Compositions comprising antibodies that bind to human SRRM2 present on 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 pharmaceutically acceptable carrier, diluent or excipient. The invention further provides the 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 is likely to suffer from cancer, the method comprising determining, in a sample obtained from the human subject, whether SRRM2 is present on the cell surface of cells contained in the sample. In addition, antibodies that bind to human SRRM2 present on the cell surface of a target cell and antibodies that bind to human SRRM2 present on the cell surface of a target cell are provided for use in a method of killing said target cell having SRRM2 present on its cell surface.

Description

Technical Field

[0001] 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 an optional pharmaceutically acceptable carrier, diluent or excipient. The present invention further provides the pharmaceutical composition, which is used in a method for treating cancer in a human subject. A method for determining whether a human subject may have cancer is also provided, the method comprising determining whether SRRM2 is present on the cell surface of cells contained in the sample 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 provided. The present invention also provides an antibody that binds to human SRRM2 present on the cell surface of a target cell, which is used in a method for killing the target cell having SRRM2 present on its cell surface. In addition, a method for killing a target cell is provided, the target cell having SRRM2 present on the cell surface of the target cell, the method comprising administering an antibody that binds to human SRRM2 present on the cell surface of the target cell. The present invention also relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell, which is used in a method for treating cancer in a subject, including determining whether the target cell of the subject has SRRM2 present on the cell surface before treating the cancer of the subject. Background Art

[0002] In 2015, approximately 90.5 million people had cancer. As of 2019, there are approximately 18 million new cases each year. Each year, cancer causes approximately 8.8 million deaths (15.7% of deaths). The most common types of cancer in men are lung, prostate, colorectal, and stomach cancers. In women, the most common types are breast, colorectal, lung, and cervical cancers. If skin cancer other than melanoma were included in the total number of new cancer cases each year, it would account for about 40% of cases. In children, acute lymphoblastic leukemia and brain tumors are the most common, but in Africa, non-Hodgkin lymphoma occurs more often. 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 are more common in developed countries. As more people age, and as lifestyles change in developing countries, incidence is rising. As of 2010, the fiscal cost of cancer was estimated at $1.16 trillion per year.

[0003] Therefore, there is still a need for further cancer biomarkers that allow to distinguish healthy non-cancerous cells from cancer cells.The technical problem underlying the present application is therefore to provide further cancer biomarkers. Summary of the invention

[0004] The above technical problem is solved by the subject matter defined in the claims. The inventors surprisingly found that serine / arginine repeat matrix protein 2 (SRRM2; UniProt Q9UQ35) is expressed on cancer cells but not in healthy, non-cancerous cells. Therefore, the expression of SRRM2 on the cell surface of cells, such as cells obtained from patients, is a biomarker for cancer. In addition, the expression only on the surface of cancer cells allows novel cancer-specific therapies.

[0005] Therefore, 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 pharmaceutically acceptable carrier, diluent or excipient.

[0006] Preferably, the target cell is a cancer cell.

[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 by a T cell, a NK cell, a NK-T cell, or a macrophage.

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

[0010] Preferably, the antibody that binds to human SRRM2 is not an intrabody.

[0011] Preferably, the antibody that binds to human SRRM2 is

[0012] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0013] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0014] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0015] (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26; or

[0016] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0017] Preferably, the antibody that binds to human SRRM2 is

[0018] (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and

[0019] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 12;

[0020] (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and

[0021] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0022] (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and

[0023] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24;

[0024] (d) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and

[0025] 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

[0026] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0027] The present invention further relates to a 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, wherein human SRRM2 is present on the cell surface of the cells. Preferably, the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, cholangiogenic cancer, oral squamous cell carcinoma, hematological malignancy or glioma.

[0028] The present invention also relates to a method for determining whether a human subject is likely to have cancer, the method comprising determining, in a sample obtained from the human subject, the presence or absence of SRRM2 on the cell surface of cells contained in the sample.

[0029] The present invention also relates to a method for determining whether a human subject is likely to have cancer, the method comprising determining the presence or absence of SRRM2 on the surface of extracellular vesicles in a sample obtained from the human subject.

[0030] The present invention also relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell, wherein the antibody is

[0031] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0032] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0033] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0034] (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26; or

[0035] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0036] The present invention also relates to an antibody that binds to human SRRM2 present on the cell surface of a target cell, the antibody comprising

[0037] (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and

[0038] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 12;

[0039] (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and

[0040] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0041] (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and

[0042] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24;

[0043] (d) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and

[0044] 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

[0045] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0046] The present invention also relates to an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell, which is used in a method of killing the target cell having SRRM2 present on its cell surface.

[0047] Preferably, such an antibody is

[0048] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0049] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0050] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0051] (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26; or

[0052] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0053] Preferably, such an antibody is or comprises

[0054] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0055] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0056] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0057] (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26; or

[0058] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0059] The present invention also relates to a method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the method comprising administering an antibody that binds to human SRRM2 present on the cell surface of the target cell.

[0060] For the killing method, preferably the antibody is

[0061] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0062] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0063] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0064] (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26; or

[0065] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0066] For the killing method, the antibody is preferably

[0067] (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:12;

[0068] (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0069] (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24;

[0070] (d) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 27, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 28, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 29; or

[0071] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0072] The present invention also relates to an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell, which is used in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject.

[0073] This antibody that binds to human SRRM2 present on the cell surface of a target cell is used in a method for treating cancer in a subject, comprising determining whether the target cell of the subject has SRRM2 present on the cell surface before treating the cancer of the subject, preferably

[0074] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0075] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0076] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0077] (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 26; or

[0078] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

[0079] This antibody that binds to human SRRM2 present on the cell surface of a target cell is used in a method for treating cancer in a subject, comprising, before treating the cancer in the subject, determining whether the target cell of the subject has SRRM2 present on the cell surface, preferably or comprising

[0080] (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:12;

[0081] (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0082] (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24;

[0083] (d) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 27, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 28, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 29; or

[0084] (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d). BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Figure 1Antibodies 13F11, 23A7, and 18A4 are shown to precipitate SRRM2. Cyanogen bromide beads coupled to any of the three antibodies or to an isotype control antibody were incubated overnight with lysates from OVCAR-3 or UWB1.289 ovarian cancer cells. After the beads were precipitated and incubated in Laemmli buffer, the eluate was analyzed by mass spectrometry, showing that any of the antibodies significantly enriched SRRM2 compared to the isotype control antibody.

[0086] Figure 2 Surface expression of SRRM2 on various cancer cell lines is shown. The cell lines were compared with 13F11 ( Figure 2 A and Figure 2 Solid line in B) or isotype control antibody ( Figure 2 The dotted line in A, Figure 2 The 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).

[0087] Figure 3 It is shown that 13F11, 23A7 and 18A4 are SRRM2 specific: A549 cells are transfected with a ribonucleoprotein complex consisting of SRRM2-specific gRNA and Cas9. After 7 days, the binding of antibodies to knockout cells and wild-type cells was measured by flow cytometry. To this end, A549 wild type (bold line) and A549SRRM knockout line #25 (colored histogram) were incubated with any of the three antibodies 13F11, 18A4 and 23A7. The cells were washed and then incubated with Alexa647-labeled anti-rat secondary antibodies. Fluorescence was then measured with FACS Canto. Isotype control antibodies were included as negative controls (dashed lines).

[0088] Figure 4 13F11 is shown to bind 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 an appropriate anti-rat IgG secondary antibody conjugated to Alexa647. Surface staining is clearly visible.

[0089] Figure 518A4 colocalizes with the surface molecule CD47. A549 or UWB1.289 cells were cultured on coverslips, washed and incubated with antibodies 18A4 (SRRM2, magenta) and 18F10 (CD47, green). Cells were fixed with 4% paraformaldehyde and analyzed by confocal fluorescence microscopy. Nuclei were counter-stained with DAPI (blue).

[0090] Figure 6 SRRM2 is shown to be localized to lipid rafts or another insoluble membrane subdomain. Cells were lysed in RIPA buffer and the lysate was placed on a density gradient. After centrifugation, 10 fractions of 400 μL each were taken and samples of these fractions were spotted onto nitrocellulose membranes. The membrane was incubated with antibody 13F11 or with an antibody specific for the four-time transmembrane protein CD63. Fractions 2 and 3 correspond to a density of about 1.13-1.19 g / ml, thus being within the range of lipid rafts. Soluble proteins with a higher specific density are mainly located in fractions 7-10.

[0091] Figure 7 Surface SRRM2 positive SK-OV-3- cells are shown to activate SRRM2 specific 13F11CAR-T cells. Primary T cells from two donors (1 and 2) were transduced with a retroviral vector encoding a CAR construct, wherein the CAR construct had a single-chain construct derived from antibody 13F11. The expression of CAR was determined by flow cytometry using goat anti-rat IgG antibodies (not shown). SK-OV-3 cells were incubated with 13F11CAR-T cells (columns 3-4 of the blot) or with untransduced control T cells (columns 1-2 of the blot) at a ratio indicated on the X-axis for 24 hours. Then, interferon-γ in the quantitative supernatant was determined using commercial ELISA, which is a marker of T cell activation.

[0092] Figure 8 SRRM2-specific CAR-T cells are shown to kill SRRM2-positive HO-8910 target cells. Primary T cells from a donor were transduced with a retroviral vector encoding a CAR construct having a single-chain construct derived from antibody 13F11. The expression of CAR was tested by flow cytometry using goat anti-rat IgG antibodies (not shown). SK-OV-3 cells were incubated with 13F11CAR-T cells or untransduced control T cells (simulated T) at a ratio indicated on the X-axis for 24 hours. Then, killing was measured using a commercial lactate dehydrogenase (LDH) assay.

