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WO2025059486A1 - Anticorps anti-tdp-43 et leurs utilisations - Google Patents

Anticorps anti-tdp-43 et leurs utilisations Download PDF

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Publication number
WO2025059486A1
WO2025059486A1 PCT/US2024/046651 US2024046651W WO2025059486A1 WO 2025059486 A1 WO2025059486 A1 WO 2025059486A1 US 2024046651 W US2024046651 W US 2024046651W WO 2025059486 A1 WO2025059486 A1 WO 2025059486A1
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seq
antibody
variable domain
chain variable
occupied
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Tarlochan S. Nijjar
Stephen Jed TAM
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Prothena Biosciences Ltd
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Prothena Biosciences Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • TDP-43 BACKGROUND Transactive response DNA binding protein 43
  • TDP-43 is a predominantly nuclear protein that is involved in RNA splicing, trafficking, stabilization, and ultimately regulation of gene expression.
  • TDP-43 is a nucleic acid binding protein containing two highly conserved nucleic acid recognition motifs and has been shown to form dimers and oligomers. While TDP- 43 is expressed ubiquitously in all cell types, it has been shown to be highly expressed in the neuroepithelium, which contains all CNS progenitors for neurons and glia.
  • TDP-43 has been shown to specifically bind numerous RNAs in neuronal cells.
  • TDP-43 cytoplasmic aggregates are associated with several neurodegenerative diseases, disorders, or conditions.
  • TDP-43 cytoplasmic aggregates and/or misfolding of TDP-43 have been associated with neurodegenerative diseases including Amyotrophic Lateral Sclerosis (“ALS”), frontotemporal dementia (“FTD” or “FTLD- TDP-43”), limbic-predominant age-related TDP-43 encephalopathy (“LATE”), Alzheimer's disease, multisystem proteinopathy, and chronic traumatic encephalopathy.
  • ALS Amyotrophic Lateral Sclerosis
  • FDD frontotemporal dementia
  • LATE limbic-predominant age-related TDP-43 encephalopathy
  • Alzheimer's disease multisystem proteinopathy
  • chronic traumatic encephalopathy Attorney Docket Ref.
  • ALS is the most common motor neuron disorder in adults ultimately resulting in the loss of motor neurons that control voluntary muscles.
  • ALS has an incidence of about 1-2/100,000 and a prevalence of about 4-6/100,000 cases each year. ALS results in the progressive degeneration of both upper and lower motor neurons which generally leads to death primarily due to respiratory failure in three to five years after diagnosis. Typical symptoms include stiff muscles, muscle twitches, gradual muscle weakness, and muscle wasting. Around half of all people suffering from ALS have difficulties thinking and/or behavioral symptoms and about 15% develop frontotemporal dementia.
  • the present disclosure relates to antibodies and antigen-binding antibody fragments that specifically bind to human TDP-43, compositions comprising these antibodies or antigen- binding antibody fragments, and methods of using these antibodies and antigen-binding antibody fragments to treat TDP-43 related diseases, including Amyotrophic Lateral Sclerosis (ALS).
  • ALS Amyotrophic Lateral Sclerosis
  • isolated monoclonal antibodies that compete for binding to TDP-43 (e.g., human TDP-43) with: an antibody including a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 24; an antibody including a heavy chain variable domain of SEQ ID NO: 63 and a light chain variable domain of SEQ ID NO: 65; an antibody including a heavy chain variable domain of SEQ ID NO: 67 and a light chain variable domain of SEQ ID NO: 69; an antibody including a heavy chain variable domain of SEQ ID NO: 71 and a light chain variable domain of SEQ ID NO: 73; an antibody including a heavy chain variable domain of SEQ ID NO: 75 and a light chain variable domain of SEQ ID NO: 77; or an antibody including a heavy chain variable domain of SEQ ID NO: 79 and a light chain variable domain of SEQ ID NO: 81.
  • TDP-43 e.g., human TDP-43
  • the antibodies bind to the same epitope on TDP-43 (e.g., human TDP-43) as an antibody including a heavy chain variable domain of SEQ ID NO: 1 and a light Attorney Docket Ref. No.: 50887-0006WO1 // Client Ref: 792-PCT chain variable domain of SEQ ID NO: 24; an antibody including a heavy chain variable domain of SEQ ID NO: 63 and a light chain variable domain of SEQ ID NO: 65; an antibody including a heavy chain variable domain of SEQ ID NO: 67 and a light chain variable domain of SEQ ID NO: 69; an antibody including a heavy chain variable domain of SEQ ID NO: 71 and a light chain variable domain of SEQ ID NO: 73; an antibody including a heavy chain variable domain of SEQ ID NO: 75 and a light chain variable domain of SEQ ID NO: 77; or an antibody including a heavy chain variable domain of SEQ ID NO: 79 and a light chain variable domain of SEQ ID NO: 81.
  • antibodies that specifically bind to TDP-43 including three light chain CDRs and three heavy chain CDRs of a mouse antibody characterized by a heavy chain variable domain including SEQ ID NO: 1 and a light chain variable domain including SEQ ID NO: 24.
  • the antibody is a humanized antibody, a chimeric antibody, or a veneered antibody.
  • the CDRs are of a definition selected from the group of Kabat, Chothia, Kabat/Chothia Composite, AbM, and Contact.
  • the antibody includes a humanized mature heavy variable domain including: a heavy chain CDR1 as defined by Kabat/Chothia Composite, including SEQ ID NO: 49; a heavy chain CDR2 as defined by Kabat, including SEQ ID NO: 51; and a heavy chain CDR3 as defined by Kabat or Chothia, including SEQ ID NO: 52; and a humanized mature light chain variable domain including the three Kabat light chain CDRs of SEQ ID NOs: 53-55.
