Srrm2 binding agents for the treatment and diagnosis of hematological cancers

Abstract

The present invention provides a pharmaceutical composition comprising an antibody that binds human SRRM2 present on the cell surface of a target cell and optionally a pharmaceutically acceptable carrier, diluent or excipient for use in a method for treating a hematological cancer (such as MM, PCL or AML) in a patient.

Description

Technical Field

[0001] This invention provides a pharmaceutical composition comprising an antibody binding to human SRRM2 present on the cell surface of target cells and optionally a pharmaceutically acceptable carrier, diluent, or excipient. The invention further provides the pharmaceutical composition for use in a method of treating a patient with hematologic malignancies, wherein the patient to be treated weighs 16 to 150 kg. Additionally, a method for determining whether a patient is likely to have hematologic malignancies is provided, the method comprising determining the presence of SRRM2 on the cell surface of cells contained in a sample obtained from the patient. Furthermore, an antibody binding to human SRRM2 present on the cell surface of target cells is provided. The invention also provides an antibody binding to human SRRM2 present on the cell surface of target cells for use in a method of killing target cells having SRRM2 present on their cell surface. Furthermore, a method for killing target cells having SRRM2 present on the cell surface of the target cells is provided, the method comprising administering an antibody binding to human SRRM2 present on the cell surface of the target cells. Background Technology

[0002] Hematologic malignancies are those caused by the excessive proliferation of blood cells, which disrupt the physiological functions of the blood, bone marrow, and lymphatic tissues, often leading to immune dysfunction. Based on the primary cell type affected, hematologic malignancies are generally classified into three categories: leukemia, lymphoma, and myeloma. Globally, 720,000 people die from hematologic malignancies each year, accounting for approximately 7% of all cancer-related deaths (Bray et al., 2018). While innovative treatments have improved survival rates, some types of hematologic malignancies still show relatively low 5-year survival rates. Multiple myeloma (MM) has a 5-year survival rate of only 50-55%, and this rate drops significantly if diagnosed at a late stage of disease progression. For acute myeloid leukemia (AML), using current treatment modalities, only 35-45% of AML patients <60 years of age and 10-15% of those ≥60 years of age achieve long-term survival (Short et al., 2018). Several tumor antigens have been investigated as potential targets for immunotherapy in MM and AML, but overall treatment outcomes have been largely unsatisfactory. Therefore, there is an urgent need for improved treatment and diagnostic methods. Blood cancers are primarily an age-related disease, and with the continued increase in global life expectancy, the need for improved treatments will only increase further.

[0003] This invention represents a technological advancement in both the treatment and diagnosis of blood cancers. Therefore, this invention aims to address the potential technical problems in these areas. Summary of the Invention

[0004] The aforementioned technical problems are solved by the subject matter as defined in the claims, described in the claims, demonstrated by the embodiments, and illustrated in the drawings. The inventors have surprisingly discovered that serine / arginine repeat matrix protein 2 (SRRM2; UniProt Q9UQ35), which is normally located in the cell nucleus, is expressed on the surface of leukemia cells but not on healthy non-cancerous cells. Therefore, surface SRRM2 on cells obtained from patients is a biomarker for hematologic cancers. Furthermore, this selective expression of SRRM2 on the surface of leukemia cells makes it possible to develop novel hematologic cancer-specific therapies. The utility of the invention is demonstrated by its successful application in treating hematologic cancers in two patients (as defined herein). Specifically, the number of surface SRRM2-positive (abnormal) plasma cells was significantly increased in MM patients compared to the number of SRRM2-positive cells in healthy subjects. Furthermore, treatment of MM and PCL patients with SRRM2-specific CAR-T cells resulted in a reduction of cancer-associated plasma cells. Additionally, it was found that surface SRRM2 was significantly elevated on leukemia cells, particularly leukemia blasts from AML and MM patients, compared to expression on normal blood cells and HSCs. Notably, AML patients with FMS-like tyrosine kinase-3 (FLT3) mutations showed significantly higher surface SRRM2 expression than AML patients without any gene mutations or other mutations. Furthermore, SRRM2 was highly expressed in both newly diagnosed and previously diagnosed MM patients. Additionally, SRRM2-specific CAR-T cells demonstrated potent cytotoxic activity in myeloid leukemia cell lines in vitro. Moreover, the elimination of leukemia blasts was observed in vivo in an AML tumor-bearing mouse model. Furthermore, significant tumor suppression was observed in a KMS-11-luc CDX MM mouse model. In conclusion, the data presented in this article strongly suggest that SRRM2 is an optimal and promising target for immunotherapy in patients with hematologic malignancies (particularly AML, PCL, or MM) and for diagnosing hematologic malignancies (particularly AML, PCL, or MM) based on SRRM2 located on the cell surface.

[0005] Therefore, the present invention provides an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of target cells, which is used in a method for treating blood cancers in human patients, wherein the patient to be treated weighs 16 to 150 kg.

[0006] The antibody binding to human SRRM2 is used in the treatment method, wherein the patient to be treated weighs 16 to 150 kg, preferably 18 to 140 kg, more preferably 20 to 130 kg, and even more preferably 22 to 120 kg.

[0007] Antibodies binding to human SRRM2 can be used in treatment methods in which the patient to be treated is at least 1 year old, preferably 2 years old, and more preferably 2 to 80 years old.

[0008] Antibodies binding to human SRRM2 can be used in treatment methods in which the height of the patient to be treated is 70 to 220 cm, preferably 80 to 200 cm, and more preferably 90 to 190 cm.

[0009] Antibodies that bind to human SRRM2 may have cytotoxic activity, preferably antigen-dependent cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).

[0010] Antibodies that bind to human SRRM2 can be part of a chimeric antigen receptor (CAR).

[0011] Antibodies that bind to human SRRM2 can be part of a chimeric antigen receptor (CAR), wherein the CAR is expressed by T cells (referred to herein as "CAR-T cells"), NK cells, NK-T cells, or macrophages.

[0012] Antibodies that bind to human SRRM2 can be expressed by autologous cell populations.

[0013] Antibodies that bind to human SRRM2 can be expressed by allogeneic cell populations.

[0014] Antibodies that bind to human SRRM2 can be used in therapeutic applications where the SRRM2 present on the surface of target cells is externalized.

[0015] An antibody that binds to human SRRM2, wherein the antibody may not be an intracellular antibody.

[0016] Antibodies that bind to human SRRM2 can be used in treatments in which the blood cancer to be treated is characterized by cells expressing human SRRM2 on their cell surface.

[0017] Antibodies that bind to human SRRM2 can be used in treatments where the blood cancer to be treated is multiple myeloma.

[0018] Antibodies binding to human SRRM2 can be used in treatments where the blood cancer to be treated is leukemia, including acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), mast cell leukemia (MCL), or plasma cell leukemia (PCL).

[0019] Antibodies that bind to human SRRM2 can be used in treatments where the blood cancer to be treated is acute myeloid leukemia (AML).

[0020] Antibodies that bind to human SRRM2 can be used in the treatment of AML, wherein the AML to be treated is characterized by cells expressing human SRRM2 on their cell surface and also having a gene mutation, preferably an FMS-like tyrosine kinase-3 (FLT3) mutation.

[0021] Antibodies binding to human SRRM2 can be used in treatments where the blood cancer to be treated is plasma cell leukemia (PCL). The PCL can be primary PCL or secondary PCL.

[0022] Antibodies binding to human SRRM2 can be used in treatments where the blood cancer to be treated is a lymphoma, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), post-transplant lymphoproliferative disorder (PTLD), or Waldenström macroglobulinemia (WM).

[0023] Antibodies binding to human SRRM2 can be used in treatments where the hematologic malignancies to be treated are myelodysplastic syndromes, myeloproliferative neoplasms (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

[0024] In the context of this invention, it is further envisioned that patients with blood cancers treated with antibodies that bind to human SRRM2 are refractory to previous cancer therapies and / or have relapsed after previous cancer therapies.

[0025] Antibodies that bind to human SRRM2 can be used in treatments, with the antibody being administered via parenteral routes, including but not limited to intravenous, intradermal, intramuscular, intrathecal, epidural, intracerebral, or intraperitoneal administration.

[0026] Antibodies that bind to human SRRM2, which is present on the surface of target cells, can conjugate with cytotoxic substances.

[0027] Antibodies that bind to human SRRM2, which is present on the cell surface of target cells, can bind to impermeable cells.

[0028] Antibodies that bind to human SRRM2, which is present on the surface of target cells, can bind to living cells.

[0029] Furthermore, this invention relates to an antibody binding to human SRRM2, wherein the antibody is used in a method for determining whether a patient may have blood cancer, the method comprising determining, in a sample obtained from the patient, the presence of SRRM2 on the cell surface of cells and / or on the surface of extracellular vesicles contained in the sample. In the method for determining whether a patient may have blood cancer, an increase in the amount of SRRM2 present on the cell surface of cells and / or on the surface of extracellular vesicles contained in a sample obtained from the patient, compared to the amount of SRRM2 on the cell surface of cells and / or on extracellular vesicles in a sample obtained from a healthy subject, indicates that the patient may have blood cancer. No difference in the amount of SRRM2 present on the cell surface of cells and / or on the surface of extracellular vesicles contained in a sample obtained from the patient, compared to the amount of SRRM2 on the cell surface of cells and / or on extracellular vesicles in a sample obtained from a healthy subject, indicates that the patient may not have blood cancer.

