Compositions Comprising Antibodies That Bind to Human SRRM2 Present on the Cell Surface of Target Cells

Abstract

The present invention provides a pharmaceutical composition comprising an antibody that binds to human SRRM2 present on the cell surface of a target cell, and optionally a pharma- ceutically acceptable carrier, diluent, or excipient. The present invention also provides a pharmaceutical composition for use in a method for treating cancer in a human subject. In addition, a method for determining whether a human subject may be affected by cancer is provided, the method comprising determining whether SRRM2 is present on the cell surface of cells contained in a sample obtained from the human subject. In addition, an antibody that binds to human SRRM2 present on the cell surface of a target cell and an antibody that binds to human SRRM2 present on the cell surface of a target cell for use in a method for killing a target cell having human SRRM2 present on its cell surface are also provided.

Description

[Technical field]

[0001] TECHNICAL FIELD OF THEINVENTION The present invention provides a pharmaceutical composition comprising an antibody that binds to human SRRM2 present on the cell surface of a target cell, and optionally a pharma- ceutically acceptable carrier, diluent, or excipient. The present invention further provides a pharmaceutical composition for use in a method for treating cancer in a human subject. Also provided is a method for determining whether a human subject may be suffering from cancer, comprising determining whether SRRM2 is present on the cell surface of cells contained in a sample obtained from the human subject. In addition, an antibody that binds to human SRRM2 present on the cell surface of a target cell is also provided. The present invention further provides an antibody that binds to human SRRM2 present on the cell surface of a target cell for use in a method for killing a target cell having SRRM2 present on its cell surface. Also provided is a method for killing a target cell having SRRM2 present on its cell surface, comprising administering an antibody that binds to human SRRM2 present on the cell surface of the target cell. The present invention further relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell for use in a method for treating cancer in a subject, comprising determining whether a target cell of the subject has SRRM2 present on its cell surface prior to treating the cancer in the subject. [Background technology]

[0002] In 2015, approximately 90.5 million people were affected by cancer. As of 2019, approximately 18 million new cases occur annually. Each year, cancer caused approximately 8.8 million deaths (15.7% of deaths). The most common types of cancer in men are lung, prostate, colorectal, and gastric cancer. In women, the most common types are breast, colorectal, lung, and cervical cancer. Non-melanoma skin cancers would account for approximately 40% of cases if included in the total new cancer cases each year. In children, acute lymphoblastic leukemia and brain tumors are the most common, except in Africa, where non-Hodgkin's lymphoma occurs more frequently. In 2012, approximately 165,000 children under the age of 15 were diagnosed with cancer. The risk of cancer increases significantly with age, and many cancers occur more commonly in developed countries. The rate is increasing as more people are living longer and as lifestyle changes occur in developing countries. The economic burden of cancer was estimated at US$ 1.16 trillion per year in 2010.

[0003] Therefore, there remains a need for further cancer biomarkers that allow for the discrimination between healthy non-cancerous cells and cancerous cells.The technical problem underlying this application is therefore the provision of further cancer biomarkers. Summary of the Invention

[0004] This technical problem is solved by the subject matter defined in the claims. The inventors have surprisingly found that serine / arginine repeat matrix protein 2 (SRRM2; UniProt Q9UQ35) is expressed on cancer cells but not on healthy non-cancerous cells. Thus, expression of SRRM2, for example on the cell surface of cells obtained from a patient, is a biomarker for cancer. Moreover, being exclusively expressed on the surface of cancer cells allows for novel cancer-specific therapies.

[0005] Thus, the present invention provides a pharmaceutical composition comprising an antibody that binds to human SRRM2 present on the cell surface of a target cell, and, optionally, a pharma- ceutically acceptable carrier, diluent, or excipient.

[0006] The target cells are preferably cancer cells.

[0007] The antibody that binds to human SRRM2 may have cytotoxic activity. The antibody that binds to human SRRM2 may have ADCC or CDC. The antibody that binds to human SRRM2 may be conjugated with a cytotoxic substance.

[0008] The antibody that binds to human SRRM2 can be part of a chimeric antigen receptor (CAR). The CAR can be contained in a T cell, a NK cell, a NK-T cell, or a macrophage.

[0009] SRRM2, which is preferably present on the cell surface of a target cell, is preferably externalized.

[0010] Antibodies that bind to human SRRM2 are preferably not intracellular antibodies.

[0011] The antibody that binds to human SRRM2 is preferably: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody comprising a heavy chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0012] The antibody that binds to human SRRM2 is preferably: (a) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 9; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 12; an antibody; (b) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 15; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 18; an antibody; (c) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 24; an antibody; (d) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 29; an antibody; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0013] The present invention further relates to the pharmaceutical composition of the present invention for use in a method for treating cancer in a human subject.Preferably, the cancer is characterized by cells that have human SRRM2 present on their cell surface.Preferably, the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, bile duct cancer, oral squamous cell carcinoma, hematological malignancies, or glioma.

[0014] The present invention further relates to a method for determining whether a human subject may be suffering from cancer, the method comprising a step of determining whether SRRM2 is present on the cell surface of cells contained in a sample obtained from the human subject.

[0015] The present invention further relates to a method for determining whether a human subject may be suffering from cancer, the method comprising determining whether SRRM2 is present on the surface of extracellular vesicles in a sample obtained from the human subject.

[0016] The present invention further relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell, the antibody being: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody comprising a heavy chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0017] The present invention further relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell, the antibody comprising: (a) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 9; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 12; an antibody; (b) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 15; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 18; an antibody; (c) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 24; an antibody; (d) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 29; an antibody; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0018] The present invention further relates to antibodies that bind to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of target cells for use in methods of killing target cells having SRRM2 present on their cell surface.

[0019] Such antibodies are preferably: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody comprising a heavy chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0020] Such antibodies preferably are or comprise: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody comprising a heavy chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0021] The present invention further relates to a method for killing a target cell having human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, comprising administering an antibody that binds to SRRM2 present on the cell surface of the target cell.

[0022] For the killing method, it is preferred that the antibody is: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody comprising a heavy chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0023] For the killing method, the antibody is preferably: (a) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 9; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 12; an antibody; (b) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 15; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 18; an antibody; (c) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 24; an antibody; (d) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 29; an antibody; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0024] The present invention further relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell, for use in a method for treating cancer in a subject, comprising the step of determining whether a target cell of the subject has serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface prior to treating the cancer in the subject.

[0025] Such an antibody that binds to human SRRM2 present on the cell surface of target cells for use in a method for treating cancer in a subject, comprising the step of determining whether target cells of the subject have SRRM2 present on their cell surface prior to treating the cancer in the subject, is preferably: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody comprising a heavy chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d).

[0026] Such an antibody that binds to human SRRM2 present on the cell surface of target cells, for use in a method for treating cancer in a subject, comprising the step of determining whether target cells of the subject have SRRM2 present on their cell surface prior to treating the cancer in the subject, preferably is or comprises the following: (a) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 9; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 12; an antibody; (b) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 15; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 18; an antibody; (c) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 24; an antibody; (d) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 29; an antibody; or (e) An antibody that binds to the same epitope on the human SRRM2 protein as that bound by any one of antibodies (a) to (d). [Brief description of the drawings]

