US-12624095-B2 - Monoclonal antibodies against pathological tau, and methods of detection thereof

US12624095B2US 12624095 B2US12624095 B2US 12624095B2US-12624095-B2

Abstract

The present disclosure provides monoclonal antibodies that selectively bind to pathological tau over native tau. In certain aspects, the antibodies inhibit or minimize propagation of tau aggregates and/or reduce spread of pathological tau in vivo. In other aspects, the disclosure comprises a method of treating, ameliorating, and/or preventing a tauopathy in a subject, comprising administering any one of the antibodies of the disclosure to the subject. In yet other aspects, the disclosure comprises methods of detecting pathological tau using any one of the antibodies of the disclosure.

Inventors

Garrett S. Gibbons
Dawn M. Riddle
John Q. Trojanowski
Virginia M.Y. Lee

Assignees

THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

Dates

Publication Date: 20260512
Application Date: 20210525

Claims (11)

1 . An isolated monoclonal antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH), wherein: (a) the VL comprises a Complementarity-Determining Region 1 (CDR1) region comprising the amino acid sequence of SEQ ID NO: 23; a Complementarity-Determining Region 2 (CDR2) region comprising the amino acid sequence of SEQ ID NO: 25; and a Complementarity-Determining Region 3 (CDR3) region comprising the amino acid sequence of SEQ ID NO: 27, and the VH comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 9; a CDR2 region comprising the amino acid sequence of SEQ ID NO: 11; and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 13, or (b) the VL comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 51; a CDR2 region comprising the amino acid sequence of SEQ ID NO: 53; and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 55, and the VH comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 37; a CDR2 region comprising the amino acid sequence of SEQ ID NO: 39; and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 41.
2 . The monoclonal antibody of claim 1 , wherein: (a) the VL comprises the amino acid sequence of SEQ ID NO: 60, and the VH comprises SEQ ID NO: 58; or (b) the VL comprises the amino acid sequence of SEQ ID NO: 64, and the VH comprises SEQ ID NO: 62.
3 . The monoclonal antibody of claim 1 , which is humanized.
4 . The monoclonal antibody of claim 1 , which is labeled.
5 . A pharmaceutical composition comprising the monoclonal antibody of claim 1 and at least one pharmaceutical excipient.
6 . An isolated nucleic acid molecule comprising polynucleotides encoding the monoclonal antibody (a) or (b) of claim 1 .
7 . The nucleic acid molecule of claim 6 , wherein the polynucleotides encoding the monoclonal antibody (a) comprise the nucleic acid sequences of SEQ ID NOs: 57 and 59; and the polynucleotides encoding the monoclonal antibody (b) comprise (b) the nucleic acid sequences of SEQ ID NOs: 61 and 63.
8 . An expression vector comprising a recombinant nucleic acid encoding the monoclonal antibody of claim 1 .
9 . The expression vector of claim 8 , wherein the expression vector is (a) a plasmid or a virus vector; or (b) a mammalian cell expression vector.
10 . An isolated host cell comprising the vector of claim 8 , optionally wherein the host cell is a non-human cell or a mammalian cell.
11 . A method of detecting pathological tau in a sample isolated from a subject, the method comprising contacting the sample with a labeled isolated monoclonal antibody of claim 1 , and detecting presence or absence of a complex of the labeled isolated monoclonal antibody with any pathological tau present in the sample, wherein the pathological tau comprises a misfolded tau comprising amino acids 151-244 and amino acids 369-441 of Tau-F (SEQ ID NO:69); and wherein the presence of the complex of the labeled isolated monoclonal antibody with the pathological tau indicates that the subject has tauopathy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a 35 U.S.C. § 371 national phase application of, and claims priority to, International Application No. PCT/US2021/034056, filed May 25, 2021, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/029,977, filed May 26, 2020, all of which are is incorporated herein by reference in their entireties. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under AG017586, AG053036, AG010124, and AG062418 awarded by the National Institutes of Health. The government has certain rights in the invention BACKGROUND The neuropathological hallmarks of Alzheimer's Disease (AD) comprise extracellular amyloid-beta (Aβ) plaques and intraneuronal tau protein aggregates (inclusions) manifesting as neuritic plaques (NPs), neuropil threads (NTs), and neurofibrillary tangles (NFTs). Tau is a natively unstructured microtubule-associated protein expressed in the central nervous system as six differentially-spliced isoforms containing either 0, 1, or 2 N-terminal acidic exons and 3 or 4 microtubule-binding repeats (MTBRs). The typically unstructured tau protein can adopt a misfolded beta-sheet conformation that aggregates into fibrils with a filament core comprised of the MTBRs and folding that enables contact of the N-terminus with the core domains, to form paired helical filaments (PHFs) that assemble into NFTs. Accumulations of tau protein closely correlate with cognitive decline and neuron death in AD patients more so than the presence of Aβ plaques. Although there are no mutations in the gene encoding tau protein associated with AD, mutation of the tau (MAPT) gene results in Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Furthermore, tau forms intracellular inclusions in additional neurodegenerative tauopathies such as fronto-temporal lobar degeneration with tau (FLTD-tau) including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Therefore, tau plays a central role in the neurodegenerative disease process and presents an attractive target for therapeutic intervention in AD and related tauopathies. Tau aggregates propagate throughout the brain in a stereotypical spatiotemporal pattern that progresses with disease severity, beginning in the locus coeruleus and transentorhinal cortex, followed by the hippocampus and neocortex, and reaching the visual cortex at the latest disease stages. Growing evidence suggests this process is mediated by cell-to-cell transmission of pathological tau seeds from a neuron containing fibrillar tau species to a normal recipient neuron. Release of monomeric tau and polymeric misfolded tau from neurons may result from cell death or neuronal activity, generating both free extracellular tau and a small percentage of vesicle encapsulated tau. Once taken up into a recipient neuron, pathological tau seeds act as a template to recruit native cellular tau into newly formed oligomers and fibrils. Mouse models have demonstrated that intracerebral injection of either synthetic tau preformed fibrils (PFFs) or human AD-brain-derived pathological tau (AD-tau) can instigate tau pathology in regions of the brain distant from the injection site in either transgenic (Tg) mice expressing mutant human tau or non-transgenic wildtype (WT) mice. Together, these findings provide impetus for the development of anti-tau antibodies as immunotherapeutics for AD based on the hypothesis that antibody binding to extracellular tau prevents spread of pathological tau aggregates throughout the brain. There is thus a need for novel agents that can be used for treating, ameliorating, and/or preventing AD, based in one aspect on neutralizing pathological tau. This disclosure addresses and meets those needs. BRIEF SUMMARY In one aspect, the present disclosure provides an isolated monoclonal antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises a CDR1 region comprising the amino acid sequence of SEQ ID NOs: 23 or 51: a CDR2 region comprising the amino acid sequence of SEQ ID NOs: 25 or 53; and a CDR3 region comprising the amino acid sequence of SEQ ID NOs: 27 or 55, and wherein the VH comprises a CDR1 region comprising the amino acid sequence of SEQ ID NOs: 9 or 37: a CDR2 region comprising the amino acid sequence of SEQ ID NOs: 11 or 39; and a CDR3 region comprising the amino acid sequence of SEQ ID NOs: 13 or 41. In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one monoclonal antibody of the disclosure and at least one pharmaceutical excipient. In yet another aspect, the present disclosure provides an isolated polynucleotide comprising at least one of the nucleic acid sequences of SEQ ID NOs: 57, 59, 61, or 63. In yet another aspect, the present disclosure provides a method of preventing, minimizing,