  • the humanized mature heavy variable domain includes a sequence that is at least 80% identical to any one of SEQ ID NOs: 4-23 and the humanized mature light chain variable domain includes a sequence that is at least 80% identical to any one of SEQ ID NOs: 27-48.
  • the humanized mature heavy variable domain includes a sequence that is at least 85% to any one of SEQ ID NOs: 4-23 and the humanized mature light chain variable region includes a sequence that is at least 85% identical to any one of SEQ ID NOs: 27-48. In some embodiments, the humanized mature heavy variable domain includes a sequence that is at least 90% identical, to any one of SEQ ID NOs: 4-23 and the humanized mature light chain variable region includes a sequence that is at least 90% identical, to any one of SEQ ID NOs: 27-48. In some embodiments, the humanized mature heavy variable domain Attorney Docket Ref.
  • At least one of the following positions in the humanized heavy chain variable domain is occupied by the amino acid as specified: K19 is occupied by R; S35 is occupied by G; T40 is occupied by A; E42 is occupied by G; A49 is occupied by S; K43 is occupied by E; R44 is occupied by G or D; A49 is occupied by S; A74 is occupied by S; T77 is occupied by S; L78 is occupied by A or G; L80 is occupied by A or G; L82c is occupied by G; M83 is occupied by R; S84 is occupied by A; M89 is occupied by V; or F91 is occupied by Y.
  • At least one of the following positions in the humanized heavy chain variable domain is occupied by the amino acid as specified: K43 is occupied by E; R44 is occupied by G or D; A49 is occupied by S; A74 is occupied by S; T77 is occupied by S; or F91 is occupied by Y. In some embodiments, at least one of the following positions in the humanized heavy chain variable domain is occupied by the amino acid as specified: S35 is occupied by G; L78 is occupied by A or G; L80 is occupied by A or G; or L82c is occupied by G.
  • F91 of the humanized heavy chain variable domain is occupied by Y; and at least one of the following positions in the humanized heavy chain variable domain is occupied by the amino acid as specified: R44 is occupied by G; A49 is occupied by S; A74 is occupied by S; T77 is occupied by S; L78 is occupied by A or G; or M83 is occupied by R.
  • At least one of the following positions in the humanized light chain variable domain is occupied by the amino acid as specified: V3 is occupied by Q; L9 is occupied by S; D17 is occupied by Q; Q18 is occupied by P; K39 is occupied by R; K45 is occupied by R; T80 is occupied by A or S; L83 is occupied by V; L92 is occupied by G or A; V94 is occupied by I or A; A100 is occupied by G, D, or R; or L104 is occupied by V. In some embodiments, at least one of the following positions in the humanized light chain variable domain is occupied by the amino acid as specified: V3 is occupied by Q or A100 is occupied by D or R.
  • At least one of the following positions in the humanized light chain variable domain is occupied by the amino acid as specified: L9 is occupied by S; T80 is occupied by A or S; L92 is occupied by G or A; or V94 is occupied by I or A.
  • V3 is occupied by Q; Q18 is occupied by P; A100 is occupied by D; and at least one of the following positions in the humanized light chain variable domain is occupied by the amino acid as specified: T80 is occupied by A or L92 is occupied by A.
  • At least one of the following positions in the humanized heavy chain variable domain is occupied by the amino acid as specified: L5 is occupied by V; G44 is occupied by R; A49 is occupied by S; A74 is occupied by S; T77 is occupied by S; L78 is occupied by A or G; M89 is occupied by V, or F91 is occupied by Y; and at least one of the following positions in the humanized light chain variable domain is occupied by the amino acid as specified: V3 is occupied by Q; D17 is occupied by Q; Q18 is occupied by P; K39 is occupied by R; K45 is occupied by R; T80 is occupied by A; L83 is occupied by V; L92 is occupied by A; A100 is occupied by D; or L104 is occupied by V.
  • the humanized antibody has increased thermal stability as compared to a reference antibody including a heavy chain variable domain including SEQ ID NO: 1 and a light chain variable domain including SEQ ID NO: 24. In some embodiments, the humanized antibody has a melting temperature of 55°C or greater.
  • antibodies that specifically binds to TDP-43 including a heavy chain variable domain including: a heavy chain CDR1, as defined by Kabat/Chothia Composite, including SEQ ID NO: 49 or SEQ ID NO: 50; a heavy chain CDR2, as defined by Kabat, including SEQ ID NO: 51; a heavy chain CDR3, as defined by Kabat or Chothia, including SEQ ID NO: 52; a light chain CDR1, as defined by Kabat, including SEQ ID NO: 53; a light chain CDR2, as defined by Kabat, including SEQ ID NO: 54; and a light chain CDR3, as defined by Kabat, including one of SEQ ID NOs: 55-61.
  • the heavy chain CDR1, as defined by Kabat/Chothia Composite includes SEQ ID NO: 49; the heavy chain CDR2, as defined by Kabat, includes SEQ ID NO: 51; the heavy chain CDR3, as defined by Kabat or Chothia, includes SEQ ID NO: 52; the light chain CDR1, as defined by Kabat, includes SEQ ID NO: 53; the light chain CDR2, as defined by Kabat, includes SEQ ID NO: 54; and the light chain CDR3, as defined by Kabat, includes SEQ ID NO: 55 or SEQ ID NO: 61.
  • the heavy chain variable domain includes a sequence that is at least 95% identical to any one of SEQ ID NOs: 4-23.
  • the light chain variable domain includes a sequence that is at least 95% identical to any one of: SEQ ID NOs: 27-48. In some embodiments, the light chain variable domain includes a sequence that is at least 95% identical to SEQ ID NO: 47 or SEQ ID NO: 48. In some embodiments, the light chain variable domain includes a sequence that is at least 98% identical to SEQ ID NO: 47 or SEQ ID NO: 48. In some embodiments, the light chain variable domain includes SEQ ID NO: 47. In some embodiments, the light chain variable domain includes SEQ ID NO: 48.
