WO2023174897A1 - Composition comprenant un anticorps se liant à srrm2 humain présent sur la surface cellulaire d'une cellule cible - Google Patents

Composition comprenant un anticorps se liant à srrm2 humain présent sur la surface cellulaire d'une cellule cible Download PDF

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WO2023174897A1
WO2023174897A1 PCT/EP2023/056397 EP2023056397W WO2023174897A1 WO 2023174897 A1 WO2023174897 A1 WO 2023174897A1 EP 2023056397 W EP2023056397 W EP 2023056397W WO 2023174897 A1 WO2023174897 A1 WO 2023174897A1
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amino acid
acid sequence
seq
antibody
set forth
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PCT/EP2023/056397
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English (en)
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Reinhard Zeidler
Kathrin GAERTNER
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Helmholtz Zentrum Muenchen - Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh)
Eximmium Biotechnologies Gmbh
Klinikum Der Universitaet Muenchen
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Publication of WO2023174897A1 publication Critical patent/WO2023174897A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • 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
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5156—Animal cells expressing foreign proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment

Definitions

  • the present invention provides a pharmaceutical composition comprising an antibody, which binds to human SRRM2 present on the cell surface of a target cell and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention further provides said pharmaceutical composition for use in a method for the treatment of cancer in a human subject. Further is provided a method for determining whether a human subject may suffer from cancer, comprising determining in a sample obtained from said human subject whether SRRM2 is present on the cell surface of cells comprised by said sample. Additionally, an antibody which binds to human SRRM2 present on the cell surface of a target cell is provided.
  • the present invention further provides an antibody, which binds to human SRRM2 present on the cell surface of a target cell for use in a method of killing said target cell having SRRM2 present on the cell surface. Further, a method of killing a target cell having SRRM2 present on the cell surface of said target cell, comprising administering an antibody, which binds to human SRRM2 present on the cell surface of said target cell is provided.
  • the present invention further relates to an antibody, which binds to human SRRM2 present on the cell surface of a target cell for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface.
  • SRRM2 Serine/arginine repetitive matrix protein 2
  • UniProt Q9UQ35 Serine/arginine repetitive matrix protein 2
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody which binds to human SRRM2 present on the cell surface of a target cell and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • the target cell preferably is a cancer cell.
  • the antibody, which binds to human SRRM2 may have cytotoxic activity.
  • the antibody, which binds to human SRRM2 may have ADCC or CDC.
  • the antibody, which binds to human SRRM2 may be conjugated with a cytotoxic substance.
  • the antibody, which binds to human SRRM2 may be part of a chimeric antigen receptor (CAR).
  • the CAR may be comprised by a T cell, NK cell, NK-T cell or macrophage.
  • SRRM2 preferably being present on the cell surface of a target cell, preferably is externalized.
  • the antibody which binds to human SRRM2, preferably is not an intracellular antibody.
  • the antibody which binds to human SRRM2, preferably is
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26; or
  • the antibody which binds to human SRRM2, preferably is
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29; or
  • the present invention further relates to the pharmaceutical composition of the invention for use in a method for the treatment of cancer in a human subject.
  • said cancer is characterized by cells, wherein human SRRM2 is present on their cell surface.
  • said cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, stomach cancer, cholangiogenic cancer, oral cavity squamous carcinoma, hematologic malignancy tumor, or glioma.
  • the present invention further relates to a method for determining whether a human subject may suffer from cancer, comprising determining in a sample obtained from said human subject whether SRRM2 is present on the cell surface of cells comprised by said sample.
  • the present invention further relates to a method for determining whether a human subject may suffer from cancer, comprising determining in a sample obtained from said human subject whether SRRM2 is present on the surface of extracellular vesicles.
  • the present invention further relates to an antibody, which binds to human SRRM2 present on the cell surface of a target cell, wherein said antibody is
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26; or
  • the present invention further relates to an antibody, which binds to human SRRM2 present on the cell surface of a target cell, comprising
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29; or
  • the present invention further relates to an antibody, which binds to human Serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of a target cell for use in a method of killing said target cell having SRRM2 present on the cell surface.
  • SRRM2 human Serine/arginine repetitive matrix protein 2
  • Such an antibody preferably is
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26; or
  • Such an antibody preferably is or comprises
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26; or
  • the present invention further relates to a method of killing a target cell having Serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of said target cell, comprising administering an antibody, which binds to human SRRM2 present on the cell surface of said target cell.
  • SRRM2 Serine/arginine repetitive matrix protein 2
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26; or
  • the antibody preferably is
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29; or
  • the invention further relates to an antibody, which binds to human Serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of a target cell for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface.
  • SRRM2 human Serine/arginine repetitive matrix protein 2
  • Such an antibody which binds to human SRRM2 present on the cell surface of a target cell for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, preferably is
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26; or
  • Such an antibody which binds to human SRRM2 present on the cell surface of a target cell for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, preferably is or comprises
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29; or
  • Figure 1 shows that the antibodies 13F11, 23A7 and 18A4 precipitate SRRM2.
  • Cyanogen bromide beads coupled with any of the three antibodies or with an isotype control antibody were incubated overnight with lysates from OVCAR-3 or UWB1.289 ovarian cancer cells. After precipitation of the beads and incubation in Laemmli buffer, eluates were analyzed by mass spectrometry, which revealed a clear enrichment of SRRM2 with either antibody as compared to the isotype control antibody.
  • Figure 2 shows the surface expression of SRRM2 on various cancer cell lines.
  • Cell lines were incubated with13F11 (solid lines in Fig. 2A and Fig. 2B) or an isotype control antibody (dotted line in Fig. 2A, tinted histogram in Fig. 2B).
  • Cells were then washed and incubated with an Alexa647 labeled anti-rat IgG antibody. Fluorescence was then measured with a FACS Canto. Normal PBMCs do not express surface SRRM2 (not shown).
  • FIG. 3 shows that 13F11, 23A7 and 18A4 are SRRM2-specific: A549 cells were transfected with a ribonucleoprotein complex consisting of SRRM2-specific gRNAs and Cas9. Seven days later, binding of the antibodies to knockout and wildtype cells was measured by flow cytometry. For this, A549 Wildtype (bold line) and the A549 SRRM Knockout line #25 (tinted histogram) were incubated with any of the three antibodies 13F11, 18A4 and 23A7. Cells were washed and then incubated with an Alexa647 labeled anti-rat secondary antibody. Fluorescence was then measured with a FACS Canto. An isotype control antibody was included as a negative control (dotted line).
  • FIG. 4 shows that 13F11 binds to vital SK-OV-3 cells.
  • SK-OV-3 cells were grown on microscope slides, washed in PBS, and incubated with the antibody 13F11. Then, cells were fixed with 4 % paraformaldehyde and incubated with an Alexa647-coupled suitable anti-rat IgG secondary antibody. Surface staining is clearly visible.
  • FIG. 5 shows that 18A4 co-localizes with the surface molecule CD47.
  • A549 or UWB1.289 cells were cultivated on a cover slip, washed and incubated with the antibodies 18A4 (SRRM2, magenta) and 18F10 (CD47, green). Cells were fixed with 4% paraformaldehyde and analyzed by confocal fluorescence microscopy. Nuclei were counterstained with DAPI (blue).
  • FIG. 6 shows that SRRM2 localizes to lipid rafts or another kind of insoluble membrane subdomains.
  • Cells were lysed in RIPA buffer and the lysate was put onto of a density gradient. After centrifugation, 10 fractions of 400 pl each were taken and samples of these fractions were spotted onto a nitrocellulose membrane. The membrane was incubated with antibody 13F11 or with an antibody specific for the tetraspanin CD63.
  • Fractions 2 and 3 correspond to a density of approximately 1.13-1.19 g/ml, and thus in the range of lipid rafts. Soluble proteins, which have higher specific density, are mainly located in fractions 7-10.
  • FIG. 7 shows that surface-SRRM2-positive SK-OV-3-cells activate SRRM2-specific 13F11 CAR-T-cells.
  • Primary T-cells from two donors (1 and 2) were transduced with a retroviral vector encoding a CAR construct with a single-chain construct derived from antibody 13F11. Expression of the CAR was tested by flow cytometry with a goat-anti rat IgG antibody (not shown).