[0093] Fig. 9SRRM2 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 the EV preparation was then spotted onto nitrocellulose membranes and incubated with 13F11, 18A4, 23A7, or isotype control antibodies (from left to right) at 4°C overnight. After washing, the membranes were incubated with appropriate secondary antibodies (goat anti-rat IgG, conjugated with horseradish peroxidase) for 2 hours and developed with ECL.

[0094] Fig.10 It is shown that SRRM2 surface expression on 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 with Alexa647 labeled 13F11. The mean fluorescence level is given. Isotype antibodies were used as controls.

[0095] Fig.11 The antibody 13F11 is shown to be internalized after binding to SRRM2. SK-OV-3 ovarian cancer cells were incubated with 13F11 for 10 minutes at room temperature and then washed to remove free antibodies. The cell samples were then incubated at 37°C for 1 to 5 hours or kept on ice (=0 hours). The cells were then stained with Alexa647-conjugated anti-rat IgG secondary antibodies and fluorescence was measured by flow cytometry. The decrease in fluorescence over time indicates internalization of the SRRM2-13F11 complex. The fluorescence measured after 0 hours at 37°C was set to 100%.

[0096] Fig.12 Shown are sections of pancreatic cancer and normal pancreas stained with 18A4. Membranous staining is visible in cancer cells, while normal pancreatic cells show nuclear staining.

[0097] Fig.13 Membrane localization of SRRM2 in xenografted human HUCCT-1 cells is shown. Again, normal mouse tissues clearly showed only nuclear staining.

[0098] Fig.14 The corresponding sequences of antibodies 13F11, 23A7 and 18A4 are shown, including light and heavy chains with corresponding CDR1, CDR2 and CDR3 sequences.

[0099] Fig.1513F11, 18A4-2 and 23A7 are shown to bind to a fragment spanning amino acids 1889 to 2150 of SRRM2 (referred to herein as tr04, SEQ ID NO: 30). HEK293 cells (HEK293-tr04) were transfected with an expression plasmid encoding amino acids 1889 to 2150 of SRRM2 fused to a HIS-tag. Immunoprecipitation was performed with beads-coupled SRRM2-specific antibodies 13F11, 18A4-2 and 23A7 and lysates of transfected cells or non-transfected 293 cells (HEK293) as controls. The precipitated proteins were separated by PAGE and transferred to a PVDF membrane, which was then incubated with an anti-rat antibody coupled to HRP. Finally, the blot was developed with ECL. As an additional control, lysates from transfected and untransfected cells were included.

[0100] Fig.16 Normal tissues from cynomolgus monkeys were shown to be either negative for SRRM2 staining or to show cytoplasmic / nuclear staining as revealed by immunohistochemistry. No membrane staining was observed. Mem = membrane; Cyto = cytoplasmic; Nucl = nuclear. FFPE tissues from cynomolgus monkeys were incubated with 13F11 antibody and then with goat anti-rat IgG antibody conjugated to HRP (ImmPRESS HRP Peroxidase Detection Kit; https: / / vectorlabs.com / products / enzyme-polymer / immpress-hrp-goat-anti-rat-igg-kit).

[0101] Fig.17 It was shown that most tumor samples from different locations (bile duct, ovary, pancreas, stomach) showed SRRM2 membrane staining. Formalin-fixed paraffin-embedded (FFPE) tumor tissues and adjacent normal tissues were stained with antibody 13F11 and then incubated with a rat-specific secondary antibody conjugated to HRP. Tissues were examined by a trained pathologist and the staining intensity was scored from 0 (negative) to 3+ (strong expression on most cells).

[0102] Fig.18 The sequences of the variable portions of the light and heavy chains of antibody 18A4-2 are shown.

[0103] Fig.19SRRM2-specific antibodies 13F11, 18A4-2 and 23A7 binding fragment tr04 are shown. A 96-well culture plate was coated overnight with purified SRRM2-tr04-HIS or MISP-HIS protein as a control (each at 50 μg / ml) and then blocked with skim milk powder in TBST. Then, antibodies 13F11, 18A4-2, 23A7 or anti-MISP antibodies were added at room temperature for 2 hours. After washing, the plate was incubated with a second anti-rat IgG antibody coupled to HRP and developed with TMB. After stopping the reaction with H2SO4, the absorbance was measured at 450nm. DETAILED DESCRIPTION

[0104] Although SRRM2 is widely described in the prior art as a protein localized in the cell nucleus, particularly in nuclear speckles, the present inventors surprisingly discovered that SRRM2 is present on the cell surface of cancer cells (see e.g. Figure 2-5 , 12 and 13). Serine / arginine repeat matrix protein 2 (SRRM2; UniProt Q9UQ35) plays an important role in pre-mRNA splicing and is a major component of the spliceosome. Therefore, it is not present on the cell surface of healthy cells. However, in the context of cancer, SRRM can be regarded as becoming "externalized", i.e. it is no longer present not only in the nucleus, but also on the surface of cells that are then cancer cells. Therefore, until now, SRRM2 was not known to be useful for therapy due to its localization in the nucleus, in particular in nuclear speckles. However, since the inventors surprisingly found that SRRM2 is present on the cell surface of cancer cells, these cells can then be targeted for cancer therapy. An exemplary sequence of SRRM2 is provided by the UniProt database entry Q9UQ35 (version 2, March 6, 2007) and is illustrated in SEQ ID NO:25.

[0105] In the context of the present invention, the SRRM2 protein may be an SRRM2 protein having SEQ ID NO: 25, or may be a modified protein having an amino acid sequence derived from the above sequence by modifying one or more amino acids. Examples of modified proteins having an amino acid sequence derived from the above sequence by modifying one or more amino acids may include polypeptides having 70% or more, preferably 80% or more, more preferably 90% or more, and even more preferably 95% or more homology with the amino acid sequence. Alternatively, partial peptides of these SRRM2 proteins may be used.

[0106] The term "homology" as used herein is its usual meaning, including identical amino acids and equivalent positions in the linear amino acid sequences of two proteins compared to each other are considered to be conservatively substituted amino acids (e.g., exchanging glutamic acid residues with aspartic acid residues). "Identity" or "sequence identity" refers to a sequence property that measures their similarity or relationship. The term "sequence identity" or "identity" used in the present invention refers to the percentage of the number of identical residues that form a pair relative to the longer of the two sequences after the sequence of the polypeptide of the present invention is aligned with the sequence in question (homology). Identity is determined by dividing the number of identical residues by the total number of residues and then multiplying the result by 100.

[0107] Sequence homology or sequence identity, for example, can be determined herein using the program BLASTP blastp version 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 the alignment of the complete polypeptide sequence, optionally including the propeptide sequence (matrix: BLOSUM 62; gap weight: 11.1; cutoff value set to 10 -3 ), using human IL-4 as a reference in the pairwise comparison. It is calculated as the percentage of the number of "positives" (homologous amino acids) represented by the results output by the BLASTP program divided by the total number of amino acids selected by the program for comparison. In this regard, it should be noted that the total number of amino acids selected may differ from the length of porcine NTCP.

[0108] The SRRM2 protein used in the present invention is not limited by its source, but is preferably a human SRRM2 protein.

[0109] The term "antibody" as used herein and in the context of the present invention may include a chimeric antibody, a humanized antibody, a monovalent antibody, a multivalent antibody, a low molecular weight antibody, a diabody or a scFv.

[0110] Chimeric antibodies refer to antibodies comprising variable regions and constant regions of different sources connected to each other. For example, mouse-human heterologous chimeric antibodies are antibodies comprising the heavy and light chain variable regions of mouse antibodies and the heavy and light chain constant regions of human antibodies. The DNA encoding the mouse antibody variable regions is connected to the DNA encoding the human antibody constant regions, and the connection product can be integrated into the expression vector to prepare a recombinant vector expressing the chimeric antibody. Cells (recombinant cells) transformed with these vectors can be cultivated to express the DNA insert fragment, thereby obtaining the chimeric antibodies produced during the culture process.

[0111] Generally, chimeric antibodies include antibody variable regions of non-human animal origin and constant regions of human antibody origin. In contrast, humanized antibodies include antibody complementary determining regions (CDRs) of non-human animal origin, framework regions (FRs) of human antibody origin, and constant regions of human antibody origin. Humanized antibodies are also referred to as reshaped human antibodies. Specifically, for example, humanized antibodies comprising non-human animal (e.g., mouse) antibody CDRs transplanted in human antibodies are known in the art. Because the antigenicity of humanized antibodies in the human body is reduced, they can be used as active ingredients of therapeutic agents of the present invention.

[0112] Each antibody variable region usually contains 3 CDRs, flanked by 4 FRs. The CDR region basically determines the binding specificity of the antibody. CDRs have different amino acid sequences. On the other hand, the amino acid sequences that constitute FRs often show a high degree of homology between antibodies with different binding specificities. Therefore, it is generally said that through CDR transplantation, the binding specificity of a certain antibody can be transplanted to other antibodies.

[0113] The antibodies that bind to human SRRM2 present in the pharmaceutical composition of the present invention may include bivalent antibodies represented by IgG (IgG1, IgG2, IgG4, etc.), and monovalent antibodies or multivalent antibodies represented by IgM, as long as these antibodies bind to the SRRM2 protein. The multivalent antibodies that may be present in the pharmaceutical composition of the present invention may include multivalent antibodies having antigen binding sites, all multivalent antibodies are identical to each other or some or all multivalent antibodies are different from each other. Preferably, the antibody that binds to human SRRM2 is an IgG antibody.

[0114] The antibody binding to human SRRM2 present in the pharmaceutical composition of the present invention may also be a low molecular weight antibody, which covers an antibody fragment lacking a portion of a complete antibody (e.g., complete IgG). As long as the resulting antibody fragment is able to bind to SRRM2, this partial lack of the antibody molecule is accepted. Preferably, the antibody fragment used in the pharmaceutical composition according to the present invention should contain one or both of the heavy chain variable region (VH) and the light chain variable region (VL). It is also preferred that the antibody fragment used in the pharmaceutical composition according to the present invention should contain CDR. The number of CDRs contained in the antibody fragment used in the pharmaceutical composition of the present invention is not particularly limited, preferably at least 6 CDRs: heavy chain CDR1, CDR2 and CDR3, and light chain CDR1, CDR2 and CDR3.