  • antibodies that specifically binds to TDP-43 including a heavy chain variable domain and a light chain variable domain including: a heavy chain CDR1 including SEQ ID NO: 84; a heavy chain CDR2 including SEQ ID NO: 85; a heavy chain CDR3 including SEQ ID NO: 86; a light chain CDR1 including SEQ ID NO: 87; a light chain CDR2 including SEQ ID NO: 88; and a light chain CDR3 including SEQ ID NO: 89.
  • the heavy chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 63.
  • the heavy chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 63.
  • the heavy chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 67. In some embodiments, the heavy chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 67. In some embodiments, the heavy chain variable domain comprises a sequence of SEQ ID NO: 67. In some embodiments, the light chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 69.
  • the light chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 69. In some embodiments, the light chain variable domain comprises a sequence of SEQ ID NO: 69. Also provided herein are antibodies that specifically binds to TDP-43 including a heavy chain variable domain and a light chain variable domain including: a heavy chain CDR1 including SEQ ID NO: 96; a heavy chain CDR2 including SEQ ID NO: 97; a heavy chain CDR3 including SEQ ID NO: 98; a light chain CDR1 including SEQ ID NO: 99; a light chain CDR2 including SEQ ID NO: 100; and a light chain CDR3 including SEQ ID NO: 101.
  • the heavy chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 71. In some embodiments, the heavy chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 71. In some embodiments, the heavy chain variable domain comprises a sequence of SEQ ID NO: 71. In some embodiments, the light chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 73. In some embodiments, the light chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 73. In some embodiments, the light chain variable domain comprises a sequence of SEQ ID NO: 73.
  • antibodies that specifically binds to TDP-43 including a heavy chain variable domain and a light chain variable domain including: a heavy chain CDR1 including SEQ ID NO: 102; a heavy chain CDR2 including SEQ ID NO: 103; a heavy chain CDR3 including SEQ ID NO: 104; a light chain CDR1 including SEQ ID NO: 105; a light chain CDR2 including SEQ ID NO: 106; and a light chain CDR3 including SEQ ID NO: 107.
  • the heavy chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 75.
  • the heavy chain variable domain Attorney Docket Ref.
  • No.: 50887-0006WO1 // Client Ref: 792-PCT comprises a sequence that is at least 98% identical to SEQ ID NO: 75.
  • the heavy chain variable domain comprises a sequence of SEQ ID NO: 75.
  • the light chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 77.
  • the light chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 77.
  • the light chain variable domain comprises a sequence of SEQ ID NO: 77.
  • the antibody is an intact antibody. In some embodiments, the antibody has a human IgG1 isotype. In some embodiments, the heavy chain variable domain is fused to a heavy chain constant region and the light chain variable domain is fused to a light chain constant region. In some embodiments, the heavy chain constant region is a mutant form of a natural human heavy chain constant region which has reduced binding to an Fc ⁇ receptor relative to the natural heavy chain constant region. In some embodiments, the heavy chain constant region is of IgG1 isotype. In some embodiments, the antibody has at least one mutation in a constant region. Attorney Docket Ref.
  • the at least one mutation reduces complement fixation or activation by the constant region.
  • the at least one mutation is at one or more positions of: 241, 264, 265, 270, 296, 297, 318, 320, 322, 329, and 331 by EU numbering.
  • the antibody has an alanine at positions 318, 320, and 322 by EU numbering.
  • the antibody selectively binds to phosphorylated TDP-43 (e.g., phosphorylated human TDP-43).
  • the antibody binds to phosphorylated TDP-43 (e.g., phosphorylated human TDP-43) with at least 1000-fold greater affinity as compared to unphosphorylated TDP-43 (e.g., unphosphorylated human TDP-43).
  • phosphorylated TDP-43 e.g., phosphorylated human TDP-43 includes phosphorylation of at least one amino acid residue selected from S409 and S410.
  • phosphorylated TDP-43 e.g., phosphorylated human TDP-43) includes phosphorylation of both S409 and S410.
  • the antibody selectively binds to cytoplasmic aggregates of TDP- 43 (e.g., cytoplasmic aggregates of human TDP-43). In some embodiments, the antibody selectively binds to cytoplasmic aggregates of TDP-43 (e.g., cytoplasmic aggregates of human TDP-43) compared to nuclear TDP-43 (e.g., nuclear human TDP-43). In some embodiments, the cytoplasmic aggregates of TDP-43 include phosphorylated aggregates of TDP-43 (e.g., phosphorylated aggregates of human TDP-43). In some embodiments, the antibody does not substantially bind unphosphorylated TDP-43 (e.g., unphosphorylated human TDP-43).
  • the antibody is conjugated to a therapeutic, cytotoxic, cytostatic, immunomodulatory, neurotrophic, or neuroprotective agent.
  • pharmaceutical compositions including any of the antibodies described herein and a pharmaceutically acceptable carrier.
  • nucleic acids encoding the heavy chain variable domain and/or the light chain variable domain of any of the antibodies described herein.
  • vectors including a nucleic acid encoding a mature heavy chain variable domain and a light chain variable domain operably linked to one or more regulatory sequences to effect expression in a mammalian cell of any one of the antibodies described herein.
  • the one or more regulatory sequences include one or more of a enhancer, ribosome binding site, transcription termination signal, and promoter, optionally, where the promoter is a eukaryotic promoter.
  • the nucleic acid is codon- optimized for expression in a host cell. Also provided herein are host cells transformed with any of the vectors described herein. Also provided herein are host cells including any of the nucleic acids described herein.
  • the TDP-43-related disease is amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD-TDP), primary lateral sclerosis, and progressive muscular atrophy, and Parkinson’s disease.