[0030] The antibody binding to human SRRM2 may preferably comprise an antibody having: (a) a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 2; (b) a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 3 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 4; (c) a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 6; or (d) a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 5 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 7.

[0031] Antibodies binding to human SRRM2 are preferably antibodies comprising the following:

[0032] (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 9, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 10, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 11, and

[0033] The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 14.

[0034] (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 15, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 16, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 17, and

[0035] The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 20.

[0036] (c) Heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and

[0037] A light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 24, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 25, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 26; or

[0038] (d) Heavy chain variable region, said heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and

[0039] 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.

[0040] Antibodies that bind to human SRRM2 can be used in methods for determining whether a patient may have a blood cancer, such as multiple myeloma.

[0041] Antibodies binding to human SRRM2 can be used in methods for determining whether a patient may have a blood cancer, which is leukemia, including acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), mast cell leukemia (MCL), or plasma cell leukemia (PCL).

[0042] Antibodies that bind to human SRRM2 can be used in methods for determining whether a patient may have a blood cancer, namely acute myeloid leukemia (AML).

[0043] Antibodies binding to human SRRM2 can be used in methods for determining whether a patient may have a blood cancer, namely plasma cell leukemia (PCL). PCL can be primary or secondary PCL.

[0044] Antibodies binding to human SRRM2 can be used in methods for determining whether a patient may have a blood cancer, which is a lymphoma, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), post-transplant lymphoproliferative disorder (PTLD), or Waldenström macroglobulinemia (WM).

[0045] Antibodies binding to human SRRM2 can be used in methods for determining whether a patient has a blood cancer, which is myelodysplastic syndrome, myeloproliferative neoplasms (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

[0046] Antibodies that bind to human SRRM2 can be used in pharmaceutical compositions, wherein the antibodies are contained in a buffer solution or in a composition containing a buffer solution and sodium chloride. Attached Figure Description

[0047] The invention will be better understood when referred to in detail and when considered in conjunction with the non-limiting embodiments and accompanying drawings, wherein:

[0048] Figure 1A The figure shows that most abnormal plasma cells are positive for the surface SRRM2. An example of an immunophenotypic analysis strategy is illustrated in the figure, using white blood cells (WBCs) or bone marrow cells from patients with plasma cell leukemia.

[0049] Figure 1b shows that the immunophenotypic analysis of WBCs as described above indicates that 92.94% of the abnormal plasma cells in patient 1 were positive for SRRM2 staining.

[0050] Figure 2 The CD138 level was observed after SRRM2 CAR-T cell therapy. + Cell reduction. CD138 immunohistochemistry was performed on bone marrow extracted from patient 2.

[0051] Figure 3 The image shows that abnormal plasma cells were eliminated through SRRM2 CAR-T cell therapy. The figure shows bone marrow smears of Patient 2 before and 50 days after SRRM2 CAR-T cell infusion.

[0052] Figure 4 The in vivo expansion of the SRRM2-specific CAR T cell population (quantified as a proportion of the total number of T cells present in each sample) peaked at week 3 post-infusion. A single dose of 5 × 10⁻⁶ CARs was administered. 7 SRRM2-specific CAR-T cells were infused into patient 2 (=day 0), and blood samples were collected periodically after infusion to assess CAR-T cell proliferation.

[0053] Figure 5 The study shows that CAR-T cell therapy targeting SRRM2 restored the κ / λ light chain ratio in the blood. The figure shows the measurement results of immunoglobulin (Ig) light chains in the serum of patient 2, as measured by an automated immunoassay. Total concentration (top inset) and κ / λ ratio (bottom inset) are presented.

[0054] Figure 6 The study showed a reduction in cancer-associated plasma cells in patient 2 after infusion of SRRM2-specific CAR-T cells, quantified by counting the number of abnormal plasma cells (gated) characterized by the marker CD138. + CD19 – CD56 – CD45 dim The combination of .

[0055] Figure 7 Clinical data from patient 1 are shown, demonstrating the antitumor activity of the infused SRRM2 CAR-T cells.

[0056] Figure 8The workflow (gating strategy) for detecting SRRM2-positive abnormal plasma cells in the blood of myeloma patients is shown. In this example, 90.02% of myeloma plasma cells were surface SRRM2 positive, while normal cells were surface SRRM2 negative (not shown). EX-02 is the internal name of the SRRM2 antibody described herein. Preferred EX-02 antibodies are 23A7 or 13F11 as described herein.

[0057] Figure 9 The results showed that in patient 1, the percentage of plasma cells (CD38+ + CD138+ CD19-CD56-CD45dim) in peripheral blood decreased from 43% (before) to 6.4% of the total white blood cell count on day 16 post-infusion. SRRM2 CAR-T cells were infused twice (indicated by arrows): 3.4 × 10⁻⁶ cells on day 0. 7 The values ​​for (first) and day 2 were 1.18 × 10⁻⁶. 8 .

[0058] Figure 10 The results showed that the infusion of SRRM2 CAR-T cells led to the recovery of hematopoietic function in patient 2 on day 50 post-infusion, without the need for further blood transfusions to assist in the recovery. Platelet levels increased from only 36 g / L on the day of infusion to 62 g / L on day 50 post-infusion.

[0059] Figure 11 This study presents a correlation analysis between SRRM2 expression on leukemia blast cells and clinical data from AML patients. (A) Survival analysis based on SRRM2 RNA levels. Data extracted from the public database (TCGA, https: / / www.cancer.gov / ccg / ). (B) SRRM2 RNA levels in AML cells with cytogenetic abnormalities and in normal hematopoietic stem cells (HSCs). Data extracted from the public database (TCGA, https: / / www.cancer.gov / ccg / ). (C) Surface SRRM2 expression on leukemia blast cells derived from bone marrow (BM) and peripheral blood (PB). (DE) Surface SRRM2 expression levels in patients of different ages and sexes. (F) Surface SRRM2 expression in newly diagnosed (ND) and relapsed / refractory (RR) AML cases. (G) Surface SRRM2 expression in AML with normal and abnormal karyotypes. (H) Surface SRRM2 expression in patients with and without gene mutations. (IJ) Surface SRRM2 expression on tumor cell membranes in AML patients carrying different gene mutations. Figure 11 The surface SRRM2 expression shown in CJ was measured by flow cytometry using EX-02 as the primary antibody and Alexa647-labeled anti-rat IgG antibody as the secondary antibody.

[0060] Figure 12 The expression of SRRM2 on the surface of peripheral blood cells from AML patients and healthy donors is shown. (AB) SRRM2 expression on the surface of leukemia blasts, lymphocytes, monocytes, and neutrophils from two AML patients was assessed by flow cytometry using an SRRM2-specific EX-02 antibody. (C) Surface SRRM2 on peripheral lymphocytes, monocytes, and neutrophils from healthy donors. (D) Surface SRRM2 on lymphocytes, monocytes, neutrophils, and hematopoietic stem cells from bone marrow of healthy donors.

[0061] Figure 13 Surface SRRM2 expression was shown in different AML cell lines. SRRM2 expression was identified using anti-SRRM2 and appropriate secondary antibodies as described herein.

[0062] Figure 14 The optimized conditions for preparing SRRM2-specific CAR-T cells are shown. (A) Schematic diagram of the SRRM2 CAR construct, which consists of an SRRM2-specific single-stranded variable fragment (SRRM2-scFv); a hinge region derived from CD8; a transmembrane domain (TMD); and intracellular co-stimulatory domains of 4-1BB and CD3ζ. (B) CAR-T preparation workflow. (CG) Transfection rate of CAR-T cells under different culture conditions. HSA = human serum albumin.

[0063] Figure 15 The efficacy of SRRM2 CAR-T cells in vitro was demonstrated. (AD) In ​​vitro cytotoxicity of SRRM2 CAR-T cells against four AML cell lines, measured using an LDH cytotoxicity assay. Untransduced T cells (mock-T) were used as controls. Effector-target (E:T) ratios were 1.0:1, 2.5:1, and 5.0:1, with triplicate for each condition. (E) Cytotoxicity of SRRM2 CAR-T cells against four AML cell lines indicates efficacy against FLT3. mut+ The cell line MOLM-13 exhibited the highest cytotoxicity.

[0064] Figure 16 This study demonstrated the potent antitumor activity of SRRM2 CAR-T cells in vivo. (A) In NCG mice (NOD-Prkdc em26Cd52 Il2rg em26Cd22(A) Schematic diagram of in vivo experiments using SRRM2 CAR-T cells in an AML model (Charles River). (B) Wright-Giemsa staining of an AML mouse model shows successful elimination of leukemia blasts after treatment with SRRM2 CAR-T cells compared to treatment with mimic T cells. The images shown are magnified at ×10 and ×100. (C) CAR copy number analysis in heart blood samples by PCR using a CAR gene copy number assay kit (Hillgene, PX-CA001). (D) Continuous monitoring of mouse body weight showed no difference between groups before administration of CAR-T or mimic T cells. However, over time, the difference in body weight between the two groups became statistically significant after CAR-T injection. (E) Kaplan-Meyer curves for both groups.

[0065] Figure 17 It has been shown that commercial antibodies cannot bind to SRRM2 on the cell surface of living cells, while the SRRM2-specific antibody EX-02 of the present invention binds to SRRM2 on the cell surface of living cells.