[0115] The amino acid sequence of VH or VL may contain one or more substitutions, deletions, additions and / or insertions. In addition, 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 is able to bind to human SRRM2. In addition, its variable region may be chimeric or humanized. Specific examples of antibody fragments may include Fab, Fab', F(ab')2 and Fv. In addition, specific examples of low molecular weight antibodies may include Fab, Fab', F(ab')2, Fv, scFv (single chain Fv), diabodies, sc(Fv)2 (single chain (Fv)2) and scFv-Fc. In the present invention, the low molecular weight antibody is preferably a diabody or sc(Fv)2, and these antibody multimers (e.g., dimers, trimers, tetramers and polymers) are also covered by the low molecular weight antibodies that can be used in the pharmaceutical composition of the present invention.

[0116] 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. Diabodies are dimers comprising two polypeptide chains. Typically, each polypeptide chain constituting the dimer comprises a heavy chain and a light chain variable region connected via a joint on the same chain. The joint in the diabody is typically too short to allow pairing between the heavy chain and light chain variable regions on the same chain. Specifically, the number of amino acid residues constituting the joint is, for example, about 5 residues. Therefore, the heavy chain and light chain variable regions encoded on the same polypeptide chain cannot form a single-chain variable region fragment together. Instead, they form a dimer by pairing with another single-chain variable region fragment. As a result, the diabody has two antigen binding sites.

[0117] As used in the context of the present invention, scFv can be obtained by connecting the heavy chain and light chain variable regions of an antibody. In scFv, the heavy chain and light chain variable regions are connected via a joint, preferably a peptide joint. The heavy chain and light chain variable regions in the scFv can be derived from any antibody described in this specification. The peptide joint connecting the variable regions is not particularly limited. For example, any single-chain peptide of about 3 to 25 residues can be used as a joint.

[0118] The antibody binding to human SRRM2 as used in the pharmaceutical composition and the antibody binding to human SRRM2 according to the present invention may also encompass binding entities such as lipocalin, aptamer or anticalin.

[0119] The antibody that binds to human SRRM2 used in the present invention may have a variety of forms. However, it needs to bind to the SRRM2 protein and is not particularly limited by its source, type, shape, etc., but may have cytotoxic activity. Specifically, antibodies such as antibodies of non-human animal origin (e.g., mouse, rat or camel antibodies), antibodies of human origin, 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 or monoclonal antibody, preferably a monoclonal antibody.

[0120] The antibody binding to human SRRM2 used in the present invention can be obtained as a polyclonal or monoclonal antibody using means known in the art. The antibody used in the present invention is particularly preferably a monoclonal antibody of mammalian origin. Monoclonal antibodies of mammalian origin include, for example, those produced by hybridomas and those produced by hosts transformed with expression vectors containing antibody genes by genetic engineering methods.

[0121] The antibody that binds to human SRRM2 can be modified with various molecules such as polyethylene glycol (PEG). In addition, the antibody that binds to human SRRM2 can also be modified with cytotoxic substances such as chemotherapeutic agents, radioactive chemicals, etc.

[0122] Specific examples of the antibody that recognizes and binds to SRRM2 present on the cell surface of a target cell (such as a cancer cell) used in the present invention may include the antibodies given and described herein.

[0123] As described above, antibodies binding to human SRRM2 of the present invention or as used in the pharmaceutical composition of the present invention or as used in the method of the present invention, including substitution, deletion, addition and / or insertion of one or more amino acids, are also included in the scope of the present invention, and may be prepared or naturally occurring. Examples of methods for introducing mutations in polypeptides 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 known to those skilled in the art for preparing a polypeptide functionally equivalent to a certain polypeptide. Those skilled in the art can use such methods to appropriately introduce mutations in the antibodies of the present invention or as used in the pharmaceutical composition of the present invention or as used in the method of the present invention, thereby preparing antibodies functionally equivalent to such antibodies. In addition, amino acid mutations may occur in nature. Such an antibody having an amino acid sequence comprising one or more amino acid mutations derived from the amino acid sequence of the antibody of the present invention or the antibody as used in the pharmaceutical composition of the present invention or the method of the present invention is functionally equivalent to the antibody or is a variant of the antibody, and is also encompassed by the antibody of the present invention or the antibody as used in the pharmaceutical composition of the present invention or the method of the present invention.

[0124] The number of amino acids mutated in such a variant is usually within 50 amino acids, preferably within 30 amino acids, more preferably within 10 amino acids (eg, within 5 amino acids).

[0125] For the amino acid residue to be mutated, it is preferred that the mutation should be conservatively performed between amino acids with the same side chain properties. For example, the following classification based on the side chain properties of amino acids has 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 hydroxyl side chains (S, T and Y), amino acids with sulfur atom side chains (C and M), amino acids with carboxylic acid and amide side chains (D, N, E and Q), amino acids with base side chains (R, K and H) and amino acids with aromatic group side chains (H, F, Y and W) (all symbols in brackets represent single letter codes of amino acids).

[0126] It is known that a polypeptide having an amino acid sequence modified from a certain amino acid sequence by deletion and / or addition of one or more amino acid residues and / or substitution with other amino acids maintains the biological activity of the original polypeptide (Mark, DF et al., 1984) (Wang, A. et al., 1982). Specifically, when the amino acids in the amino acid sequence constituting a certain polypeptide are replaced by amino acids classified in the same group as the amino acid sequence, it is generally believed that the polypeptide may maintain its activity. In the present invention, the substitution between amino acids in the same amino acid group as described above is referred to as conservative substitution.

[0127] As used herein, the term "surface" or specifically "cell surface" refers to the cell membrane. The cell membrane, which may also be referred to as the plasma membrane, is a thin membrane surrounding each living cell, demarcating the cell from its surrounding environment. The cell membrane surrounds the cell components, which are usually large, water-soluble, highly charged molecules such as proteins, nucleic acids, carbohydrates, and substances involved in cell metabolism. Therefore, the cell membrane has at least two functions: first, a barrier, keeping the components of the cell inside and unwanted substances outside, and secondly, a gate, allowing essential nutrients to be transported into the cell and removing waste from the cell. ER-derived vesicles may also be involved in the construction or formation of the cell membrane.

[0128] Antibodies that bind to human SRRM2 are preferably capable of binding to SRRM2 polypeptides extracellularly. In other words, antibodies as described herein are capable of binding to SRRM2 when extracellular, and the SRRM2 also includes SRRM2 specifically on the cell surface. Therefore, antibodies that bind to human SRRM2 are preferably not intracellular antibodies (also called intrabodies). "Intrabodies" (from intracellular and antibody) are antibodies that act within cells to bind to intracellular proteins. This requires expression of antibodies within target cells, which can be achieved, for example, in transgenic animals or by gene therapy. Therefore, intrabodies are antibodies modified by intracellular localization and include antibodies produced in prokaryotes or other non-target cells. The term "intrabodies" can be applied to several types of protein targeting: the antibody can be retained in the cytoplasm, or it can have a nuclear localization signal, or it can enter the lumen of the endoplasmic reticulum through co-translational translocation across the membrane, provided that it is retained in that compartment by the KDEL sequence. However, as shown in Example 11, the antibodies of the present invention that bind to human SRRM2 are preferably capable of being internalized.

[0129] The "target cell" is preferably a cancer cell. The term "cancer" as used herein may include any one or more of the following: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical 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 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, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, cancer of the nervous system, neuroblastoma, non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumor, plasma cell tumor, primary CNS 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, cancer of the vascular system, Waldenstrom's macroglobulinemia and Wilms' tumor.

[0130] 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 known to those skilled in the art for use in pharmaceutical compositions. It should be understood that the antibodies or pharmaceutical compositions as described herein may be mixed with a carrier or diluent, which will not interfere with the intended purpose of the present invention. For example, such a carrier as used in the present invention may be a carrier protein, such as bovine serum albumin (BSA) or keyhole limpet hemocyanin (KLH).

[0131] 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 phrase "cytotoxic activity" refers to having SRRM2 binding activity, and may also include activity equivalent to the activity of the antibody that binds to human SRRM2 of the present invention. In the present invention, equivalent activity does not necessarily have to be the same activity, for example, compared to the activity of any one of antibodies (a) to (e) as described herein, it may be 50% or more, preferably 70% or more, more preferably 90% or more activity. Examples of upper limits 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.

[0132] In another 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). Therefore, examples of cytotoxic activity according to the present invention may include ADCC and / or CDC activity. In the context of the present invention, ADCC activity means the activity of destroying target cells by binding to the Fc domain of an antibody that specifically attaches to a cell surface antigen of a target cell through a cell (immune cell, etc.) carrying an Fcγ receptor via the Fcγ receptor. On the other hand, CDC activity means cytotoxic activity mediated by the complement system. Whether an antibody has ADCC activity or CDC activity can be determined by methods known in the art.

[0133] Therefore, the antibody that binds to human SRRM2 used in the pharmaceutical composition of the present invention may have an activity such as ADCC activity, and thus can be used as a drug, preferably as an anticancer agent, wherein the cancer is, for example, breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, cholangiogenic cancer, oral squamous cell carcinoma, hematological malignancies or gliomas.

[0134] In one embodiment of the present invention, the antibody that binds to human SRRM2 is conjugated to a cytotoxic substance.

[0135] In a preferred embodiment, the antibody that binds to human SRRM2 can be conjugated to a cytotoxic substance, such as a chemotherapeutic agent, a toxic peptide or a radioactive chemical. Such a modified antibody (hereinafter referred to as an antibody conjugate) can be obtained by chemically modifying the obtained antibody. Methods for antibody modification have been established in the art.