  • the TDP-43-related disease is ALS.
  • Also provided herein are methods of detecting TDP-43 deposits (e.g., human TDP-43 deposits) in a subject having or at risk of developing a TDP-43-related disease, including administering to a subject any of the antibodies described herein, and detecting the antibody bound to TDP-43 in the subject.
  • the antibody is administered by intravenous injection into the body of the subject.
  • the antibody is labeled.
  • the antibody is labeled with a fluorescent label, a paramagnetic label, or a radioactive label.
  • the radioactive label is detected using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • Figure 5 is a graph showing binding data of a humanized version of 13D3 antibody, hu13D2Hd5Ld2, to phosphorylated human TDP-43 peptide.
  • Figures 6A-C show immunohistochemical images of frontotemporal dementia (“FTD”) brain tissue (Figs. 6A and 6B) and healthy brain tissue (Fig. 6C) stained with the 13D3 antibody.
  • Fig. 6B is an inset of Fig. 6A showing co-localization of 13D3 antibody with phosphorylated human TDP-43 FTD-associated neuronal cytoplasmic aggregates.
  • FTD frontotemporal dementia
  • isolated monoclonal antibody that competes for binding to TDP-43 (e.g., human TDP-43) with: an antibody comprising a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 24; an antibody comprising a heavy chain variable domain of SEQ ID NO: 63 and a light chain variable domain of SEQ ID NO: 65; an antibody comprising a heavy chain variable domain of SEQ ID NO: 67 and a light chain variable domain of SEQ ID NO: 69; an antibody comprising a heavy chain variable domain of SEQ ID NO: 71 and a light chain variable domain of SEQ ID NO: 73; an antibody comprising a heavy chain variable domain of SEQ ID NO: 75 and a light chain variable domain of SEQ ID NO: 77; or an antibody comprising a heavy chain variable domain of SEQ ID NO: 79 and a light chain variable domain of SEQ ID NO: 81.
  • TDP-43 e.g., human TDP-43
  • epitope refers to a site on an antigen to which an antibody binds.
  • An epitope can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of one or more proteins. Epitopes formed from contiguous amino acids (also known as linear epitopes) are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding (also known as conformational epitopes) are typically lost on treatment with denaturing solvents.
  • the epitope of an antibody can also be defined X-ray crystallography of the antibody bound to its antigen to identify contact residues.
  • two antibodies have the same epitope if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.
  • Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.
  • humanized immunoglobulin or “humanized antibody” refers to an immunoglobulin or antibody that includes at least one humanized immunoglobulin or antibody chain (i.e., at least one humanized light or heavy chain).
  • humanized immunoglobulin chain or “humanized antibody chain” refers to an immunoglobulin or antibody chain (i.e., a light or heavy chain, respectively) having a variable region that includes a variable framework region substantially from a human immunoglobulin or antibody and complementarity determining regions (CDRs) (e.g., at least one CDR, preferably two CDRs, more preferably three CDRs) substantially from a non-human immunoglobulin or antibody, and further includes constant regions (e.g., at least one constant region or portion thereof, in the case of a light chain, and preferably three constant regions in the case of a heavy chain).
  • CDRs complementarity determining regions
  • humanized variable region refers to a variable region that includes a variable framework region substantially from a human immunoglobulin or antibody and complementarity determining regions (CDRs) substantially from a non-human immunoglobulin or antibody.
  • CDRs complementarity determining regions
  • test antibody competes with a reference antibody if an excess of a test antibody (e.g., at least 2x, 5x, l0x, 20x or l00x) inhibits binding of the reference Attorney Docket Ref. No.: 50887-0006WO1 // Client Ref: 792-PCT antibody by at least 50% as measured in a competitive binding assay.
  • Some test antibodies inhibit binding of the reference antibody by at least 75%, 90% or 99%.
  • Antibodies identified by competition assay include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur.
  • TDP-43-related disease means a disease or disorder that is characterized and/or mediated at least in part, either directly or indirectly, by formation of TDP-43 aggregates and/or mislocalization of TDP-43.
  • Non-limiting examples of TDP-43-related diseases are described herein.
  • patient includes human and other mammalian subjects (e.g., human) that receive either prophylactic or therapeutic treatment.
  • biological sample refers to a sample of biological material within or obtainable from a biological source, for example a human or mammalian subject. Such samples can be organs, organelles, tissues, sections of tissues, bodily fluids, peripheral blood, blood plasma, blood serum, cells, molecules such as proteins and peptides, and any parts or combinations derived therefrom.
  • biological sample can also encompass any material derived by processing the sample. Derived material can include cells or their progeny.
  • control sample refers to a biological sample not known or suspected to include TDP-43 affected regions, or at least not known or suspect to include diseased regions of a given type. Control samples can be obtained from individuals not afflicted with the TDP-43- related disease. Alternatively, control samples can be obtained from patients afflicted with the TDP-43-related disease. Such samples can be obtained at the same time as a biological sample Attorney Docket Ref. No.: 50887-0006WO1 // Client Ref: 792-PCT thought to comprise the TDP-43-related disease or on a different occasion.
  • a biological sample and a control sample can both be obtained from the same tissue.
  • control samples consist essentially or entirely of normal, healthy regions and can be used in comparison to a biological sample thought to comprise TDP-43-related disease-affected regions.
  • the tissue in the control sample is the same type as the tissue in the biological sample.
  • the TDP-43-related disease-affected cells thought to be in the biological sample arise from the same cell type (e.g., neurons or glia) as the type of cells in the control sample.
  • amino acids are grouped as follows: Group I (hydrophobic side chains): Met, Ala, Val, Leu, Ile; Group II (neutral hydrophilic side chains): Cys, Ser, Thr; Group III (acidic side chains): Asp, Glu; Group IV (basic side chains): Asn, Gln, His, Lys, Arg; Group V (residues influencing chain orientation): Gly, Pro; and Group VI (aromatic side chains): Trp, Tyr, Phe. Conservative substitutions involve substitutions between amino acids in the same class. Non-conservative substitutions constitute exchanging a member of one of these classes for a member of another.