  • SK-OV-3 cells were incubated with 13F11 CAR-T cells (columns 3-4 of the blots) of non-transduced control T cells (column 1-2 of the blots) at the ratios indicated on the X-axis for 24 h. Then, interferon-gamma in the supernatants, as a marker for T-cell activation, was quantified with a commercial ELISA assay.
  • FIG. 8 shows that SRRM2-specific CAR-T cells kill SRRM2-positive HO-8910 target cells.
  • Primary T-cells from one donors were transduced with a retroviral vector encoding a CAR construct with a single-chain construct derived from antibody 13F11. Expression of the CAR was tested by flow cytometry with a goat-anti rat IgG antibody (not shown).
  • SK-OV-3 cells were incubated with 13F11 CAR-T cells of non-transduced control T cells (Mock-T) at the ratios indicated on the X-axis for 24 h. Then, killing was measured with a commercial lactate dehydrogenase (LDH) assay.
  • LDH lactate dehydrogenase
  • FIG. 9 shows that SRRM2 is released via extracellular vesicles (EVs): EVs isolated from ascites of a patient with ovarian cancer were isolated by established technologies comprising differential centrifugation, ultracentrifugation, and density gradient purification. 2 pl each of this EV preparation were then spotted onto pieces of nitrocellulose membrane and incubated (from left to right) with 13F11, 18A4, 23A7 or an isotype control antibody at 4°C overnight. After washing, membranes were incubated with a suitable secondary antibody (goat anti-rat IgG, coupled with horseradish peroxidase) for 2 h and developed with ECL.
  • Figure 10 shows that SRRM2 surface expression on cancer cells is induced by hypoxia.
  • SRRM2 surface expression was measured with 13F11 labeled with Alexa647. Mean fluorescence levels are given.
  • An isotype antibody was used as a control.
  • FIG. 11 shows that the antibody 13F11 is internalized upon binding to SRRM2.
  • Figure 12 shows sections of a pancreatic cancer and normal pancreas, stained with 18A4. Membrane staining is visible in cancer cells, while normal pancreas cell reveal nuclear staining.
  • Figure 13 shows membrane localization of SRRM2 in xenotransplanted human HUCCT- 1 cells. Again, normal mouse tissue clearly reveal nuclear staining, only.
  • Figure 14 shows the respective sequences of the antibodies 13F11, 23A7 and 18A4, including the light chains and heavy chains with the respective CDR1, CDR2 and CDR3 sequences.
  • FIG. 15 shows that 13F11, 18A4-2 and 23A7 binds to a fragment (called herein tr04, SEQ ID NO: 30) spanning amino acids 1889 to 2150 of SRRM2.
  • HEK293 cells were transfected with an expression plasmid encoding amino acids 1889 to 2150 of SRRM2 fused to a HIS-tag (HEK293-trO4). Immunoprecipitations were performed with bead-coupled SRRM2-specific antibodies 13F11, 18A4-2 and 23A7 and lysates of transfected cells or, as control, nontransfected 293 cells (HEK293).
  • Precipitated proteins were separated by PAGE and transferred to a PVDF membrane, which was then incubated with an anti-rat antibody coupled to HRP. Finally, the blot was developed with ECL. As additional controls, lysates from transfected and non-transfected cells were included.
  • FIG 16 shows that normal tissues from Cynomolgus monkeys either stain negative for SRRM2 or show cytoplasmic/nuclear staining as revealed by immunohistochemistry. No membrane staining was observed.
  • FFPE tissues from cynomolgus monkey were incubated with 13F11 antibody, followed by incubation with a goat anti-rat IgG antibody coupled with HRP (ImmPRESS HRP Peroxidase detection kit; https://vectorlabs.com/products/enzyme-polymer/immpress-hrp-goat-anti-rat-igg- kit).
  • Figure 17 shows that the majority of tumor samples derived from different locations (bile duct, ovary, pancreas, stomach) reveal SRRM2 membrane staining.
  • Formalin-fixed paraffin embedded (FFPE) tumor tissues and adjacent normal tissues were stained with antibody 13F11 , followed by incubation with a rat-specific secondary antibody coupled with HRP. Tissues were inspected by a trained pathologist and staining intensity was scored from 0 (negative) to 3+ (strong expression on the majority of cells).
  • FFPE paraffin embedded
  • Figure 18 shows the sequences of the variable parts of the light and heavy chains of antibody 18A4-2.
  • FIG. 19 shows that the SRRM2-specific antibodies 13F11, 18A4-2 and 23A7 bind to fragment tr04.
  • a 96-well cell cluster plate was coated with purified SRRM2-trO4-HIS or, as a control, MISP-HIS protein (each at 50 pg/ml) overnight and then blocked with non-fat milk powder in TBST. Then, antibodies 13F11, 18A4-2, 23A7 or an anti-MISP antibody were added for 2 hours at room temperature. After washing, the plate was incubated with a secondary antirat IgG antibody coupled to HRP and developed with TMB. After stopping the reaction with H 2 SO 4 , the absorbance was measured at 450 nm.
  • SRRM2 is present on the cell surface of cancer cells (see e.g., Figs. 2-5, 12 and 13) although widely described in prior art as being a protein localized in the nucleus, in particular in nuclear speckles.
  • Serine/arginine repetitive matrix protein 2 (SRRM2; UniProt Q9UQ35) plays an important role in pre-mRNA splicing and is a major component of the spliceosome. As such, it is not present on the cell surface of healthy cells.
  • SRRM can be seen as becoming “externalized”, i.e. it is no longer not only present in the nucleus, but also present on the cell surface of a then cancer cell.
  • SRRM2 was not known to be available for therapy for being localized in the nucleus, in particular in the nuclear speckles.
  • SRRM2 is present on the cell surface of cancer cells, those cells can now be targeted for the treatment of cancer.
  • An exemplary sequence of SRRM2 is provided by UniProt database entry Q9UQ35, version 2 of 6 March 2007 and exemplified in SEQ ID NO: 25.
  • the SRRM2 protein within the context of the present invention may be a SRRM2 protein having SEQ ID NO: 25 or may be a modified protein having an amino acid sequence derived from the sequence described above by the modification of one or more amino acids.
  • the modified protein having a sequence derived from the sequence described above by the modification of one or more amino acids can include polypeptides having 70 % or more, preferably 80 % or more, more preferably 90 % or more, even more preferably 95 % or more homology to the amino acid sequence.
  • partial peptides of these SRRM2 proteins may be used.
  • sequence identity as used herein in its usual meaning includes identical amino acids as well as amino acids, which are regarded to be conservative substitutions (for example, exchange of a glutamate residue by an aspartate residue) at equivalent positions in the linear amino acid sequence of two proteins that are compared with each other.
  • identity or “sequence identity” is meant a property of sequences that measures their similarity or relationship.
  • sequence identity or “identity” as used in the present invention means the percentage of pair-wise identical residues - following (homology) alignment of a sequence of a polypeptide of the invention with a sequence in question - with respect to the number of residues in the longer of these two sequences. Identity is measured by dividing the number of identical residues by the total number of residues and multiplying the product by 100.
  • the percentage of sequence homology or sequence identity can, for example, be determined herein using the program BLASTP, version blastp 2.2.5 (November 16, 2002; cf. Altschul, S. F. et al. (1997) Nucl. Acids Res. 25, 3389-3402).
  • the percentage of homology is based on the alignment of the entire polypeptide sequences (matrix: BLOSLIM 62; gap costs: 11.1; cutoff value set to 10' 3 ), optionally including the propeptide sequences, using the human IL-4 as reference in a pairwise comparison.
  • the SRRM2 protein used in the present invention is not limited by its origin and is preferably a human SRRM2 protein.
  • antibody as used herein and in the context of the present invention may comprise chimeric antibodies, humanized antibodies, monovalent antibodies, polyvalent antibodies, low-molecular antibodies, a diabody or a scFv.
  • Chimeric antibodies refer to antibodies comprising variable and constant regions of different origins ligated with each other.
  • mouse-human heterogeneous chimeric antibodies are antibodies comprising the heavy and light chain variable regions of a mouse antibody and the heavy and light chain constant regions of a human antibody.
  • Mouse antibody variable region-encoding DNAs are ligated with human antibody constant region-encoding DNAs, and the ligation products can be incorporated into expression vectors to prepare chimeric antibody-expressing recombinant vectors. Cells transformed with these vectors (recombinant cells) can be cultured for the expression of the DNA insert to obtain the chimeric antibodies produced during the culture.
