Tau binding compounds
Inventors
Liu, Wencheng • Carter, Todd • Shah, Ishan Sanjeev • Murray, Christopher Joseph • McCLORY, James Bernard • Sah, Dinah Wen-Yee
Assignees
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Publication Number
US-12291565-B2
Publication Date
2025-05-06
Expiration Date
Abstract
The present disclosure provides anti-tau antibodies and vectorization thereof (e.g., into AAV particles). Also provided are methods of using anti-tau antibodies and/or AAV particles for prevention, treatment, and/or diagnosis of neurological indications.
Core Innovation
The invention relates to an antibody that binds to human tau and is defined by heavy chain and light chain complementarity determining region amino acid sequences. The VH includes HC CDR1 comprising SEQ ID NO: 1144, HC CDR2 comprising SEQ ID NO: 1145, and HC CDR3 comprising SEQ ID NO: 410, and the VL includes LC CDR1 comprising SEQ ID NO: 1146, LC CDR2 comprising SEQ ID NO: 529, and LC CDR3 comprising SEQ ID NO: 571. The antibody is further constrained by specified amino acids at defined positions within the VH and VL, numbered according to cited reference sequences.
In particular embodiments, the VH and VL sequences are defined by SEQ ID NO: 69 and SEQ ID NO: 73, and other embodiments require at least 95% identity to specified VH and VL sequence pairs. The invention also includes nucleic acids encoding the antibody and AAV viral genome components that include an anti-tau antibody payload organized within an exemplar ITR-to-ITR viral genome sequence.
The antibody binds tau in a manner that includes binding tau C-terminus residues 409-436 and phosphorylated residues, including pS422. It is described as preferentially binding pathological tau as compared to wild-type tau, recognizing an epitope formed by complexes of at least two tau proteins, and reducing or inhibiting tau aggregation. Optional humanization is also indicated in the description.
Claims Coverage
The independent claims cover four themes: a tau-binding antibody defined by VH and VL CDR sequences and positional amino-acid constraints, a tau-binding antibody defined by specific VH and VL sequences, an antibody defined by CDR sequences with alternative at-least-95% identity relationships to specified SEQ ID NO pairs, and a nucleic acid encoding an antibody with defined VH and VL sequences. Across these independent claims, the inventive features are centered on sequence-defined tau binding, encoded expression embodiments, and tau-binding characteristics.
Sequence-defined tau-binding antibody with VH/VL CDRs and position constraints
An antibody that binds to human tau comprising a heavy chain variable region with HC CDR1 comprising SEQ ID NO: 1144, HC CDR2 comprising SEQ ID NO: 1145, and HC CDR3 comprising SEQ ID NO: 410; and a light chain variable region with LC CDR1 comprising SEQ ID NO: 1146, LC CDR2 comprising SEQ ID NO: 529, and LC CDR3 comprising SEQ ID NO: 571; wherein the VH and VL comprise specified amino acids at specified positions.
Tau-binding antibody with defined VH and VL sequences
An antibody that binds to human tau comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 73.
Tau-binding antibody with CDR sequences and 95% identity alternatives
An antibody that binds to human tau comprising HC CDR1 comprising SEQ ID NO: 1144, HC CDR2 comprising SEQ ID NO: 1145, HC CDR3 comprising SEQ ID NO: 410, LC CDR1 comprising SEQ ID NO: 1146, LC CDR2 comprising SEQ ID NO: 529, and LC CDR3 comprising SEQ ID NO: 571; wherein the heavy and light chains each have at least 95% identity to one of specified pairs of SEQ ID NOs.
Nucleic acid encoding a tau-binding antibody with defined VH and VL sequences
A nucleic acid encoding an antibody that binds to human tau, wherein the encoded antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 73.
Overall, the claim coverage is directed to tau-binding antibodies whose identity is defined by specific VH and VL CDR sequences and, depending on the independent claim, by either specified amino-acid positions or by at-least-95% identity relationships to specified VH/VL reference sequences. The coverage further extends to a nucleic acid encoding an antibody with the specified VH and VL variable-region sequences.
Stated Advantages
Preferential binding to pathological tau over wild-type tau.
Reducing or inhibiting tau aggregation.
Recognizing an epitope formed by complexes of at least two tau proteins.
Documented Applications
AAV-based delivery of an anti-tau antibody payload within an AAV viral genome component organization, including an exemplar ITR-to-ITR viral genome.
A pharmaceutical composition including the antibody and a pharmaceutically acceptable excipient.
Detecting or determining the level of a tau protein in a sample by contacting the sample with the antibody.
Delivering an antibody that binds to tau to a subject by administering an effective amount.
A method of delivering an antibody to a subject via intravenous administration.
Using the antibody or an AAV vector encoding the antibody for reducing or inhibiting tau aggregation.
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