Search

US-12625149-B2 - Pathologic TDP-43 as a biomarker for the diagnosis of TDP-43 proteinopathy

US12625149B2US 12625149 B2US12625149 B2US 12625149B2US-12625149-B2

Abstract

Disclosed herein are antibodies or antigen-binding fragments thereof and compositions comprising the same. Also disclosed are methods of detecting TAR DNA-binding protein 43 (TDP-43) in a biological sample, diagnosing a neurodegenerative disease in a subject, and selecting whether to enroll a subject in a clinical trial for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) using the antibodies or antigen-binding fragments thereof described herein. In addition, disclosed herein are immunoassay kits for selectively detecting TDP-43 in a biological sample.

Inventors

  • Qinwen Mao

Assignees

  • UNIVERSITY OF UTAH RESEARCH FOUNDATION

Dates

Publication Date
20260512
Application Date
20220930

Claims (8)

  1. 1 . An antibody or antigen-binding fragment thereof comprising an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein: (a) the immunoglobulin HC variable domain sequence comprises (i) an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 6; and (b) the immunoglobulin LC variable domain sequence comprises (i) an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 8, (ii) an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and (iii) an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 10.
  2. 2 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the immunoglobulin HC variable domain sequence comprises the amino acid sequence of SEQ ID NO: 3; and the immunoglobulin LC variable domain sequence comprises the amino acid sequence of SEQ ID NO: 7.
  3. 3 . An immunoassay kit comprising one or more of the antibodies or antigen-binding fragments thereof of claim 1 .
  4. 4 . An immunoassay kit for selectively detecting TAR DNA-binding protein 43 (TDP-43; SEQ ID NO: 1) in a biological sample, the kit comprising: an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein: (a) the immunoglobulin HC variable domain sequence comprises (i) an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 6; and (b) the immunoglobulin LC variable domain sequence comprises (i) an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 8, (ii) an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and (iii) an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and, a detection reagent.
  5. 5 . The kit of claim 4 , further comprising a solid support for the antibody or antigen-binding fragment thereof.
  6. 6 . The kit of claim 4 , wherein the detection reagent is one or more of colorimetric substrates, chemiluminescent substrates, and fluorescent substrates.
  7. 7 . The kit of claim 4 , further comprising a second antibody or antigen-binding fragment thereof, wherein the second antibody or antigen-binding fragment comprises an immunoglobulin HC variable domain sequence and an immunoglobulin LC variable domain sequence, wherein: (a) the immunoglobulin HC variable domain sequence comprises (i) an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 12, (ii) an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and (iii) an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and (b) the immunoglobulin LC variable domain sequence comprises (i) an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 16, (ii) an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (iii) an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 18.
  8. 8 . The kit of claim 4 , further comprising a second antibody or antigen-binding fragment thereof, wherein the second antibody or antigen-binding fragment comprises an immunoglobulin HC variable domain sequence and an immunoglobulin LC variable domain sequence, wherein: (a) the immunoglobulin HC variable domain sequence comprises (i) an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 20, (ii) an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and (iii) an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 22; and (b) the immunoglobulin LC variable domain sequence comprises (i) an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 24, (ii) an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and (iii) an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 26.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63/251,383, filed Oct. 1, 2021, and U.S. Provisional Patent Application No. 63/252,353 filed Oct. 5, 2021, which are incorporated herein by reference in their entireties. REFERENCE TO SEQUENCE LISTING This application was filed with a Sequence Listing XML in ST.26 XML format in accordance with 37 C.F.R. § 1.821. The Sequence Listing XML file submitted in the USPTO Patent Center, “026389-9326-US03_sequence_listing_xml_7 May 2025.xml,” was created on May 7, 2025, contains 26 sequences, has a file size of 28.0 kilobytes (28,672 bytes), and is incorporated by reference in its entirety into the specification. FIELD This disclosure relates to antibodies or antigen-binding fragments thereof and compositions comprising the same. The disclosure further relates to methods of detecting TAR DNA-binding protein 43 (TDP-43) in a biological sample, diagnosing a neurodegenerative disease in a subject, and selecting whether to enroll a subject in a clinical trial for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) using the antibodies or antigen-binding fragments thereof described herein. In addition, the disclosure relates to immunoassay kits for selectively detecting TDP-43 in a biological sample. BACKGROUND Populations are aging and neurodegenerative disease is becoming a growing and intractable health challenge. While Alzheimer's disease (AD) is the most common cause of dementia, frontotemporal dementia (FTD) is the second most common in people under 65. FTD is a heterogeneous neurodegenerative disease characterized by progressive behavior and/or language impairments that include a range of clinical subtypes, e.g., behavioral variant FTD, progressive non-fluent aphasia, and semantic dementia. Pathologically, most patients have frontotemporal lobar degeneration (FTLD). About half of those patients show an accumulation of hyperphosphorylated tau proteins (in a subtype called FTLD-tau), while most others show an accumulation of the transactive DNA-binding protein TDP-43 (the subtype FTLD-TDP). However, these clinical conditions may also be caused by unusual presentations of AD. Because different underlying pathologies require specific therapeutic interventions, robust biomarkers are urgently needed to correctly select appropriate drugs for individual patients based on their specific underlying molecular pathology (i.e., FTLD-tau, FTLD-TDP, or AD). Though signature cerebrospinal fluid (CSF) markers exist for AD (low Aβ42 together with high T-tau and P-tau), currently there are no reliable structural/functional imaging methodologies nor CSF/serum liquid biomarker-based methodologies available for diagnosing FTLD-tau or FTLD-TDP. Thus, there is a need for identification of a robust plasma biomarkers for diagnosing FTLD-TDP and highly sensitive and specific immunoassays for the detection and quantification of the biomarker. SUMMARY In an aspect, the disclosure relates to an antibody or antigen-binding fragment thereof comprising an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein: (a) the immunoglobulin HC variable domain sequence comprises (i) an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 6; and (b) the immunoglobulin LC variable domain sequence comprises (i) an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 8, (ii) an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and (iii) an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 10. In an embodiment, the immunoglobulin HC variable domain sequence comprises the amino acid sequence of SEQ ID NO: 3; and the immunoglobulin LC variable domain sequence comprises the amino acid sequence of SEQ ID NO: 7. In a further aspect, the disclosure relates to an antibody or antigen-binding fragment thereof comprising an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein: (a) the immunoglobulin HC variable domain sequence comprises (i) an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 12, (ii) an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and (iii) an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and (b) the immunoglobulin LC variable domain sequence comprises (i) an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 16, (ii) an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (iii) an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 18. In an embodiment, the immunoglobulin HC variable domain sequence comprises the amino acid sequence of SEQ ID NO: 11; and the immunoglobulin LC variable domain sequence comprises the amino acid sequence of SEQ ID NO: 15