  • the chimeric antibodies comprise non-human animal-derived antibody variable regions and human antibody-derived constant regions.
  • the humanized antibodies comprise non-human animal-derived antibody complementarity-determining regions (CDRs), human antibody-derived framework regions (FRs), and human antibody-derived constant regions.
  • CDRs non-human animal-derived antibody complementarity-determining regions
  • FRs human antibody-derived framework regions
  • human antibody-derived constant regions are also called reshaped human antibodies.
  • humanized antibodies comprising non-human animal (e.g., mouse) antibody CDRs grafted in human antibodies are known in the art.
  • the humanized antibodies are useful as active ingredients for a therapeutic agent of the present invention, owing to their reduced antigenicity in the human body.
  • Each antibody variable region usually comprises 3 CDRs flanked by 4 FRs.
  • the CDR regions substantially determine the binding specificity of the antibody.
  • the CDRs have diverse amino acid sequences.
  • amino acid sequences constituting the FRs often exhibit high homology among antibodies having different binding specificities. Therefore, in general, the binding specificity of a certain antibody can allegedly be transplanted to other antibodies through CDR grafting.
  • the antibody, which binds to human SRRM2 present in a pharmaceutical composition of the present invention may encompass bivalent antibodies typified by IgG (lgG1 , lgG2, lgG4, etc.) and also monovalent antibodies or polyvalent antibodies typified by IgM as long as these antibodies bind to the SRRM2 protein.
  • the polyvalent antibody that may be present in the pharmaceutical composition of the present invention may encompass polyvalent antibodies having antigen-binding sites, all of which are the same as each other or some or all of which are different from each other.
  • the antibody, which binds to human SRRM2 is an IgG antibody.
  • the antibody, which binds to human SRRM2 present in the pharmaceutical composition of the present invention may also be a low-molecular antibody that encompasses an antibody fragment deficient in a portion of the whole antibody (e.g., whole IgG). Such partial deficiency of the antibody molecule is accepted as long as the resultant antibody fragment is capable of binding to the SRRM2. It is preferred that the antibody fragment employed in the pharmaceutical composition according to the present invention should contain one or both of heavy chain variable (VH) and light chain variable (VL) regions. It is also preferred that the antibody fragment employed in the pharmaceutical composition according to the present invention should contain CDRs.
  • VH heavy chain variable
  • VL light chain variable
  • the number of CDRs contained in the antibody fragment employed in the pharmaceutical composition of the present invention is not particularly limited and is preferably at least 6 CDRs: heavy chain CDR1 , CDR2, and CDR3 and light chain CDR1 , CDR2, and CDR3.
  • the amino acid sequence of VH or VL can contain one or more substitution, deletion, addition, and/or insertion.
  • the antibody or antibody fragment that may be employed in the pharmaceutical composition of the present invention may be deficient in a portion of one or both of VH and VL, as long as the resultant antibody fragment is capable of binding to the human SRRM2.
  • its variable region may be chimerized or humanized.
  • Specific examples of the antibody fragment can include Fab, Fab’, F(ab’)2, and Fv.
  • the low-molecular antibody can include Fab, Fab’, F(ab’)2, Fv, scFv (single chain Fv), diabody, sc(Fv)2 (single chain (Fv)2), and scFv-Fc.
  • the low- molecular antibody is preferably a diabody or sc(Fv)2.
  • These antibody multimers e.g., dimers, trimers, tetramers, and polymers
  • the term “diabody” as used herein and in the context of the present invention may refer to a bivalent antibody fragment constructed by gene fusion.
  • the diabody is a dimer comprising two polypeptide chains.
  • each of the polypeptide chains constituting the dimer comprises heavy and light chain variable regions linked via a linker on the same chain.
  • the linker in the diabody is generally too short to allow paring between heavy and light chain variable regions on the same chain.
  • the number of amino acid residues constituting the linker is, for example, approximately 5 residues. Therefore, heavy and light chain variable regions encoded on the same polypeptide chain cannot together form a single chain variable region fragment. Instead, they form a dimer by pairing with another single chain variable region fragment. As a result, the diabody has two antigen-binding sites.
  • the scFv may be obtained by linking heavy and light chain variable regions of the antibody.
  • the heavy and light chain variable regions are linked via a linker, preferably, a peptide linker.
  • the heavy and light chain variable regions in the scFv can be derived from any of the antibodies described in the present specification.
  • the peptide linker that links the variable regions is not particularly limited. For example, an arbitrary single chain peptide of approximately 3 to 25 residues can be used as the linker.
  • the antibody, which binds to human SRRM2 as used in the pharmaceutical composition and the antibody, which binds to human SRRM2 according to the present invention may also encompass binding entities, such as lipocalins, an aptamer or an anticalin.
  • the antibody, which binds to human SRRM2, used in the present invention can have various formats. However, it needs to bind to the SRRM2 protein and is not particularly limited by its origin, type, shape, etc., but may have a cytotoxic activity.
  • an antibody can be used, such as a non-human animal-derived antibody (e.g., a mouse, rat, or camel antibody), a human-derived antibody, a chimeric antibody, or a humanized antibody as described above.
  • the antibody, which binds to human SRRM2 used in the present invention may in one embodiment be a polyclonal or monoclonal antibody and is preferably a monoclonal antibody.
  • the antibody, which binds to human SRRM2 used in the present invention can be obtained as a polyclonal or monoclonal antibody using means known in the art.
  • the antibody used in the present invention is in particular preferably a mammal-derived monoclonal antibody.
  • the mammal-derived monoclonal antibody encompasses, for example, those produced by hybridomas and those produced by hosts transformed with expression vectors containing an antibody gene by a genetic engineering approach.
  • the antibody, which binds to human SRRM2 may be modified with various molecules such as polyethylene glycol (PEG). Further, the antibody, which binds to human SRRM2 may also be modified with cytotoxic substance such as a chemotherapeutic agent, a radioactive chemical, or the like.
  • PEG polyethylene glycol
  • cytotoxic substance such as a chemotherapeutic agent, a radioactive chemical, or the like.
  • Specific examples of the antibody used in the present invention which recognizes SRRM2 present on the cell surface of a target cell such as a cancer cell and binds thereto, may include the antibodies given and described herein.
  • an antibody which binds to human SRRM2 of the present invention or as used in the pharmaceutical composition of the present invention or as used in the methods of the present invention including the substitution, deletion, addition, and/or insertion of one or more amino acids is also incorporated in the scope of the present invention and may be prepared or occur naturally.
  • Examples of a method for introducing a mutation in the polypeptide include site-directed mutagenesis (Hashimoto-Gotoh, T. et al., 1995) (Zoller, MJ, and Smith, M., 1983) (Kramer, W. et al., 1984) (Kramer W, and Fritz HJ, 1987) (Kunkel, TA, 1985) (Kunkel, 1988).
  • Such an antibody that has an amino acid sequence derived from the amino acid sequence of the antibody of the present invention or the antibody as used in the pharmaceutical composition of the present invention or as used in the methods of the present invention comprising the mutation of one or more amino acids, is functionally equivalent or a variant to the antibody and is also encompassed by the antibody of the present invention or the antibody as used in the pharmaceutical composition of the present invention or as used in the methods of the present invention.
  • the number of amino acids mutated in such a variant is usually within 50 amino acids, preferably within 30 amino acids, more preferably within 10 amino acids (e.g., within 5 amino acids).
  • amino acid residues to be mutated it is preferred that this mutation should be performed conservatively between amino acids having the same side chain property.
  • hydrophobic amino acids A, I, L, M, F, P, W, Y, and V
  • hydrophilic amino acids R, D, N, C, E, Q, G, H, K, S, and T
  • amino acids having an aliphatic side chain G, A, V, L, I, and P
  • amino acids having a hydroxyl group-containing side chain S, T, and Y
  • amino acids having a sulphur atom-containing side chain C and M
  • amino acids having a side chain containing carboxylic acid and amide D, N, E, and Q
  • amino acids having a base-containing side chain R, K, and H
  • amino acids having an aromatic group-containing side chain H, F, Y, and W
  • a polypeptide having an amino acid sequence modified from a certain amino acid sequence by the deletion and/or addition of one or more amino acid residue(s) and/or the substitution thereof by other amino acids is already known to maintain the biological activity of the original polypeptide (Mark, D. F. et al., 1984) (Wang, A. et al., 1982). Specifically, when amino acids in an amino acid sequence constituting a certain polypeptide are substituted by amino acids classified in the same group thereas, it is generally said that the polypeptide is likely to maintain its activity. In the present invention, the substitution between amino acids within the same amino acid group described above is referred to as conservative substitution.
