Antibodies binding to phospho-tau comprising phosphorylated Ser396 and Ser404 and methods of detecting thereof
Inventors
Assignees
Publication Number
US-12365724-B2
Publication Date
2025-07-22
Expiration Date
2039-12-10
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Abstract
The present invention relates to antibody-based molecules that are capable of preferentially and selectively binding to the C-terminal di-phosphorylated {p}Ser396/{p}Ser404 Tau peptide as well as to the {p}Ser404 Tau peptide and the non-phosphorylated Tau peptide, but does not bind to the {p}Ser396 Tau peptide. Such antibody-based molecules are useful to detect pathological Tau protein conformer if present in a biological sample, especially in conjunction with the diagnosis and/or treatment of Alzheimer's disease or other Tauopathy, and thus provide a diagnostic for Alzheimer's disease and other Tau pathologies. The antibody-based molecules of the present invention also have particular utility as prophylactic and therapeutic molecules for the treatment and/or prevention of Alzheimer's disease and related tauopathies.
Core Innovation
The invention relates to antibody-based molecules, including full-length antibodies, epitope-binding domains, and derivatives, that preferentially and selectively bind to a specific Tau protein epitope. This epitope corresponds to the Tau sequence TDHGAEIVYKS{p}PVVSGDTS{p}PRHL (SEQ ID NO:1), where serine residues at positions 11 and 19 are phosphorylated, corresponding to residues 396 and 404 in full-length Tau. These antibody-based molecules also bind to Tau peptides phosphorylated only at serine 19 and to non-phosphorylated Tau peptides but show negligible binding to Tau phosphorylated only at serine 11.
The problem addressed is the difficulty in diagnosing and treating Alzheimer's disease and related tauopathies due to the lack of effective therapies and accurate diagnostics for pathological Tau protein aggregates. Tau hyperphosphorylation leads to pathological conformers that aggregate and impair neuronal function, causing neurodegeneration in Alzheimer's disease and other tauopathies. Existing antibody and imaging ligands have limitations in specificity and sensitivity, especially across diverse tauopathies. Hence, there is a need for antibody-based molecules that can specifically detect and treat pathological Tau conformers.
The invention includes antibodies with defined complementarity-determining regions (CDRs) that provide selective binding affinity to the above Tau epitope. The antibodies display a binding preference hierarchy of dual phosphorylation at Ser396/Ser404 > phosphorylation at Ser404 alone > non-phosphorylated Tau > phosphorylation at Ser396 alone. These molecules can be used for diagnostic, prophylactic, and therapeutic purposes related to Alzheimer's disease and other tauopathies. The invention also encompasses nucleic acids encoding these antibodies, vectors, pharmaceutical compositions, and methods for detecting, monitoring, treating, and preventing Tau-related diseases.
Claims Coverage
The patent discloses 18 claims with multiple inventive features across antibody structure, binding specificity, molecular formats, diagnostic labeling, pharmaceutical compositions, and genetic constructs. The independent claims focus on the antibody-based molecule, its structural characteristics, and related compositions and methods.
Antibody variable domains with specific CDR sequences
An antibody-based molecule binds a Tau epitope within SEQ ID NO:1 and comprises VH domain with H-CDR1 (SEQ ID NO:2), H-CDR2 (SEQ ID NO:3), H-CDR3 (SEQ ID NO:4), and VL domain with L-CDR1 (SEQ ID NO:5), L-CDR2 (SEQ ID NO:6), and L-CDR3 (SEQ ID NO:7).
Variable heavy and light chain amino acid sequences
The VH domain comprises the amino acid sequence of SEQ ID NO:8 and the VL domain comprises the amino acid sequence of SEQ ID NO:9. The antibody may comprise both VH of SEQ ID NO:8 and VL of SEQ ID NO:9.
Binding specificity to phosphorylated Tau epitopes
The antibody binds phosphorylated Tau protein comprising SEQ ID NO:1 with serines at positions 11 and 19 phosphorylated or only the serine at position 19 phosphorylated.
Molecular formats of the antibody-based molecule
The antibody-based molecule is a full-length antibody, an epitope-binding fragment thereof such as Fab, Fab′, or F(ab′)2, or a single chain variable fragment (scFv). The scFv can comprise the amino acid sequence of SEQ ID NO:18.
Humanization and framework modification
The VH and VL domains may be humanized comprising human or humanized immunoglobulin heavy and light chain framework regions.
Conjugation to detectable labels
The antibody-based molecule can be conjugated to detectable labels including fluorescent, chemiluminescent, radioisotope, paramagnetic, positron-emitting metal, enzyme labels, or streptavidin/biotin complexes.
Pharmaceutical compositions containing the antibody-based molecule
Compositions comprising the antibody-based molecule and a pharmaceutically acceptable carrier.
Diagnostic kits
Kits comprising the antibody-based molecule conjugated or associated with a detectable label for diagnostic use.
Methods of detecting Tau aggregates
Detecting presence of aggregates of phosphorylated and/or non-phosphorylated Tau protein in neurons from brain tissue of subjects with tauopathy by contacting brain neurons with the antibody-based molecule and detecting accumulated Tau protein by immunohistochemical methods.
Isolated nucleic acid molecules encoding the antibody-based molecule
Isolated polynucleotides encoding the antibody-based molecules comprising the specified CDRs and variable domains.
Vectors comprising nucleic acids encoding the antibody-based molecules
Vectors carrying the polynucleotides encoding the antibody-based molecule for therapeutic or research use.
Host cells comprising expression vectors
Host cells genetically engineered to express the antibody-based molecules encoded by the vectors.
The claims comprehensively cover the antibody-based molecules with defined CDR sequences binding phosphorylated Tau epitopes, various antibody formats including scFv, humanized variants, labeled versions for diagnostics, pharmaceutical compositions, and nucleic acid and vector constructs enabling expression and therapeutic or diagnostic applications.
Stated Advantages
Specific and preferential binding to pathological Tau epitopes, enabling accurate detection of pathological Tau conformers.
Utility in diagnosing Alzheimer's disease and tauopathies, including early and accurate detection of Tau aggregates in biological samples or in vivo.
Therapeutic and prophylactic potential to inhibit onset, treat disease, prevent Tau aggregation, and clear pathological Tau protein.
Versatility in formats including full-length antibodies, fragments, and humanized forms suitable for clinical applications.
Documented Applications
Detecting pathological Tau protein aggregates in brain tissue via immunohistochemical staining for diagnosis of Alzheimer's disease and tauopathies.
Monitoring progression of Alzheimer's disease or other tauopathies by repeated detection of pathological Tau protein.
Treatment and prevention of conditions involving pathological Tau protein such as Alzheimer's disease and related tauopathies by administration of the antibody-based molecules.
Therapeutic clearing of pathological Tau aggregates from neuronal cultures and mouse brain models, reducing neurotoxicity.
Use in pharmaceutical compositions administered parenterally or via sustained release formulations for clinical therapy.
Diagnostic kits comprising antibody-based molecules labeled with detectable moieties for in vitro or in vivo diagnosis.
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