[0066] Figure 18 The results showed that the percentage of plasma cells (CD38+ + CD138+ CD19-CD56-CD45dim) in the peripheral blood of patient 3 decreased from 29.0% before infusion of SRRM2 CAR-T cells (e.g., EX-02 CAR-T cells) to 0.55% of the total peripheral plasma cell count on day 28 post-infusion. Three intravenous infusions of SRRM2 CAR-T cells were administered (EX-02 CAR T cells / kg: Day 0 (before) 0.54 × 10⁻⁶). 7 Day 1: 2.34 × 10 7 And 1.06 × 10 on day 18 7 ).

[0067] Figure 19 This study summarizes flow cytometry data on lymphocyte / plasma cell counts in bone marrow and peripheral blood samples from patients with multiple myeloma (MM), plasma cell leukemia (PCL), reactive plasmacytosis, and other plasma cell disorders. (A) Surface SRRM2 expression on plasma cells in newly diagnosed MM patients (N=35, all from bone marrow). (B) Surface SRRM2 expression on plasma cells in patients previously diagnosed with plasma cell disorders (N=67, including relapsed and refractory MM, PCL, reactive plasmacytosis, and other plasma cell disorders) during or after standard treatment.

[0068] Figure 20This study demonstrates the potent antitumor activity of SRRM2 CAR-T cells in an in vivo MM model. (A) Schematic diagram of an in vivo experiment using SRRM2 CAR-T cells in an NSG mouse xenograft model using human MM KMS-11 cells engineered to overexpress the luciferase reporter gene in the cells. Mice (n=5 / group) received 3.3 × 10⁻⁶ CAR-T cells intravenously on day –5. 6 Kawasaki Medical School (KMS) -11-luc cells, 5 days later (=day 0), received 1.5×10 6 EX-02 CAR-T cells (CAR-T) or the same number of analog-T cells (analog-T). CAR-T cells used in this experiment were generated from T cells isolated from peripheral blood of healthy donors. (B) Longitudinal monitoring of bioluminescent signals in Luc+ KMS-11 cells in NSG mice treated with intravenous analog-T cells and CAR-T cells, imaging at days 7, 15, 24, 34, and 50. The y-axis represents photon flux (p s⁻¹ cm⁻² sr⁻¹). (C) Blood was collected on the same day and analyzed by flow cytometry for human CD4+ and CD8+ cells. The CD8 / CD4 ratio was calculated. (D) From Figure 20 Bioluminescent images of the animals in the experiment showed that EX-02 CAR-T cells had therapeutic effects compared to simulated T cells.

[0069] Figure 21 (A) shows that since Figure 20 The number of human CAR-T cells per mL in peripheral blood collected from mice in the experiment on day 50. (B) shows the number of human CAR-T cells identified in the spleen of the animals. Figure 20 The spleen was separated on day 50 of the experiment. (C) Figure 20 The weight of the animals used in the experiment. Detailed Implementation

[0070] The inventors were surprised to discover that SRRM2 is present on the cell surface of cancer cells, as it is widely described in the prior art as a protein localized to the cell nucleus, particularly to nuclear spots. Serine / arginine repeat matrix protein 2 (SRRM2; UniProt Q9UQ35) plays a crucial 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, SRRM2 can be seen to become "externalized," meaning it is no longer confined to the cell nucleus but is also present on the cell surface of cancer cells. Antibodies that bind SRRM2 have been described in the art. However, these commercially available antibodies cannot bind SRRM2 exposed on the surface of living cells. Figure 17 Therefore, in contrast to the antibodies used in the context of this invention, these prior art antibodies have different binding properties and cannot be used to identify or treat blood cancers characterized by cells with significantly increased amounts of membrane-expressed (i.e., externalized) SRRM2. However, due to this invention, SRRM2 is known to be present on the cell surface of blood cancer cells. Therefore, other antibodies targeting SRRM2 present on the cell surface of blood cancer cells can also be provided. Thus, until now, since SRRM2 was considered to be located in the cell nucleus, it was not considered to be an accessible target molecule, such as antibodies or CAR-T cells. However, since the inventors have surprisingly discovered that SRRM2 is present on the cell surface of blood cancer cells, these cells can be targeted for cancer treatment. An exemplary sequence of SRRM2 is provided by UniProt database entry Q9UQ35 (2nd edition, March 6, 2007) and is illustrated in SEQ ID NO: 8. The utility of this invention is demonstrated by its use in the successful treatment of blood cancers in patients as defined herein. Specifically, treatment of patients with multiple myeloma and plasma cell leukemia with SRRM2-specific CAR-T cells resulted in a reduction of cancer-associated plasma cells in the patients, and a significant increase in the number of SRRM2-positive plasma cells could be detected in the blood and bone marrow of the patients when compared with the number of SRRM2-positive cells in healthy subjects.

[0071] Furthermore, surface SRRM2 expression was found to be significantly elevated in leukemia cells, particularly leukemia blasts from AML patients, compared to expression on normal blood cells and HSCs. This suggests a lower likelihood of SRRM2-related targeted extratumor toxicity, making it a potential candidate for CAR-T therapy. Notably, SRRM2 is expressed on the cell membrane, particularly in AML blasts and cell lines, especially those with FMS-like tyrosine kinase-3 (FLT3) mutations (FLT2...). mut The SRRM2 CAR-T therapy showed a specific increase in FLT3 expression. This observation is likely due to FLT3 mutations, which lead to constitutive activation of FLT3 independent of its ligands, thereby maintaining tumor cell survival and proliferation. This suggests that AML patients, particularly those with FLT3 mutations and elevated SRRM2 expression, could be considered promising candidates for SRRM2 CAR-T therapy. Furthermore, the function of SRRM2 CAR-T was investigated, revealing its specific cytotoxicity against SRRM2-positive AML cell lines in vitro. Finally, SRRM2 CAR-T therapy demonstrated significant safety and efficacy in mice carrying AML cells.

[0072] Therefore, the data presented in this article impressively highlight that SRRM2 expression is significantly elevated in patients with hematologic malignancies, such as MM, PCL and AML, and is therefore an optimal target for immunotherapy, especially CAR-T cell therapy.

[0073] Therefore, the present invention includes an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of target cells, which is used in a method for treating blood cancers in human patients, wherein the patient to be treated preferably weighs 16 to 150 kg.

[0074] In the context of this invention, the SRRM2 protein can be the SRRM2 protein having SEQ ID NO: 8, or it can 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 a sequence derived from the above sequence by modifying one or more amino acids can include polypeptides having 70% or more, preferably 80% or more, more preferably 90% or more, or even more preferably 95% or more homology with the amino acid sequence. Alternatively, partial peptides of these SRRM2 proteins can be used.

[0075] As used herein, the term "homology" has its general meaning, including identical amino acids and equivalent positions in the linear amino acid sequences of two proteins being compared that are considered to be conserved substitutions (e.g., exchanging glutamic acid residues for aspartic acid residues). "Identity" or "sequence identity" refers to a sequence property that measures their similarity or relationship. As used in this invention, "sequence identity" or "identity" refers to the percentage of identical residues forming a pair relative to the longer of the two sequences after the sequence of the polypeptide of this invention is aligned with the sequence discussed (homology). Identity is determined by dividing the number of identical residues by the total number of residues and then multiplying the result by 100.

[0076] Sequence homology or sequence identity percentage, for example, can be determined 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 homology percentage is based on the alignment of a 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 paired comparisons. It is calculated as the number of “positive” (homological amino acids) expressed in the BLASTP program output divided by the percentage of the total number of amino acids selected by the program for alignment. It should be noted in this regard that the total number of selected amino acids may differ from the length of porcine NTCP.

[0077] The SRRM2 protein used in this invention is not limited by its source, but is preferably human SRRM2 protein.

[0078] As used herein and in the context of this invention, the term "antibody" may include chimeric antibodies, humanized antibodies, monovalent antibodies, multivalent antibodies, low molecular weight antibodies, biantibodies, or scFv.

[0079] Chimeric antibodies are antibodies containing variable and constant regions from different sources linked together. For example, a mouse-human heterochimeric antibody contains the heavy and light chain variable regions of a mouse antibody and the heavy and light chain constant regions of a human antibody. DNA encoding the variable region of a mouse antibody is ligated to DNA encoding the constant region of a human antibody, and the ligation product can be integrated into an expression vector to prepare a recombinant vector expressing the chimeric antibody. Cells transformed with these vectors (recombinant cells) can be cultured to express the DNA insert, thereby obtaining the chimeric antibody produced during culture.

[0080] Typically, chimeric antibodies comprise a variable region of antibody derived from a non-human animal and a constant region derived from a human antibody. In contrast, humanized antibodies comprise a complementarity-determining region (CDR) of antibody derived from a non-human animal, a framework region (FR) of antibody derived from a human antibody, and a constant region derived from a human antibody. Humanized antibodies are also known as reshaped human antibodies. Specifically, for example, humanized antibodies comprising a CDR of a non-human animal (e.g., mouse) antibody transplanted into a human antibody are known in the art. Because humanized antibodies have reduced antigenicity in the human body, they can be used as the active ingredient of the therapeutic agents of the present invention.

[0081] Each antibody variable region typically contains three cored receptors (CDRs) and four flanking receptors (FRs). The CDRs essentially determine the antibody's binding specificity. CDRs have distinct amino acid sequences. On the other hand, the amino acid sequences constituting the FRs often exhibit high homology among antibodies with different binding specificities. Therefore, it is generally believed that the binding specificity of one antibody can be transferred to other antibodies through CDR transfer.