  • the term “surface” or specifically “cell surface” as used herein means the cell membrane.
  • the cell membrane which may also be known as plasma membrane, is the thin membrane that surrounds every living cell, delimiting the cell from the environment around it. Enclosed by this cell membrane are the cell’s constituents, often large, water-soluble, highly charged molecules such as proteins, nucleic acids, carbohydrates, and substances involved in cellular metabolism.
  • the cell membrane therefore, has at least two functions: first, to be a barrier keeping the constituents of the cell in and unwanted substances out and, second, to be a gate allowing transport into the cell of essential nutrients and removal of waste products from the cell.
  • ER-derived vesicles may also participate in the building or formation of the cell membrane.
  • the antibody, which binds to human SRRM2 preferably is capable of binding to a SRRM2 polypeptide extracellularly.
  • an antibody as described herein may be capable of binding to SRRM2 when it is outside the cell, which also comprises SRRM2 to be specifically on the surface of the cell.
  • the antibody, which binds to human SRRM2 preferably is no intracellular antibody, which is also called an intrabody.
  • An “intrabody” is an antibody that works within the cell to bind to an intracellular protein. This requires the expression of the antibody within the target cell, which can be accomplished, e.g., in transgenic animals or by gene therapy.
  • intrabodies are antibodies that have been modified for intracellular localization and include antibodies, which are produced in prokaryotes or other non-target cells.
  • the term “intrabody” can apply to several types of protein targeting: the antibody may remain in the cytoplasm, or it may have a nuclear localization signal, or it may undergo cotranslational translocation across the membrane into the lumen of the endoplasmic reticulum, provided that it is retained in that compartment through a KDEL sequence.
  • the antibodies, which bind to human SRRM2 of the invention preferably are capable of being internalized as shown in Example 11.
  • the “target cell” preferably is a cancer cell.
  • cancer can comprise any one or more of the following: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, breast cancer, cancer of the female genital system, cancer of the male genital system, central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon and rectal cancer, colon cancer, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal tract cancer, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Hodgkin’s disease, hypopharyngeal cancer, Kaposi’s sarcom
  • ALL acute lymphocytic le
  • pharmaceutically acceptable carrier, diluent or excipient may comprise any pharmaceutically acceptable carrier, diluent or excipient for a pharmaceutical composition known by the person skilled in the art. It will be understood that such antibodies or pharmaceutical composition as described herein may be mixed with carriers or diluents, which will not interfere with the intended purpose of the present invention.
  • a carrier as used within the present invention may be a carrier protein, such as bovine serum albumin (BSA) or keyhole limpet haemocyanin (KLH).
  • BSA bovine serum albumin
  • KLH keyhole limpet haemocyanin
  • said antibody which binds to human SRRM2 has cytotoxic activity.
  • cytotoxic activity may refer to having a SRRM2 binding activity and may also include having an activity equivalent to that of the antibody, which binds to human SRRM2 of the present invention.
  • the equivalent activity is not necessarily required to be an identical activity and may be, for example, 50% or more, preferably 70% or more, more preferably 90% or more activity compared with the activity of any of the antibodies (a) to (e) as described herein.
  • the upper limit of the activity can include, but is not particularly limited to, 1000% or less, 500% or less, 300% or less, 150% or less, and 100% or less.
  • said antibody which binds to human SRRM2 has (antibody-dependent cell-mediated cytotoxicity) ADCC or complement-dependent cytotoxicity (CDC).
  • examples of the cytotoxic activity according to the present invention can include ADCC and/or CDC activities.
  • the ADCC activity means the activity of damaging target cells through the binding of Fey receptor-bearing cells (immunocytes, etc.) via the Fey receptors to the Fc domains of antibodies specifically attached to the cell surface antigens of the target cells.
  • the CDC activity means a cytotoxic activity mediated by the complement system. Whether or not the antibody has an ADCC activity or has a CDC activity can be determined by a method known in the art.
  • the antibody, which binds to human SRRM2 employed in the pharmaceutical composition of the present invention may have activities such as an ADCC activity and as such, may be useful as a pharmaceutical drug, preferably, an anti-cancer agent, wherein the cancer is e.g. breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, stomach cancer, cholangiogenic cancer, oral cavity squamous carcinoma, hematologic malignancy tumor, or glioma.
  • the cancer is e.g. breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, stomach cancer, cholangiogenic cancer, oral cavity squamous carcinoma, hematologic malignancy tumor, or glioma.
  • said antibody which binds to human SRRM2, is conjugated with a cytotoxic substance.
  • the antibody, which binds to human SRRM2 may be conjugated with a cytotoxic substance, such as a chemotherapeutic agent, a toxic peptide, or a radioactive chemical.
  • a cytotoxic substance such as a chemotherapeutic agent, a toxic peptide, or a radioactive chemical.
  • an antibody conjugate can be obtained by chemically modifying the obtained antibody. A method for the antibody modification has already been established in the art.
  • Examples of the chemotherapeutic agent whose cytotoxic activity functions through the conjugation to the antibody that binds SRRM2 can include the following chemotherapeutic agents: azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1 , busulfan, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, doxorubicin glucuronide, epirubicin, ethinyl estradiol, estramustine, etoposide, etop
  • the chemotherapeutic agent is preferably a low-molecular chemotherapeutic agent.
  • the low-molecular chemotherapeutic agent is unlikely to interfere with the antibody even after its conjugation to the antibody.
  • the low-molecular chemotherapeutic agent usually has a molecular weight of 100 to 2000, preferably 200 to 1000. All of the chemotherapeutic agents exemplified above are low-molecular chemotherapeutic agents.
  • These chemotherapeutic agents encompass prodrugs that are converted in vivo to active chemotherapeutic agents.
  • the prodrug activation may be an enzymatic conversion or a non-enzymatic conversion.
  • SRRM2-specific cancer therapy is enabled by the present invention.
  • said antibody, which binds to human SRRM2 is part of a chimeric antigen receptor (CAR).
  • CAR chimeric antigen receptor
  • said CAR is comprised by a T cell, NK cell, NK-T cell or macrophage.
  • Chimeric antigen receptors are receptor proteins that have been engineered to give T cells the ability to target a specific protein.
  • said antibody, which binds to human SRRM2 is less than 20 % cross-reactive with SRRM2-related proteins.
  • said antibody, which binds to human SRRM2 is less than 20 % cross-reactive with other serine/arginine repetitive matrix proteins such as SRRM1 , SRRM3, SRRM4 or SRRM5.
  • said antibody, which binds to human SRRM2 is less than 15 % cross-reactive with SRRM2-related proteins, e.g. SRRM1 , SRRM3, SRRM4 or SRRM5.
  • said antibody, which binds to human SRRM2 is less than 10 % cross-reactive with SRRM2-related proteins, e.g. SRRM1 , SRRM3, SRRM4 or SRRM5. Even more preferably, said antibody, which binds to human SRRM2, is less than 5 % cross-reactive with SRRM2-related proteins, e.g. SRRM1 , SRRM3, SRRM4 or SRRM5. Even more preferably, said antibody, which binds to human SRRM2, is less than 3 % cross-reactive with SRRM2- related proteins, e.g. SRRM1 , SRRM3, SRRM4 or SRRM5.
  • said antibody, which binds to human SRRM2 is less than 2 % cross-reactive with SRRM2-related proteins, e.g. SRRM1 , SRRM3, SRRM4 or SRRM5. Even more preferably, said antibody, which binds to human SRRM2, is less than 1 % cross-reactive with SRRM2-related proteins, e.g. SRRM1 , SRRM3, SRRM4 or SRRM5.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody, which binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11 , and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12, or an antibody, which binds to the same epitope.
  • said antibody, which binds to human SRRM2 is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18, or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24, or an antibody, which binds to the same epitope.
  • said antibody which binds to human SRRM2
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29, or an antibody, which binds to the same epitope.
  • the antibodies described herein may contain constant regions.
  • the constant regions used are not particularly limited, and any constant region may be used.
  • Preferable examples of the constant regions used in the present invention can include human-derived constant regions.