[0136] Examples of chemotherapeutic agents whose cytotoxic activity works by conjugation to an antibody that binds to SRRM2 may include the following chemotherapeutic agents: azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, camptothecin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatin, irinotecan, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, doxorubicin glucuronide, epirubicin, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, fluoroquinolone Uridine, fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, leucovorin, cyclohexyl lomustine, nitrogen mustard, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, methotrexate, mitronquinone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisolone, procarbazine, paclitaxel, pentostatin, semustine, streptozotocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uramustine, vinblastine, vinorelbine, vincristine.

[0137] The chemotherapeutic agent is preferably a low molecular weight chemotherapeutic agent. Low molecular weight chemotherapeutic agents are less likely to interfere with antibodies, even after they are conjugated to antibodies. Low molecular weight chemotherapeutic agents typically have a molecular weight of 100 to 2000, preferably 200 to 1000. All chemotherapeutic agents exemplified above are low molecular weight chemotherapeutic agents. These chemotherapeutic agents encompass prodrugs that are converted into active chemotherapeutic agents in vivo. The activation of the prodrug can be an enzymatic conversion or a non-enzymatic conversion.

[0138] like Figure 7 and Figure 8 As shown, the surface presence of SRRM2 can be used for SRRM2-specific CAR-T cell therapy. Therefore, the present invention makes SRRM2-specific cancer therapy possible. Therefore, in another embodiment of the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 is part of a chimeric antigen receptor (CAR). For the embodiment, it is preferred that the CAR is contained by T cells, NK cells, NK-T cells or macrophages. Chimeric antigen receptors (CAR, also known as chimeric immune receptors, chimeric T cell receptors or artificial T cell receptors) are receptor proteins that have been engineered to give T cells the ability to target specific proteins.

[0139] In one embodiment of the pharmaceutical composition of the present invention, the cross-reactivity of the antibody binding to human SRRM2 with SRRM2-related proteins is less than 20%. This means that preferably the cross-reactivity of the antibody binding to human SRRM2 with other serine / arginine repeat matrix proteins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 20%. More preferably, the cross-reactivity of the antibody binding to human SRRM2 with SRRM2-related proteins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 15%. Even more preferably, the cross-reactivity of the antibody binding to human SRRM2 with SRRM2-related proteins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 10%. Even more preferably, the cross-reactivity of the antibody binding to human SRRM2 with SRRM2-related proteins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 5%. Even more preferably, the cross-reactivity of the antibody binding to human SRRM2 with SRRM2-related proteins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 3%. Even more preferably, the cross-reactivity of the antibody binding to human SRRM2 with SRRM2-related proteins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 2%. Even more preferably, the cross-reactivity of the antibody binding to human SRRM2 with SRRM2-related proteins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 1%.

[0140] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0141] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0142] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0143] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0144] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0145] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0146] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0147] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0148] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0149] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0150] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0151] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0152] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0153] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0154] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0155] In one embodiment, the antibody that binds to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0156] 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, wherein the heavy chain variable region comprises a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region, wherein the light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:12; or an antibody that binds to the same epitope.

[0157] 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, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18; or an antibody that binds to the same epitope.

[0158] 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, wherein the heavy chain variable region comprises a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region, wherein the light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24; or an antibody that binds to the same epitope.

[0159] 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, wherein the heavy chain variable region comprises a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region, wherein the light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 27, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 28, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 29; or an antibody that binds to the same epitope.

[0160] The antibodies described herein may contain a constant region. The constant region used is not particularly limited, and any constant region can be used. Preferred examples of the constant region used in the present invention may include a constant region of human origin. For example, a constant region derived from human IgG1, human IgG2, human IgG3, or human IgG4 can be used as a heavy chain constant region. In addition, for example, a constant region derived from a human κ chain or a human λ chain can be used as a light chain constant region. The constant region used in the present invention may be a constant region with a native sequence, or may be a constant region with a modification derived from a native sequence by modifying one or more amino acids.

[0161] The antibodies described herein may also contain a framework region (FR). The FR used is not particularly limited, and any FR may be used as long as the resulting antibody maintains its binding activity to human SRRM2 present on the cell surface of the target cell. Preferred examples of FRs used in the present invention may include FRs derived from human antibodies. Since FR replacement techniques that maintain the antigen binding activity of antibodies are known in the art, those skilled in the art may appropriately select FRs. The FRs used in the present invention may be FRs having a native sequence, or may be FRs having a sequence derived from a native sequence by modifying one or more amino acids.

[0162] Whether an antibody shares an epitope with a certain antibody can be confirmed based on their competition for the same epitope. Competition between antibodies is detected by cross-blocking assays and the like. The cross-blocking assay is preferably a competitive ELISA assay, for example. Specifically, in the cross-blocking assay, the SRRM2 protein coated on the wells of a microtiter plate may be pre-incubated in the presence or absence of a candidate competing antibody, and then the antibody of the present invention that binds to human SRRM2 is added to the well. The amount of the antibody of the present invention bound to the SRRM2 protein in the well is indirectly related to 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 of the antibody to be tested for the same epitope, the smaller the amount of the antibody of the present invention bound to the well coated with the SRRM2 protein, and the greater the amount of the antibody to be tested bound to the well coated with the SRRM2 protein.

[0163] By pre-labeling the antibody, the amount of the antibody bound to the hole can be easily measured. For example, biotin-labeled antibodies can be measured by using avidin-peroxidase conjugates and suitable substrates. Cross-blocking assays using enzyme (e.g., peroxidase) labels are particularly referred to as competitive ELISA assays. Antibodies can be labeled with other detectable or measurable markers. Specifically, radiolabels or fluorescent labels, etc. are known in the art.

[0164] Assuming that the candidate antibody can bind to human SRRM2 present on the cell surface of target cells by at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even further preferably at least 99%, as 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 an epitope substantially the same as the epitope bound by the antibody of the present invention or the epitope bound by the antibody used in the pharmaceutical composition.

[0165] In another aspect, the present invention provides a pharmaceutical composition according to the invention for use in a method of treating cancer in a human subject. For said embodiment, preferably, the cancer is characterized by cells, wherein human SRRM2 is present on the cell surface of said cells. For said embodiment, it is also preferred that the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, cholangiogenic cancer, oral squamous cell carcinoma, hematological malignancy or glioma.

[0166] The pharmaceutical compositions according to the present invention can be administered by standard routes. These include, but are 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) routes.

[0167] The present invention also includes a method of treating cancer, wherein the method comprises administering to a human subject a therapeutically effective amount of a pharmaceutical composition according to the present invention. For said embodiment, preferably, the cancer is characterized by cells, wherein human SRRM2 is present on the cell surface of the cells. For said embodiment, it is also preferred that the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, cholangiogenic cancer, oral squamous cell carcinoma, hematological malignancy or glioma.

[0168] In addition, the present invention includes a method of treating cancer, wherein the method comprises administering to a human subject a therapeutically effective amount of an antibody that binds to human SRRM2 as described herein. For said embodiment, it is preferred that the cancer is characterized by cells, wherein human SRRM2 is present on the cell surface of said cells. For said embodiment, it is also preferred that the cancer is breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, pancreatic cancer, gastric cancer, cholangiogenic cancer, oral squamous cell carcinoma, hematological malignancy or glioma.

[0169] The term "therapeutically effective amount" refers to an amount of an antibody or pharmaceutical composition or drug according to the invention that is effective to "treat" cancer in a human subject. Specifically, in the case of cancer, a therapeutically effective amount of an antibody / pharmaceutical composition / drug may reduce the number of cancer cells; reduce tumor size; inhibit or stop cancer cell infiltration into peripheral organs; inhibit and stop tumor metastasis; inhibit and stop tumor growth; alleviate one or more symptoms associated with cancer to some extent, or a combination of these effects on cancer cells. To the extent that an antibody / pharmaceutical composition / drug prevents the growth of existing cancer cells and / or kills existing cancer cells, it may be referred to as cytostatic and / or cytotoxic.

[0170] The present invention also encompasses the use of the pharmaceutical composition according to the present invention in the preparation of a medicament for the treatment of cancer.

[0171] In one embodiment, the present invention also encompasses the use of an antibody that binds to human SRRM2 as described herein in the preparation of a medicament for treating cancer.

[0172] Terms such as "treat" or "treatment" refer to 1) therapeutic measures that cure, slow, alleviate the symptoms of, and / or halt the progression of a diagnosed pathological condition or disorder, and 2) prophylactic or preventative measures that prevent or slow the development of a targeted pathological condition or disorder. Therefore, those in need of treatment include those already suffering from the disorder; those prone to suffering from the disorder; and those in need of prevention of the disorder. A subject is successfully "treated" according to the methods of the invention or with a pharmaceutical composition or antibody that binds to human SRRM2 according to the invention if the patient exhibits one or more of the following: a decrease in the number of cancer cells or the complete absence of cancer; a decrease in tumor size; inhibition or absence of cancer cell infiltration into peripheral organs (including cancer spread to soft tissue and bone); inhibition or absence of tumor metastasis; inhibition or absence of tumor growth; alleviation of one or more symptoms associated with a particular cancer; reduced morbidity and mortality; and improved quality of life.

[0173] The antibody to be administered to a human can also be converted into a genetically recombinant antibody that has been artificially modified, for example, to reduce heterologous antigenicity in humans. Genetically recombinant antibodies include, for example, chimeric antibodies and humanized antibodies as defined herein. These modified antibodies can be produced using methods known in the art.

[0174] In another aspect, the present invention provides a method for determining whether a human subject is likely to have cancer, the method comprising determining, in a sample obtained from the human subject, whether SRRM2 is present on the cell surface of (cancer) cells comprised in the sample.