[0027] [Figure 1] We show that antibodies 13F11, 23A7, and 18A4 precipitate SRRM2. Cyanogen bromide beads conjugated with any of the three antibodies or an isotype control antibody were incubated overnight with lysates from OVCAR-3 or UWB1.289 ovarian cancer cells. After sedimentation of the beads and incubation in Ramueli buffer, analysis of the eluates by mass spectrometry revealed clear enrichment of SRRM2 by all antibodies compared to the isotype control antibody. [Figure 2A]Surface expression of SRRM2 in various cancer cell lines is shown. Cell lines were incubated with 13F11 (solid lines in Figure 2A and Figure 2B) or isotype control antibody (dotted lines in Figure 2A, lightly colored histogram in Figure 2B). Cells were then washed and incubated with Alexa647-labeled anti-rat IgG antibody. Fluorescence was then measured using a FACS Canto. Normal PBMCs do not express surface SRRM2 (not shown). [Figure 2B] See legend to Figure 2A. [Diagram 3] Showing that 13F11, 23A7, and 18A4 are SRRM2 specific: A549 cells were transfected with a ribonucleoprotein complex consisting of SRRM2-specific gRNA and Cas9. After 7 days, the binding of the antibodies to knockout and wild-type cells was measured by flow cytometry. For this, A549 wild-type (bold line) and A549 SRRM knockout line no. 25 (lightly colored histogram) were incubated with one of the three antibodies 13F11, 18A4, and 23A7. The cells were washed and then incubated with an Alexa647-labeled anti-rat secondary antibody. Fluorescence was then measured using a FACS Canto. An isotype control antibody was included as a negative control (dotted line). [Figure 4] We show that 13F11 binds to live SK-OV-3 cells. SK-OV-3 cells were grown on microscope slides, washed in PBS, and incubated with antibody 13F11. The cells were then fixed with 4% paraformaldehyde and incubated with the appropriate anti-rat IgG secondary antibody conjugated with Alexa647. Surface staining is clearly visible. [Diagram 5] Showing that 18A4 colocalizes with the surface molecule CD47. A549 or UWB1.289 cells were grown on coverslips, washed, and incubated with antibodies 18A4 (SRRM2, magenta) and 18F10 (CD47, green). Cells were fixed with 4% paraformaldehyde and analyzed using confocal fluorescence microscopy. Nuclei were counterstained with DAPI (blue). [Figure 6] We show that SRRM2 localizes to lipid rafts or another type of insoluble membrane subdomain. Cells were lysed in RIPA buffer and the lysates were loaded onto a density gradient. After centrifugation, 10 fractions of 400 μl each were collected and samples of these fractions were spotted onto a nitrocellulose membrane. The membrane was incubated with the 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 are therefore included in the range of lipid rafts. Soluble proteins with a higher specific density are mainly present in fractions 7-10. [Figure 7] We show that SK-OV-3 cells positive for surface SRRM2 activate SRRM2-specific 13F11 CAR-T cells. Primary T cells from two donors (1 and 2) were transduced with retroviral vectors encoding CAR constructs with single-chain constructs derived from antibody 13F11. CAR expression was examined by flow cytometry using a goat anti-rat IgG antibody (not shown). SK-OV-3 cells were incubated with 13F11 CAR-T cells (columns 3-4 of the blot) or non-transduced control T cells (columns 1-2 of the blot) at the ratios indicated on the x-axis for 24 h. Interferon-γ in the supernatants, as a marker of T cell activation, was then quantified using a commercially available ELISA assay. [Figure 8] Figure 1 shows that SRRM2-specific CAR-T cells kill SRRM2-positive HO-8910 target cells. Primary T cells from one donor were transduced with a retroviral vector encoding a CAR construct with a single-chain construct derived from the antibody 13F11. CAR expression was examined by flow cytometry using a goat anti-rat IgG antibody (not shown). SK-OV-3 cells were incubated with 13F11 CAR-T cells or non-transduced control T cells (mock-T) at the ratios shown on the X-axis for 24 hours. Killing was then measured using a commercially available lactate dehydrogenase (LDH) assay. [Figure 9]We show that SRRM2 is released via extracellular vesicles (EVs): EVs isolated from ascites of ovarian cancer patients were isolated by established techniques including differential centrifugation, ultracentrifugation, and density gradient purification. 2 μl of each of this EV preparation was then spotted onto strips of nitrocellulose membrane and incubated overnight at 4 °C with (from left to right) 13F11, 18A4, 23A7, or isotype control antibodies. After washing, the membranes were incubated with the appropriate secondary antibody (goat anti-rat IgG conjugated with horseradish peroxidase) for 2 h and developed using ECL. [Figure 10] Figure 1 shows that SRRM2 surface expression in cancer cells is induced by hypoxia. Various cancer cell lines were incubated in normoxia or hypoxia (1% O2) for 72 hours. SRRM2 surface expression was measured using 13F11 labeled with Alexa647. Mean fluorescence levels are shown. Isotype antibody was used as a control. [Figure 11] We show that the antibody 13F11 is internalized upon binding to SRRM2. SK-OV-3 ovarian cancer cells were incubated with 13F11 for 10 min at room temperature and then washed to remove free antibody. Cell samples were then incubated at 37°C for 1-5 h or stored on ice (=0 h). Cells were then stained with an anti-rat IgG secondary antibody conjugated with Alexa647 and fluorescence was measured by flow cytometry. The decrease in fluorescence over time indicates internalization of the SRRM2-13F11 complex. Fluorescence measured after 0 h at 37°C was set to 100%. [Figure 12] Sections of pancreatic cancer and normal pancreas stained with 18A4 are shown, where membranous staining is visible in the cancer cells, whereas normal pancreatic cells show nuclear staining. [Figure 13] Shows membrane localization of SRRM2 in xenografted human HUCCT-1 cells. Again, normal mouse tissues clearly show only nuclear staining. [Figure 14] The sequences of antibodies 13F11, 23A7, and 18A4 are shown, including the light and heavy chains with their respective CDR1, CDR2, and CDR3 sequences. [Figure 15] We show that 13F11, 18A4-2, and 23A7 bind to a fragment spanning amino acids 1889-2150 of SRRM2 (herein referred to as tr04, SEQ ID NO: 30). HEK293 cells were transfected with an expression plasmid encoding amino acids 1889-2150 of SRRM2 fused to a HIS tag (HEK293-tr04). Immunoprecipitation was performed using bead-bound SRRM2-specific antibodies 13F11, 18A4-2, and 23A7 and lysates of transfected cells or non-transfected 293 cells (HEK293) as a control. Precipitated proteins were separated by PAGE and transferred to a PVDF membrane, which was then incubated with an anti-rat antibody conjugated to HRP. Finally, the blots were developed using ECL. As additional controls, lysates of transfected and non-transfected cells were included. [Figure 16] Figure 1 shows that normal tissues from cynomolgus monkeys stain negatively or show cytoplasmic / nuclear staining for SRRM2 as revealed by immunohistochemistry. No membrane staining was observed. Mem=membrane; Cyto=cytoplasmic; Nucl=nucleus. FFPE tissues from cynomolgus monkeys were incubated with 13F11 antibody followed by incubation with goat anti-rat IgG antibody conjugated with HRP (ImmPRESS HRP Peroxidase Detection Kit; https: / / vectorlabs.com / products / enzyme-polymer / immpress-hrp-goat-anti-rat-igg-kit). [Figure 17] We show that the majority of tumor samples from various sites (bile duct, ovary, pancreas, stomach) show 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 conjugated to HRP. Tissues were examined by trained pathologists and the staining intensity was scored from 0 (negative) to 3+ (strong expression in the majority of cells). [Figure 18]The sequences of the light and heavy chain variable regions of antibody 18A4-2 are shown. [Figure 19] We show that SRRM2-specific antibodies 13F11, 18A4-2, and 23A7 bind to fragment tr04. 96-well cell cluster plates were coated overnight with purified SRRM2-tr04-HIS, or MISP-HIS protein as a control (50 μg / ml each), and then blocked with nonfat dry milk in TBST. Antibodies 13F11, 18A4-2, 23A7, or anti-MISP antibodies were then added for 2 h at room temperature. After washing, the plates were incubated with anti-rat IgG secondary antibody conjugated to HRP and developed with TMB. After stopping the reaction with H2SO4, the absorbance was measured at 450 nm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Detailed Description of the Invention Although SRRM2 has been widely described in the prior art as a protein that is localized in the nucleus, particularly in nuclear speckles, the present inventors have surprisingly found that SRRM2 is present on the cell surface of cancer cells (see, for example, Figures 2-5, 12, and 13). Serine / arginine repeat matrix protein 2 (SRRM2; UniProt Q9UQ35) plays a key role in pre-mRNA splicing and is a major component of the spliceosome. Thus, SRRM2 is not present on the cell surface of healthy cells. However, in the context of cancer, SRRM can be considered to be "externalized", i.e., it is no longer only present in the nucleus, but also on the cell surface of cancer cells. Thus, due to its localization in the nucleus, particularly in nuclear speckles, it was not previously known that SRRM2 could be used for therapeutic purposes. However, the present inventors have surprisingly found that SRRM2 is present on the cell surface of cancer cells, and thus it is now possible to target these cells for the treatment of cancer. An exemplary sequence of SRRM2 is provided by UniProt database entry Q9UQ35, version 2, on March 6, 2007, and is exemplified in SEQ ID NO:25.

[0029] The SRRM2 protein in the context of the present invention may be the SRRM2 protein having SEQ ID NO: 25, or may be a modified protein having an amino acid sequence derived from the aforementioned sequence by modifying one or more amino acids. Examples of modified proteins having a sequence derived from the aforementioned sequence by modifying one or more amino acids may 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. Alternatively, partial peptides of these SRRM2 proteins may be used.

[0030] The term "homology", as used herein in its ordinary sense, includes identical amino acids as well as amino acids that are considered to be conservative substitutions (e.g., replacing glutamic acid residues with aspartic acid residues) at equivalent positions in the linear amino acid sequences of two proteins being compared to each other. "Identity" or "sequence identity" refers to a property of sequences that indicates the degree of their similarity or relatedness. The term "sequence identity" or "identity", as used herein, refers to the percentage of pairwise identical residues relative to the number of residues in the longer of the two sequences after (homology) alignment of the sequence of the polypeptide of the present invention with the sequence in question. Identity is evaluated by dividing the number of identical residues by the total number of residues and multiplying the result by 100.

[0031] The percentage of sequence homology or sequence identity can be measured herein, for example, using the BLASTP program, version blastp 2.2.5 (November 16, 2002; see Altschul, SF et al. (1997) Nucl. Acids Res. 25, 3389-3402). In this embodiment, the percentage of homology is based on an alignment of the entire polypeptide sequence (matrix: BLOSUM62; gap cost: 11.1; cutoff value 10 -3 ), optionally including the propeptide sequence, and using human IL-4 as a reference in pairwise comparisons. This is calculated as a percentage of the number of resulting "positives" (homologous amino acids) in the BLASTP program output divided by the total number of amino acids selected by the program for the alignment. Note in this context that this total number of selected amino acids may differ from the length of the porcine NTCP.

[0032] The SRRM2 protein used in the present invention is not limited by its origin, and is preferably a human SRRM2 protein.

[0033] The term "antibody", as used herein and in the context of the present invention, may include chimeric antibodies, humanized antibodies, monovalent antibodies, multivalent antibodies, minibodies, diabodies, or scFvs.

[0034] Chimeric antibody refers to an antibody that contains variable and constant regions of different origins linked together. For example, a mouse-human heterochimeric antibody is an antibody that contains the heavy and light chain variable regions of a mouse antibody and the heavy and light chain constant regions of a human antibody. The DNA encoding the variable region of a mouse antibody and the DNA encoding the constant region of a human antibody can be linked, and the linked product can be incorporated into an expression vector to produce a recombinant vector that expresses a chimeric antibody. Cells transformed with these vectors (recombinant cells) can be cultured to express the DNA insert, and the chimeric antibody produced during the culture can be obtained.

[0035] Generally, a chimeric antibody comprises an antibody variable region derived from a non-human animal and a constant region derived from a human antibody. On the other hand, a humanized antibody comprises an antibody complementarity determining region (CDR) derived from a non-human animal, a framework region (FR) derived from a human antibody, and a constant region derived from a human antibody. A humanized antibody is also called a reshaped human antibody. Specifically, for example, a humanized antibody comprising a non-human animal (e.g., mouse) antibody CDR grafted onto a human antibody is known in the art. A humanized antibody is useful as an active ingredient of a therapeutic substance of the present invention because it has reduced antigenicity in the human body.

[0036] Each antibody variable region usually contains three CDRs flanked by four FRs. The CDR region essentially determines the binding specificity of the antibody. CDRs have diverse amino acid sequences. In contrast, the amino acid sequences constituting FRs often show high homology between antibodies with different binding specificities. Therefore, it is generally believed that the binding specificity of one antibody can be transferred to another antibody by CDR grafting.

[0037] The antibody that binds to human SRRM2 and is present in the pharmaceutical composition of the present invention may include bivalent antibodies, such as IgG (IgG1, IgG2, IgG4, etc.), and also monovalent antibodies, or multivalent antibodies, such as IgM, as long as these antibodies bind to SRRM2 protein. The multivalent antibody that may be present in the pharmaceutical composition of the present invention may include a multivalent antibody in which all of the antigen-binding sites are the same as each other, or a multivalent antibody in which some or all of the antigen-binding sites are different from each other. Preferably, the antibody that binds to human SRRM2 is an IgG antibody.