[0082] The antibodies binding to human SRRM2 present in the pharmaceutical compositions of the present invention can encompass bivalent antibodies represented by IgG (IgG1, IgG2, IgG4, etc.), as well as monovalent antibodies or multivalent antibodies represented by IgM, as long as these antibodies bind to the SRRM2 protein. The multivalent antibodies present in the pharmaceutical compositions of the present invention can encompass multivalent antibodies having multiple antigen-binding sites, where these binding sites are identical or some or all of them are different. Preferably, the antibody binding to human SRRM2 is an IgG antibody.

[0083] The antibody binding human SRRM2 present in the pharmaceutical compositions of the present invention may also be a low-molecular-weight antibody, which covers an antibody fragment lacking a portion of the complete antibody (e.g., complete IgG). Such a partial deficiency of the antibody molecule is accepted as long as the resulting antibody fragment can bind SRRM2. Preferably, the antibody fragment used in the pharmaceutical compositions according to the present invention should contain one or both of a heavy chain variable region (VH) and a light chain variable region (VL). It is also preferred that the antibody fragment used in the pharmaceutical compositions according to the present invention should contain a CDR. The number of CDRs contained in the antibody fragment used in the pharmaceutical compositions of the present invention is not particularly limited, but preferably at least six CDRs: heavy chain CDR1, CDR2, and CDR3, and light chain CDR1, CDR2, and CDR3.

[0084] The amino acid sequence of VH or VL may contain one or more substitutions, deletions, additions, and / or insertions. Furthermore, antibodies or antibody fragments that can be used in the pharmaceutical compositions of the present invention may lack one or a portion of VH and VL, provided that the resulting antibody fragment can bind to human SRRM2. Additionally, its variable region may be chimeric or humanized. Specific examples of antibody fragments may include Fab, Fab', F(ab')2, and Fv. Furthermore, specific examples of low molecular weight antibodies may include Fab, Fab', F(ab')2, Fv, scFv (single-chain Fv), biantibodies, sc(Fv)2 (single-chain (Fv)2), and scFv-Fc. In the present invention, low molecular weight antibodies are preferably biantibodies or sc(Fv)2, and these antibody polymers (e.g., dimers, trimers, tetramers, and polymers) are also covered by low molecular weight antibodies that can be used in the pharmaceutical compositions of the present invention.

[0085] As used herein and in the context of this invention, the term "biantibody" can refer to a divalent antibody fragment constructed via gene fusion. A biantibody is a dimer comprising two polypeptide chains. Typically, each polypeptide chain constituting the dimer contains a heavy chain and a light chain variable region linked via a linker on the same chain. The linker in a biantibody is often 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 linker is, for example, about five residues. Therefore, the heavy chain and light chain variable regions encoded on the same polypeptide chain cannot together form a single-chain variable region fragment. Instead, they form a dimer by pairing with another single-chain variable region fragment. As a result, a biantibody has two antigen-binding sites.

[0086] As used in the context of this invention, the scFv can be obtained by linking the heavy and light chain variable regions of an antibody. In the scFv, the heavy and light chain variable regions are linked via a linker, preferably a peptide linker. The heavy and light chain variable regions in the scFv can be derived from any antibody described herein. There are no particular limitations on the peptide linker for linking the variable regions. For example, any single-chain peptide of about 3 to 25 residues can be used as the linker.

[0087] Antibodies binding to human SRRM2 used in the pharmaceutical compositions and antibodies binding to human SRRM2 according to the present invention may also cover binding entities such as lipid transport proteins, aptamers, or anticalins.

[0088] The antibody binding human SRRM2 used in this invention can be in various forms. However, it needs to bind to the SRRM2 protein and is not particularly limited in its source, type, shape, etc., but should have cytotoxic activity. Specifically, antibodies such as non-human animal-derived antibodies (e.g., mouse, rat, or camel antibodies) as described above, human-derived antibodies, chimeric antibodies, or humanized antibodies can be used. In one embodiment, the antibody binding human SRRM2 used in this invention can be a polyclonal or monoclonal antibody, preferably a monoclonal antibody.

[0089] The antibodies binding to human SRRM2 used in this invention can be obtained using methods known in the art as polyclonal or monoclonal antibodies. The antibodies used in this invention are particularly preferably mammalian-derived monoclonal antibodies. Mammalian-derived monoclonal antibodies encompass, for example, those produced by hybridomas and those produced by hosts transformed using genetic engineering methods with expression vectors containing antibody genes.

[0090] In some embodiments of the invention, antibodies binding to human SRRM2 may be modified to form chimeric antigen receptors (CARs), which are expressed by immune cells, preferably NK cells, NK-T cells, or macrophages, and most preferably T cells (CAR T cells). A CAR (also known as a chimeric immune receptor, chimeric T cell receptor, or artificial T cell receptor) is a receptor protein engineered to endow T cells with the ability to target specific proteins. The CAR links an extracellular antigen recognition domain to an internal signaling domain capable of mediating T cell activation upon antigen binding. In this invention, the extracellular region may contain light and heavy chains of antibodies recognizing human SRRM2, forming single-chain variable fragments (scFvs). CARs thus described will lead to T cell activation upon binding to SRRM2. Furthermore, hinge regions and transmembrane domains should also constitute part of the CAR.

[0091] In some embodiments of the present invention, antibodies binding to human SRRM2 may be modified to form chimeric antigen receptors (CARs) expressed by immune cells, including but not limited to T cells, NK cells, NK-T cells, or macrophages, wherein the immune cells may be derived from induced pluripotent stem cells (iPSCs).

[0092] In some embodiments of the present invention, antibodies binding to human SRRM2 may be modified to form chimeric antigen receptors (CARs) expressed by immune cells, including but not limited to T cells, NK cells, NK-T cells, or macrophages, wherein the immune cells are immune cells inactivated with β2-immunoglobulin.

[0093] As described above, the present invention includes the discovery that SRRM2 is present on the cell surface of blood cancer cells obtained from patients with blood cancers, such as MM and AML patients, and can be bound by the antibodies used in the present invention. Therefore, in the context of the present invention, it is particularly contemplated that antibodies binding to the surface of target cells bind to impermeable cells. “Cell permeability” refers to the disruption of the cell membrane by electrical, mechanical, or chemical means, i.e., the cell membrane becomes permeable. However, in contrast, cells bound by the antibodies of the present invention have intact cell membranes expressing SRRM2, i.e., these cells are impermeable. Similarly, it is contemplated that antibodies binding to the surface of target cells bind to live cells in the context of the present invention. A “live cell” is a structural and functional unit that at least contains an intact cell membrane, nucleus, and cytoplasm, controls the entry and exit of substances into and out of the cell, and is capable of functioning independently.

[0094] Antibodies binding to human SRRM2 can be modified with various molecules such as polyethylene glycol (PEG). Furthermore, antibodies binding to human SRRM2 can also be modified with cytotoxic substances such as chemotherapeutic agents with cytotoxic activity, toxic peptides, and radiochemicals.

[0095] Specific examples of antibodies used in this invention that recognize and bind to SRRM2 present on the cell surface of target cells (such as blood cancer cells) may include antibodies given and described herein.

[0096] As described above, antibodies binding to human SRRM2 comprising substitutions, deletions, additions, and / or insertions of one or more amino acids, as used in the pharmaceutical compositions of the present invention or in the methods of the present invention, are also included within the scope of the present invention and may be prepared or naturally occurring. Examples of methods for introducing mutations into peptides include site-directed mutagenesis (Hashimoto-Gotoh, T et al., 1995) (Zoller, MJ and Smith, M., 1983) (Kramer, W et al., 1984) (Kramer W and Fritz HJ, 1987) (Kunkel, TA, 1985) (Kunkel, 1988). This is one of the methods well known to those skilled in the art for preparing peptides functionally equivalent to a given peptide. Those skilled in the art can use such methods to appropriately introduce mutations into the antibodies of the present invention or antibodies used in the pharmaceutical compositions of the present invention or in the methods of the present invention, thereby preparing antibodies functionally equivalent to such antibodies. Furthermore, amino acid mutations can occur in nature. Such an antibody having an amino acid sequence containing one or more amino acid mutations, derived from the antibody of the present invention or an antibody used in the pharmaceutical composition of the present invention or as used in the method of the present invention, is functionally equivalent to the antibody or a variant of the antibody, and is also covered by the antibody of the present invention or an antibody used in the pharmaceutical composition of the present invention or as used in the method of the present invention.

[0097] In such variants, the number of mutated amino acids is typically within 50 amino acids, preferably within 30 amino acids, and more preferably within 10 amino acids (e.g., within 5 amino acids).

[0098] For the amino acid residue to be mutated, the mutation should preferably be conserved among 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-containing 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 side chains (H, F, Y, and W) (all symbols in parentheses represent single-letter codes for amino acids).

[0099] It is known that polypeptides with amino acid sequences modified from a given amino acid sequence by deletion and / or addition of one or more amino acid residues and / or substitution with other amino acids retain the biological activity of the original polypeptide (Mark, DF et al., 1984) (Wang, A. et al., 1982). Specifically, when amino acids in the amino acid sequence constituting a polypeptide are substituted with amino acids classified in the same group, the polypeptide is generally considered to retain its activity. In this invention, substitutions between amino acids within the same amino acid group as described above are referred to as conserved substitutions.

