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CN-121991223-A - Antibody for neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, preparation method and application thereof

CN121991223ACN 121991223 ACN121991223 ACN 121991223ACN-121991223-A

Abstract

The invention discloses an antibody for a neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, a preparation method and application thereof. The antibody or antigen binding fragment thereof of the present invention is capable of specifically binding PolyGN C-iso2, which includes heavy chain CDR1-3 shown in SEQ ID NO.1-3 and light chain CDR1-3 shown in SEQ ID NO. 4-6. The antibody has extremely low cross reaction with uN2CpolyG and extremely high accuracy, so that the method is beneficial to realizing the accurate diagnosis of the neuronal nuclear inclusion body disease. In addition, the monoclonal antibodies of the invention are capable of treating neuronal nuclear inclusion body disorders caused by PolyGN C-iso 2.

Inventors

  • ZHANG KANG
  • ZHANG ZAIQIANG
  • ZHOU YI
  • TAI HONGFEI

Assignees

  • 首都医科大学附属北京天坛医院

Dates

Publication Date
20260508
Application Date
20260213

Claims (10)

  1. 1. An antibody or antigen-binding fragment thereof, which is capable of specifically binding to neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, said antibody or antigen-binding fragment thereof comprising heavy chain CDR1-3 as shown in SEQ ID No.1-3 and light chain CDR1-3 as shown in SEQ ID No. 4-6.
  2. 2. The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof has any one of the amino acid sequences shown in (I) - (III): (I) A heavy chain variable region sequence shown in SEQ ID NO.7 and a light chain variable region sequence shown in SEQ ID NO. 8; (II) an amino acid sequence having at least 90% homology with the amino acid sequence shown in (I) and having the same function; (III) an amino acid sequence having the same function as the amino acid sequence shown in (I) or (II) obtained by modifying, substituting, deleting or adding one or more than one amino acid.
  3. 3. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody comprises a monoclonal antibody, chimeric antibody, humanized antibody or murine antibody and the antigen-binding fragment comprises a Fab, fab ', F (ab') 2 , scFv or scFv Fc fragment.
  4. 4. An isolated neoantigenic peptide, characterized in that it is a neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, said neoantigenic peptide having the amino acid sequence shown in SEQ ID No. 12.
  5. 5. A nucleic acid molecule comprising a nucleotide sequence encoding the isolated neoantigenic peptide of claim 4 or the antibody or antigen binding fragment thereof of any one of claims 1-3.
  6. 6. A vector molecule, characterized in that it comprises a nucleic acid molecule according to claim 7.
  7. 7. Host cell, characterized in that it comprises a nucleic acid molecule according to claim 5 or a vector molecule according to claim 6.
  8. 8. The method of producing an isolated neoantigenic peptide of claim 4 or an antibody or antigen binding fragment thereof of any one of claims 1-3, wherein the isolated neoantigenic peptide or the antibody or antigen binding fragment thereof is produced synthetically or by genetic engineering.
  9. 9. A test product for neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, characterized in that it comprises an antibody or antigen-binding fragment thereof according to any one of claims 1-3.
  10. 10. Use of an antibody or antigen binding fragment thereof according to any one of claims 1-3 for the manufacture of a neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2 detection product or a medicament for the treatment of neuronal nuclear inclusion body disease.

Description

Antibody for neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicine manufacturing, and particularly relates to an antibody for a neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, a preparation method and application thereof. Background Neuronal nuclear inclusion body disease (NIID) is a rare and progressive neurodegenerative disease of the nervous system, has various clinical manifestations and undefined pathogenic mechanism at present, and has no effective treatment method. Current studies indicate that NIID onset is closely related to the repeated aberrant amplification of GGC trinucleotide of NOTCH2NLC gene. Current research is focused mainly on a polyglycine (polyG) protein called uN2CpolyG, translated from transcript variant 1 of the NOTCH2NLC gene. It is widely accepted in the academia that abnormal accumulation and aggregation of the uN2CpolyG protein is a central cause of neuronal damage and dysfunction. One of the clinical diagnostic aids for NIID is the detection of p62 protein positive nuclear inclusion bodies in skin sweat gland cells or neural tissue. However, p62 is a universal marker associated with autophagy, lacking specificity for NIID, e.g. p62 histochemical staining does not distinguish NIID disease from Fragile X-related tremor/ataxia syndrome (Fragile X-related tremor/ataxia syndrome, FXTAS). Histopathological staining of p62 also fails to distinguish the specific protein species that are pathogenic, nor can it be used as an accurate therapeutic target. Disclosure of Invention In order to solve at least part of the technical problems in the prior art, the invention identifies a brand new pathogenic protein PolyGN C-iso2 generated by NOTCH2NLC transcript 2 in NIID patients for the first time and proves that the protein has independent pathogenic capability. Specifically, the present invention includes the following. In a first aspect of the invention, there is provided an isolated neoantigenic peptide which is a neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, said neoantigenic peptide having the amino acid sequence shown in SEQ ID No. 12. In a second aspect of the invention, there is provided an antibody or antigen binding fragment thereof capable of specifically binding to neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2, said antibody or antigen binding fragment thereof comprising heavy chain CDR1-3 as shown in SEQ ID NO.1-3 and/or light chain CDR1-3 as shown in SEQ ID NO. 4-6. In certain embodiments, an antibody or antigen-binding fragment thereof according to the invention, wherein the antibody or antigen-binding fragment thereof has any one of the amino acid sequences shown in (I) - (III): (I) A heavy chain variable region sequence shown in SEQ ID NO.7 and/or a light chain variable region sequence shown in SEQ ID NO. 8; (II) an amino acid sequence having at least 90% homology with the amino acid sequence shown in (I) and having the same function; (III) an amino acid sequence having the same function as the amino acid sequence shown in (I) or (II) obtained by modifying, substituting, deleting or adding one or more than one amino acid. In certain embodiments, an antibody or antigen-binding fragment thereof according to the invention, wherein the antibody comprises a monoclonal antibody, chimeric antibody, humanized antibody or murine antibody, and the antigen-binding fragment comprises Fab, fab ', F (ab') 2, scFv, or scFv Fc fragment. In a third aspect of the invention there is provided a nucleic acid molecule comprising a nucleotide sequence encoding an isolated neoantigenic peptide according to the first aspect of the invention or an antibody or antigen binding fragment thereof according to the second aspect of the invention. In a fourth aspect of the invention there is provided a vector molecule comprising a nucleic acid molecule according to the third aspect of the invention. In a fifth aspect of the invention there is provided a host cell comprising a nucleic acid molecule according to the third aspect of the invention or a vector molecule according to the fourth aspect of the invention. In a sixth aspect of the present invention there is provided a method of preparing an isolated neoantigenic peptide according to the first aspect of the present invention or an antibody or antigen binding fragment thereof according to the second aspect of the present invention, wherein the isolated neoantigenic peptide or the antibody or antigen binding fragment thereof is prepared by artificial synthesis or genetic engineering. In a seventh aspect of the invention there is provided a detection product for neuronal nuclear inclusion body disease pathogenic protein PolyGN C-iso2 comprising an antibody or antigen-binding fragment thereof according to the first aspect of the inventi