[0038] The antibody that binds to human SRRM2 and is present in the pharmaceutical composition of the present invention may also be a small molecule antibody including an antibody fragment in which a part of a full-length antibody (e.g., full-length IgG) is deleted. Such partial deletion of an antibody molecule is acceptable as long as the resulting antibody fragment can bind to SRRM2. The antibody fragment used in the pharmaceutical composition of the present invention preferably includes one or both of a heavy chain variable (VH) region and a light chain variable (VL) region. In addition, the antibody fragment used in the pharmaceutical composition of the present invention preferably includes a CDR. The number of CDRs included in the antibody fragment used in the pharmaceutical composition of the present invention is not particularly limited, but is preferably at least six CDRs, i.e., CDR1, CDR2, and CDR3 of the heavy chain, and CDR1, CDR2, and CDR3 of the light chain.

[0039] The amino acid sequence of VH or VL may include one or more substitutions, deletions, additions, and / or insertions. Furthermore, the antibody or antibody fragment that can be used in the pharmaceutical composition of the present invention may lack a portion of one or both of VH and VL, as long as the resulting antibody fragment can bind to human SRRM2. Furthermore, the variable region may be chimerized or humanized. Specific examples of antibody fragments may include Fab, Fab', F(ab')2, and Fv. Furthermore, specific examples of small molecule antibodies may include Fab, Fab', F(ab')2, Fv, scFv (single chain Fv), diabody, sc(Fv)2 (single chain (Fv)2), and scFv-Fc. In the present invention, the small molecule antibody is preferably a diabody or sc(Fv)2. These antibody multimers (e.g., dimers, trimers, tetramers, and polymers) are also included in the small molecule antibodies that can be used in the pharmaceutical composition of the present invention.

[0040] 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. A diabody is a dimer containing two polypeptide chains. Usually, each polypeptide chain constituting a dimer contains a heavy chain variable region and a light chain variable region on the same chain, linked via a linker. The linker in a diabody is generally very short, so that pairing between the heavy chain variable region and the light chain variable region on the same chain is not possible. Specifically, the number of amino acid residues constituting the linker is, for example, about 5 residues. Therefore, the heavy chain variable region and the light chain variable region encoded on the same polypeptide chain cannot be combined to form a single chain variable region fragment. Instead, they form a dimer by pairing with another single chain variable region fragment. As a result, a diabody has two antigen binding sites.

[0041] When used in the context of the present invention, scFv may be obtained by linking the heavy and light chain variable regions of an antibody. In scFv, the heavy and light chain variable regions are linked via a linker, preferably a peptide linker. The heavy and light chain variable regions in scFv may be derived from any of the antibodies described herein. The peptide linker linking the variable regions is not particularly limited. For example, any single chain peptide of about 3 to 25 residues can be used as a linker.

[0042] Antibodies that bind to human SRRM2 used in pharmaceutical compositions, and that bind to human SRRM2 according to the present invention, can also include binding entities, such as lipocalins, aptamers, or anticalins.

[0043] The antibody that binds to human SRRM2 used in the present invention can have various forms. However, the antibody must bind to SRRM2 protein, and is not particularly limited by its origin, type, shape, etc., but may have cytotoxic activity. Specifically, antibodies such as those derived from non-human animals (e.g., mouse antibodies, rat antibodies, or camel antibodies), antibodies derived from humans, chimeric antibodies, or humanized antibodies, as described above, can be used. In one embodiment, the antibody that binds to human SRRM2 used in the present invention may be a polyclonal antibody or a monoclonal antibody, and is preferably a monoclonal antibody.

[0044] The antibody that binds to human SRRM2 used in the present invention can be obtained as a polyclonal antibody or a monoclonal antibody by using a means known in the art. The antibody used in the present invention is particularly preferably a monoclonal antibody derived from a mammal. The monoclonal antibody derived from a mammal includes, for example, those produced by hybridomas and those produced by a host transformed with an expression vector containing an antibody gene by a genetic engineering approach.

[0045] The antibody that binds to human SRRM2 may be modified with various molecules, such as polyethylene glycol (PEG). Furthermore, the antibody that binds to human SRRM2 may also be modified with a cytotoxic agent, such as a chemotherapeutic agent or a radioactive chemical.

[0046] Specific examples of antibodies used in the present invention that recognize and bind to SRRM2 present on the cell surface of target cells, such as cancer cells, may include the antibodies shown and described herein.

[0047] As mentioned above, the antibody that binds to human SRRM2 of the present invention or that is used in the pharmaceutical composition of the present invention or in the method of the present invention, which contains one or more amino acid substitutions, deletions, additions, and / or insertions, is also included in the scope of the present invention and may be generated or naturally occurring. Examples of methods for introducing mutations into a 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). This is one of the methods well known to those skilled in the art for generating a polypeptide functionally equivalent to a certain polypeptide. Those skilled in the art can use such methods to appropriately introduce mutations into the antibody of the present invention or the antibody used in the pharmaceutical composition of the present invention or in the method of the present invention, thereby generating an antibody functionally equivalent to such an antibody. Furthermore, amino acid mutations may occur in nature.An antibody having an amino acid sequence derived from the amino acid sequence of the antibody of the present invention or the antibody used in the pharmaceutical composition of the present invention or the method of the present invention, which contains one or more amino acid mutations, is a functional equivalent or variant of the antibody, and is also included in the antibody of the present invention or the antibody used in the pharmaceutical composition of the present invention or the method of the present invention.

[0048] The number of amino acids to be mutated in such variants is usually within 50 amino acids, preferably within 30 amino acids, and more preferably within 10 amino acids (eg, within 5 amino acids).

[0049] For the amino acid residues to be mutated, this mutation is preferably made conservatively between amino acids with the same side chain properties.For example, the following classifications based on the properties of amino acid side chains have been established: 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 with aliphatic side chains (G, A, V, L, I, and P), amino acids with side chains that contain hydroxyl groups (S, T, and Y), amino acids with side chains that contain sulfur atoms (C and M), amino acids with side chains that contain carboxylic acids and amides (D, N, E, and Q), amino acids with side chains that contain bases (R, K, and H), and amino acids with side chains that contain aromatic groups (H, F, Y, and W) (all symbols in brackets represent the one-letter code of amino acids).

[0050] It is known that a polypeptide having an amino acid sequence modified by the deletion and / or addition of one or more amino acid residues from a certain amino acid sequence and / or their replacement with other amino acids maintains the biological activity of the original polypeptide (Mark, DF et al., 1984) (Wang, A. et al., 1982). Specifically, when an amino acid in an amino acid sequence constituting a certain polypeptide is replaced with an amino acid classified in the same group, it is generally said that the polypeptide is likely to maintain its activity. In the present invention, the substitution between amino acids in the same amino acid group as described above is called a conservative substitution.

[0051] The term "surface" or specifically "cell surface" as used herein refers to cell membrane. Cell membrane (also known as plasma membrane) is a thin membrane that surrounds every living cell and defines the boundary between the cell and its surrounding environment. Enclosed by this cell membrane are the components of the cell, often large, water-soluble, highly charged molecules, such as proteins, nucleic acids, carbohydrates, and substances involved in cell metabolism. Thus, the cell membrane has at least two functions: first, it is a barrier that keeps the components of the cell inside and the unwanted substances outside; second, it is a gate that allows the transport of essential nutrients into the cell and the removal of waste products from the cell. ER-derived vesicles can also participate in the assembly or formation of the cell membrane.

[0052] The antibody that binds to human SRRM2 can preferably bind to the SRRM2 polypeptide outside the cell. In other words, the antibody described herein can have the ability to bind to SRRM2, including SRRM2 present on the cell surface when it is outside the cell. Therefore, the antibody that binds to human SRRM2 is preferably not an intracellular antibody, also called an intracellular antibody. An "intracellular antibody" (from "intracellular" and "antibody") is an antibody that acts intracellularly to bind to an intracellular protein. This requires the expression of the antibody in the target cell, which can be achieved, for example, in transgenic animals or by gene therapy. As a result, an intracellular antibody is an antibody that has been modified for intracellular localization, including antibodies produced in prokaryotes or other non-target cells. The term "intracellular antibody" can be applied to several types of protein targeting. That is, the antibody can persist in the cytoplasm, or can have a nuclear localization signal, or can undergo co-translational transport through the membrane of the endoplasmic reticulum into the lumen, provided that it is retained in that compartment by the KDEL sequence. However, the antibodies of the present invention that bind to human SRRM2 preferably have the ability to be internalized, as shown in Example 11.

[0053] "Target cells" are preferably cancer cells. As used herein, the term "cancer" can include any one or more of the following: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenal cortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, breast cancer, female reproductive system cancer, male reproductive system cancer, 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, stomach cancer, gastrointestinal tract cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin's disease, hypopharyngeal cancer, Kaposi's sarcoma , kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, malignant fibrous histiocytoma, malignant thymoma, melanoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumors, plasma cell neoplasms, primary central nervous system lymphoma, prostate cancer, rectal cancer, respiratory system cancer, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine sarcoma, vaginal cancer, vascular system cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0054] The term "pharmaceutically acceptable carrier, diluent, or excipient" as used in the context of the present invention may include any pharmaceutically acceptable carrier, diluent, or excipient for pharmaceutical compositions known to those skilled in the art. It will be understood that such antibodies or pharmaceutical compositions described herein may be mixed with a carrier or diluent that does not interfere with the intended purpose of the present invention. For example, such a carrier used in the present invention may be a carrier protein, such as bovine serum albumin (BSA) or keyhole limpet hemocyanin (KLH).

[0055] In one embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 has cytotoxic activity. In the context of the present invention, the term "cytotoxic activity" may mean having SRRM2 binding activity, and may also include having activity equivalent to the activity of the antibody that binds to human SRRM2 of the present invention. In the present invention, the equivalent activity does not necessarily have to be the same activity, and may be, for example, 50% or more, preferably 70% or more, and more preferably 90% or more compared to the activity of any of the antibodies (a) to (e) described herein. Examples of the upper limit of activity may include, but are not limited to, 1000% or less, 500% or less, 300% or less, 150% or less, and 100% or less.