[0100] As used herein, the term "surface" or specifically "cell surface" refers to the cell membrane. The cell membrane, also known as the plasma membrane, is the thin membrane surrounding each living cell, demarcating the cell from its surrounding environment. This membrane surrounds the cellular components, typically large, water-soluble, highly charged molecules such as proteins, nucleic acids, carbohydrates, and substances involved in cellular metabolism. Therefore, the cell membrane has at least two functions: firstly, as a barrier, keeping the cellular components inside while keeping unwanted substances outside; and secondly, as a phylogenetic link, allowing essential nutrients to enter the cell and removing waste products. ER-derived vesicles may also participate in the construction or formation of the cell membrane.

[0101] Antibodies binding to human SRRM2 are preferably capable of binding the SRRM2 peptide extracellularly. In other words, antibodies as described herein are capable of binding SRRM2 extracellularly, including SRRM2 specifically on the cell surface. Therefore, antibodies binding to human SRRM2 are preferably not intracellular antibodies (also known as intracellular antibodies). "Intracellular antibodies" (derived from intracellular and antibody) are antibodies that function within the cell to bind intracellular proteins. This requires expression of the antibody within the target cell, which can be achieved, for example, in transgenic animals or through gene therapy. Thus, intracellular antibodies are antibodies modified for intracellular localization and include antibodies produced in prokaryotes or other non-target cells. The term "intracellular antibody" can be applied to several types of protein targeting: the antibody may be retained in the cytoplasm, or it may have a nuclear localization signal, or it may enter the lumen of the endoplasmic reticulum via transmembrane cotranslational translocation, provided that it is retained in that compartment via a KDEL sequence.

[0102] "Target cells" are preferably blood cancer cells. As used herein, the term "blood cancer" may include any one or more of the following: multiple myeloma; leukemia, including acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), mast cell leukemia (MCL), or plasma cell leukemia (PCL); lymphoma, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), or post-transplant lymphoproliferative disorder (PTLD); or Waldenström macroglobulinemia (WM); myelodysplastic syndrome, myeloproliferative neoplasms (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

[0103] As used in the context of this invention, the term "pharmaceutically acceptable carrier, diluent, or excipient" can encompass any pharmaceutically acceptable carrier, diluent, or excipient known to those skilled in the art for use in pharmaceutical compositions. It should be understood that these antibody or pharmaceutical compositions described herein can be mixed with carriers or diluents that do not interfere with the intended purpose of this invention. For example, such a carrier as used in this invention can be a carrier protein, such as bovine serum albumin (BSA) or keyhole hemocyanin (KLH).

[0104] In one embodiment of the pharmaceutical composition of the present invention, the antibody binding 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 having equivalent activity to the antibody binding to human SRRM2 of the present invention. In the present invention, equivalent activity does not necessarily have to be the same activity; for example, it may be 50% or more, preferably 70% or more, more preferably 90% or more activity compared to the activity of any of the antibodies (a) to (e) as described herein. 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.

[0105] In another embodiment of the pharmaceutical composition of the present invention, the antibody binding 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 refers to the activity by which cells (immune cells, etc.) carrying Fcγ receptors bind to the Fc domain of an antibody that specifically attaches to the cell surface antigen of the target cell via the Fcγ receptor. On the other hand, CDC activity refers to 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.

[0106] Therefore, the antibody binding to human SRRM2 used in the pharmaceutical compositions of the present invention can have activities such as ADCC activity, and thus can be used as a medicine, preferably as an anticancer agent, wherein the cancer is a blood cancer, such as acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), and mast cell leukemia (MCL). Or plasma cell leukemia (PCL), Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), post-transplant lymphoproliferative disorder (PTLD), or Waldenström macroglobulinemia (WM), myelodysplastic syndrome, myeloproliferative neoplasms (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

[0107] In one embodiment of the invention, the antibody binding to human SRRM2 is conjugated with a cytotoxic substance.

[0108] In a preferred embodiment, the antibody binding to human SRRM2 can be conjugated to a cytotoxic substance, such as a chemotherapeutic agent, a toxic peptide, or a radiochemical. Such modified antibodies (hereinafter referred to as antibody conjugates) can be obtained by chemically modifying the resulting antibody. Methods for antibody modification have been established in the art.

[0109] Examples of chemotherapeutic agents whose cytotoxic activity is achieved through conjugation with antibodies binding to SRRM2 include the following chemotherapeutic agents: azalipine, anastrozole, azithromycin, bleomycin, bortezomib, lichenin-1, busulfan, camptothecin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatin, irinotecan, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, actinomycin, daunorubicin glucoside, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, doxorubicin glucoside, epirubicin, ethinylestradiol, estradiol, etoposide, etoposide glucoside, fluoride Uric acid, fludarabine, flutamide, fluorouracil, fluorometholone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, leucovorin, cyclohexanenitrosourea, nitrogen mustard, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, methotrexate, mitoxantrone, photomycin, mitomycin, mitotane, phenylbutyrate, prednisolone, procarbazine, paclitaxel, pentostatin, semustine, streptozotocin, tamoxifen, taxanes, tacrolimus, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uramustine, vinblastine, vinorelbine, vincristine.

[0110] Chemotherapy agents are preferably low-molecular-weight chemotherapeutic agents. Low-molecular-weight chemotherapeutic agents are less likely to interfere with antibodies, even after conjugation with 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. Activation of the prodrug can be enzymatic or non-enzymatic.

[0111] Examples of toxic peptides are snake venom peptides, including three-fingered toxins (3FTx), detegrins, Kunitz-type inhibitors, natriuretic peptides, or viper toxins, as reviewed by Munawar et al., 2018. Other examples include trypsin inhibitors, penicillin islands, pallotoxins, or amatoxins, as mentioned by Khan et al., 2018.

[0112] Examples of radiochemicals are those containing cytotoxic radionuclides, such as iodine-131, indium-111, yttrium-90, lutetium-177, actinium-225, gallium-68, or bismuth-213, as reviewed in Hofland et al., 2022, and Martiniova et al., 2022. Antibodies conjugated to cytotoxic substances can be used to specifically deliver cytotoxic substances to target cells, which can reduce undesirable side effects.

[0113] 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%.

[0114] In one embodiment, the antibody binding 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0115] In one embodiment, the antibody binding 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0116] In one embodiment, the antibody binding 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0117] In one embodiment, the antibody binding 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0118] In one embodiment, the antibody binding 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0119] In one embodiment, the antibody binding 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0120] In one embodiment, the antibody binding 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0121] In one embodiment, the antibody binding 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0122] In one embodiment, the antibody binding 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0123] In one embodiment, the antibody binding 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0124] In one embodiment, the antibody binding 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0125] In one embodiment, the antibody binding 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0126] In one embodiment, the antibody binding 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0127] In one embodiment, the antibody binding 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0128] In one embodiment, the antibody binding 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0129] In one embodiment, the antibody binding 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0130] In one embodiment of the invention, the antibody binding to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 9, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 10, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 11, and the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 14; or an antibody that binds to the same epitope.

[0131] In one embodiment of the invention, the antibody binding to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 15, heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 16, and heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 17, and the light chain variable region comprising light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 20; or an antibody that binds to the same epitope.

[0132] In one embodiment of the invention, the antibody binding to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 21, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 22, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 23, and the light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 24, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 25, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 26; or an antibody that binds to the same epitope.

[0133] In one embodiment of the invention, the antibody binding to human SRRM2 is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 21, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 22, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 23, and 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.

[0134] The antibodies described herein may contain constant regions. There are no particular limitations on the constant regions used, and any constant region may be used. Preferred examples of constant regions used in this invention may include human-derived constant regions. For example, constant regions derived from human IgG1, human IgG2, human IgG3, or human IgG4 may be used as heavy chain constant regions. Additionally, constant regions derived from human κ chain or human λ chain may be used as light chain constant regions, for example. The constant regions used in this invention may be constant regions having a natural sequence, or they may be modified constant regions having a sequence derived from a natural sequence by modifying one or more amino acids.

[0135] The antibodies described herein may also contain a frame region (FR). There are no particular limitations on the FR used, and any FR may be used, as long as the resulting antibody retains its binding activity against human SRRM2 present on the cell surface of the target cells. Preferred examples of FRs used in this invention may include FRs derived from human antibodies. Since FR substitution techniques for maintaining the antigen-binding activity of the antibody are known in the art, those skilled in the art can appropriately select the FR. The FR used in this invention may be an FR having a natural sequence, or an FR having a sequence derived from a natural sequence by modifying one or more amino acids.

[0136] Whether an antibody shares an epitope with another antibody can be confirmed based on their competition for the same epitope. Competition between antibodies is detected through methods such as cross-blocking assays. Cross-blocking assays are preferably, for example, competitive ELISA assays. Specifically, in a cross-blocking assay, SRRM2 protein coated on the wells of a microtiter plate is 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 wells. The amount of the present invention's antibody binding 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 present invention's antibody binding to the well coated with SRRM2 protein, and the larger the amount of the antibody to be tested binding to the well coated with SRRM2 protein.

[0137] By pre-labeling antibodies, the amount of antibody bound to the well can be easily measured. For example, biotin-labeled antibodies can be measured using an avidin-peroxidase conjugate and a suitable substrate. Cross-blocking assays using enzyme (e.g., peroxidase) labeling are specifically called competitive ELISA assays. Antibodies can be labeled with other detectable or measurable labeling substances. Specifically, radioactive labeling or fluorescent labeling, etc., are known in the art.