  • Percentage sequence identities are determined with antibody sequences maximally aligned by the Kabat numbering convention. After alignment, if a subject antibody region (e.g., the entire mature variable region of a heavy or light chain) is being compared with the same region of a reference antibody, the percentage sequence identity between the subject and reference antibody regions is the number of positions occupied by the same amino acid in both the subject and reference antibody region divided by the total number of aligned positions of the two regions, with gaps not counted, multiplied by 100 to convert to percentage. Unless otherwise apparent from the context, the term “about” encompasses insubstantial variations, such as values within a standard margin of error of measurement (e.g., SEM) of a stated value.
  • SEM standard margin of error of measurement
  • substantially from a human immunoglobulin or antibody means that, when aligned to a human immunoglobulin or antibody amino sequence for comparison purposes, the region shares at least 80-90%, preferably 90-95%, more preferably 95-99% identity (i.e., local sequence identity) with the human framework or constant region sequence, allowing, for example, for conservative substitutions, consensus sequence substitutions, germline substitutions, backmutations, and the like.
  • conservative substitutions, consensus sequence substitutions, germline substitutions, backmutations, and the like is often Attorney Docket Ref. No.: 50887-0006WO1 // Client Ref: 792-PCT referred to as “optimization” of a humanized antibody or chain.
  • substantially from a non-human immunoglobulin or antibody or “substantially non-human” means having an immunoglobulin or antibody sequence at least 80-95%, preferably 90-95%, more preferably, 96%, 97%, 98%, or 99% identical to that of a non-human organism, e.g., a non-human mammal. Accordingly, all regions or residues of a humanized immunoglobulin or antibody, or of a humanized immunoglobulin or antibody chain, except possibly the CDRs, are substantially identical to the corresponding regions or residues of one or more native human immunoglobulin sequences.
  • TDP-43 As described herein TDP-43 is a predominantly nuclear protein that is involved in RNA splicing, trafficking, stabilization, and ultimately regulation of gene expression. More specifically, TDP-43 is a multi-domain heterogeneous ribonucleoprotein (hnRNP). Proper function of TDP-43 is essential for the regulation of hundreds of mRNA transcripts to which it binds.
  • TDP-43 One of TDP-43’s primary functions is the regulation of splicing mRNA transcripts; however, TDP-43 is also involved in different mechanisms of RNA processing and transport.
  • TDP-43 is an inhibitor of cryptic exon inclusion and regulates the alternative polyadenylation of >1,000 genes.
  • TDP-43 can form ribonucleoprotein granules in different cell types, including Cajal bodies and paraspeckles in the nucleus and is recruited to mRNA transport granules in neurons.
  • Various neurodegenerative diseases are associated with cytoplasmic aggregates of TDP-43 (e.g., TDP-43-related diseases) as described herein.
  • TDP-43 means a natural human form of TDP-43, including any isoforms and/or post-translational modifications (e.g., phosphorylation, glycosylation, and/or acetylation).
  • TDP-43 The amino acid sequence of human TDP-43 is shown below (SEQ ID NO: 82): MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGI LHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSDLIVLGLPWKTT EQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWC DCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDELREFFSQYGDVMDVFIPKPFRAFAFV Attorney Docket Ref.
  • TDP-43 can be phosphorylated at one or more positions including 373, 375, 379, 387, 389, 393, 395, 403, 404, 407, 409, and 410 (See, e.g., Gruijs da Silva, L.A., et al., Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation, The EMBO Journal, 41: e108443 (2022)).
  • reference to TDP-43, or its fragments includes the natural human amino acid sequences including isoforms, mutants, and allelic variants thereof.
  • an antibody or antigen-binding antibody fragment to bind to TDP-43 can be determined using, e.g., surface plasmon resonance.
  • the present disclosure provides antibodies or antigen-binding antibody fragments that specifically bind to TDP-43 (e.g., human TDP-43).
  • the antibodies or antigen-binding antibody fragments described herein specifically bind to phosphorylated TDP-43 (e.g., phosphorylated human TDP-43).
  • the antibodies or antigen-binding antibody fragments described herein specifically bind phosphorylated TDP-43 (e.g., phosphorylated human TDP-43) where one or both of serine at position 409 and/or 410 of SEQ ID NO: 82 is phosphorylated.
  • the antibodies or antigen-binding antibody fragments bind a 23 amino acid peptide (“TDP-43 (pS409/pS410)”) comprising amino acids from position 392 to position 414 of SEQ ID NO: 82 and where the serines at positions 409 and 410 are phosphorylated.
  • TDP-43 e.g., human TDP-43
  • an antibody including a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 24 an antibody including a heavy chain variable domain of SEQ ID NO: 63 and a light chain variable domain of SEQ ID NO: 65
  • an antibody including a heavy chain variable domain of SEQ ID NO: 67 and a light chain variable domain of SEQ ID NO: 69 an antibody including a Attorney Docket Ref.
  • No.: 50887-0006WO1 // Client Ref: 792-PCT heavy chain variable domain of SEQ ID NO: 71 and a light chain variable domain of SEQ ID NO: 73; an antibody including a heavy chain variable domain of SEQ ID NO: 75 and a light chain variable domain of SEQ ID NO: 77; or an antibody including a heavy chain variable domain of SEQ ID NO: 79 and a light chain variable domain of SEQ ID NO: 81.