[0056] In a further embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 has (antibody-dependent cell-mediated cytotoxicity) ADCC or complement-dependent cytotoxicity (CDC). Thus, examples of cytotoxic activity according to the present invention may include ADCC activity and / or CDC activity. In the context of the present invention, ADCC activity refers to the activity of cells having Fcγ receptors (such as immune cells) binding to the Fc domain of an antibody that is specifically bound to a cell surface antigen of the target cell via the Fcγ receptor, thereby damaging the target cell. In contrast, CDC activity refers to the cytotoxic activity mediated by the complement system. Whether an antibody has ADCC activity or CDC activity can be determined by a method known in the art.

[0057] Therefore, the antibody that binds to human SRRM2 used in the pharmaceutical composition of the present invention may have activity such as ADCC activity and thus may be useful as a pharmaceutical agent, preferably an anti-cancer agent, where the cancer is, for example, breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, bile duct cancer, oral squamous cell carcinoma, hematological malignancies, or glioma.

[0058] In one embodiment of the present invention, an antibody that binds to human SRRM2 is conjugated to a cytotoxic agent.

[0059] In a preferred embodiment, the antibody that binds to human SRRM2 may be conjugated with a cytotoxic agent, such as a chemotherapeutic agent, a toxic peptide, or a radioactive chemical. Such modified antibodies (hereinafter referred to as antibody conjugates) can be obtained by chemically modifying the obtained antibody. Methods for antibody modification have already been established in the art.

[0060] Examples of chemotherapeutic agents whose cytotoxic activity functions via conjugation to an antibody that binds SRRM2 may include the following chemotherapeutic agents: azaribine, anastrozole, azacitidine, 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, etoposide glucuronide. , floxuridine, fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, leucovorin, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenylbutyrate, prednisone, procarbazine, paclitaxel, pentostatin, semustine, streptozocin, tamoxifen, taxane, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinblastine, vinorelbine, vincristine.

[0061] The chemotherapeutic agent is preferably a small molecule chemotherapeutic agent. The small molecule chemotherapeutic agent is less likely to interfere with the antibody even after conjugation to the antibody. The molecular weight of the small molecule chemotherapeutic agent is usually 100-2000, preferably 200-1000. All of the chemotherapeutic agents exemplified above are small molecule chemotherapeutic agents. These chemotherapeutic agents include prodrugs that are converted in vivo into active chemotherapeutic agents. The activation of the prodrug may be enzymatic or non-enzymatic.

[0062] As shown in Figure 7 and Figure 8, the presence of SRRM2 on the surface can be utilized for SRRM2-specific CAR-T cell therapy. Thus, SRRM2-specific cancer therapy is made possible by the present invention. Thus, in one alternative embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 is a part of a chimeric antigen receptor (CAR). In said embodiment, the CAR is preferably contained in a T cell, a NK cell, a NK-T cell, or a macrophage. A chimeric antigen receptor (also known as a CAR, a chimeric immune receptor, a chimeric T cell receptor, or an artificial T cell receptor) is a receptor protein that is engineered to give T cells the ability to target specific proteins.

[0063] In one embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 has less than 20% cross-reactivity with SRRM2-related proteins. This preferably means that the antibody that binds to human SRRM2 has less than 20% cross-reactivity with other serine / arginine repeat matrix proteins, such as SRRM1, SRRM3, SRRM4, or SRRM5. More preferably, the antibody that binds to human SRRM2 has less than 15% cross-reactivity with SRRM2-related proteins, such as SRRM1, SRRM3, SRRM4, or SRRM5. Even more preferably, the antibody that binds to human SRRM2 has less than 10% cross-reactivity with SRRM2-related proteins, such as SRRM1, SRRM3, SRRM4, or SRRM5. Even more preferably, the antibody that binds to human SRRM2 has less than 5% cross-reactivity with SRRM2-related proteins, such as SRRM1, SRRM3, SRRM4, or SRRM5. Even more preferably, the antibody that binds to human SRRM2 has less than 3% cross-reactivity with SRRM2-related proteins, such as SRRM1, SRRM3, SRRM4, or SRRM5. Even more preferably, the antibody that binds to human SRRM2 has less than 2% cross-reactivity with SRRM2-related proteins, such as SRRM1, SRRM3, SRRM4, or SRRM5. Even more preferably, the antibody that binds to human SRRM2 has less than 1% cross-reactivity with SRRM2-related proteins, such as SRRM1, SRRM3, SRRM4, or SRRM5.

[0064] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0065] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0066] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0067] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0068] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0069] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0070] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0071] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0072] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0073] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0074] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0075] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0076] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0077] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0078] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0079] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0080] In one embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region including a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, and a light chain variable region including a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 12, or an antibody that binds to the same epitope.

[0081] In one embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region including a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region including a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 18, or an antibody that binds to the same epitope.

[0082] In one embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region including a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region including a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 24, or an antibody that binds to the same epitope.

[0083] In one embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region including a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region including a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 29, or an antibody that binds to the same epitope.

[0084] The antibody described herein may include a constant region. The constant region used is not particularly limited, and any constant region may be used. A preferred example of the constant region used in the present invention may include a constant region derived from human. For example, a constant region derived from human IgG1, human IgG2, human IgG3, or human IgG4 may be used as the heavy chain constant region. Also, for example, a constant region derived from human κ chain or human λ chain may be used as the light chain constant region. The constant region used in the present invention may be a constant region having a natural sequence, or may be a modified constant region having a sequence derived from a natural sequence that has been modified by one or more amino acids.

[0085] The antibody described herein may also include a framework region (FR). The FR used is not particularly limited, and any FR may be used as long as the resulting antibody maintains the binding activity to human SRRM2 present on the cell surface of the target cell. A preferred example of the FR used in the present invention may include a FR derived from a human antibody. Since the technology of replacing the FR while maintaining the antigen-binding activity of the antibody is known in the art, a person skilled in the art can appropriately select the FR. The FR used in the present invention may be a FR having a natural sequence, or a FR having a sequence derived from a natural sequence with one or more amino acid modifications.

[0086] Whether an antibody shares an epitope with another antibody can be confirmed based on their competition for the same epitope. Competition between antibodies is detected by cross-blocking assay, etc. The cross-blocking assay is preferably, for example, a competitive ELISA assay. Specifically, in the cross-blocking assay, SRRM2 protein coated on the well of a microtiter plate may be pre-incubated in the presence or absence of a candidate competing antibody, and then an antibody that binds to human SRRM2 of the present invention is added to the well. 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 (the antibody to be tested) that competes with it for binding to the same epitope. Specifically, the greater the affinity that the antibody to be tested has for the same epitope, the less the antibody of the present invention will bind to the well coated with the SRRM2 protein, and the more the antibody to be tested will bind to the well coated with the SRRM2 protein.

[0087] The amount of antibody bound to the well can be easily measured by labeling the antibody in advance.For example, the antibody labeled with biotin can be measured by using avidin-peroxidase conjugate and suitable substrate.The cross-blocking assay method using enzyme (e.g. peroxidase) label is specifically called competitive ELISA assay.Antibody can be labeled with other detectable or measurable labeling substances.Specifically, radiolabel or fluorescent label and the like are known in the art.

[0088] If a candidate antibody is able to bind to human SRRM2 present on the cell surface of a target cell with a binding activity of at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, and even more preferably at least 99%, compared to the binding activity obtained in a control test performed in the absence of the candidate antibody, the candidate antibody is determined to be an antibody that binds to substantially the same epitope as the antibody of the present invention or the antibody that binds to human SRRM2 used in a pharmaceutical composition.

[0089] In a further aspect, the present invention provides a pharmaceutical composition according to the present invention for use in a method for treating cancer in a human subject.Preferably for said embodiment, the cancer is characterized by a cell in which human SRRM2 is present on the cell surface.Also preferably for said embodiment, the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, bile duct cancer, oral squamous cell carcinoma, hematological malignancies, or glioma.

[0090] Pharmaceutical compositions according to the invention can be administered by standard routes, including, but not limited to, oral, rectal, ocular (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, intraventricular, intracerebral, intravaginal, intrauterine, or parenteral (e.g., intravenous, intraspinal, subcutaneous, or intramuscular).

[0091] The present invention also includes a method for treating cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition according to the present invention to a human subject. It is preferred for the above embodiment that the cancer is characterized by cells in which human SRRM2 is present on the cell surface. It is also preferred for the above embodiment that the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, bile duct cancer, oral squamous cell carcinoma, hematological malignancies, or glioma.

[0092] Furthermore, the present invention also includes a method of treating cancer, comprising administering to a human subject a therapeutically effective amount of an antibody that binds to human SRRM2 as described herein. It is preferred for the above embodiment that the cancer is characterized by cells that have human SRRM2 present on their cell surface. It is also preferred for the above embodiment that the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, bile duct cancer, oral squamous cell carcinoma, hematological malignancies, or glioma.

[0093] The term "therapeutically effective amount" refers to an amount of the antibody or pharmaceutical composition or drug according to the present invention that is effective to "treat" cancer in a human subject. Specifically, in the case of cancer, a therapeutically effective amount of the antibody / pharmaceutical composition / drug can reduce the number of cancer cells; reduce tumor size; inhibit or stop cancer cell invasion 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 cancer; or a combination of such effects on cancer cells. To the extent that the antibody / pharmaceutical composition / drug prevents the growth of existing cancer cells and / or kills existing cancer cells, it can be referred to as cytostatic and / or cytotoxic.

[0094] The present invention also encompasses the use of a pharmaceutical composition according to the present invention for the manufacture of a medicament for treating cancer.

[0095] In one embodiment, the invention also encompasses the use of an antibody that binds to human SRRM2 described herein for the manufacture of a medicament for treating cancer.

[0096] Terms such as "treating" or "treatment" or "to treat" refer to both (1) therapeutic measures that cure, delay, reduce symptoms, and / or halt the progression of a diagnosed pathological condition or disorder, and (2) prophylactic or preventative measures that prevent or delay the onset of the targeted pathological condition or disorder. Thus, those in need of treatment include those who already have the disorder; those who are prone to have the disorder; and those in whom the disorder is to be prevented. A subject has been successfully "treated" according to the method of the present invention, or with a pharmaceutical composition or an antibody that binds human SRRM2 according to the present invention, if the patient exhibits one or more of the following: a reduction in the number of cancer cells or the complete absence of cancer cells; a reduction in tumor size; an inhibition of cancer cell invasion (including spread of cancer to soft tissue and bone) or the absence of cell invasion into peripheral organs; an inhibition of tumor metastasis or the absence of tumor metastasis; an inhibition of tumor growth or the absence of tumor growth; an alleviation of one or more symptoms associated with the respective cancer; a reduction in morbidity and mortality; and an improvement in quality of life.