[0138] If a candidate antibody can bind at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 99% of human SRRM2 present on the surface of target cells compared to the binding activity obtained in a control test in the absence of a candidate antibody, then the candidate antibody is identified as an antibody that binds to an epitope that is substantially the same as the epitope that binds to the antibody of the present invention or to an epitope that binds to an antibody that binds human SRRM2 used in a pharmaceutical composition.

[0139] On the other hand, the antibody referred to herein is contained in a pharmaceutical composition used in a method of treating a patient with a blood cancer. Preferably, the blood cancer is characterized by cells in which human SRRM2 is present on its cell surface, i.e., the SRRM2 bound by the antibody of the present invention is membrane-expressed SRRM2. Further preferably, the blood cancer is multiple myeloma (MM). Also preferably, the blood cancer is plasma cell leukemia (PCL). Also preferably, the blood cancer is acute myeloid leukemia (AML).

[0140] The present invention also covers the use of the pharmaceutical compositions of the present invention in the preparation of medicaments for treating blood cancers, preferably MM, PCL and AML.

[0141] In one embodiment, the invention also covers the use of an antibody incorporating human SRRM2 as described herein in the preparation of a medicament for treating blood cancers, preferably MM, PCL, and AML.

[0142] In some embodiments of the invention, it is further envisioned that AML treated with the antibody of the invention is characterized by cells carrying a gene mutation. Preferably, said gene mutation is an FMS-like tyrosine kinase-3 (FLT-3) mutation. Thus, the AML to be treated is characterized by cells expressing human SRRM2 on the cancer cell membrane and carrying a gene mutation, preferably an FLT3 mutation. Mutations in FLT3 are the most common genetic alterations in AML, occurring in approximately 30% of AML cases, with internal tandem repeats (ITDs) representing the most common type of FLT3 mutation. FLT3-ITD is a driver mutation that manifests as a high leukemia burden and leads to a poor prognosis in AML patients (Daver et al., 2019).

[0143] In some embodiments of the invention, it is further envisioned that the PCL treated with the antibody of the present invention is primary or secondary PCL. In this regard, "primary PCL" means that the PCL is primary, i.e., the patient has not previously been diagnosed with MM (see Patient 1 described in the examples). In this regard, "secondary PCL" means that the patient has previously been diagnosed with MM. In this case, MM undergoes leukemic transformation, i.e., it progresses to PCL (see Patient 3 described in the examples).

[0144] In the context of this invention, it is also envisioned that patients with blood cancers to be treated with the antibody conjugated with human SRRM2 described herein are refractory to previous cancer therapies and / or have relapsed after previous cancer therapies, i.e., the patient has received a first (or even several) cancer treatments but is now in a state of illness or requires further cancer treatment. The previous blood cancer therapies or treatments may include, for example, one or more cycles of chemotherapy, targeted cancer therapy, and / or allogeneic stem cell therapy known to those skilled in the art. In this regard, "relapsed" means that the blood cancer had been in remission after previous cancer treatment and subsequently relapsed. In this regard, "refractory" means that the blood cancer has ceased to respond to previous cancer treatments.

[0145] The present invention also includes a method for treating hematologic malignancies, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a patient. The pharmaceutical composition of the present invention is preferably administered via a parenteral route, including but not limited to intravenous, intradermal, intramuscular, intrathecal, or intraperitoneal administration. Alternative routes include, but are not limited to, oral, rectal, ocular (including intravitreal or anterior chamber), nasal, local (including buccal and sublingual), intrauterine, vaginal or subcutaneous, intracranial, intratracheal, epidural, percutaneous, intraventricular, intracerebral, intravaginal, intrauterine, or intraspinal routes.

[0146] Furthermore, the present invention includes a method for treating blood cancers, wherein the method comprises administering to a patient a therapeutically effective amount of an antibody binding to human SRRM2 as described herein. Preferably, for the embodiments described, the blood cancer is characterized in cells in which human SRRM2 is present on the cell surface. In this regard, such a method for treating a subject's blood cancer is also envisioned to include determining, prior to treating the subject's blood cancer, whether the subject's target cells possess SRRM2 present on the cell surface as described elsewhere herein.

[0147] The term "therapeuticly effective amount" refers to the amount of the antibody or pharmaceutical composition or drug of the present invention that effectively "treats" cancer in a subject. Specifically, in the case of cancer, a therapeutically effective amount of antibody / pharmaceutical composition / drug can 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 cancer-related symptoms to a certain extent, or a combination of these effects on cancer cells. In terms of the extent to which the antibody / pharmaceutical composition / drug prevents the growth of existing cancer cells and / or kills existing cancer cells, it may be described as cytotoxic and / or cellular inhibitory.

[0148] Terms such as “treatment” or “management” refer to 1) therapeutic measures that cure, slow, or alleviate the symptoms of a diagnosed pathological condition or symptom and / or stop the progression of a diagnosed pathological condition or symptom, and 2) preventive or preventative measures that prevent or slow the progression of a targeted pathological condition or symptom. Therefore, those requiring treatment include those who already have the condition; those who are prone to having the condition; and those who need to prevent the condition. A subject is successfully “treated” according to the method of the invention or with the pharmaceutical composition of the invention or with an antibody conjugated to human SRRM2 if the patient exhibits one or more of the following: a reduction or complete disappearance of the number of cancer cells; a reduction in tumor size; inhibition or disappearance of cancer cell infiltration into peripheral organs (including cancer spread to soft tissue and bone); inhibition or disappearance of tumor metastasis; inhibition or disappearance of tumor growth; relief of one or more symptoms associated with a specific cancer; a reduction in morbidity and mortality; and an improvement in quality of life.

[0149] Antibodies intended for human administration can also be converted into artificially modified recombinant antibodies, such modification being intended, for example, to reduce xenoantigenicity in humans. 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.

[0150] In another aspect, the present invention provides a method for determining whether a patient may have a blood cancer, the method comprising determining whether SRRM2 is present on the cell surface of (blood cancer) cells contained in a sample obtained from the patient and / or whether SRRM2 is present on the surface of extracellular vesicles.

[0151] As used in this article, “extracellular vesicles” (EVs) can refer to lipid bilayer-bound particles that are naturally released from almost all types of cells and, unlike cells, cannot replicate. Although the vast majority of EVs are smaller than 200 nm, the diameter of EVs typically ranges from close to the size of the smallest physically possible monolayer liposome (about 20–30 nm) to as large as 10 μm or larger.

[0152] Based on size and synthetic pathway, EVs can be classified into exosomes, microvesicles, and apoptotic bodies. Therefore, EVs are preferably selected from exosomes, microvesicles, and apoptotic bodies. Typically, they carry cargo from the mother cell, including proteins, nucleic acids, lipids, metabolites, and even organelles. Different EV subtypes have been proposed. Therefore, EVs can also be one or more of the following: ectosomes, microvesicles, microparticles, exosomes, tumor bodies, apoptotic bodies, exomers, etc. Preferably, the EV is a tumor body. In the case of EVs, the sample is preferably ascites fluid.

[0153] Before determining the presence of SRRM2 on the surface of extracellular vesicles in samples obtained from the patients, EVs can be isolated and / or enriched from the samples by using antibodies or antibody fragments that specifically bind to biomarkers present on the EV surface. Such biomarkers for EVs include, for example, Alix, Tsg101 for exosomes, tetrapermeabilizing proteins such as CD81, CD63, and CD9, or flotillin; for microvesicles, integrin, selectins, or CD40; and for apoptotic bodies, Annexin V or phosphatidylserine. Antibodies against these biomarkers are available, for example, commercially from Abcam. Methods for isolating 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.

[0154] Preferably, when the antibody described herein is used in the context of a method for determining whether a patient may have a blood cancer, the antibody may also be included in 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 target cells (preferably blood cancer cells), and optionally a pharmaceutically acceptable carrier, diluent, or excipient; preferably, the antibody is a monoclonal antibody.

[0155] The method for determining whether a patient may have blood cancer may include the following steps:

[0156] - Provide samples obtained from the patient.

[0157] - Determine the presence of SRRM2 on the cell surface of the (blood cancer) cells contained in the sample obtained from the patient.

[0158] The presence of SRRM2 on the cell surface of (blood cancer) cells contained in the sample is associated with determining whether the patient may have cancer.

[0159] In this regard, the amount of SRRM2 present on the surface of cells containing (blood cancer) cells or on the surface of extracellular vesicles in samples from the patient is compared with reference data, such as reference data from healthy subjects known not to have blood cancer. An increase in the amount of SRRM2 on the surface of cells and / or on the surface of extracellular vesicles in the sample compared to the amount of SRRM2 on the surface of cells and / or on the surface of extracellular vesicles in the sample indicates that the patient may have blood cancer. No difference in the amount of SRRM2 on the surface of cells and / or on the surface of extracellular vesicles in the sample obtained from the patient compared to the amount of SRRM2 on the surface of cells and / or on the surface of extracellular vesicles in the sample obtained from the patient indicates that the patient may not have blood cancer.

[0160] To determine or diagnose whether a patient may have blood cancer, antibodies that bind to human SRRM2 on the surface of target cells can be used to modify the diagnostic material, such as radioactive chemicals, magnetic chemicals, or fluorescent components known to those skilled in the art.

[0161] In the context of this invention, "subject" or "patient" refers to a human being. For example, a patient may be someone suspected of having a disease or clinical condition related to blood cancers, or someone diagnosed with such a disease or clinical condition.

[0162] The “sample” obtained from the patient is preferably, but not limited to, a blood, lymph, lymphatic tissue, or bone marrow sample.