  • the antibodies bind to the same epitope on TDP-43 (e.g., human TDP-43) as an antibody including a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 24; an antibody including a heavy chain variable domain of SEQ ID NO: 63 and a light chain variable domain of SEQ ID NO: 65; an antibody including a heavy chain variable domain of SEQ ID NO: 67 and a light chain variable domain of SEQ ID NO: 69; an antibody including a heavy chain variable domain of SEQ ID NO: 71 and a light chain variable domain of SEQ ID NO: 73; an antibody including a heavy chain variable domain of SEQ ID NO: 75 and a light chain variable domain of SEQ ID NO: 77; or an antibody including a heavy chain variable domain of SEQ ID NO: 79 and a light chain variable domain of SEQ ID NO: 81.
  • TDP-43 e.g., human TDP-43
  • antibodies that specifically binds to TDP-43 including a heavy chain variable domain and a light chain variable domain including: a heavy chain CDR1 including SEQ ID NO: 84; a heavy chain CDR2 including SEQ ID NO: 85; a heavy chain CDR3 including SEQ ID NO: 86; a light chain CDR1 including SEQ ID NO: 87; a light chain CDR2 including SEQ ID NO: 88; and a light chain CDR3 including SEQ ID NO: 89.
  • the heavy chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 63.
  • the heavy chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 63.
  • the heavy chain variable domain comprises a sequence of SEQ ID NO: 63. In some embodiments, the light chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 65. In some embodiments, the light chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 65. In some embodiments, the light chain variable domain comprises a sequence of SEQ ID NO: 65. Also provided herein are antibodies that specifically binds to TDP-43 including a heavy chain variable domain and a light chain variable domain including: a heavy chain CDR1 including SEQ ID NO: 90; a heavy chain CDR2 including SEQ ID NO: 91; a heavy chain CDR3 Attorney Docket Ref.
  • the heavy chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 67. In some embodiments, the heavy chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 68. In some embodiments, the heavy chain variable domain comprises a sequence of SEQ ID NO: 67. In some embodiments, the light chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 69.
  • the light chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 69. In some embodiments, the light chain variable domain comprises a sequence of SEQ ID NO: 69. Also provided herein are antibodies that specifically binds to TDP-43 including a heavy chain variable domain and a light chain variable domain including: a heavy chain CDR1 including SEQ ID NO: 96; a heavy chain CDR2 including SEQ ID NO: 97; a heavy chain CDR3 including SEQ ID NO: 98; a light chain CDR1 including SEQ ID NO: 99; a light chain CDR2 including SEQ ID NO: 100; and a light chain CDR3 including SEQ ID NO: 101.
  • the heavy chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 71. In some embodiments, the heavy chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 71. In some embodiments, the heavy chain variable domain comprises a sequence of SEQ ID NO: 71. In some embodiments, the light chain variable domain comprises a sequence that is at least 95% identical to SEQ ID NO: 73. In some embodiments, the light chain variable domain comprises a sequence that is at least 98% identical to SEQ ID NO: 73. In some embodiments, the light chain variable domain comprises a sequence of SEQ ID NO: 73.
  • kits comprising any of the antibodies or antigen-binding antibody fragments thereof disclosed herein and related materials, such as instructions for use (e.g., package insert).
  • 5BK5 antibody is a human germline derived antibody and has the same canonical classes belonging to human germline IGHV3-48’03 (SEQ ID NO: 2) for the variable heavy chain domain and IGKV2-30*02 (SEQ ID NO: 25) for the variable light chain domain these sequences were used as a human acceptor framework. Accordingly, the framework regions of 5BK5 VH and 5BK5 VL were chosen as the acceptor sequences for the CDRs of 13D3. A model of the 13D3 CDRs grafted onto the respective human frameworks for VH and VL was built and used as guidance for further backmutations to increase binding specificity and reduce immunogenicity. Attorney Docket Ref.
  • hu13D3VH and hu13D3VL were designed to enable assessment of various framework residues for their contributions to antigen binding, thermostability, developability (e.g., deamination, oxidation, N-glycosylation, proteolysis, and aggregation) and immunogenicity.
  • the positions considered for substitution were based on a variety of factors including: positions that define the canonical CDR conformations (See, Martin, A.C.R., Protein sequence and structure analysis of antibody variable domains, In: Kontermann R and Dübel S (eds). Antibody Engineering.
  • Leucine at position 78 is immunogenic as indicated by Immune Epitope Database (“IEDB”) Analysis. Therefore, deimmunization analysis predicts immunogenicity reduction with an alanine substitution at position 78.
  • hu13D3VHv3d (SEQ ID NO: 22) includes the following substitutions: G44R, S49A, and S74A.
  • Arginine at position 44 makes de novo contacts with a G100D (glycine to aspartic acid) substitution made in the variable light chain domain thereby strengthening the heavy chain variable domain: light chain variable domain interface. Specifically, arginine at position 44 forms a hydrogen bond and a salt bridge with G100D and also forms a hydrogen bond with F98 in the variable light chain domain.
  • hu13D3VLv1d (SEQ ID NO: 47) consists of the CDR-L1, CDR- L2, and CDR-L3 loops of 13D3VL grafted onto the framework of 5BK5 VL along with reverting all framework substitutions at positions that are key for defining the Chothia canonical classes, are part of the Vernier zone, and locate to the VH/VL domain interface.
  • Hu1353VLv1d includes the following substitutions: V3Q, P15L, E17Q, L38Q, K39R, Q100D, and L104V.
  • Substitution of valine for glutamine at position 3 reduces immunogenicity of the light chain variable domain.
  • Substitution of leucine for proline at position 15 is a germline substitution.
  • Substitution of glutamine for glutamic acid at position 17 is a rare substitution.
  • Position 17 has significant surface exposure thereby contributing to a negative charge patch at the protein surface.
  • Substitution to glutamine reduces antibody surface negative patches.