[0175] As shown in Example 9, SRRM2 is also present on the surface of extracellular vesicles obtained from subjects diagnosed with cancer. Therefore, the present invention also relates to a method for determining whether a human subject may have cancer, the method comprising determining whether SRRM2 is present on the surface of an extracellular vesicle in a sample obtained from the human subject. As used herein, "extracellular vesicle" (EV) may refer to a lipid bilayer-defined particle that is naturally released from almost all types of cells and, unlike cells, cannot replicate. Although the vast majority of EVs are less than 200 nm, the diameter of EVs typically ranges from a size close to the smallest physically possible unilamellar liposome (approximately 20-30 nanometers) to as large as 10 μm or more.

[0176] According to size and synthesis pathway, EV can be divided into exosomes, microvesicles and apoptotic bodies. Therefore, EV is preferably selected from exosomes, microvesicles and apoptotic bodies. Usually, they carry cargo from parent cells such as proteins, nucleic acids, lipids, metabolites, and even organelles. Different EV subtypes have been proposed. Therefore, EV can also be one or more of the following: extranuclear granules, microvesicles, microparticles, exosomes, carcinogens, apoptotic bodies, exomeres, etc. Preferably, EV is a carcinogen. In the case of EV, the sample is preferably ascites.

[0177] Before determining the presence of SRRM2 on the surface of extracellular vesicles in a sample obtained from the human subject, EVs can be isolated and / or enriched from the sample using antibodies or antibody fragments that specifically bind to biomarkers present on the surface of EVs. Such biomarkers for EVs include, for example, Alix, Tsg101 for exosomes, four transmembrane proteins or flotillins such as CD81, CD63, and CD9, integrins, selectins, or CD40 for microvesicles, and Annexin V or phosphatidylserine for apoptotic bodies. Antibodies to these markers can be commercially available, for example, from Abcam. Methods for separating and / or enriching EVs are also 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.

[0178] Preferably, in the context of a method for determining whether a human subject may have cancer or a neurodegenerative disease, the pharmaceutical composition may be a diagnostic composition. Therefore, the present invention also relates to a diagnostic composition comprising an 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 pharmaceutically acceptable carrier, diluent or excipient, preferably, the antibody is a monoclonal antibody.

[0179] The method for determining whether a human subject is likely to have cancer may include the following steps:

[0180] - providing a sample obtained from said human subject,

[0181] - determining in said sample obtained from said human subject the presence or absence of SRRM2 on the cell surface of (cancer) cells comprised by said sample,

[0182] - correlating the presence of SRRM2 on the cell surface of (cancer) cells comprised by said sample with determining whether said human subject is likely to suffer from cancer.

[0183] In the context of the present invention, a "subject" or "human subject" is a human being. For example, a subject can be a patient suspected of having a disease or clinical condition associated with cancer or diagnosed with such a disease or clinical condition. A subject can be a patient suspected of having a disease or clinical condition associated with a neurodegenerative disease or diagnosed with such a disease or clinical condition.

[0184] The "sample" obtained from the human subject is preferably selected from a blood sample, a serum sample, a plasma sample, a cerebrospinal fluid sample, a saliva sample, a dissolved tissue sample and a 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 have cancer.

[0185] The step of "determining in said sample obtained from said human subject whether SRRM2 is present on the cell surface of target cells comprised by said sample" may comprise determining the presence of SRRM2 or a fragment thereof by contacting said sample with at least one SRRM2 binder. Said at least one binder may be, for example, an antibody according to the present invention or as described herein. Preferably, the cross-reactivity of at least one binder with other proteins, in particular other peroxiredoxins (such as SRRM1, SRRM3, SRRM4 or SRRM5) is less than 20%, 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%, even more preferably less than 1%.

[0186] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0187] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0188] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0189] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0190] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0191] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0192] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0193] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0194] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0195] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0196] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0197] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0198] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0199] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0200] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0201] The present invention also relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0202] The present invention further relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:12; or an antibody that binds to the same epitope.

[0203] The present invention further relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18; or an antibody that binds to the same epitope.

[0204] The present invention further relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:21, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:24; or an antibody that binds to the same epitope.

[0205] The present invention further relates to an antibody that binds to human SRRM2, wherein the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:21, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:27, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:28, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:29; or an antibody that binds to the same epitope.

[0206] The present invention also provides use of the antibody binding to human SRRM2 of the present invention in preparing a medicament for treating cancer.

[0207] The present invention further provides antibodies that bind to human SRRM2 of the present invention for use in a method for treating cancer.

[0208] In some embodiments, antibodies that bind to human SRRM2 of the present invention or described herein may contain 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 in the Fc region of the antibody. For example, cysteine ​​residues can be introduced into the Fc region to allow the formation of interchain disulfide bonds in this region, thereby improving complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as known to those skilled in the art. Alternatively, antibodies with dual Fc regions can be engineered.

[0209] In addition, the antibodies described herein may have one or more amino acid substitutions, deletions, additions and / or insertions in their CDR sequences, as long as the resulting antibody is functionally equivalent to antibodies (a) to (d). The term "functionally equivalent" means equivalent in affinity and cytotoxicity to SRRM2. The term "equivalent" means having 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%, even more preferably at least 99% activity compared to antibodies (a) to (d). The upper limit of the activity is not particularly limited and may be higher than antibodies (a) to (d). Affinity or cytotoxicity can be determined by methods generally known to those skilled in the art.

[0210] The presence of SRRM2 on the cell surface of a target cell or an extracellular vesicle may also indicate that the subject from whom the sample containing the target cell has been obtained suffers from a neurodegenerative disease. In this case, the target cell is preferably a neuron. The target cell may also be a glial cell. Glial cells include, but are not limited to, astrocytes, oligodendrocytes, ependymal cells, radial glial cells, Schwann cells, satellite cells, enteric glial cells, and microglial cells. In this case, the sample is preferably obtained from brain tissue, neuronal tissue, and / or cerebrospinal fluid.

[0211] As used herein, "neurodegenerative disease" is characterized by the progressive loss of structure or function of neurons in a process known as neurodegeneration. This neuronal damage may ultimately involve cell death. Neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, Batten disease, multiple system atrophy, and prion diseases.

[0212] Therefore, the present invention also relates to a pharmaceutical composition of the present invention for use in a method for treating a neurodegenerative disease in a human subject. The present invention also relates to an antibody that binds to human SRRM2 as used herein for use in a method for treating a neurodegenerative disease in a human subject. Preferably, the neurodegenerative disease is characterized by cells, wherein human SRRM2 is present on the cell surface of the cells.

[0213] The present invention also includes a method for treating a neurodegenerative disease, wherein the method comprises administering to a human subject a therapeutically effective amount of a pharmaceutical composition according to the present invention. In addition, the present invention includes a method for treating a neurodegenerative disease, wherein the method comprises administering to a human subject a therapeutically effective amount of an antibody that binds to human SRRM2 as described herein. For said embodiment, it is preferred that the neurodegenerative disease is characterized by cells, wherein human SRRM2 is present on the cell surface of said cells.

[0214] The present invention also relates to a method for determining whether a human subject is likely to suffer from a neurodegenerative disease, the method comprising determining, in a sample obtained from the human subject, the presence or absence of SRRM2 on the cell surface of cells comprised in the sample.

[0215] The present invention also relates to a method for determining whether a human subject is likely to suffer from a neurodegenerative disease, the method comprising determining the presence or absence of SRRM2 on the surface of an extracellular vesicle in a sample obtained from the human subject.

[0216] The method for determining whether a human subject is likely to suffer from a neurodegenerative disease may include the following steps:

[0217] - providing a sample obtained from said human subject,

[0218] - determining, in said sample obtained from said human subject, the presence or absence of SRRM2 on the cell surface of target cells comprised in said sample,

[0219] - correlating the presence of SRRM2 on the cell surface of said target cells comprised in said sample with determining whether said human subject is likely to suffer from a neurodegenerative disease.

[0220] The present invention also relates to an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell, which is used in a method of killing a target cell having SRRM2 present on its cell surface.

[0221] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0222] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0223] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0224] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0225] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0226] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0227] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0228] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0229] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0230] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0231] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0232] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0233] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0234] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0235] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0236] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0237] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:12; or an antibody that binds to the same epitope.

[0238] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18; or an antibody that binds to the same epitope.

[0239] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:24; or an antibody that binds to the same epitope.

[0240] In one embodiment of the antibody used in the method of killing the target cell having SRRM2 present on its cell surface, the antibody is an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:27, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:28, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:29; or an antibody that binds to the same epitope.

[0241] All embodiments described herein for the pharmaceutical compositions of the present invention, and antibodies that bind to human SRRM2 present on the cell surface of the target cells of the present invention, and the methods of the present invention described herein, as well as the various definitions described above, also apply to the antibodies of the present invention described herein for use in the method of killing the target cells having SRRM2 present on their cell surface.

[0242] The present invention also relates to a method for killing a target cell having serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell, the method comprising administering an antibody that binds to human SRRM2 present on the cell surface of the target cell.

[0243] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0244] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0245] In one embodiment of a 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 and a light chain variable region, the 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 the 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.

[0246] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0247] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0248] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0249] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0250] In one embodiment of a 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 and a light chain variable region, the 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 the 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.

[0251] In one embodiment of a 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 and a light chain variable region, the 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 the 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.

[0252] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0253] In one embodiment of a 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 and a light chain variable region, the 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 the 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.

[0254] In one embodiment of a 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 and a light chain variable region, the 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 the 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.

[0255] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0256] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0257] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0258] In one embodiment of a 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 and a light chain variable region, the 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 the 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.

[0259] In one embodiment of a method for killing a target cell, wherein the target cell has 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 an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:12; or an antibody that binds to the same epitope.

[0260] In one embodiment of a 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 an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18; or an antibody that binds to the same epitope.

[0261] In one embodiment of a method for killing a target cell, wherein the target cell has 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 an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24; or an antibody that binds to the same epitope.

[0262] In one embodiment of a 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 an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 27, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 28, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 29; or an antibody that binds to the same epitope.