[0097] The antibody administered to humans can also be converted into an artificially engineered recombinant antibody, for example, to reduce xenoantigenicity in humans. The recombinant antibody includes, for example, chimeric and humanized antibodies as defined herein. These engineered antibodies can be produced using methods known in the art.

[0098] In a further aspect, the present invention provides a method for determining whether a human subject is likely to be suffering from cancer, the method comprising determining whether SRRM2 is present on the cell surface of (cancer) cells contained in a sample obtained from the human subject.

[0099] As shown in Example 9, SRRM2 is also present on the surface of extracellular vesicles obtained from subjects diagnosed with cancer. Thus, the present invention further relates to a method for determining whether a human subject may be suffering from cancer, comprising determining whether SRRM2 is present on the surface of extracellular vesicles in a sample obtained from the human subject. "Extracellular vesicles" (EVs), as used herein, may refer to lipid bilayer-bound particles that are naturally released from almost all types of cells and that, unlike cells, cannot replicate. EVs typically range in diameter from approximately the size of the smallest physically possible unilamellar liposome (about 20-30 nanometers) to 10 μm or even more, although the vast majority of EVs are smaller than 200 nm.

[0100] EVs can be divided into exosomes, microvesicles, and apoptotic bodies based on size and synthesis pathway. Therefore, EVs are preferably selected from the group consisting of exosomes, microvesicles, and apoptotic bodies. Usually, they carry the cargo of proteins, nucleic acids, lipids, metabolites, and even organelles from parent cells. Various EV subtypes have been presented. Thus, EVs can also be one or more of the following: ectosomes, microvesicles, microparticles, exosomes, oncosomes, apoptotic bodies, and exomers, etc. Preferably, EVs are oncosomes. In the context of EVs, the sample is preferably ascites.

[0101] Before determining whether SRRM2 is present on the surface of extracellular vesicles in a sample obtained from a human subject, 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 EVs. Such biomarkers for EVs include, for example, Alix, Tsg101, tetraspanins such as CD81, CD63, and CD9, or flotillins for exosomes, integrins, selectins, or CD40 for microvesicles, and annexin V or phosphatidylserine for apoptotic bodies. Antibodies against these markers are commercially available, for example, from Abcam. Methods for isolating and / or enriching EVs are further described in Campos-Silva et al. (2019), Scientific Reports, 9:2042(2019) or Pugholm et al. (2015), Biomed Res Int., 2015:524817, both of which are incorporated herein by reference in their entirety.

[0102] The pharmaceutical composition can also be a diagnostic composition, preferably when used in a method for determining whether a human subject may be affected by cancer or a neurodegenerative disease.Thus, the present invention also relates to a diagnostic composition comprising an antibody, preferably a monoclonal antibody, that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell, preferably a cancer cell, and optionally a pharma- ceutically acceptable carrier, diluent, or excipient.

[0103] A method for determining whether a human subject may be afflicted with cancer may include the following steps: - providing a sample obtained from a human subject; - determining in said sample obtained from a human subject whether SRRM2 is present on the cell surface of (cancer) cells contained in said sample; - Correlating the presence of SRRM2 on the cell surface of (cancer) cells contained in the sample with determining whether the human subject is likely to be suffering from cancer.

[0104] "Subject" or "human subject" in the context of the present invention is a human.For example, the subject may be a patient suspected of having a disease or clinical condition related to cancer or diagnosed with such a disease or clinical condition.The subject may be a patient suspected of having a disease or clinical condition related to neurodegenerative disease or diagnosed with such a disease or clinical condition.

[0105] The "sample" obtained from a human subject is preferably selected from the group consisting of blood sample, serum sample, plasma sample, cerebrospinal fluid sample, saliva sample, solubilized tissue sample, and urine sample, or an extract of any of the above samples.Preferably, the sample is a serum sample or a plasma sample.Most preferably, the sample is a serum sample for determining whether a human subject may be affected by cancer.

[0106] The step of "determining whether SRRM2 is present on the cell surface of target cells contained in a sample obtained from a human subject" may comprise determining the presence of SRRM2 or a fragment thereof by contacting the sample with at least one SRRM2 binder. The at least one binder may be, for example, an antibody according to the present invention or as described herein. It is preferred that the at least one binder has less than 20% cross-reactivity with other proteins, in particular 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-reactivity.

[0107] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0108] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0109] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0110] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0111] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0112] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0113] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0114] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0115] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0116] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0117] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0118] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0119] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0120] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0121] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0122] The present invention further relates to an antibody that binds to human SRRM2, the antibody comprising a heavy chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0123] The present invention further relates to an antibody that binds to human SRRM2, comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO:7, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO:8, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO:10, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO:11, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO:12, or an antibody that binds to the same epitope.

[0124] The present invention further relates to an antibody that binds to human SRRM2, comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 18, or an antibody that binds to the same epitope.

[0125] The present invention further relates to an antibody that binds to human SRRM2, comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 24, or an antibody that binds to the same epitope.

[0126] The present invention further relates to an antibody that binds to human SRRM2, comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 29, or an antibody that binds to the same epitope.

[0127] The present invention also provides use of an antibody that binds to human SRRM2 of the present invention in the manufacture of a medicament for the treatment of cancer.

[0128] In addition, the present invention provides antibodies that bind to human SRRM2 of the present invention for use in methods of treating cancer.

[0129] In some embodiments, the antibody of the present invention or described herein that binds to human SRRM2 may comprise a human Fc region that has been modified to enhance effector functions, such as antigen-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC). This can be achieved by introducing one or more amino acid substitutions into the Fc region of the antibody. For example, cysteine ​​residues can be introduced into the Fc region to allow interchain disulfide bond formation in this region to enhance complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). Homodimeric antibodies with enhanced anti-tumor activity can also be produced using heterobifunctional crosslinkers known to those skilled in the art. Alternatively, antibodies with two Fc regions can be engineered.

[0130] Furthermore, the antibodies described herein may have one or more amino acid substitutions, deletions, additions, and / or insertions in their CDR sequences, so long as the resulting antibody is functionally equivalent to the antibodies (a) to (d). The term "functionally equivalent" means that the binding activity and cytotoxicity to SRRM2 are equivalent. The term "equivalent" means that the antibody has at least 50%, preferably at least 60%, more preferably at least 70%, more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95%, and even more preferably at least 99% activity compared to the antibodies (a) to (d). The upper limit of the activity is not particularly limited and may be higher than the activity of the antibodies (a) to (d). The binding activity or cytotoxicity can be evaluated by methods generally known to those skilled in the art.

[0131] The presence of SRRM2 on the cell surface of target cells or extracellular vesicles can also indicate that the subject from which the sample containing the target cells is obtained suffers from a neurodegenerative disease. In this context, the target cells are preferably neurons. The target cells can also be glial cells. Glial cells include, but are not limited to, astrocytes, oligodendrocytes, ependymal cells, radial glia, Schwann cells, satellite cells, enteric glial cells, and microglia. In this context, the sample is preferably obtained from brain tissue, nervous tissue, and / or cerebrospinal fluid.

[0132] As used herein, "neurodegenerative disease" is characterized by the progressive loss of neuronal structure or function in a process known as neurodegeneration. Such neuronal damage may ultimately result in 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 disease.

[0133] Therefore, the present invention also relates to the pharmaceutical composition of the present invention for use in a method for treating a neurodegenerative disease in a human subject.The present invention further relates to an antibody that binds to human SRRM2, which is used herein for use in a method for treating a neurodegenerative disease in a human subject.Preferably, the neurodegenerative disease is characterized by cells that have human SRRM2 present on their cell surface.

[0134] The present invention also includes a method of treating a neurodegenerative disease, comprising administering to a human subject a therapeutically effective amount of a pharmaceutical composition according to the present invention. Additionally, the present invention also includes a method of treating a neurodegenerative disease, comprising administering to a human subject a therapeutically effective amount of an antibody that binds to human SRRM2 as described herein. It is preferred for this embodiment that the neurodegenerative disease is characterized by cells on whose cell surface human SRRM2 is present.

[0135] The present invention further relates to a method for determining whether a human subject may be suffering from a neurodegenerative disease, the method comprising a step of determining whether SRRM2 is present on the cell surface of cells contained in a sample obtained from the human subject.

[0136] The present invention further relates to a method for determining whether a human subject may be suffering from a neurodegenerative disease, the method comprising a step of determining whether SRRM2 is present on the surface of extracellular vesicles in a sample obtained from the human subject.

[0137] The method for determining whether a human subject may be suffering from a neurodegenerative disease may comprise the steps of: - providing a sample obtained from a human subject; - determining in said sample obtained from a human subject whether SRRM2 is present on the cell surface of target cells contained in said sample; - correlating the presence of SRRM2 on the cell surface of target cells contained in the sample with determining whether the human subject is likely to be suffering from a neurodegenerative disease.

[0138] The present invention further relates to antibodies that bind to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of target cells for use in methods of killing target cells having SRRM2 present on their cell surface.

[0139] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0140] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0141] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0142] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0143] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0144] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0145] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0146] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0147] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0148] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0149] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 95% identity to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0150] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0151] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0152] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0153] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0154] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0155] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 12, or an antibody that binds to the same epitope.

[0156] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 18, or an antibody that binds to the same epitope.

[0157] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 24, or an antibody that binds to the same epitope.

[0158] In one embodiment of the antibody for use in the method of killing a target cell having SRRM2 present on the cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 29, or an antibody that binds to the same epitope.

[0159] With respect to the pharmaceutical compositions of the present invention and the antibodies of the present invention that bind to human SRRM2 present on the cell surface of a target cell, as well as the methods of the present invention described herein, and each of the above definitions, all aspects described herein also apply to the antibodies of the present invention for use in the methods of killing target cells having SRRM2 present on their cell surface, as described herein.