[0163] The step of “determining the presence of SRRM2 on the cell surface of target cells contained in the sample obtained from the patient” may include determining the presence of SRRM2 or fragments thereof by contacting the sample with at least one SRRM2 binder. The at least one binder may be, for example, an antibody according to the invention or as described herein. Preferably, the cross-reactivity of the at least one binder with other proteins, particularly 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%.

[0164] In some embodiments, the antibodies binding to human SRRM2 as described herein may contain a human Fc region modified to enhance effector functions such as antigen-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC). This can be achieved by introducing one or more amino acid substitutions into the Fc region of the antibody. For example, cysteine ​​residues may be introduced into the Fc region to allow the formation of interchain disulfide bonds in that region, thereby improving complement-mediated cell killing and antibody-dependent cytotoxicity (ADCC). Homodimeric antibodies with enhanced antitumor activity may also be prepared using heterobifunctional crosslinking agents as known to those skilled in the art. Alternatively, antibodies having dual Fc regions may be modified.

[0165] Furthermore, antibodies as described herein may have one or more amino acid substitutions, deletions, additions, and / or insertions in their CDR sequences, provided that the resulting antibodies are functionally equivalent to antibodies (a) to (d). The term "functionally equivalent" means comparable in affinity for SRRM2 and cytotoxicity. 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% of the activity compared to antibodies (a) to (d). There is no particular upper limit to the activity, which may be higher than that of antibodies (a) to (d). Affinity or cytotoxicity can be determined by methods generally known to those skilled in the art.

[0166] 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 target cells, used in a method of killing said target cells, wherein said target cells are blood cancer cells having SRRM2 present on their cell surface. Specifically, the present invention provides an antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the surface of target cells, used in a method of treating blood cancers as defined elsewhere herein.

[0167] Unless otherwise stated, “target cells” as used in this article refers to blood cancer cells that express human serine / arginine repeat matrix protein 2 (SRRM2) on their surface.

[0168] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0169] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0170] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0171] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0172] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0173] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0174] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0175] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0176] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0177] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0178] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0179] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0180] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0181] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0182] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0183] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0184] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 9, heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 10, and heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 11, and the light chain variable region comprising light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 14; or an antibody that binds to the same epitope.

[0185] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 15, heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 16, and heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 17, and the light chain variable region comprising light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 20; or an antibody that binds to the same epitope.

[0186] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 21, heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 22, and heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 23, and the light chain variable region comprising light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 24, light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 25, and light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 26; or an antibody that binds to the same epitope.

[0187] In one embodiment of an antibody used in a method for killing target cells having SRRM2 present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 21, heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 22, and heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 23, and the light chain variable region comprising light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 27, light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 28, and light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 29; or an antibody that binds to the same epitope.

[0188] This document pertains to the pharmaceutical compositions of the present invention and the antibodies of the present invention that are present on the surface of target cells and the methods of the present invention described herein, as well as all embodiments thereof, and the definitions described herein also apply to the antibodies of the present invention used in methods for killing target cells having SRRM2 present on their cell surfaces as described herein.

[0189] The present invention also relates to a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their cell surface, the method comprising administering an antibody that binds to human SRRM2 present on the cell surface of the target cells.

[0190] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0191] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0192] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0193] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0194] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0195] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0196] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0197] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0198] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0199] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0200] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0201] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0202] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0203] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0204] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0205] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0206] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 9, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 10, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 11, and the light chain variable region comprising light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 12, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 13, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 14; or an antibody that binds to the same epitope.

[0207] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 15, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 16, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 17, and the light chain variable region comprising light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 18, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 19, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 20; or an antibody that binds to the same epitope.

[0208] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and the light chain variable region comprising light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 24, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 25, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 26; or an antibody that binds to the same epitope.

[0209] In one embodiment of a method for killing target cells having serine / arginine repeat matrix protein 2 (SRRM2) present on their cell surface, the antibody is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and the light chain variable region comprising light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 29; or an antibody that binds to the same epitope.

[0210] In one embodiment of an antibody used in a method for treating a subject's blood cancer, the method optionally includes determining, prior to treating the subject's blood cancer, whether the subject's target cells have SRRM2 present on the cell surface as described herein. The antibody used in a method for treating blood cancer or in a method for determining whether a patient is likely to have blood cancer 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0211] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0212] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0213] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 1, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 2; or an antibody that binds to the same epitope.

[0214] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0215] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0216] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0217] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 3, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 4; or an antibody that binds to the same epitope.

[0218] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0219] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0220] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0221] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 6; or an antibody that binds to the same epitope.

[0222] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 85% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0223] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0224] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0225] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers 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 having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region having an amino acid sequence having at least 99% identity with the amino acid sequence shown in SEQ ID NO: 7; or an antibody that binds to the same epitope.

[0226] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers is an antibody comprising a heavy chain variable region and a light 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: 9, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 10, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 11, and the light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 14; or an antibody that binds to the same epitope.

[0227] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers is an antibody comprising a heavy chain variable region and a light 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: 15, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 16, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 17, and the light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 20; or an antibody that binds to the same epitope.

[0228] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 21, heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 22, and heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 23, and the light chain variable region comprising light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 24, light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 25, and light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 26; or an antibody that binds to the same epitope.

[0229] In one embodiment, the antibody used in a method for treating blood cancers or in a method for determining whether a patient may have blood cancers is an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 21, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 22, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 23, and 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.

[0230] This document pertains to the pharmaceutical compositions of the present invention, the antibodies of the present invention that bind to human SRRM2 present on the cell surface of target cells, the methods for determining whether a patient is likely to have cancer as described herein, and the definitions stated above also apply to antibodies used in methods for treating blood cancers in subjects, the methods including determining whether the target cells of the subject have SRRM2 present on the cell surface as described herein prior to treating the blood cancer of the subject.

[0231] The sequences shown in the sequence listing and used in the context of this invention are described as follows:

[0232] SEQ ID NO: 1 shows the amino acid sequence of the VH region of antibody 13F11.

[0233] SEQ ID NO: 2 shows the amino acid sequence of the VL region of antibody 13F11.

[0234] SEQ ID NO: 3 shows the amino acid sequence of the VH region of antibody 23A7.

[0235] SEQ ID NO: 4 shows the amino acid sequence of the VL region of antibody 23A7.

[0236] SEQ ID NO: 5 shows the amino acid sequences of the VH region of antibody 18A4 and antibody 18A4-2.

[0237] SEQ ID NO: 6 shows the amino acid sequence of the VL region of antibody 18A4.

[0238] SEQ ID NO: 7 shows the amino acid sequence of the VL region of antibody 18A4-2.

[0239] SEQ ID NO: 8 shows the amino acid sequence of SRRM2, as shown in UniProt Database accession number Q9UQ35, edition 2, March 6, 2007.

[0240] SEQ ID NO: 9 shows the amino acid sequence of VH-CDR1 of antibody 13F11.

[0241] SEQ ID NO: 10 shows the amino acid sequence of VH-CDR2 of antibody 13F11.

[0242] SEQ ID NO: 11 shows the amino acid sequence of VH-CDR3 of antibody 13F11.

[0243] SEQ ID NO: 12 shows the amino acid sequence of VL-CDR1 of antibody 13F11.

[0244] SEQ ID NO: 13 shows the amino acid sequence of VL-CDR2 of antibody 13F11.

[0245] SEQ ID NO: 14 shows the amino acid sequence of VL-CDR3 of antibody 13F11.

[0246] SEQ ID NO: 15 shows the amino acid sequence of VH-CDR1 of antibody 23A7.

[0247] SEQ ID NO: 16 shows the amino acid sequence of VH-CDR2 of antibody 23A7.

[0248] SEQ ID NO: 17 shows the amino acid sequence of VH-CDR3 of antibody 23A7.

[0249] SEQ ID NO: 18 shows the amino acid sequence of VL-CDR1 of antibody 23A7.

[0250] SEQ ID NO: 19 shows the amino acid sequence of VL-CDR2 of antibody 23A7.

[0251] SEQ ID NO: 20 shows the amino acid sequence of VH-CDR3 of antibody 23A7.

[0252] SEQ ID NO: 21 shows the amino acid sequence of VH-CDR1 of antibody 18A4 and antibody 18A4-2.

[0253] SEQ ID NO: 22 shows the amino acid sequence of VH-CDR2 of antibody 18A4 and antibody 18A4-2.

[0254] SEQ ID NO: 23 shows the amino acid sequence of VH-CDR3 of antibody 18A4 and antibody 18A4-2.

[0255] SEQ ID NO: 24 shows the amino acid sequence of VL-CDR1 of antibody 18A4.

[0256] SEQ ID NO: 25 shows the amino acid sequence of VL-CDR2 of antibody 18A4.

[0257] SEQ ID NO: 26 shows the amino acid sequence of VL-CDR3 of antibody 18A4.

[0258] SEQ ID NO: 27 shows the amino acid sequence of the VL region of antibody 18A4-2.

[0259] SEQ ID NO: 28 shows the amino acid sequence of VL-CDR1 of antibody 18A4-2.

[0260] SEQ ID NO: 29 shows the amino acid sequence of VL-CDR2 of antibody 18A4-2.