[0263] All embodiments described herein for the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 present on the cell surface of the target cell of the present invention, the method for determining whether a human subject is likely to have the cancer of the present invention as described herein, and the corresponding definitions as described above are also applicable to the method of killing target cells as described herein, wherein the target cell has serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of the target cell.

[0264] The present invention also relates to an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell, which is used in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject.

[0265] In one embodiment of the antibody and the method for using the antibody in treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0266] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0267] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0268] In one embodiment of the antibody and the method for using the antibody in treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0269] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0270] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0271] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0272] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0273] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0274] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0275] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0276] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0277] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0278] In one embodiment of a method for killing a target cell, wherein the target cell has 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 and a light chain variable region, the 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 the 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.

[0279] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0280] In one embodiment of the antibody and its use in a method for treating cancer in a subject, comprising determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the 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 the 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.

[0281] In one embodiment of the antibody and its use in a method for treating cancer in a subject, including determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO:10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO:11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:12; or an antibody that binds to the same epitope.

[0282] In one embodiment of the antibody and its use in a method for treating cancer in a subject, including determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18; or an antibody that binds to the same epitope.

[0283] In one embodiment of the antibody and its use in a method for treating cancer in a subject, including determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24; or an antibody that binds to the same epitope.

[0284] In one embodiment of the antibody and its use in a method for treating cancer in a subject, including determining whether the target cells of the subject have SRRM2 present on the cell surface before treating the cancer in the subject, the antibody is an antibody comprising a heavy chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region, the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 27, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 28, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 29; or an antibody that binds to the same epitope.

[0285] All embodiments described herein for the pharmaceutical composition of the present invention, the antibody that binds to human SRRM2 present on the cell surface of the target cell of the present invention, the method for determining whether a human subject is likely to have the cancer of the present invention as described herein, and the corresponding definitions as described above also apply to the antibody, and its use in a method for treating cancer in a subject, comprising, before treating the cancer in the subject, determining whether the target cell of the subject has SRRM2 present on the cell surface.

[0286] A description of the sequences shown in the sequence listing and used in the context of the present invention is as follows:

[0287] SEQ ID NO: 1 shows the amino acid sequence of the VH region of antibody 13F11.

[0288] SEQ ID NO: 2 shows the amino acid sequence of the VL region of antibody 13F11.

[0289] SEQ ID NO: 3 shows the amino acid sequence of the VH region of antibody 23A7.

[0290] SEQ ID NO: 4 shows the amino acid sequence of the VL region of antibody 23A7.

[0291] SEQ ID NO: 5 shows the amino acid sequences of the VH regions of antibody 18A4 and antibody 18A4-2.

[0292] SEQ ID NO: 6 shows the amino acid sequence of the VL region of antibody 18A4.

[0293] SEQ ID NO: 7 shows the amino acid sequence of VH-CDR1 of antibody 13F11.

[0294] SEQ ID NO: 8 shows the amino acid sequence of VH-CDR2 of antibody 13F11.

[0295] SEQ ID NO: 9 shows the amino acid sequence of VH-CDR3 of antibody 13F11.

[0296] SEQ ID NO: 10 shows the amino acid sequence of VL-CDR1 of antibody 13F11.

[0297] SEQ ID NO: 11 shows the amino acid sequence of VL-CDR2 of antibody 13F11.

[0298] SEQ ID NO: 12 shows the amino acid sequence of VL-CDR3 of antibody 13F11.

[0299] SEQ ID NO: 13 shows the amino acid sequence of VH-CDR1 of antibody 23A7.

[0300] SEQ ID NO: 14 shows the amino acid sequence of VH-CDR2 of antibody 23A7.

[0301] SEQ ID NO: 15 shows the amino acid sequence of VH-CDR3 of antibody 23A7.

[0302] SEQ ID NO: 16 shows the amino acid sequence of VL-CDR1 of antibody 23A7.

[0303] SEQ ID NO: 17 shows the amino acid sequence of VL-CDR2 of antibody 23A7.

[0304] SEQ ID NO: 18 shows the amino acid sequence of VH-CDR3 of antibody 23A7.

[0305] SEQ ID NO: 19 shows the amino acid sequence of VH-CDR1 of antibody 18A4 and antibody 18A4-2.

[0306] SEQ ID NO: 20 shows the amino acid sequence of VH-CDR2 of antibody 18A4 and antibody 18A4-2.

[0307] SEQ ID NO: 21 shows the amino acid sequence of VH-CDR3 of antibody 18A4 and antibody 18A4-2.

[0308] SEQ ID NO: 22 shows the amino acid sequence of VL-CDR1 of antibody 18A4.

[0309] SEQ ID NO: 23 shows the amino acid sequence of VL-CDR2 of antibody 18A4.

[0310] SEQ ID NO: 24 shows the amino acid sequence of VL-CDR3 of antibody 18A4.

[0311] SEQ ID NO: 25 shows the amino acid sequence of SRRM2 as shown in the UniProt database entry Q9UQ35 (version 2 of March 6, 2007).

[0312] SEQ ID NO: 26 shows the amino acid sequence of the VL region of antibody 18A4-2.

[0313] SEQ ID NO: 27 shows the amino acid sequence of VL-CDR1 of antibody 18A4-2.

[0314] SEQ ID NO: 28 shows the amino acid sequence of VL-CDR2 of antibody 18A4-2.

[0315] SEQ ID NO: 29 shows the amino acid sequence of VL-CDR2 of antibody 18A4-2.

[0316] SEQ ID NO:30 shows the amino acid sequence of fragment tr04.

[0317] An overview of the SEQ ID NOs and detailed sequences as used in the context of the present invention is given in the following Table 1 (in case of conflict between the sequences shown in Table 1 and the sequences of the sequence listing which has to be submitted for formal reasons, the sequences of Table 1 replace the sequences of the sequence listing):

[0318] Table 1:

[0319]

[0320]

[0321]

[0322]

[0323]

[0324] In the context of the present invention the following abbreviations are used: VH = variable heavy chain; VH = variable heavy chain; VL = variable light chain; CDR = complementarity determining region; VH-CDR = CDR of the variable heavy region; VL-CDR = CDR of the variable light region; CDRs can be determined by using the Kabat algorithm, for example http: / / abysis.org / abysis / .

[0325] *****

[0326] Note that as used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes one or more of such different agents, and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art, which may be modified or substituted for the methods described herein.

[0327] Unless otherwise indicated, the term "at least" preceding a series of elements is understood to refer to each element in the series. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These equivalents are also intended to be encompassed by the present invention.

[0328] Wherever used, the term "and / or" includes the meanings of "and," "or," and "all or any other combination of elements connected by the term."

[0329] The term "less than" or conversely "greater than" does not include specific numbers.

[0330] For example, "less than 20" means less than the indicated number. Similarly, "greater than" or "higher than" means more than or greater than the specified number, for example, "greater than 80%" means more than or greater than 80% of the specified number.

[0331] Throughout the specification and in the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprising" and "containing" are understood to mean the inclusion of stated integers or steps or groups of integers or steps, but not the exclusion of any other integers or steps or groups of integers or steps. When used herein, the term "comprising" may be replaced by the terms "containing" or "including", or sometimes, when used herein, by the term "having". When used herein, "consisting of excludes any element, step or ingredient not specified.

[0332] The term "including" means "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0333] It should be understood that the present invention is not limited to the specific methodology, protocols, materials, reagents and substances, etc. described herein, and thus may vary. The terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention, which is limited only by the claims.

[0334] All publications cited throughout this specification (including all patents, patent applications, scientific publications, specifications, etc.), whether above or below, are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate these disclosures by virtue of prior invention. To the extent that material incorporated by reference is inconsistent or inconsistent with this specification, this specification will supersede any such material.

[0335] The contents of all literature and patent documents cited herein are incorporated by reference in their entirety.

[0336] The present invention and its advantages will be better understood from the following examples, which are provided for illustrative purposes only. These examples are not intended to limit the scope of the present invention in any way.

[0337] The present invention is also characterized by the following items:

[0338] 1. A pharmaceutical composition comprising an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell and optionally a pharmaceutically acceptable carrier, diluent or excipient, preferably, the antibody is a monoclonal antibody.

[0339] 2. The pharmaceutical composition according to item 1, wherein the antibody has cytotoxic activity.

[0340] 3. The pharmaceutical composition according to any one of the preceding items, wherein the antibody has ADCC or CDC.

[0341] 4. The pharmaceutical composition according to any one of the preceding items, wherein the antibody is conjugated to a cytotoxic substance.

[0342] 5. The pharmaceutical composition according to any one of the preceding items, wherein the antibody is part of a chimeric antigen receptor (CAR).

[0343] 6. A pharmaceutical composition according to item 5, wherein the CAR is contained by T cells, NK cells, NK-T cells or macrophages.

[0344] 7. The pharmaceutical composition according to any one of the preceding items, wherein the SRRM2 present on the cell surface of the target cell is externalized.

[0345] 8. The pharmaceutical composition according to any one of the preceding items, wherein the antibody is not an intracellular antibody.

[0346] 9. The pharmaceutical composition according to any one of the preceding items, wherein the antibody is

[0347] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0348] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0349] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0350] (d) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (c).

[0351] 10. The pharmaceutical composition according to any one of the preceding items, wherein the antibody is

[0352] (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and

[0353] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 12;

[0354] (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and

[0355] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0356] (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and

[0357] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24;

[0358] (d) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (c).

[0359] 11. The pharmaceutical composition according to any one of the preceding items, for use in a method for treating cancer in a human subject, preferably, wherein the cancer is characterized by cells, wherein human SRRM2 is present on the cell surface of the cells.

[0360] 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, cholangiogenic cancer, oral squamous cell carcinoma, hematological malignancy or glioma.

[0361] 13. A method for determining whether a human subject is likely to have cancer, the method comprising determining, in a sample obtained from the human subject, whether SRRM2 is present on the cell surface of cells contained in the sample and / or whether SRRM2 is present on the surface of extracellular vesicles.