  • Substitution of glutamine for leucine at position 38 was made since glutamine in mouse structural models forms inter-strand contacts within the light chain variable domain to maintain structural conformation. In contrast, a leucine reside cannot form the same contacts and therefore this back mutation increases conformational stability.
  • Substitution of arginine for lysine at position 39 increases conformation stability by forming additional contacts with adjacent residues that a lysine residue cannot.
  • Position 100 in the light chain variable domain is a located at the heavy chain variable domain and light chain variable domain interface, however, no interchain contacts are formed with the glutamine residue.
  • Substitution to aspartic acid along with a concurrent substitution of arginine at position 44 in the heavy chain variable domain results in stronger do novo contacts and therefore increases thermal stability of the antibody.
  • Substitution of valine for leucine position 104 is predicted to reduce immunogenicity.
  • hu13D3VLv2d (SEQ ID NO: 48) consists of the aforementioned substitutions described above in hu13D3VLv1d, but also includes the following substitution: L92A.
  • Leucine at position 92 is predicted to be immunogenic, therefore, substitution with alanine at position 92 reduces the immunogenicity of the variable light chain domain.
  • Table 1 and Table 2 below show 13D3 variable heavy chain domain sequence alignment and variable light chain domain sequence alignment, respectively, compared to humanized versions.
  • Attorney Docket Ref. No.: 50887-0006WO1 // Client Ref: 792-PCT Table 1.
  • This kappa light chain has the same canonical classes for CDR-L1 & L2 and belongs to human germline IGKV2-30*02 (SEQ ID NO: 25) according to IMGT convention.
  • human Ig heavy chain AEX28899 SEQ ID Attorney Docket Ref. No.: 50887-0006WO1 // Client Ref: 792-PCT NO: 3
  • GenBank: AEX28899 Bowers et al., 2014
  • AEX28899 and ABC66863 antibodies are human germline derived antibodies that have the same canonical classes and belong to human germline IGHV3-48’03 (SEQ ID NO: 2) for the heavy chain variable domain and IGHV3-48*03 (SEQ ID NO: 25) for the light chain variable domain. Therefore, the AEX28899 heavy chain variable domain and ABC66863 light chain variable domain sequences were used as human acceptor framework for the CDRs of 13D3. A model of the 13D3 CDRs grafted onto the respective human frameworks for VH and VL was built and used as a guidance for further backmutations.
  • Humanized versions of AEX28899 heavy chain variable domain and ABC66863 light chain variable domain sequences were used as human acceptor framework for the CDRs of 13D3 and were designed to enable assessment of various framework residues for their contributions to antigen binding, thermostability, developability (e.g., deamination, oxidation, N-glycosylation, proteolysis, and aggregation) and immunogenicity.
  • the positions considered for substitution were based on a variety of factors including: positions that define the canonical CDR conformations (See, Martin, A.C.R., Protein sequence and structure analysis of antibody variable domains, In: Kontermann R and Dübel S (eds). Antibody Engineering.
  • VL domain substitutions in SEQ ID NO: 26 I2V is a Vernier zone residue, valine is retained to preserve CDR conformation; L9S: leucine is predicted to be immunogenic, substitution with serine lowers predicted immunogenicity; P18Q: mouse antibody model glutamine forms a H-bond with K74 (LC) thereby stabilizing interchain interaction; R46L: is an interface and Vernier zone residue and therefore Leu is retained; A80S: serine lowers predicted immunogenicity; L92G: L92 is a CDR residue and is predicted to be immunogenic, a glycine residue is predicted to reduce immunogenicity; V94I: valine at position 94 is predicted to be low level immunogenic, isoleucine is predicted to reduce immunogenicity; and V94A: alanine is an alternative substitution that is predicted to lower immunogenicity.
  • cytoplasmic aggregates of TDP-43 are found in many neurodegenerative diseases and in particular, ALS.
  • the individual TDP-43 proteins found in the cytoplasmic aggregates are phosphorylated at serine residues at position 409 and/or 410.
  • a binding screening assay was established to determine whether 13D3 and humanized variants thereof would selectively bind to phosphorylated TDP-43 found in cytoplasmic aggregates.
  • About 50 RU of biotin-phosphoTDP43 proteins were immobilized on a CM3 chip with NeutrAvidin.
  • TDP-43 peptide (pS409/pS410) 23 amino acid TDP-43 peptide phosphorylated at positions 409 and 410
  • SEQ ID NO: 83 23 amino acid TDP-43 peptide that was not phosphorylated at positions 409 or 410 was also tested between 12 nM and 1 ⁇ M.
  • humanized version hu13D3H5L2 demonstrated 1:1 binding with TDP-43 peptide (pS409/pS410) at various concentrations (1.2345 nM; 3.703 nM; 11.111 nM; 33.33 nM; and 100 nM) which was similar to the 13D3 murine antibody (Figure 5). Furthermore, hu13D3H5L2 showed no affinity for the non-phosphorylated 22 amino acid TDP-43 peptide at 12.345 nM, 37.03 nM, 111.111 nM, 333.333 nM, and 1 ⁇ M (data not shown). Thermal stability of the antibodies was also assessed.
  • Thermal stability analysis was performed with Different Scanning Calorimetry which characterizes the stability of a protein or other biomolecule (e.g., an antibody or antigen-binding fragment thereof).
  • Antibodies were tested 2.66 mM (0.4 mg/mL) in 1xPBS at pH 7.4. Temperature range tested was from 25°C to 100°C.
  • Binding data for chimeric 13D3 and humanized versions thereof is summarized in Tables 3 and 4. Tables 3 and 4 also summarize thermal stability data and immunogenecity data.
  • the immunogenicity prediction method used is based on predicted potential binding of a peptide within a protein sequence to major histocompatibility class (MHC) class II.
  • MHC major histocompatibility class
  • the program identifies potential immunogenic regions within the protein sequence.
