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Publication Number
US-11466077-B2
Publication Date
2022-10-11
Expiration Date
Abstract
The present invention is in the field of transactive response DNA binding protein with a molecular weight of 43 kDa (TARDB or also TDP-43). The invention relates to TDP-43 specific binding molecules, in particular to anti-TDP-43 antibodies or an antigen-binding fragment or a derivative thereof and uses thereof. The present invention provides means and methods to diagnose, prevent, alleviate and/or treat a disorder and/or abnormality associated with misfolded TDP-43 including but not limited to frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD, sporadic and familial), and/or Parkinson's disease (PD). The present invention provides modified conformation-specific antigenic peptides and peptide fragments derived from the TDP-43 protein and the antibodies obtainable by said peptides or fragments for use in the diagnosis, prevention, alleviation and/or treatment of TDP-43-related disorders and/or abnormalities.
Core Innovation
The invention relates to a binding molecule that specifically recognizes misfolded mature human TDP-43 and specifically binds to an epitope within amino acids 215-222 of mature human TDP-43. The binding molecule comprises CDR sequences selected from groups of VL-CDR1, VL-CDR2, VL-CDR3 and VH-CDR1, VH-CDR2, VH-CDR3 sequences defined by amino acid sequences of SEQ ID NOs.
The disclosure further defines antibody formats and regions, including scFv, Fab, Fab’, F(ab’)2, Fv and Fc, and related CDR concepts. Allowable modifications described include humanization, sequence variants, and mutational strategies that include sequence variants and affinity-maturation concepts.
The document describes binding and epitope mapping for TDP-43-binding antibodies, including epitope mapping to peptides spanning residues 215-222 and competition concepts based on epitope sharing. It also addresses detection and antigen-binding performance for monomeric versus aggregated TDP-43, including binding and affinity readouts such as dissociation constant (KD) ranges and avidity concepts using monomeric versus aggregated forms.
Claims Coverage
The independent claim covers a binding molecule that specifically recognizes misfolded TDP-43 by epitope binding and is defined by alternative CDR-sequence sets. The claim set also includes additional inventive features such as specified antibody or fragment classes and quantitative binding thresholds, and it further expands into detection and therapeutic outcomes in dependent claims.
Epitope binding to misfolded mature human TDP-43 (amino acids 215-222)
The binding molecule specifically binds to an epitope within amino acids 215-222 of mature human TDP-43 and specifically recognizes misfolded TDP-43.
CDR-defined VL and VH sequences targeting the 215-222 epitope
The binding molecule comprises CDR sequences selected from groups in which VL-CDR1, VL-CDR2, VL-CDR3 and VH-CDR1, VH-CDR2, VH-CDR3 are provided by specified SEQ ID NO amino acid sequences (multiple alternative sets).
Antibody or antigen-binding fragment binding molecule
The binding molecule is an antibody or an antigen-binding fragment thereof.
CDR-defined antibody variable regions with sequence-identity constraints
The Light Chain Variable Region (VL) and Heavy Chain Variable Region (VH) of an antibody are defined as specific SEQ ID NO amino acid sequences or variants having at least a specified sequence identity threshold to those sequences.
Quantified binding affinity threshold by dissociation constant (KD)
The binding molecule has a dissociation constant (KD) at or below one of several listed threshold values.
Detection of misfolded TDP-43 using the binding molecule or an immunoconjugate
A method detects misfolded TDP-43 by contacting a sample with the binding molecule or an immunoconjugate.
Reducing brain TDP-43 aggregates
A method reduces the level of TDP-43 aggregates in the brain.
Across the independent claim and its dependents, coverage is centered on CDR-defined antibody binding molecules that specifically recognize misfolded mature human TDP-43 by binding an epitope within amino acids 215-222, with additional dependents refining the molecule as an antibody or fragment, specifying sequence-identity and KD-based binding thresholds, and expanding into detection and brain-aggregate reduction outcomes.
Stated Advantages
Blocks TDP-43 cell-to-cell spreading.
Disaggregates aggregates.
Inhibits aggregation.
Documented Applications
Diagnosing TDP-43 proteinopathies using patient samples including blood, CSF, and urine.
Preventing, alleviating, and treating TDP-43 proteinopathies, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) and related conditions.
Detecting misfolded TDP-43 by contacting a sample with a binding molecule or an immunoconjugate.
Therapeutic use aimed at reducing the level of TDP-43 aggregates in the brain.
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