  • a human lgG1-derived, human lgG2-derived, human lgG3-derived, or human lgG4-derived constant region can be used as a heavy chain constant region.
  • human K chain-derived or human A chain-derived constant region can be used as a light chain constant region.
  • the constant regions used in the present invention may be constant regions having a native sequence or may be modified constant regions having a sequence derived from the native sequence by the modification of one or more amino acids.
  • the antibodies described herein may also contain framework regions (FRs).
  • the FRs used are not particularly limited, and any FR may be used as long as the resulting antibody maintains its binding activity to human SRRM2 present on the cell surface of a target cell.
  • Preferable examples of the FRs used in the present invention can include human antibody- derived FRs. Since the technique of FR replacement with the antigen binding activity of an antibody maintained is known in the art, those skilled in the art can appropriately select FRs.
  • the FRs used in the present invention may be FRs having a native sequence or may be FRs having a sequence derived from the native sequence by the modification of one or more amino acids.
  • the competition between the antibodies is detected by cross-blocking assay or the like.
  • the cross-blocking assay is preferably, for example, competitive ELISA assay.
  • SRRM2 proteins coated on the wells of a microtiter plate may be preincubated in the presence or absence of a candidate competing antibody and the antibody, which binds to human SRRM2 of the present invention is then added to the wells.
  • the amount of the antibody of the present invention bound to the SRRM2 protein in the well indirectly correlates with the binding ability of the candidate competing antibody (antibody to be tested) that competes therewith for the binding to the same epitope. Specifically, the larger affinity the antibody to be tested has for the same epitope, the smaller amount of the antibody of the present invention is bound to the SRRM2 protein-coated well, while the larger amount of the antibody to be tested is bound to the SRRM2 protein-coated well.
  • the amount of the antibody bound to the well can be measured easily by labeling the antibody in advance.
  • a biotin-labeled antibody can be measured by use of an avidin-peroxidase conjugate and an appropriate substrate.
  • the cross-blocking assay using enzyme (e.g., peroxidase) labeling is particularly referred to as competitive ELISA assay.
  • the antibody can be labeled with other detectable or measurable labeling substances. Specifically, radio-labeling or fluorescent labeling or the like is known in the art.
  • a candidate antibody can bind to human SRRM2 present on the cell surface of a target cell by at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 99%, compared to the binding activity obtained in a control test performed in the absence of the candidate antibody, this candidate antibody is determined as an antibody that binds to substantially the same epitope as that to which the antibody of the present invention binds or to which the antibody, which binds to human SRRM2 used in the pharmaceutical composition binds.
  • the present invention provides the pharmaceutical composition according to the present invention for use in a method for the treatment of cancer in a human subject.
  • said cancer is characterized by cells, wherein human SRRM2 is present on their cell surface.
  • said cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, stomach cancer, cholangiogenic cancer, oral cavity squamous carcinoma, hematologic malignancy tumor, or glioma.
  • the pharmaceutical composition according to the present invention can be administered by standard routes. These include, but are not limited to: oral, rectal, ophthalmic (including intravitreal or intracameral), nasal, topical (including buccal and sublingual), intrauterine, vaginal or parenteral (including subcutaneous, intraperitoneal, intramuscular, intravenous, intradermal, intracranial, intratracheal, and epidural) transdermal, intraperitoneal, intracranial, intracerebroventricular, intracerebral, intravaginal, intrauterine, or parenteral (e.g., intravenous, intraspinal, subcutaneous or intramuscular) routes.
  • the present invention also comprises a method of treating cancer, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a human subject.
  • said cancer is characterized by cells, wherein human SRRM2 is present on their cell surface.
  • said cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, stomach cancer, cholangiogenic cancer, oral cavity squamous carcinoma, hematologic malignancy tumor, or glioma.
  • the present invention comprises a method of treating cancer, wherein the method comprises administering a therapeutically effective amount of the antibody, which binds to human SRRM2 described herein to a human subject.
  • said cancer is characterized by cells, wherein human SRRM2 is present on their cell surface.
  • said cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, stomach cancer, cholangiogenic cancer, oral cavity squamous carcinoma, hematologic malignancy tumor, or glioma.
  • the term “therapeutically effective amount” refers to an amount of the antibody or pharmaceutical composition according to the present invention or drug effective to “treat” cancer in the human subject.
  • the therapeutically effective amount of the antibody/ pharmaceutical composition/ drug can reduce the number of cancer cells; reduce the tumor size; inhibit or stop cancer cell infiltration into peripheral organs; inhibit and stop tumor metastasis; inhibit and stop tumor growth; relieve to some extent one or more of the symptoms associated with the cancer, or a combination of such effects on cancer cells.
  • the antibody/ pharmaceutical composition/ drug prevents the growth and/or kills existing cancer cells, it can be referred to as cytostatic and/or cytotoxic.
  • the present invention also covers the use of the pharmaceutical composition according to the present invention for the manufacture of a medicament for the treatment of cancer.
  • the present invention also covers the use of an antibody, which binds to human SRRM2 as described herein, for the manufacture of a medicament for the treatment of cancer.
  • Terms such as “treating” or “treatment” or “to treat” refer to both 1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and 2) prophylactic or preventative measures that prevent or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • a subject is successfully “treated” according to the methods of the present invention or with the pharmaceutical composition or antibody, which binds to human SRRM2 according to the present invention if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; a reduction in the tumor size; inhibition of or an absence of cancer cell infiltration into peripheral organs including the spread of cancer into soft tissue and bone; inhibition of or an absence of tumor metastasis; inhibition or an absence of tumor growth; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; and improvement in quality of life.
  • the antibody to be administered to humans can also be converted to a genetically recombinant antibody that has been engineered artificially, for example, for the purpose of reducing heteroantigenicity in humans.
  • the genetically recombinant antibody encompasses, for example, chimeric antibodies and humanized antibodies as defined herein. These engineered antibodies can be produced using a method known in the art.
  • the present invention provides a method for determining whether a human subject may suffer from cancer, comprising determining in a sample obtained from said human subject whether SRRM2 is present on the cell surface of (cancer) cells comprised by said sample.
  • SRRM2 is also present on the surface of extracellular vesicles obtained from a subject diagnosed with cancer. Accordingly, the present invention further relates to a method for determining whether a human subject may suffer from cancer, comprising determining in a sample obtained from said human subject whether SRRM2 is present on the surface of extracellular vesicles.
  • Extracellular vesicles as used herein may relate to lipid bilayer-delimited particles that are naturally released from almost all types of cell and, unlike a cell, cannot replicate. EVs typically range in diameter from near the size of the smallest physically possible unilamellar liposome (around 20-30 nanometers) to as large as 10 pm or more, although the vast majority of EVs are smaller than 200 nm.
  • EVs can be divided according to size and synthesis route into exosomes, microvesicles and apoptotic bodies. Accordingly, the EV is preferably selected from the group consisting of exosomes, microvesicles and apoptotic bodies. Usually, they carry a cargo of proteins, nucleic acids, lipids, metabolites, and even organelles from the parent cell. Diverse EV subtypes have been proposed. Accordingly, the EV may also be one or more of the following: ectosomes, microvesicles, microparticles, exosomes, oncosomes, apoptotic bodies, exomeres and the like. Preferably, the EV is an oncosome. In the context of EVs, the sample preferably is ascites fluid.
  • EVs may be isolated and/or enriched from the sample by using an antibody or antibody fragment that specifically binds to a biomarker present on the surface of an EV prior to determining in a sample obtained from said human subject whether SRRM2 is present on the surface of extracellular vesicles.
  • biomarkers for EV include, e.g., for exosomes Alix, Tsg101 , tetraspanins such as CD81, CD63 and CD9 or flotillin, for microvesicles integrins, selectins or CD40 and for apoptotic bodies Annexin V or phosphatidylserine. Antibodies against these markers are commercially available, e.g., from Abeam.
  • Said pharmaceutical composition can also be a diagnostic composition, preferably in case it is used in the context of a method for determining whether a human subject may suffer from cancer or a neurodegenerative disease.
  • the present invention also relates to a diagnostic composition, comprising an antibody, preferably a monoclonal antibody, which binds to human Serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of a target cell, preferably a cancer cell, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • SRRM2 Serine/arginine repetitive matrix protein 2
  • Said method for determining whether a human subject may suffer from cancer may comprise the following steps: providing a sample obtained from said human subject, determining in said sample obtained from said human subject whether SRRM2 is present on the cell surface of (cancer) cells comprised by said sample, correlating the presence of SRRM2 on the cell surface of (cancer) cells comprised by said sample with determining whether the human subject may suffer from cancer.