[0160] The present invention also relates to a method for killing a target cell having human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, comprising administering an antibody that binds to SRRM2 present on the cell surface of the target cell.

[0161] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0162] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0163] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0164] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0165] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0166] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0167] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence having at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0168] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0169] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0170] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0171] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0172] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0173] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence having at least 85% identity to the amino acid sequence set forth in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0174] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0175] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0176] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0177] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 12, or an antibody that binds to the same epitope.

[0178] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 18, or an antibody that binds to the same epitope.

[0179] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 24, or an antibody that binds to the same epitope.

[0180] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 29, or an antibody that binds to the same epitope.

[0181] The pharmaceutical compositions of the present invention, the antibodies of the present invention that bind to human SRRM2 present on the cell surface of a target cell, the methods of the present invention that determine whether a human subject is likely to be affected by cancer as described herein, as well as all aspects described herein for each of the above definitions, also apply to the methods of killing target cells that have serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell as described herein.

[0182] The present invention further relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell, for use in a method for treating cancer in a subject, comprising the step of determining whether a target cell of the subject has serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface prior to treating the cancer in the subject.

[0183] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0184] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0185] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 95% identity to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0186] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence shown in SEQ ID NO: 2, or an antibody that binds to the same epitope.

[0187] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0188] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0189] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 95% identity to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0190] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 99% identity to the amino acid sequence shown in SEQ ID NO: 4, or an antibody that binds to the same epitope.

[0191] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0192] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 90% identity to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0193] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 95% identity to the amino acid sequence shown in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0194] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 6, or an antibody that binds to the same epitope.

[0195] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having 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 having at least 85% identity to the amino acid sequence shown in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0196] In one embodiment of the method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0197] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0198] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 26, or an antibody that binds to the same epitope.

[0199] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 12, or an antibody that binds to the same epitope.

[0200] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 18, or an antibody that binds to the same epitope.

[0201] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 24, or an antibody that binds to the same epitope.

[0202] In one embodiment of an antibody for use in a method for treating cancer in a subject, comprising a step of determining whether target cells of the subject have SRRM2 present on the cell surface prior to treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 27, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 28, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 29, or an antibody that binds to the same epitope.

[0203] All aspects described herein for the pharmaceutical compositions of the present invention, the antibodies of the present invention that bind to human SRRM2 present on the cell surface of target cells, the methods of the present invention that determine whether a human subject is likely to be affected with cancer as described herein, as well as each of the foregoing definitions, also apply to antibodies for use in a method for treating cancer in a subject, as described herein, comprising a step of determining whether target cells of the subject have SRRM2 present on their cell surface prior to treating the cancer in the subject.

[0204] Descriptions of the sequences shown in the sequence listing and used in the present invention are as follows: 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 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 VH-CDR1 of antibody 13F11. SEQ ID NO: 8 shows the amino acid sequence of VH-CDR2 of antibody 13F11. SEQ ID NO: 9 shows the amino acid sequence of VH-CDR3 of antibody 13F11. SEQ ID NO: 10 shows the amino acid sequence of VL-CDR1 of antibody 13F11. SEQ ID NO: 11 shows the amino acid sequence of VL-CDR2 of antibody 13F11. SEQ ID NO: 12 shows the amino acid sequence of VL-CDR3 of antibody 13F11. SEQ ID NO: 13 shows the amino acid sequence of VH-CDR1 of antibody 23A7. SEQ ID NO: 14 shows the amino acid sequence of VH-CDR2 of antibody 23A7. SEQ ID NO: 15 shows the amino acid sequence of VH-CDR3 of antibody 23A7. SEQ ID NO: 16 shows the amino acid sequence of VL-CDR1 of antibody 23A7. SEQ ID NO: 17 shows the amino acid sequence of VL-CDR2 of antibody 23A7. SEQ ID NO: 18 shows the amino acid sequence of VH-CDR3 of antibody 23A7. SEQ ID NO: 19 shows the amino acid sequence of VH-CDR1 of antibody 18A4 and antibody 18A4-2. SEQ ID NO: 20 shows the amino acid sequence of VH-CDR2 of antibody 18A4 and antibody 18A4-2. SEQ ID NO: 21 shows the amino acid sequence of VH-CDR3 of antibody 18A4 and antibody 18A4-2. SEQ ID NO: 22 shows the amino acid sequence of VL-CDR1 of antibody 18A4. SEQ ID NO: 23 shows the amino acid sequence of VL-CDR2 of antibody 18A4. SEQ ID NO: 24 shows the amino acid sequence of VL-CDR3 of antibody 18A4. SEQ ID NO: 25 shows the amino acid sequence of SRRM2 as shown in UniProt database entry Q9UQ35, version 2, on March 6, 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 VL-CDR1 of antibody 18A4-2. SEQ ID NO: 28 shows the amino acid sequence of VL-CDR2 of antibody 18A4-2. SEQ ID NO: 29 shows the amino acid sequence of VL-CDR2 of antibody 18A4-2. SEQ ID NO:30 shows the amino acid sequence of fragment tr04.

[0205] A summary of the sequence numbers (SEQ ID NOs) and detailed sequences used in the present invention is shown in Table 1 below (in the event of any discrepancy between the sequences shown in Table 1 and the sequences in the sequence listing which must be submitted for formal reasons, the sequences in Table 1 take precedence over the sequences in the sequence listing).

[0206] [Table 1] TIFF2025510642000002.tif251162TIFF2025510642000003.tif251109

[0207] The following abbreviations have been used in the present invention: VH = variable heavy chain; VH = variable heavy chain; VL = variable light chain; CDR = complementarity determining region; VH-CDR = CDR of the variable heavy chain region; VL-CDR = CDR of the variable light chain region; CDRs can be identified using the Kabat algorithm (e.g. http: / / abysis.org / abysis / ).

[0208] It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context specifically dictates otherwise. Thus, for example, reference to "a reagent" includes one or more of such various reagents, and reference to "the method" includes reference to equivalent steps and methods known to those skilled in the art that may be modified or used in place of the methods described herein.

[0209] Unless otherwise specified, the term "at least" preceding a series of elements should be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by this invention.

[0210] The term "and / or" whenever used herein includes the meaning of "and", "or" and "all or any other combination of the elements connected by that term".

[0211] The terms "less than" or even "more than" do not include that specific number.

[0212] For example, "fewer than 20" means fewer than a specified number. Similarly, "more" or "greater than" means more than or greater than a specified number, for example, "more than 80%" means more than or greater than 80% of a specified number.

[0213] Throughout this specification and the claims which follow, unless the context dictates otherwise, the word "comprise", and variations such as "comprises" and "comprising", are understood to mean the inclusion of a recited integer or step or group of integers or steps, but not the exclusion of any other integers and steps or groups of integers and steps. As used herein, the term "comprising" may be replaced with the terms "containing" or "including", or, as sometimes used herein, the term "having". As used herein, "consisting of" excludes any element, step, or ingredient not specified.

[0214] The term "including" means "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0215] It is to be understood that this invention is not limited to the particular methodology, protocols, materials, reagents, and substances, etc. described herein, as such may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0216] All publications cited throughout the text of this specification, whether supra or infra, including all patents, patent applications, scientific publications, instruction manuals, etc., are hereby incorporated by reference in their entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. In the event that any material incorporated by reference contradicts or is inconsistent with this specification, the present specification shall take precedence over any such material.

[0217] The contents of all publications and patent documents cited herein are incorporated by reference in their entirety.

[0218] A further understanding of the present invention and its advantages will be gained from the following experimental examples, which are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0219] The present invention is further characterized by the following items. 1. An antibody, preferably a monoclonal antibody, that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell, and optionally a pharma- ceutically acceptable carrier, diluent, or excipient. 23. A pharmaceutical composition comprising: 2. The pharmaceutical composition of item 1, wherein the antibody has cytotoxic activity. 3. The pharmaceutical composition of item 1 or item 2, wherein the antibody has ADCC or CDC. 4. The pharmaceutical composition of any one of the preceding items, wherein the antibody is conjugated to a cytotoxic agent. 5. The pharmaceutical composition of any one of the preceding items, wherein the antibody is a portion of a chimeric antigen receptor (CAR). 6. The pharmaceutical composition of item 5, wherein the CAR is comprised in a T cell, a NK cell, a NK-T cell, or a macrophage. 7. The pharmaceutical composition of any one of the preceding items, wherein SRRM2 present on the cell surface of the target cell is externalized. 8. The pharmaceutical composition of any one of the preceding items, wherein the antibody is not an intracellular antibody. 9 antibodies are: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody that binds to the same epitope of human SRRM2 protein as that bound by any one of antibodies (a) to (c) 20. The pharmaceutical composition of any one of the preceding items, 10 antibodies with: (a) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 9; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 12; an antibody; (b) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 15; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 18; an antibody; (c) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 24; an antibody; (d) an antibody that binds to the same epitope of human SRRM2 protein as that bound by any one of antibodies (a) to (c) 20. The pharmaceutical composition of any one of the preceding items, 11. The pharmaceutical composition of any one of the preceding items for use in a method for treating cancer in a human subject, preferably a cancer characterized by cells having human SRRM2 present on their cell surface. 12. The pharmaceutical composition for use according to item 11, wherein the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, bile duct cancer, oral squamous cell carcinoma, hematological malignancies, or glioma. 13 A method for determining whether a human subject may be suffering from cancer, the method comprising a step of determining whether SRRM2 is present on the cell surface of cells contained in a sample obtained from the human subject and / or whether SRRM2 is present on the surface of extracellular vesicles. 14 or less: (a) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 4; (c) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 6; (d) an antibody that binds to the same epitope of human SRRM2 protein as that bound by any one of antibodies (a) to (c) An antibody that binds to human SRRM2 present on the cell surface of a target cell. 15 or less: (a) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 7, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 9; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 12; an antibody; (b) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 13, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 15; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 16, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 18; an antibody; (c) a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 20, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 21; a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 22, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 23, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 24; an antibody; (d) an antibody that binds to the same epitope of human SRRM2 protein as that bound by any one of antibodies (a) to (c) An antibody that binds to human SRRM2 present on the cell surface of a target cell, comprising: EXAMPLES

[0220] material and method Cells and culture conditions Cells were cultured in DMEM / F12 medium (Gibco BRL, Karlsruhe, Germany) supplemented with 8% v / v fetal bovine serum, 1% v / v L-glutamine, and 1% v / v penicillin-streptomycin. All cells were incubated at 37°C in a humidified CO2 incubator with 18.3% O2 ​​and 5% CO2. Hypoxic cells were incubated at 1% O2.

