi) the vitamin is selected from the group consisting of folate and nicotinamide; (xii) the homotaurine is 3-aminopropanesulfonic acid or 3APS; and / or (xiii) The serotonin receptor activity modulator is xaliproden. The pharmaceutical composition according to any one of claims 1 to 6.

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