  • a “subject” or “human subject” in the context of the present invention is a human being.
  • the subject may be a patient being suspected of having a disease or clinical condition associated with cancer or being diagnosed with such a disease or clinical condition.
  • the subject may be a patient being suspected of having a disease or clinical condition associated with a neurodegenerative disease or being diagnosed with such a diseases or clinical condition.
  • sample obtained from said human subject is preferably selected from the group consisting of a blood sample, a serum sample, a plasma sample, a cerebrospinal fluid sample, a saliva sample, a solubilised tissue sample and an urine sample or an extract of any of the aforementioned samples.
  • the sample is a serum sample or a plasma sample.
  • the sample is a serum sample for determining whether a human subject may suffer from cancer.
  • the step of “determining in said sample obtained from said human subject whether SRRM2 is present on the cell surface of target cells comprised by said sample” may comprise to determine the presence of SRRM2 or the fragments thereof by contacting the sample with at least one SRRM2 binder.
  • the at least one binder may, for example, be the antibody according to the present invention or as described herein.
  • At least one binder is less than 20 % cross-reactive with other proteins, particularly other peroxiredoxins such as SRRM1, SRRM3, SRRM4 or SRRM5, more preferably less than 15 %, more preferably less than 10 %, more preferably less than 5 %, even more preferably less than 3 %, even more preferably less than 2 % and even more preferably less than 1 % cross reactive.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12, or an antibody, which binds to the same epitope.
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18, or an antibody, which binds to the same epitope.
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24, or an antibody, which binds to the same epitope.
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as
  • the present invention further relates to an antibody, which binds to human SRRM2, wherein said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29, or an antibody, which binds to the same epitope.
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as
  • the present invention also provides the use of the antibody, which binds to human SRRM2 of the present invention in the manufacture of a medicament for the treatment of cancer.
  • the invention additionally provides the antibody, which binds to human SRRM2, of the present invention for use in a method of treating cancer.
  • the antibody, which binds to human SRRM2, of the present invention or described herein may contain human Fc regions that are modified to enhance effector function, for example, antigen-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). This can be achieved by introducing one or more amino acid substitutions in a Fc region of the antibody. For example, cysteine residue(s) can be introduced in the Fc region to allow interchain disulfide bond formation in this region to improve complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC).
  • Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as known to the person skilled in the art.
  • an antibody may be engineered, which has dual Fc regions.
  • the antibodies as described herein may have substitution, deletion, addition and/or insertion of one or more amino acids in their CDR sequences as long as the resulting antibodies are functionally equivalent to the antibodies (a) to (d).
  • the term “functionally equivalent” refers to being comparable in avidity for SRRM2 and cytotoxicity.
  • the term “equivalent” refers to having at least 50 %, preferably having at least 60 %, more preferably having at least 70 %, more preferably having at least 80 %, even more preferably at least 90 %, even more preferably at least 95 % and even more preferably at least 99 % activity, compared with the antibodies (a) to (d).
  • the upper limit of the activity is not particularly limited and may be higher than that of the antibodies (a) to (d).
  • the avidity or cytotoxicity can be assayed by a method generally known by those skilled in the art.
  • the presence of SRRM2 on the cell surface of a target cell or extracellular vesicles can also be indicative that a subject, from whom a sample comprising target cells has been obtained, suffers from a neurodegenerative disease.
  • the target cell preferably is a neuron.
  • the target cell may also be a glial cell.
  • Glial cells include, but are not limited to, astrocytes, oligodendrocytes, ependymal cells, radial glia, Schwann cells, satellite cells, enteric glial cells, and microglia.
  • the sample preferably is obtained from brain tissue, neuronal tissue and/or cerebrospinal fluid.
  • a “neurodegenerative disease” as used herein is characterized by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death.
  • Neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, Batten disease, multiple system atrophy, and prion diseases.
  • the present invention also relates to the pharmaceutical composition of the invention for use in a method for the treatment of a neurodegenerative disease in a human subject.
  • the present invention further relates to the antibody, which binds to human SRRM2, as used herein for use in a method for the treatment of a neurodegenerative disease in a human subject.
  • said neurodegenerative disease is characterized by cells, wherein human SRRM2 is present on their cell surface.
  • the present invention also comprises a method of treating a neurodegenerative disease, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a human subject. Further, the present invention comprises a method of treating a neurodegenerative disease, wherein the method comprises administering a therapeutically effective amount of the antibody, which binds to human SRRM2, described herein to a human subject. It is preferred for said embodiment that said neurodegenerative disease is characterized by cells, wherein human SRRM2 is present on their cell surface.
  • the present invention further relates to a method for determining whether a human subject may suffer from a neurodegenerative disease, comprising determining in a sample obtained from said human subject whether SRRM2 is present on the cell surface of cells comprised by said sample.
  • the present invention further relates to a method for determining whether a human subject may suffer from a neurodegenerative disease, comprising determining in a sample obtained from said human subject whether SRRM2 is present on the surface of extracellular vesicles.
  • Said method for determining whether a human subject may suffer from a neurodegenerative disease may comprise the following steps: providing a sample obtained from said human subject, determining in said sample obtained from said human subject whether SRRM2 is present on the cell surface of target cells comprised by said sample, correlating the presence of SRRM2 on the cell surface of said target cells comprised by said sample with determining whether the human subject may suffer from a neurodegenerative disease.
  • the present invention further relates to an antibody, which binds to human serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of a target cell for use in a method of killing said target cell having SRRM2 present on the cell surface.
  • SRRM2 human serine/arginine repetitive matrix protein 2
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11 , and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12, or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18, or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24, or an antibody, which binds to the same epitope.
  • said antibody for use in a method of killing said target cell having SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29, or an antibody, which binds to the same epitope.
  • the present invention also relates to a method of killing a target cell having serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of said target cell, comprising administering an antibody, which binds to human SRRM2 present on the cell surface of said target cell.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12, or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18, or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24, or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21 , and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29, or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • the present invention further relates to an antibody, which binds to human serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of a target cell for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface.
  • SRRM2 human serine/arginine repetitive matrix protein 2
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 2 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 4 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 6 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • SRRM2 serine/arginine repetitive matrix protein 2
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 99% identity to the amino acid sequence shown in SEQ ID NO: 26 or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11 , and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12, or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18, or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24, or an antibody, which binds to the same epitope.
  • said antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface, said antibody is an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29, or an antibody, which binds to the same epitope.
  • the antibody which binds to human SRRM2 present on the cell surface of a target cell of the present invention, the method of determining whether a human subject may suffer from cancer of the present invention as described herein as well as the respective definitions as described above, also apply for the antibody for use in a method for the treatment of cancer in a subject, comprising, prior to the treatment of cancer in said subject, determining whether a target cell of said subject has SRRM2 present on the cell surface as described herein.
  • SEQ ID NO: 1 shows the amino acid sequence of the VH-region of antibody 13F11.
  • SEQ ID NO: 2 shows the amino acid sequence of the VL-region of antibody 13F11.
  • SEQ ID NO: 3 shows the amino acid sequence of the VH-region of antibody 23A7.
  • SEQ ID NO: 4 shows the amino acid sequence of the VL-region of antibody 23A7.
  • SEQ ID NO: 5 shows the amino acid sequence of the VH-region of antibody 18A4 and of antibody 18A4-2.
  • SEQ ID NO: 6 shows the amino acid sequence of the VL-region of antibody 18A4.
  • SEQ ID NO: 7 shows the amino acid sequence of the VH-CDR1 of antibody 13F11.
  • SEQ ID NO: 8 shows the amino acid sequence of the VH-CDR2 of antibody 13F11.
  • SEQ ID NO: 9 shows the amino acid sequence of the VH-CDR3 of antibody 13F11.
  • SEQ ID NO: 10 shows the amino acid sequence of the VL-CDR1 of antibody 13F11.
  • SEQ ID NO: 11 shows the amino acid sequence of the VL-CDR2 of antibody 13F11.
  • SEQ ID NO: 12 shows the amino acid sequence of the VL-CDR3 of antibody 13F11.