[0362] 14. An antibody that binds to human SRRM2 present on the cell surface of a target cell, wherein the antibody is

[0363] (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2;

[0364] (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 4;

[0365] (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 6;

[0366] (d) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (c).

[0367] 15. An antibody that binds to human SRRM2 present on the cell surface of a target cell, the antibody comprising

[0368] (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and

[0369] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 12;

[0370] (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and

[0371] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0372] (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and

[0373] a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24;

[0374] (d) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (c).

[0375] Example

[0376] Materials and methods

[0377] Cells and culture conditions

[0378] 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 in a humidified CO2 incubator at 37°C, 18.3% O2, and 5% CO2. Hypoxic cells were incubated at 1% O2.

[0379] Transfection of 293 cells

[0380] Lipofectamine was used according to the manufacturer's instructions. TM 293 cells were transfected with expression plasmids encoding human SRRM2 or its mutants using 2000 transfection reagent (ThermoFisher Scientific, Menzel, Germany). If appropriate, cells were selected with 80 μg / ml hygromycin C to obtain positively transfected cells and further cultured in normal growth medium supplemented with 80 μg / ml hygromycin C.

[0381] Isolation of primary peripheral blood mononuclear cells (PBMC) from fresh blood

[0382] 30 ml of fresh heparinized blood from a healthy donor was diluted with PBS and carefully loaded on top of a layer of 10 ml human Pancoll (Pan Biotech, Aidenbach, Germany). The tube was centrifuged at 800 × g for 25 minutes. PBMCs were then carefully collected from the middle layer between Pancoll and plasma and washed three times in PBS. Cells were either freshly used for experiments or immediately frozen and stored at -80°C for later experiments.

[0383] Flow cytometry

[0384] For flow cytometric analysis of SRRM2 expression, cells were stained with any of the three SRRM2-specific antibodies or with an isotype control antibody for 20 min in FACS buffer (PBS + 2% FSC) and then with anti-rat-Alexa Fluor 647 secondary antibody (Jackson Immuno Research). All stainings were performed on ice.

[0385] Immunoblotting

[0386] To analyze SRRM2 expression by western blotting, whole cell lysates were prepared. Adherent cells were washed with PBS, detached with trypsin and precipitated. The cell pellet was washed in PBS, after which the cells were resuspended in RIPA buffer (Roche Diagnostics) containing protease inhibitors and incubated on ice for 20 minutes. The cell fragments were centrifuged at maximum speed for 20 minutes at 4°C. The supernatant was transferred to a new test tube and the protein content was determined by Bradford assay (Bio-Rad). 20 μg of cell lysate was used for SDS-PAGE. The gel was electroblotted on a nitrocellulose membrane and blocked with a 5% milk solution in TBST. Western blotting was performed using the following primary antibodies: anti-SRRM2 (Thermo Scientific), anti-GFP (kindly donated by the "monoclonal antibody" core factory of Helmholtz Center Munich). All primary antibodies were incubated overnight at 4°C. The membrane was washed and incubated with an HRP-conjugated secondary antibody for 2 hours 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).

[0387] Immunoprecipitation

[0388] Immunoprecipitation was performed using CNBr beads (CNBr-activated Sepharose 4Fast Flow, GE Healthcare). 1 g of beads was dissolved in 10 ml of 1 mM HCl and incubated at room temperature for 20 minutes. The beads were then centrifuged at 3000 × g for 1 minute and washed 15 times. Subclass-specific mouse anti-rat IgG2a antibodies were then coupled to the beads at room temperature (2 mg antibody in coupling buffer 0.3 M NaHCO3, 1.5 M NaCl, pH 8.3) for 1 hour. Afterwards, the beads were washed in coupling buffer and all remaining binding sites were blocked with 1 M ethanolamine (1 M) at room temperature for 2 hours. After washing in 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 coupled beads were resuspended in PBS for coupling with 22E6. Therefore, 500 μl of 22E6 hybridoma supernatant was incubated with 60 μl of anti-subclass specific beads at 4°C overnight.

[0389] 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) at 4°C overnight. Afterwards, the beads were washed in RIPA buffer containing protease inhibitors, PBS+ (PBS, 0.5% N-lauroylsarcosine, 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 minutes. After centrifugation at 1,000×g for 5 minutes, the supernatant was used for western blot analysis.

[0390] Generation of SRRM2 knockout cells

[0391] SRRM2-specific CRISPR-RNAs (crRNA) were designed using a freely available online tool (IDT). Each of those different specific crRNAs was fused to a trans-activating RNA (tracrRNA) to construct a guide RNA (gRNA), which was then compounded with the CAS9 nuclease. A single composite-composition was introduced into A549 lung cancer cells by electroporation using the 4D-Nucleofector protocol from Lonza. One week later, the binding of electroporated cells to SRRM2 antibodies 13F11, 18A4, and 23A7 was analyzed by fluorescence-activated cell sorting (FACS). Cell clones were generated by sorting and limited dilution cloning. Finally, clones were reanalyzed by FACS. The knockout clones identified were then checked by screening for CRISPR / CAS9-mediated mutations. Therefore, genomic DNA of parental cells and knockout clones was isolated, sequenced, and compared with wild-type sequences.

[0392] Confocal microscopy

[0393] 1×10 5 Cells were seeded on coverslips and grown overnight. The culture medium was removed, the cells were washed with PBS, fixed in 4% PFA for 10 minutes, permeabilized with PBS containing 0.3% Tween20, and finally blocked with 3% BSA in TBS containing 0.1% Tween20. For staining, the cells were incubated at room temperature for 1 hour with the first antibody diluted in TBS containing 1% BSA and 0.1% Tween20. Then, the cells were washed three times and then incubated in the dark with the secondary antibody (goat anti-rat-Alexa 647) for 40 minutes. After the final washing step, the nuclei were stained with DAPI, mounting medium (Vectashield) was added, and the coverslip was mounted inverted on a microscope slide. The slides were analyzed on a Leica SP8X STED microscope using Leica LAS X software.

[0394] Immunohistochemistry

[0395] Paraffin sections were mounted on superform plus slides. After acetone fixation, slides were incubated with primary antibodies followed by appropriate biotinylated secondary antibodies. Slides were developed using 0.01% 3-amino-9-ethylcarbazole (AEC) as a chromogen. After counterstaining with hematoxylin, coverslips were covered with Kaiser glycerol gelatin.

[0396] result

[0397] Example 1 shows that monoclonal antibodies 13F11, 18A4 and 23A7 specifically precipitate SRRM2 from lysates of various cancer cell lines. Either antibody was coupled to activated cyanogen bromide beads and incubated with lysates of ovarian cancer cell lines overnight at 4°C. 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 showed a confidence score >60, and the precipitated SRRM2 was enriched 1824.2, 182.6 and 40.8 times compared to the precipitate using the isotype control antibody (see Figure 1 ).

[0398] Example 2 shows that SRRM2 is exposed on the surface of various cancer cell lines. Figure 2 A and Figure 2 Solid line in B) or isotype control antibody ( Figure 2 The dotted line in A, Figure 2 The cells were then washed and incubated with Alexa647 labeled anti-rat IgG antibody. Fluorescence was then measured by flow cytometry on a FACS Canto. Normal PBMCs do not express surface SRRM2.

[0399] Example 3 shows that 13F11, 23A7 and 18A4 are SRRM2 specific: A549 human lung cancer cells were transfected with a ribonucleoprotein complex consisting of SRRM2-specific gRNA and Cas9 protein. After 7 days, the binding of the antibodies to knockout cells and wild-type cells was compared by flow cytometry. To this end, A549 wild type (bold line) and A549SRRM knockout line #25 (colored histogram) were incubated with any of the three antibodies 13F11, 18A4 and 23A7. The cells were washed and then incubated with Alexa647-labeled anti-rat secondary antibodies. Fluorescence was then measured on a FACS Canto. An isotype control antibody was included as a negative control (dashed line). The reduced fluorescence intensity of line #25 indicates the specificity of the antibody for SRRM2 (see Figure 3 ).

[0400] Example 4 further illustrates the membrane localization of SRRM2 on human cancer cells. SK-OV-3 human ovarian cancer cells were grown on microscope slides, washed in PBS, and incubated with the antibody 13F11. Incubation with the antibody prior to fixation ensured that the cells were viable, so that the antibody bound to intact cells. The cells were then fixed with 4% paraformaldehyde and incubated again with the appropriate anti-rat IgG secondary antibody conjugated to Alexa647. The staining was then examined by confocal fluorescence microscopy (see Figure 4 ).

[0401] Example 5 further illustrates the membrane localization of SRRM2 on human cancer cells. Here, UWB1.289 human ovarian cancer cells were co-stained with the SRRM2-specific antibody 13F11 (magenta) and the antibody 18F10 (green) specific for the membrane protein CD47. After fixation as described above, the cells were analyzed by confocal fluorescence microscopy. The nuclei were counterstained with DAPI (blue). The white color in the merged picture indicates the colocalization of the two antibodies (see Figure 5 ).

[0402] Example 6 shows that SRRM2 is localized to lipid rafts of other membrane subdomains that resist 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 deoxycholate). The lysate was then loaded onto an Optiprep gradient and centrifuged overnight at 32.000 rpm. 400 μL fractions were taken and 2 μL of each fraction was spotted onto a nitrocellulose filter. The filters were then incubated with 13F11 or an antibody specific for the four-transmembrane protein CD63. Figure 6 As shown, SRRM2 is present in fractions 2 and 3 of the gradient, which correspond to a density of about 1.13-1.19 g / ml, thus corresponding to the putative density of lipid rafts and other insoluble membrane microdomains. Soluble proteins with higher specific densities are mainly localized in fractions 7-10 of the gradient.