[0221] Transfection of 293 cells 293 cells were transfected with expression plasmids encoding human SRRM2 or its variants using Lipofectamine™ 2000 transfection reagent (ThermoFisher Scientific, Menzel, Germany) according to the manufacturer's instructions. When necessary, cells were selected for positively transfected cells using 80 μg / ml hygromycin C and further cultured in regular growth medium supplemented with 80 μg / ml hygromycin C.

[0222] Isolation of primary peripheral blood mononuclear cells (PBMCs) from fresh blood Thirty ml of freshly heparinized blood from healthy donors was diluted with PBS and carefully layered on top of a layer of 10 ml human Pancoll (Pan Biotech, Aidenbach, Germany). The tubes were centrifuged at 800 × g for 25 min. PBMCs were then carefully harvested from the interlayer between Pancoll and plasma and washed three times with PBS. Cells were either used directly in experiments or immediately frozen and stored at -80 °C for later experiments.

[0223] Flow cytometry For flow cytometric analysis of SRRM2 expression, cells were stained with one of three SRRM2-specific antibodies or an isotype control antibody in FACS buffer (PBS + 2% FSC) for 20 minutes, followed by staining with anti-rat Alexa Fluor® 647 secondary antibody (Jackson Immuno Research). All staining was performed on ice.

[0224] Immunoblotting To analyze SRRM2 expression by Western blotting, whole cell lysates were prepared. Adherent cells were washed with PBS, detached with trypsin, and pelleted. The cell pellet was washed with PBS, after which the cells were resuspended in RIPA buffer containing protease inhibitors (Roche Diagnostics) and incubated on ice for 20 min. The cell debris was centrifuged at maximum speed for 20 min at 4°C. The supernatant was transferred to a new tube, and the protein content was measured by Bradford assay (Bio-Rad). 20 μg of cell lysate was used for SDS-PAGE. The gel was electroblotted onto a nitrocellulose membrane and blocked with 5% milk in TBST. The following primary antibodies were used for Western blotting: anti-SRRM2 (Thermo Scientific), anti-GFP (kindly provided by the "Monoclonal Antibody" Core Facility, Helmholtz Center Munich). All primary antibodies were incubated overnight at 4°C. The membrane was washed and incubated with HRP-conjugated secondary antibodies for 2 h at room temperature. The following secondary antibodies were used: anti-rat IgG-HRP (Cell Signaling), anti-mouse IgG-HRP (Cell Signaling Technology, Frankfurt a. Main, Germany), and anti-rabbit IgG-HRP (Cell Signaling). Protein detection was performed using the ECL system (GE Healthcare).

[0225] Immunoprecipitation Immunoprecipitation was performed with CNBr beads (CNBr-activated Sepharose 4 high flow, GE Healthcare). 1 g of beads was dissolved in 10 ml of 1 mM HCl and incubated at room temperature for 20 min. Afterwards, the beads were spun down at 3000×g for 1 min and washed 15 times. Subclass-specific mouse anti-rat IgG2a antibodies were then bound to the beads for 1 h at room temperature (2 mg of antibody in binding buffer 0.3 M NaHCO3, 1.5 M NaCl, pH 8.3). The beads were then washed in binding buffer and all remaining binding sites were blocked with 1 M ethanolamine (1 M) for 2 h at room temperature. After washing with washing buffer (0.1 M Tris / HCl, 0.5 M NaCl, pH 4) and NaOAc buffer (0.1 M NaOAc, 0.5 M NaCl), the bound beads were resuspended in PBS and used for binding with 22E6. Therefore, 500 μl of 22E6 hybridoma supernatant was incubated with 60 μl of anti-subclass specific beads overnight at 4°C.

[0226] The beads were then washed in PBS and incubated with 2 mg of cell lysate or 0.75 μg of sCD73 (human CD73 / NT5E protein, his-tagged, Sino Biologicals) overnight at 4°C. The beads were then washed in RIPA buffer containing protease inhibitors, PBS+ (PBS, 0.5% N-lauryl sarcosine, 0.1% SDS), and PBS. The supernatant was discarded and the beads were resuspended in 3× Laemmli buffer and incubated at room temperature for 3 min. After centrifugation at 1,000×g for 5 min, the supernatant was used for Western blot analysis.

[0227] Generation of SRRM2 knockout cells SRRM2-specific CRISPR-RNA (crRNA) was designed using a freely available online tool (IDT). Each of these different specific crRNAs was fused to a transactivating RNA (tracrRNA) to form a guide RNA (gRNA), which was then complexed with CAS9 nuclease. Individual complex combinations were introduced into A549 lung cancer cells by electroporation using Lonza's 4D-nucleofector protocol. Electroporated cells were analyzed by fluorescence-activated cell sorting (FACS) for binding of SRRM2 antibodies 13F11, 18A4, and 23A7 after one week. Cell clones were generated by sorting and limiting dilution cloning. Finally, the clones were reanalyzed by FACS. The identified knockout clones were then confirmed by screening for CRISPR / CAS9-mediated mutations. Thus, genomic DNA from parental cells and knockout clones was isolated, sequenced, and compared to wild-type sequences.

[0228] Confocal microscopy 1×10 5 Cells were seeded on glass coverslips and grown overnight. The medium was removed, cells were washed with PBS, fixed in 4% PFA for 10 min, permeabilized with PBS containing 0.3% Tween 20, and finally blocked with 3% BSA in TBS containing 0.1% Tween 20. For staining, cells were incubated with primary antibodies diluted in TBS containing 1% BSA and 0.1% Tween 20 for 1 h at room temperature. Cells were then washed three times and then incubated with secondary antibodies (goat anti-rat Alexa 647) for 40 min in the dark. After the final washing step, nuclei were stained with DAPI, mounting medium (Vectashield) was added, and the glass coverslips were mounted upside down on microscope slides. Slides were analyzed with a Leica SP8X STED microscope using Leica LAS X software.

[0229] Immunohistochemistry Paraffin sections were mounted on Superform Plus slides. After fixation in acetone, slides were incubated with primary antibodies followed by incubation with appropriate biotin-labeled secondary antibodies. Slides were developed using 0.01% 3-amino-9-ethylcarbazole (AEC) as a chromogen. After counterstaining with hematoxylin, slides were coverslipped with Kaiser's glycerin gelatin.

[0230] result Example 1 shows that monoclonal antibodies 13F11, 18A4, and 23A7 specifically precipitate SRRM2 from the lysates of various cancer cell lines. Either of the antibodies was bound to activated cyanogen bromide beads and incubated with the lysates of ovarian cancer cell lines at 4°C overnight. The next day, the beads were precipitated by centrifugation, and the bound proteins were eluted in Laemmli buffer and analyzed by mass spectrometry. Three independent experiments revealed a reliability score of over 60 and a 1824.2-fold, 182.6-fold, and 40.8-fold increase in precipitated SRRM2 compared to precipitation by isotype control antibody (see Figure 1).

[0231] Example 2 shows that SRRM2 is exposed on the surface of various cancer cell lines. Cells were incubated with 13F11 (solid lines in Figure 2A and Figure 2B) or isotype control antibody (dotted lines in Figure 2A, light-colored histogram in Figure 2B). Cells were then washed and incubated with Alexa647-labeled anti-rat IgG antibody. Fluorescence was then measured by flow cytometry using a FACS Canto. Normal PBMCs do not express surface SRRM2.

[0232] Example 3 shows that 13F11, 23A7, and 18A4 are specific for SRRM2: A549 human lung cancer cells were transfected with a ribonucleoprotein complex consisting of SRRM2-specific gRNA and Cas9 protein. After 7 days, the binding of the antibodies to knockout and wild-type cells was compared by flow cytometry. For this, A549 wild-type (bold line) and A549 SRRM knockout strain #25 (lightly colored histogram) were incubated with one of the three antibodies 13F11, 18A4, and 23A7. The cells were washed and then incubated with an Alexa647-labeled anti-rat secondary antibody. The fluorescence was then measured in a FACS Canto. An isotype control antibody was included as a negative control (dotted line). The reduced fluorescence intensity of strain #25 indicates the specificity of the antibodies for SRRM2 (see Figure 3).

[0233] Example 4 further shows the membrane localization of SRRM2 on human cancer cells. SK-OV-3 human ovarian cancer cells are grown on microscope slides, washed in PBS, and incubated with antibody 13F11. Incubating with antibody before fixation ensures that cells are alive, and therefore that antibody binds to intact cells. Cells are then fixed with 4% paraformaldehyde and incubated again with appropriate anti-rat IgG secondary antibody conjugated with Alexa647. Staining is then examined by confocal fluorescence microscopy (see FIG. 4).

[0234] Example 5 further shows the membrane localization of SRRM2 on human cancer cells. In this case, UWB1.289 human ovarian cancer cells were co-stained with SRRM2-specific antibody 13F11 (magenta) and antibody 18F10 (green) specific for membrane protein CD47. After fixation as described above, cells were analyzed by confocal fluorescence microscopy. Nuclei were counterstained with DAPI (blue). White in the merged photograph indicates the co-localization of both antibodies (see Figure 5).

[0235] Example 6 shows that SRRM2 is localized in lipid rafts in other membrane subdomains that are resistant to lysis by RIPA buffer. SK-OV-3 cells were lysed in RIPA buffer (150 mM NaCl, 50 mM Tris / HCl (pH 7.4), 1% Igepal, 0.5% sodium desoxycholate). The lysate was then loaded onto an Optiprep gradient and centrifuged overnight at 32,000 rpm. Fractions of 400 μl were collected and 2 μl of each fraction was spotted onto nitrocellulose filters. These filters were then incubated with antibodies specific for 13F11 or the tetraspanin CD63. As can be seen in FIG. 6, SRRM2 was present in fractions 2 and 3 of the gradient, which corresponds to a density of about 1.13-1.19 g / ml, i.e., the estimated density of lipid rafts and other insoluble membrane microdomains. Soluble proteins, which have a higher density per unit volume, are primarily localized in fractions 7-10 of the gradient.