  • SEQ ID NO: 13 shows the amino acid sequence of the VH-CDR1 of antibody 23A7.
  • SEQ ID NO: 14 shows the amino acid sequence of the VH-CDR2 of antibody 23A7.
  • SEQ ID NO: 15 shows the amino acid sequence of the VH-CDR3 of antibody 23A7.
  • SEQ ID NO: 16 shows the amino acid sequence of the VL-CDR1 of antibody 23A7.
  • SEQ ID NO: 17 shows the amino acid sequence of the VL-CDR2 of antibody 23A7.
  • SEQ ID NO: 18 shows the amino acid sequence of the VH-CDR3 of antibody 23A7.
  • SEQ ID NO: 19 shows the amino acid sequence of the VH-CDR1 of antibody 18A4 and of antibody 18A4-2.
  • SEQ ID NO: 20 shows the amino acid sequence of the VH-CDR2 of antibody 18A4 and of antibody 18A4-2.
  • SEQ ID NO: 21 shows the amino acid sequence of the VH-CDR3 of antibody 18A4 and of antibody 18A4-2.
  • SEQ ID NO: 22 shows the amino acid sequence of the VL-CDR1 of antibody 18A4.
  • SEQ ID NO: 23 shows the amino acid sequence of the VL-CDR2 of antibody 18A4.
  • SEQ ID NO: 24 shows the amino acid sequence of the VL-CDR3 of antibody 18A4.
  • SEQ ID NO: 25 shows the amino acid sequence of SRRM2 as shown in UniProt database entry Q9LIQ35, version 2 of 6 March 2007.
  • SEQ ID NO: 26 shows the amino acid sequence of the VL-region of antibody 18A4-2.
  • SEQ ID NO: 27 shows the amino acid sequence of the VL-CDR1 of antibody 18A4-2.
  • SEQ ID NO: 28 shows the amino acid sequence of the VL-CDR2 of antibody 18A4-2.
  • SEQ ID NO: 29 shows the amino acid sequence of the VL-CDR2 of antibody 18A4-2.
  • SEQ ID NO: 30 shows the amino acid sequence of fragment tr04.
  • VH variable heavy chain
  • VH variable heavy chain
  • VL iable light chain
  • CDR complementarity determining region
  • VH-CDR CDR of a variable heavy region
  • VL-CDR CDR of a variable light ion
  • CDRs can be determined by using the Kabat algorithm, e.g., http://abysis.org/abysis/.
  • “less than 20” means less than the number indicated.
  • “more than” or “greater than” means more than or greater than the indicated number, e.g. “more than 80 %” means more than or greater than the indicated number of 80 %.
  • the invention is further characterized by the following items:
  • composition comprising an antibody, preferably a monoclonal antibody, which binds to human Serine/arginine repetitive matrix protein 2 (SRRM2) present on the cell surface of a target cell and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • SRRM2 Serine/arginine repetitive matrix protein 2
  • composition of any one of the preceding items, wherein said antibody is part of a chimeric antigen receptor (CAR).
  • CAR chimeric antigen receptor
  • composition of item 5 wherein said CAR is comprised by a T cell, NK cell, NK-T cell or macrophage.
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24;
  • compositions of any one of the preceding items for use in a method for the treatment of cancer in a human subject preferably wherein said cancer is characterized by cells, wherein human SRRM2 is present on their cell surface.
  • a method for determining whether a human subject may suffer from cancer comprising determining in a sample obtained from said human subject whether SRRM2 is present on the cell surface of cells comprised by said sample and/or whether SRRM2 is present on the surface of extracellular vesicles.
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4;
  • an antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence with at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6;
  • An antibody which binds to human SRRM2 present on the cell surface of a target cell comprising
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 18;
  • an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 21, and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 24;
  • PBMCs peripheral blood mononuclear cells
  • SRRM2 For flow cytometric analysis of SRRM2 expression, cells were stained with either of the three SRRM2-specific antibodies in FACS-Buffer (PBS + 2 % FSC) or with an isotype control antibody for 20 min followed by staining with an anti-rat-Alexa Fluor® 647 secondary antibody (Jackson Immuno Research). All stainings were performed on ice.
  • SRRM2-specific CRISPR-RNAs were designed with a freely available online tool (IDT). Each of those different specific crRNAs were fused to a transactivating RNA (tracrRNA) building a guideRNA (gRNA), which was then complexed with CAS9 Nuclease. Individual Complex-combinations were introduced into A549 lung cancer cells by electroporation using a 4D-Nucleofector Protocol from Lonza. Electroporated cells were analyzed by Fluorescence Activated Cell Sorting (FACS) one week later for binding of SRRM2 antibodies 13F11, 18A4 and 23A7. Cell clones were generated by sorting and limited dilution cloning.
  • FACS Fluorescence Activated Cell Sorting
  • clones were re-analyzed by FACS. Identified knockout clones were then checked by screening for CRISPR/CAS9 mediated mutation. Therefore, genomic DNA from parental cells and knockout clones were isolated, sequenced and compared to the wildtype sequence.
  • nuclei were stained with DAPI, a mounting medium (Vectashield) was added and cover slips were mounted upside-down on a microscope slides. Slides were analyzed on a Leica SP8X STED microscope using the Leica LAS X software.
  • Paraffin sections were mounted onto superform plus slides. After fixation in acetone, slides were incubated with the primary antibody followed by an incubation with a suitable biotinylated secondary antibody. Slides were developed with 0.01 % 3-amino-9-ethylcarbazole (AEC) as chromogen. After counterstaining with hematoxylin, slides were cover-slipped with Kaiser’s glycerol gelatine.
  • AEC 3-amino-9-ethylcarbazole
  • Example 1 shows that the monoclonal antibodies 13F11, 18A4 and 23A7 specifically precipitate SRRM2 from the lysates of various cancer cell lines. Any of the antibody was coupled to activated cyanogen bromide beads and incubated with lysate of ovarian cancer cell lines at 4 °C overnight. The next day, beads were precipitated by centrifugation, the bound proteins were eluted in Laemmli buffer and analyzed by mass spectrometry. Three independent experiments revealed confidence scores of >60, and enrichments of precipitated SRRM2 by factors of 1824.2, 182.6 and 40.8 as compared to precipitation with an isotype control antibody (see Fig. 1).
  • Example 2 shows that SRRM2 is exposed on the surface of various cancer cell lines.
  • Cells were incubated with 13F11 (solid lines in Fig. 2A and Fig. 2B) or an isotype control antibody (dotted line in Fig. 2A, tinted histogram in Fig. 2B).
  • Cells were then washed and incubated with an Alexa647 labeled anti-rat IgG antibody. Fluorescence was then measured by flow cytometry on a FACS Canto. Normal PBMCs do not express surface SRRM2.
  • Example 3 shows that 13F11, 23A7 and 18A4 are SRRM2-specific: A549 human lung cancer cells were transfected with a ribonucleoprotein complex consisting of SRRM2-specific gRNAs and Cas9 protein. Seven days later, binding of the antibodies to knockout and wildtype cells was compared by flow cytometry. For this, A549 Wildtype (bold line) and the A549 SRRM Knockout line #25 (tinted histogram) were incubated with any of the three antibodies 13F11, 18A4 and 23A7. Cells were washed and then incubated with an Alexa647 labeled anti-rat secondary antibody. Fluorescence was then measured on a FACS Canto. An isotype control antibody was included as a negative control (dotted line). Reduced fluorescence intensity of line #25 indicates the specificities of the antibodies for SRRM2 (see Fig. 3).
  • Example 4 further illustrates the membrane localization of SRRM2 on human cancer cells.
  • SK-OV-3 human ovarian cancer cells were grown on microscope slides, washed in PBS, and incubated with the antibody 13F11. Incubation with the antibody prior to fixation secures that cells were vital and thus that the antibody bound to intact cells. Then, cells were fixed with 4 % paraformaldehyde and again incubated with an Alexa647-coupled suitable anti-rat IgG secondary antibody. The staining was then inspected by confocal fluorescence microscopy (see Fig. 4).
  • Example 5 even further illustrates the membrane localization of SRRM2 on human cancer cells.
  • UWB1.289 human ovarian cancer cells were co-stained with the SRRM2- specific antibody 13F11 (magenta) and antibody18F10, specific for the membrane protein CD47 (green). After fixation as described above, cells were analyzed by confocal fluorescence microscopy. Nuclei were counter-stained with DAPI (blue). The white color in the merged pictures indicates co-localization of both antibodies (see Fig. 5).