[0403] Example 7 shows that surface SRRM2-positive SK-OV-3-cells activate SRRM2-specific 13F11CAR-T cells. Primary T cells from two donors (1 and 2) were transduced with a retroviral vector encoding a chimeric antigen receptor (CAR) having a single-chain construct derived from the antibody 13F11. The expression of CAR on transduced T cells was determined by flow cytometry using a goat anti-rat IgG antibody (not shown). SK-OV-3 cells were incubated with 13F11CAR-T cells (columns 3-4 of the blot) or with untransduced control T cells (columns 1-2 of the blot) at the E:T ratio indicated on the X-axis for 24 hours. Finally, interferon-γ in the supernatant was quantified using a commercial ELISA, which is a marker of T cell activation (see Figure 7 ).

[0404] Example 8 shows that SRRM2-specific CAR-T cells also kill SRRM2-positive HO-8910 target cells. Here, killing was measured using a commercial LDH assay (see Figure 8 ).

[0405] Example 9 shows that extracellular vesicles (EVs) isolated from ascites of patients with ovarian cancer are SRRM2 positive. EVs were isolated by ultracentrifugation and density gradient centrifugation. Samples of EVs were spotted onto nitrocellulose membranes and incubated with 13F11, 18A4, or 23A7, followed by incubation with HRP-conjugated anti-rat secondary antibodies. The membranes were developed with ECL (see Fig. 9 As a control, an irrelevant isotype antibody ( Fig. 9 The rightmost Figure 4 ).

[0406] Example 10 shows that surface SRRM2 on cancer cells is induced by hypoxia. Most commercially available therapeutic antibodies for the treatment of solid cancers target hypoxia-induced proteins. Since hypoxia is a common feature of solid tumors, these proteins are highly expressed on cancer cells. In addition, the induction of translation under hypoxic conditions can be regarded as a hint that such proteins are related to the survival and growth of cancer cells under hypoxic conditions. In order to study whether SRRM2 is induced under hypoxic conditions, the inventors cultured human A549, U138, HT29 and SK-OV-3 cells in standard DMEM medium under normoxic conditions (about 18% O2) or hypoxia (1% O2) for 72 hours. The cells were then stained with the SRRM2-specific antibody 13F11 or an isotype control antibody. The binding of 13F11 was then quantified by flow cytometry and expressed as mean fluorescence intensity ( Fig.10The average value of hypoxic cells was approximately twice that of normoxic cells, indicating that surface SRRM2 is a hypoxia-induced protein (see Fig.10 ).

[0407] 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 internalize into target cells so that the payload can exert its activity. We tested the internalization of 13F11 by SK-OV-3 cells. To this end, SK-OV-3 cells were incubated with 13F11 for 10 minutes at room temperature and then washed thoroughly to remove free antibodies. Samples of these cells were then incubated at 37°C for 1 to 5 hours or kept on ice (=0 hours). The cells were then stained with an Alexa647-conjugated anti-rat IgG secondary antibody and fluorescence was measured by flow cytometry. The decrease in fluorescence over time indicates internalization of the SRRM2-13F11 complex, resulting in reduced binding of the secondary antibody. The fluorescence measured after 0 hours at 37°C was set to 100% (see Fig.11 ).

[0408] 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, then stained with HRP-conjugated secondary antibody, and developed with ABC. Fig.12 As shown, cancer cells clearly display membrane localization of SRRM2 (arrows), whereas in normal cells, the protein shows a nuclear staining pattern (arrowheads).

[0409] Example 13 shows that SRRM2 is expressed on the surface of lung metastases derived from human HUCT-1 cells xenografted into immunocompromised SCID mice. In contrast, normal mouse tissues (brain, kidney, liver) showed a nuclear staining pattern.

[0410] Example 14 shows that 13F11, 18A4-2, and 23A7 bind to a fragment spanning amino acids 1889 to 2150 of SRRM2 (referred to herein as tr04, SEQ ID NO: 30) (see Fig.15). HEK293 cells (HEK293-tr04) were transfected with an expression plasmid encoding amino acids 1889 to 2150 of SRRM2 fused to a HIS-tag. Immunoprecipitation was performed with bead-coupled SRRM2-specific antibodies 13F11, 18A4-2, and 23A7 and lysates of transfected cells or non-transfected 293 cells (HEK293) as controls. The precipitated proteins were separated by PAGE and transferred to a PVDF membrane, which was then incubated with an anti-rat antibody coupled to HRP. Finally, the blot was developed with ECL. As additional controls, lysates from transfected and non-transfected cells were included.

[0411] Example 15 shows that normal tissues from cynomolgus monkeys either stained negative for SRRM2 or showed cytoplasmic / nuclear staining as revealed by immunohistochemistry (see Fig.16 ). No membrane staining was observed. Mem = membrane; Cyto = cytoplasm; Nucl = nucleus. FFPE tissue from cynomolgus monkeys was incubated with 13F11 antibody and then with goat anti-rat IgG antibody conjugated to HRP (ImmPRESS HRP Peroxidase Detection Kit; https: / / vectorlabs.com / products / enzyme-polymer / immpress-hrp-goat-anti-rat-igg-kit).

[0412] Example 16 shows that most tumor samples from different locations (bile duct, ovary, pancreas, stomach) showed SRRM2 membrane staining (see Fig.17 ). Formalin-fixed paraffin-embedded (FFPE) tumor tissue and adjacent normal tissue were stained with 13F11 and then incubated with a rat-specific secondary antibody conjugated to HRP. Tissues were examined by a trained pathologist and staining intensity was scored from 0 (negative) to 3+ (strong expression on most cells).

[0413] Example 17 shows the sequences of the light and heavy chains of antibody 18A4-2 and the sequences of their fragments (see Fig.18 ).

[0414] Example 18 shows that the SRRM2-specific antibodies 13F11, 18A4-2 and 23A7 bind to fragment tr04 (see Fig.19). 96-well culture plates were coated overnight with purified SRRM2-tr04-HIS or MISP-HIS protein as a control (50 μg / ml each) and then blocked with skim milk powder 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 a secondary anti-rat IgG antibody conjugated to HRP and developed with TMB. After stopping the reaction with H2SO4, the absorbance was measured at 450 nm.

[0415] References

[0416] Hashimoto-Gotoh, T. et al., (1995) Gene 152, 271-275.

[0417] Kramer, W. et al., (1984) Nucleic Acids Res. 12, 9441-9456.

[0418] Kunkel, TA (1985) Proc Natl Acad Sci USA. 82, 488-492.

[0419] Kunkel (1988) Methods Enzymol. 85, 2763-2766.

[0420] Mark, DF et al., Proc. Natl. Acad. Sci. USA (1984) 81, 5662-5666, Zoller, MJ and Smith, M., Nucleic Acids Research (1982) 10, 6487-6500.

[0421] Wang, A. et al., Science 224, 1431-1433, Dalbadie-McFarland, G. et al., Proc. Natl. Acad. Sci. USA (1982) 79, 6409-641.

[0422] Weidle, U.H., Maisel, D., Klostermann, S., Schiller, C. and Weiss, E.H. (2011). Intracellular proteins displayed on the surface of tumor cells as targets for therapeutic intervention with antibody-related agents. Cancer Genomics Proteomics 8, 49-63。

[0423] Zoller, M.J., and Smith, M. (1983) Methods Enzymol. 100, 468-500。

Claims

1. A pharmaceutical composition comprising an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of a target cell and optionally a pharmaceutically acceptable carrier, diluent or excipient, preferably, the antibody is a monoclonal antibody.

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

3. The pharmaceutical composition according to any one of the preceding claims, wherein the antibody has ADCC or CDC.

4. A pharmaceutical composition according to any one of the preceding claims, wherein the antibody is conjugated to a cytotoxic substance.

5. A pharmaceutical composition according to any one of the preceding claims, wherein the antibody is part of a chimeric antigen receptor (CAR).

6. The pharmaceutical composition according to claim 5, wherein the CAR is contained by T cells, NK cells, NK-T cells or macrophages.

7. The pharmaceutical composition according to any one of the preceding claims, wherein the SRRM2 present on the cell surface of the target cell is externalized.

8. A pharmaceutical composition according to any one of the preceding claims, wherein the antibody is not an intrabody.

9. A pharmaceutical composition according to any one of the preceding claims, wherein the antibody is (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:4; (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:6; (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:26; or (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

10. A pharmaceutical composition according to any one of the preceding claims, wherein the antibody is (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 12; (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 15, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 18; (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 21, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 22, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 23, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 24; (d) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a heavy chain CDR3 having an amino acid sequence as 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 (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

11. The pharmaceutical composition according to any one of the preceding claims for use in a method for treating cancer in a human subject, preferably wherein the cancer is characterized by cells wherein human SRRM2 is present on the cell surface of the cells.

12. The pharmaceutical composition for use according to claim 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 malignancy or glioma.

13. A method for determining whether a human subject is likely to have cancer, the method comprising determining, in a sample obtained from the human subject, whether SRRM2 is present on the cell surface of cells contained in the sample and / or whether SRRM2 is present on the surface of extracellular vesicles.

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

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

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

17. The antibody according to claim 16, wherein the antibody is (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:4; (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:6; (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:26; or (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

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

19. A method for killing a target cell having SRRM2 present on the cell surface of the target cell, the method comprising administering an antibody that binds to human SRRM2 present on the cell surface of the target cell.

20. The method of claim 19, wherein the antibody is (a) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO: 2; (b) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:3, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:4; (c) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:6; (d) an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:5, and the light chain variable region has an amino acid sequence that is at least 85% identical to the amino acid sequence shown in SEQ ID NO:26; (e) An antibody that binds to the same epitope in human SRRM2 protein as the epitope bound by any one of antibodies (a) to (d).

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

22. An antibody that binds to human SRRM2 present on the cell surface of a target cell for use in a method of treating cancer in a subject, comprising determining whether the target cell of the subject has SRRM2 present on the cell surface before treating the cancer in the subject.

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

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

Images