[0236] Example 7 shows that SK-OV-3 cells positive for surface SRRM2 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 the antibody 13F11. The expression of the CAR in the transduced T cells was examined by flow cytometry using a goat anti-rat IgG antibody (not shown). SK-OV-3 cells were incubated with 13F11 CAR-T cells (rows 3-4 of the blot) or non-transduced control T cells (rows 1-2 of the blot) at the E:T ratios shown on the X-axis for 24 hours. Finally, interferon-γ in the supernatant, a marker of T cell activation, was quantified using a commercially available ELISA assay (see FIG. 7).

[0237] Example 8 shows that SRRM2-specific CAR-T cells also kill SRRM2-positive HO-8910 target cells. In this example, killing was measured using a commercially available LDH assay (see FIG. 8).

[0238] Example 9 shows that extracellular vesicles (EVs) isolated from ascites of ovarian cancer patients are SRRM2 positive. EVs were isolated by ultracentrifugation and density gradient centrifugation. EV samples were spotted onto nitrocellulose membranes and incubated with 13F11, 18A4, or 23A7, followed by incubation with HRP-conjugated anti-rat secondary antibody. The membranes were developed with ECL (see FIG. 9). As a control, an irrelevant isotype antibody was used (image 4 on the far right of FIG. 9).

[0239] Example 10 shows that surface SRRM2 on cancer cells is induced by hypoxia. Most therapeutic antibodies commercially available for the treatment of solid cancers target hypoxia-inducible proteins. These proteins are highly expressed on cancer cells because hypoxia is a common feature of solid tumors. And the induction of translation in hypoxia can be taken as an indication that such proteins are related to the survival and proliferation of cancer cells under hypoxic conditions. To investigate whether SRRM2 is induced by hypoxia, we cultured human A549, U138, HT29, and SK-OV-3 cells under normoxic (about 18% O2) or hypoxic (1% O2) conditions in standard DMEM medium for 72 hours. Then, cells were stained with SRRM2-specific antibody 13F11 or an isotype control antibody. 13F11 binding was then quantified by flow cytometry and expressed as mean fluorescence intensity ("Mean: Cy5-A" in Figure 10). The average value in hypoxic cells was approximately two-fold higher than under normoxia, indicating that surface SRRM2 is a hypoxia-inducible protein (see FIG. 10).

[0240] Example 11 shows that 11F11 is internalized. Monoclonal antibodies can be modified to carry toxins or radioactivity. These "antibody drug conjugates" (ADCs) are increasingly being used as therapeutic regimens. For ADCs, it is important that they bind to and are internalized into the target cell where the payload can exert its activity. We investigated the internalization of 13F11 by SK-OV-3 cells. For this, SK-OV-3 cells were incubated with 13F11 for 10 minutes at room temperature and then washed extensively to remove free antibody. Samples of these cells were then incubated at 37°C for 1-5 hours or stored on ice (=0 hours). Cells were then stained with an anti-rat IgG secondary antibody conjugated with Alexa647 and fluorescence was measured by flow cytometry. The decrease in fluorescence over time indicates internalization of the SRRM2-13F11 complex resulting in a decrease in binding of the secondary antibody. Fluorescence measured after 0 hours at 37° C. was set to 100% (see FIG. 11).

[0241] Example 12 shows that SRRM2 is expressed on the surface of primary pancreatic cancer. Paraffin sections from pancreatic cancer or normal pancreas specimens were stained with 18A4, followed by HRP-conjugated secondary antibody, and developed with ABC. As shown in Figure 12, cancer cells clearly show membrane localization of SRRM2 (arrow), while in normal cells, the protein shows a nuclear staining pattern (arrowhead).

[0242] Example 13 shows that SRRM2 is expressed on the surface of lung metastases from human HUCT-1 cells xenografted into immune-compromised SCID mice. In contrast, normal mouse tissues (brain, kidney, liver) show a nuclear staining pattern.

[0243] Example 14 shows that 13F11, 18A4-2, and 23A7 bind to a fragment spanning amino acids 1889-2150 of SRRM2 (herein referred to as tr04, SEQ ID NO: 30) (see FIG. 15). HEK293 cells were transfected with an expression plasmid encoding amino acids 1889-2150 of SRRM2 fused to a HIS tag (HEK293-tr04). Immunoprecipitation was performed with SRRM2-specific antibodies 13F11, 18A4-2, and 23A7 bound to beads and lysates of transfected cells or non-transfected 293 cells (HEK293) as a control. Precipitated proteins were separated by PAGE and transferred to a PVDF membrane, which was then incubated with an anti-rat antibody conjugated to HRP. Finally, the blot was developed using ECL. As additional controls, lysates from transfected and non-transfected cells were included.

[0244] Example 15 shows that normal tissues from cynomolgus monkeys stain negatively for SRRM2 or show cytoplasmic / nuclear staining (see FIG. 16) as revealed by immunohistochemistry. No membrane staining was observed. Mem=membrane; Cyto=cytoplasmic; Nucl=nucleus. FFPE tissues from cynomolgus monkeys were incubated with 13F11 antibody, followed by incubation with goat anti-rat IgG antibody conjugated with HRP (ImmPRESS HRP Peroxidase Detection Kit; https: / / vectorlabs.com / products / enzyme-polymer / immpress-hrp-goat-anti-rat-igg-kit).

[0245] Example 16 shows that the majority of tumor samples from various sites (bile duct, ovary, pancreas, stomach) show 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 conjugated with HRP. Trained pathologists examined the tissues and scored the staining intensity from 0 (negative) to 3+ (strong expression in the majority of cells).

[0246] Example 17 shows the sequences of the light and heavy chains of antibody 18A4-2 and fragments thereof (see FIG. 18).

[0247] Example 18 shows that SRRM2-specific antibodies 13F11, 18A4-2, and 23A7 bind to fragment tr04 (see FIG. 19). 96-well cell cluster plates were coated overnight with purified SRRM2-tr04-HIS, or MISP-HIS protein as a control (each at 50 μg / ml), and then blocked with nonfat dry milk dissolved in TBST. Antibodies 13F11, 18A4-2, 23A7, or anti-MISP antibodies were added for 2 hours at room temperature. After washing, the plates were incubated with anti-rat IgG secondary antibody conjugated to HRP and developed with TMB. After stopping the reaction with H2SO4, the absorbance was measured at 450 nm.

[0248] References TIFF2025510642000004.tif88165

Claims

1. A pharmaceutical composition containing an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of target cells.

2. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

3. The pharmaceutical composition according to claim 1, wherein the antibody is a monoclonal antibody.

4. The pharmaceutical composition according to claim 1, wherein the antibody has cytotoxic activity.

5. The pharmaceutical composition according to claim 1, wherein the antibody has ADCC or CDC.

6. The pharmaceutical composition according to claim 1, wherein the antibody is conjugated with a cytotoxic substance.

7. The pharmaceutical composition according to claim 1, wherein the antibody is a part of a chimeric antigen receptor (CAR).

8. The pharmaceutical composition according to claim 7, wherein the CAR is contained in T cells, NK cells, NK-T cells, or macrophages.

9. The pharmaceutical composition according to claim 1, wherein the SRRM2 present on the cell surface of target cells is externalized.

10. The pharmaceutical composition according to claim 1, wherein the antibody is not an intracellular antibody.

11. The aforementioned antibody is as follows: (a) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; (b) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; (c) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; (d) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The pharmaceutical composition according to claim 1.

12. The aforementioned antibody is as follows: (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

18. Antibodies containing; (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

12. Antibodies containing; (c) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

24. Antibodies containing; (d) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

29. Antibodies containing; or (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The pharmaceutical composition according to claim 1.

13. A pharmaceutical composition according to any one of claims 1 to 12, for use in a method for treating cancer in human subjects.

14. The pharmaceutical composition for use according to claim 13, wherein the cancer is characterized by cells having human SRRM2 on their cell surface.

15. The pharmaceutical composition for use according to claim 14, wherein the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, bile duct cancer, oral squamous cell carcinoma, hematological malignancy, or glioma.

16. A diagnostic composition for use in a method for determining whether a human subject may have cancer, comprising an antibody that binds to human SRRM2 present on the cell surface of a target cell, wherein the method comprises the step of determining whether SRRM2 is present on the cell surface of cells and / or on the surface of extracellular vesicles in a sample obtained from the human subject.

17. below: (a) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; (b) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; (c) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; (d) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. This is an antibody that binds to human SRRM2, which is present on the cell surface of target cells.

18. below: (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

18. Antibodies containing; (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

12. Antibodies containing; (c) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

24. Antibodies containing; (d) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

29. Antibodies containing; or (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. An antibody that contains and binds to human SRRM2 present on the cell surface of target cells.

19. An antibody that binds to human SRRM2 present on the cell surface of target cells, for use in a method for killing target cells having SRRM2 present on the cell surface.

20. below: (a) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; (b) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; (c) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; (d) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 26; or (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The antibody according to claim 19.

21. below: (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

18. Antibodies containing; (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

12. Antibodies containing; (c) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

24. Antibodies containing; (d) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

29. Antibodies containing; or (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The antibody according to claim 19 or 20.

22. A method for killing target cells having SRRM2 present on their cell surface, comprising the step of administering an antibody that binds to human SRRM2 present on the cell surface of the target cells.

23. The aforementioned antibody is as follows: (a) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; (b) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; (c) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; (d) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 26; (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The method according to claim 22.

24. The aforementioned antibody is as follows: (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

18. Antibodies containing; (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

12. Antibodies containing; (c) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

24. Antibodies containing; (d) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

29. Antibodies containing; (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The method according to claim 22 or 23.

25. A method for treating cancer in a subject, comprising the step of determining whether the target cells of the subject possess SRRM2 present on their cell surface before treating the cancer in the subject. An antibody for use in target cells that binds to human SRRM2 present on the cell surface.

26. below: (a) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; (b) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; (c) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; (d) An antibody comprising a heavy chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 26; (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The antibody according to claim 25.

27. below: (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 13, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 14, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 15, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 16, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 17, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

18. Antibodies containing; (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

12. Antibodies containing; (c) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 22, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 23, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

24. Antibodies containing; (d) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 19, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 20, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 21, The light chain variable region includes light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO:

29. Antibodies containing; or (e) An antibody that binds to the same epitope as the human SRRM2 protein to which one of the antibodies (a) to (d) binds. The antibody according to claim 25 or 26.

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