  • the MHC class II tool predicts immunogenic regions using broad spectrum alleles (i.e., 26 reference alleles) for MHC class II in the human population.
  • the software generates a series of 15 residue peptides which overlap in 10 residues. Each generated 15 residue peptide is predicted for binding to the 26 reference alleles.
  • a percentile rank for each of the three methods was generated by comparing each peptide's score against the scores of five million random 15 residue peptides selected from the SWISSPROT database.
  • the adjusted percentile rank is the percentile rank adjusted based on the frequency of peptide lengths. A low number percentile rank indicates high affinity.
  • the median percentile rank of the three methods were then used to generate the rank for consensus method. By default, prediction result is collapsed to show only the Percentile Rank and Adjusted Rank.
  • the maximum median percentile rank threshold is set at 20.
  • the EpiQuest tool ranges cytotoxic T lymphocyte (CTL) epitopes according to their predicted immunodominance.
  • the immunodominance of epitopes is defined as their relative strength in functional assays related to the target kill or release of respective cytokines. These parameters indicate functionality of the T-epitope.
  • This program is designed to analyze and sort according to their immunodominance the CTL peptide epitopes eluted from target cells. Generally, only a low number of peptide epitopes that bind to MHC class I have actual functional activity.
  • Relative strength of a CTL (T) epitope is defined by the strength of its binding to MHC class I and T cell receptor (TCR) (in the context of MHCI).
  • FIG. 6B is an inset of Fig. 6A showing co-localization of 13D3 antibody with phosphorylated TDP-43 FTD-associated neuronal cytoplasmic aggregates.
  • the data demonstrate that 13D3 antibody specifically binds to cytoplasmic aggregates in FTD brain tissue, but not in healthy brain tissue.
  • each of Figures 7A-C show 13D3 specifically binding cytoplasmic aggregates in a rNLS8 dox-suppressible model of TDP-43 proteinopathy.
  • FIG. 8A shows confocal microscopy images of HEK cells transiently transfected with GFP-2a-TDP43 [mNLS (R82L/K83Q) DCS (C173S/C175S)] or GFP only (2a is a self-cleaving peptide that releases the TDP-43 upon expression).
  • the top panels show staining for GFP, nuclei (grey), and pTDP-43 (white).
  • the bottom panels show only pTDP-43 staining which is not present in the GFP alone control transfection.
  • Figure 8B (left) is a graph showing cell count for HEK cells transfected with either GFP-2a-TDP43 or GFP alone. The data demonstrate approximately equivalent cell counts between the two populations. Further, Figure 8B (right) shows pTDP-43 foci counts for HEK cells transfected with GFP-2a-TDP43 or GFP alone. The data demonstrate TDP-43 foci are formed only in the HEK cells transfected with GFP-2a- TDP43.
  • Figure 8C shows TDP-43 staining with either commercial antibodies or antibodies of the present disclosure including 13D3, 13C13, and 2D4. Cells were treated with antibodies for 24 hours and 24 hours later, cells were incubated again with 100 ug/ml antibodies for another 24 hours.
  • the top row shows transfection with GFP-2a-TDP-43 where the phosphorylated TDP43 does not include a nuclear localization signal (i.e., phosphorylated TDP43 remains in the cytoplasm), and the bottom row shows transfection with a GFP only construct.
  • the data demonstrate that TDP-43 foci are formed only in HEK cell transfected with GFP-2a-TDP-43.
  • Various control antibodies were included in the assay including pTDP-43 (Cosmo)+, pTDP-43 (1D3)+, Total TDP-43 (PT), and 3B12 (ED)+. The control antibodies verify TDP-43 aggregation within the cytoplasm.
  • Antibodies 13D3, 13C13, and 2D4 were similarly tested and demonstrated similar binding to cytoplasmic aggregates of phosphorylated TDP-43.
  • SEQ ID NO: 24 m13D3-VL DVVMTQSPLSLPVSLGDQASISCRSSQSLVHSNGKTYLHWYQQKPGQSPKLLIYKVSDRYSGVSDRFSGSG SGTDFTLKISRVETEDLGVYFCSQSLHVPLTFGAGTKLELK
  • SEQ ID NO: 25 IGKV2-30*02 DVVMTQSPLSLPVTLGQPASISCRSSQSLVHSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGS GTDFTLKISRVEAEDVGVYYCMQGTHWPYTFGQGTKLEIK
  • SEQ ID NO: 26 ABC66863 DIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGS
  • S is position 27A L is position 27B V is position 27C H is position 27D S is position 27E, respectively.
  • SEQ ID NO: 49 HC CDR1 #1 GFTFSNYFMS SEQ ID NO: 50 HC CDR1 #2 GFTFSNYFMG SEQ ID NO: 51 HC CDR2 #1 YISTGGDSANYADNVKG SEQ ID NO: 52 HC CDR3 #1 QTYYSYGGFPY SEQ ID NO: 53 LC CDR1 #1 RSSQSLVHSNGKTYLH SEQ ID NO: 54 LC CDR2 #1 KVSDRYS SEQ ID NO: 55 LC CDR3 #1 SQSLHVPLT SEQ ID NO: 56 LC CDR3 #2 SQSGHVPLT SEQ ID NO: 57 LC CDR3 #3 SQSLHIPLT SEQ ID NO: 58 LC CDR3 #4 SQSLHAPLT SEQ ID NO: 59 LC CDR3 #5 DQSLHVPLT SEQ ID

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Abstract

La présente divulgation concerne des anticorps qui se lient spécifiquement au TDP-43 humain et des procédés d'utilisation de ces anticorps pour traiter des patients atteints de maladies associées à TDP-43, y compris la sclérose latérale amyotrophique (SLA).
PCT/US2024/046651 2023-09-15 2024-09-13 Anticorps anti-tdp-43 et leurs utilisations Pending WO2025059486A1 (fr)

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