  • Example 6 shows that SRRM2 is localized to lipid rafts of other membrane sub-domains resistant to lysis with RIPA buffer.
  • SK-OV-3 cells were lysed in RIPA buffer (150 mM NaCI, 50 mM Tris/HCI (pH 7,4), 1 % Igepal, 0.5 % Natriumdesoxycholat). The lysate was then loaded onto a Optiprep gradient and centrifuged at 32.000 rpm overnight. Fractions of 400 pl were taken and 2 pl of each fraction was spotted onto a nitrocellulose filter. These filters were then incubated with 13F11 or an antibody specific for the tetraspanin CD63.
  • SRRM2 is present in fractions 2 and 3 of the gradient, corresponding to a density of approx. 1.13-1.19 g/ml and thus to the supposed density of lipid rafts and other insoluble membrane microdomains. Soluble proteins, which have a higher specific density, are mainly localized to fractions 7-10 of the gradient.
  • Example 7 shows that surface-SRRM2-positive SK-OV-3-cells activate SRRM2-specific 13F11 CAR-T-cells.
  • Primary T cells from two donors (1 and 2) were transduced with a retroviral vector encoding a chimeric antigen receptor (CAR) with a single-chain construct derived from antibody 13F11. Expression of the CAR on transduced T cells was tested by flow cytometry with a goat-anti rat IgG antibody (not shown).
  • CAR chimeric antigen receptor
  • SK-OV-3 cells were incubated for 24 h with 13F11 CAR-T cells (columns 3-4 of the blots) of non-transduced control T cells (column 1-2 of the blots) at the E:T ratios indicated on the X-axis. Finally, interferon-gamma in the supernatants, which is a marker of T-cell activation, was quantified with a commercial ELISA assay (see Fig. 7).
  • Example 8 shows that the SRRM2-specific CAR-T cells also kill SRRM2-positive HO- 8910 target cells. Here, killing was measured with a commercial LDH assay (see Fig. 8).
  • Example 9 shows that extracellular vesicles (EVs) isolated from ascites of a patient with ovarian cancer are SRRM2-positive. EVs were isolated by ultracentrifugation and density gradient centrifugation. A sample of the EVs was spotted onto a nitrocellulose membrane and incubated with 13F11 , 18A4 or 23A7, followed by incubation with a HRP-coupled anti-rat secondary antibody. Membranes were developed with ECL (see Fig. 9). As a control, an irrelevant isotype antibody was used (rightmost image 4 in Figure 9).
  • Example 10 shows that surface SRRM2 on cancer cells is induced by hypoxia.
  • Most marketed therapeutic antibodies for the treatment of solid cancer are targeting hypoxia-induced proteins. Because hypoxia is a common hallmark of solid tumors, these proteins are highly expressed on cancer cells. Also, induction of translation in hypoxia can be considered a hint towards the relevance of such proteins for the survival and growth of cancer cells under hypoxic conditions.
  • SRRM2 is induced in hypoxia, the inventors cultivated human A549, U138, HT29 and SK-OV-3 cells under normoxic conditions (approx. 18 % O 2 ) or under hypoxia (1 % O 2 ) in standard DM EM medium for 72 h.
  • Example 11 shows 11 F11 is internalized.
  • Monoclonal antibodies can be modified to carry a toxin or radioactivity.
  • ADCs 'antibody drug conjugates'
  • the cells were stained with an Alexa647-coupled secondary anti-rat IgG antibody and fluorescence was measured by flow cytometry.
  • An decrease in fluorescence over time indicates an internalization of the SRRM2-13F11 complex, resulting in reduced binding of the secondary antibody.
  • the fluorescence measured after 0 hours at 37 °C was set to 100 % (see Fig. 11).
  • Example 12 shows that SRRM2 is expressed on the surface of primary pancreatic cancer. Paraffine sections derived from specimens of pancreatic cancer or normal pancreas were stained with 18A4, followed by a HRP-coupled secondary antibody and developed with ABC. As shown in Figure 12, cancer cells clearly reveal membrane localization of SRRM2 (arrows) while in normal cells, the protein shows a nuclear staining pattern (arrowheads).
  • Example 13 shows that SRRM2 is expressed on the surface of lung metastases from human HLICT-1 cells xenotransplanted into immunocompromised SCID mice. In contrast, normal mouse tissues (brain, kidney, liver) reveal nuclear staining pattern.
  • Example 14 shows that 13F11, 18A4-2 and 23A7 binds to a fragment (called herein tr04, SEQ ID NO: 30) spanning amino acids 1889 to 2150 of SRRM2 (see Figure 15).
  • HEK293 cells were transfected with an expression plasmid encoding amino acids 1889 to 2150 of SRRM2 fused to a HIS-tag (HEK293-trO4). Immunoprecipitations were performed with bead- coupled SRRM2-specific antibodies 13F11, 18A4-2 and 23A7 and lysates of transfected cells or, as control, non-transfected 293 cells (HEK293).
  • Precipitated proteins were separated by PAGE and transferred to a PVDF membrane, which was then incubated with an anti-rat antibody coupled to HRP. Finally, the blot was developed with ECL. As additional controls, lysates from transfected and non-transfected cells were included.
  • Example 15 shows that normal tissues from Cynomolgus monkey either stain negative for SRRM2 or show cytoplasmic/nuclear staining (see Figure 16) as revealed by immunohistochemistry. No membrane staining was observed.
  • FFPE tissues from cynomolgus monkey were incubated with 13F11 antibody, followed by incubation with a goat anti-rat IgG antibody coupled to HRP (ImmPRESS HRP Peroxidase detection kit; https://vectorlabs.com/products/enzyme- polymer/immpress-hrp-goat-anti-rat-igg-kit).
  • Example 16 shows that the majority of tumor samples derived from different locations (bile duct, ovary, pancreas, stomach) reveal SRRM2 membrane staining (see Figure 17).
  • Formalin-fixed paraffin embedded (FFPE) tumor tissues and adjacent normal tissues were stained with 13F11 , followed by incubation with a rat-specific secondary antibody coupled with HRP. Tissues were inspected by a trained pathologist and staining intensity was scored from 0 (negative) to 3+ (strong expression on the majority of cells).
  • FFPE paraffin embedded
  • Example 17 shows the sequences of the light and heavy chains and sequences of its fragments of antibody 18A4-2 (see Figure 18).
  • Example 18 shows that the SRRM2-specific antibodies 13F11 , 18A4-2 and 23A7 bind to fragment tr04 (see Figure 19).
  • a 96-well cell cluster plate was coated with purified SRRM2-trO4- HIS or, as a control, MISP-HIS protein (each at 50 pg/ml) overnight and then blocked with nonfat milk powder in TBST.
  • Antibodies 13F11 , 18A4-2, 23A7 or an anti-MISP antibody were added for 2 hours at room temperature. After washing, the plate was incubated with a secondary antirat IgG antibody coupled to HRP and developed with TMB. After stopping the reaction with H 2 SO 4 , the absorbance was measured at 450 nm.

Abstract

La présente invention concerne une composition pharmaceutique comprenant un anticorps qui se lie à SRRM2 humain présent sur la surface cellulaire d'une cellule cible et éventuellement un véhicule, un diluant ou un excipient de qualité pharmaceutique. La présente invention concerne en outre ladite composition pharmaceutique destinée à être utilisée dans une méthode de traitement du cancer chez un sujet humain. L'invention concerne en outre une méthode permettant de déterminer si un sujet humain est susceptible de souffrir d'un cancer, consistant à déterminer dans un échantillon obtenu dudit sujet humain si SRRM2 est présent sur la surface cellulaire de cellules prélevées contenues dans ledit échantillon. De plus, un anticorps, qui se lie à SRRM2 humain présent sur la surface cellulaire d'une cellule cible, est utilisé et un anticorps, qui se lie à SRRM2 humain présent sur la surface cellulaire d'une cellule cible destiné à une utilisation dans une méthode de destruction de ladite cellule cible ayant SRRM2 humain présent sur la surface cellulaire.
PCT/EP2023/056397 2022-03-14 2023-03-14 Composition comprenant un anticorps se liant à srrm2 humain présent sur la surface cellulaire d'une cellule cible WO2023174897A1 (fr)

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Citations (1)

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