[0261] Table 1 below provides an overview of the SEQ ID NO and detailed sequences used in the context of this invention (if the sequences shown in Table 1 conflict with sequences in a sequence list that must be submitted due to formal requirements, the sequences in Table 1 shall replace the sequences in the sequence list):

[0262] Table 1:

[0263]

[0264]

[0265]

[0266]

[0267] In the context of this invention, the following abbreviations are used: VH = Variable Heavy Chain; VL = Variable Light Chain; CDR = Complementarity Determination Region; VH-CDR = CDR of the Variable Heavy Region; VL-CDR = CDR of the Variable Light Region; CDR can be determined using the Kabat algorithm, for example, http: / / abysis.org / abysis / .

[0268] * * * * *

[0269] Note that as used herein, the singular forms “a,” “an,” and “the / described” include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a reagent” includes one or more such different reagents, and reference to “the method” includes reference to equivalent steps and methods known to those skilled in the art, which may be modified or substituted for the methods described herein.

[0270] Unless otherwise stated, the term "at least" preceding a series of elements should be understood to refer to each element in that series. Those skilled in the art will recognize or be able to determine many equivalent embodiments of the invention described herein using no more than conventional experiments. These equivalent embodiments are also intended to be covered by this invention.

[0271] Wherever it is used, the term “and / or” includes the meaning of “and,” “or,” and “all or any other combination of the elements connected by the term.”

[0272] The terms “less than” or conversely “greater than” do not include specific numbers.

[0273] For example, "less than 20" means less than the indicated quantity. Similarly, "greater than" or "higher than" means more than or greater than the specified quantity; for example, "greater than 80%" means more than or greater than 80% of the specified quantity.

[0274] Throughout this specification and the following claims, unless the context otherwise requires, the word “comprising” and its variations such as “including” and “containing” shall be understood to mean including the stated whole or step or group of whole or steps, but not excluding any other whole or step or group of whole 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 unspecified element, step, or component.

[0275] The term "including" means "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0276] It should be understood that the present invention is not limited to the specific methodologies, schemes, materials, reagents, and substances described herein, and therefore variations are possible. The terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the invention, which is defined only by the claims.

[0277] All publications (including all patents, patent applications, scientific publications, specifications, etc.) cited throughout this specification are incorporated herein by reference in their entirety, whether above or below. Nothing herein is to be construed as an admission that the invention is not entitled to any prior art based on such disclosures. To the extent that any material incorporated by reference contradicts or is inconsistent with this specification, this specification supersedes any such material.

[0278] All references and patent documents cited in this article are incorporated herein by reference in their entirety.

[0279] The invention and its advantages will be better understood from the following embodiments, which are provided for illustrative purposes only. These embodiments are not intended to limit the scope of the invention in any way. In this document, the terms "embodiment" and "figure" are used interchangeably.

[0280] The invention is further characterized by the following items:

[0281] 1. An antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of target cells, used in a method for treating blood cancers in human patients.

[0282] 2. The antibody according to item 1 for the stated purpose, wherein the weight of the patient to be treated is 16 to 150 kg, preferably 18 to 140 kg, more preferably 20 to 130 kg, and even more preferably 22 to 120 kg.

[0283] 3. The antibody for the purpose according to any one of the preceding items, wherein the patient to be treated is at least 1 year old, preferably 2 years old, more preferably 2 to 80 years old.

[0284] 4. The antibody for the purpose according to any one of the preceding items, wherein the height of the patient to be treated is 70 to 220 cm, preferably 80 to 200 cm, more preferably 90 to 200 cm.

[0285] 5. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody has cytotoxic activity, preferably antigen-dependent cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).

[0286] 6. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody is part of a chimeric antigen receptor (CAR).

[0287] 7. The antibody according to Project 6, wherein the CAR is expressed by T cells, NK cells, NK-T cells or macrophages.

[0288] 8. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody is expressed by an autologous cell population.

[0289] 9. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody is expressed by an allogeneic cell population.

[0290] 10. An antibody for the stated purpose according to any one of the preceding items, wherein the SRRM2 present on the cell surface of the target cell is externalized.

[0291] 11. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody is not an intracellular antibody.

[0292] 12. An antibody for the purpose according to any one of the preceding items, wherein the blood cancer to be treated is characterized by cells expressing human SRRM2 on their cell surface.

[0293] 13. An antibody for the purpose according to any one of items 1 to 12, wherein the blood cancer to be treated is multiple myeloma.

[0294] 14. An antibody for the purpose of any one of items 1 to 12, wherein the blood cancer to be treated is leukemia, including acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), mast cell leukemia (MCL), or plasma cell leukemia (PCL).

[0295] 15. An antibody for the purpose of any one of items 1 to 12, wherein the blood cancer to be treated is acute myeloid leukemia (AML).

[0296] 16. The antibody for the stated purpose as described in item 15, wherein the AML is further characterized by cells having a genetic mutation, preferably an FMS-like tyrosine kinase-3 (FLT3) mutation.

[0297] 17. An antibody for the purpose of any one of items 1 to 12, wherein the blood cancer to be treated is plasma cell leukemia (PCL).

[0298] 18. The antibody for the stated purpose as described in item 17, wherein the PCL is primary or secondary PCL.

[0299] 19. An antibody for the purpose of any one of items 1 to 12, wherein the hematologic malignancy to be treated is a lymphoma, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), post-transplant lymphoproliferative disorder (PTLD), or Waldenström macroglobulinemia (WM).

[0300] 20. An antibody for the purpose according to any one of items 1 to 12, wherein the hematologic malignancy to be treated is myelodysplastic syndrome, myeloproliferative neoplasm (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

[0301] 21. An antibody for the purpose according to any one of the preceding items, wherein the patient to be treated is refractory to previous cancer therapies and / or has relapsed after previous cancer therapies.

[0302] 22. The antibody for the stated purpose according to any one of the preceding items, wherein the route of administration of the antibody is parenteral, including but not limited to intravenous, intradermal, intramuscular, intrathecal, or intraperitoneal administration.

[0303] 23. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody is conjugated with a cytotoxic substance.

[0304] 24. An antibody for the purpose according to any one of the preceding items, wherein the antibody binds to non-permeable cells.

[0305] 25. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody binds to a living cell.

[0306] 26. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody comprises an antibody that,

[0307] (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 9, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 10, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 11, and

[0308] The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 14.

[0309] (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 15, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 16, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 17, and

[0310] The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 20.

[0311] (c) Heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and

[0312] A light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 24, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 25, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 26; or

[0313] (d) Heavy chain variable region, said heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and

[0314] 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.

[0315] 27. An antibody for the stated purpose according to any one of the foregoing items, wherein said antibody comprises an antibody that,

[0316] (a) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 2.

[0317] (b) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 4.

[0318] (c) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 6, or

[0319] (d) A heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 7.

[0320] 28. An antibody for the stated purpose according to any one of the preceding items, wherein the antibody is contained in a composition containing a buffer solution.

[0321] 29. The antibody for the stated purpose according to item 28, wherein the antibody is contained in a composition comprising a buffer solution and sodium chloride.

[0322] 30. A method for determining whether a patient may have a blood cancer, the method comprising determining, in a sample obtained from the patient, the presence of SRRM2 on the cell surface of cells contained in the sample and / or on the surface of extracellular vesicles.

[0323] 31. The method according to item 30, wherein an increase in the amount of SRRM2 present on the cell surface of the cells and / or on the surface of extracellular vesicles contained in the sample compared to the amount of SRRM2 present on the cell surface of the cells contained in the sample obtained from a healthy subject indicates that the patient may have a blood cancer.

[0324] 32. According to the method of item 30, if there is no difference in the amount of SRRM2 present on the cell surface and / or on the surface of extracellular vesicles of cells contained in a sample obtained from the patient compared with the amount of SRRM2 on the cell surface and / or on extracellular vesicles in a sample obtained from a healthy subject, it indicates that the patient may not have blood cancer.

[0325] 33. The method according to any one of items 30 to 32, wherein the antibody is an antibody comprising:

[0326] (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 9, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 10, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 11, and

[0327] The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 14.

[0328] (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 15, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 16, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 17, and

[0329] The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 20.

[0330] (c) Heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and

[0331] A light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 24, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 25, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 26; or

[0332] (d) Heavy chain variable region, said heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and

[0333] 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.

[0334] 34. The method according to any one of items 30 to 33, wherein the antibody is an antibody comprising:

[0335] (a) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 2.

[0336] (b) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 4.

[0337] (c) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 6, or

[0338] (d) A heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 7.

[0339] 35. The method according to any one of items 30 to 34, wherein the cell is a non-permeable cell.

[0340] 36. The method according to any one of items 30 to 35, wherein the cell is a living cell.

[0341] 37. The method according to any one of items 30 to 36, wherein the blood cancer is multiple myeloma.

[0342] 38. The method according to any one of items 30 to 36, wherein the blood cancer is leukemia, including acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), mast cell leukemia (MCL), or plasma cell leukemia (PCL).

[0343] 39. The method according to any one of items 30 to 36, wherein the blood cancer is acute myeloid leukemia (AML).

[0344] 40. The method according to any one of items 30 to 36, wherein the blood cancer is plasma cell leukemia (PCL).

[0345] 41. The antibody for the stated purpose according to item 40, wherein the PCL is primary or secondary PCL.

[0346] 42. The method according to any one of items 30 to 36, wherein the hematologic cancer is a lymphoma, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), post-transplant lymphoproliferative disorder (PTLD), or Waldenström macroglobulinemia (WM).

[0347] 43. The method according to any one of items 30 to 36, wherein the hematologic cancer is myelodysplastic syndrome, myeloproliferative neoplasm (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

[0348] Example

[0349] Materials and methods

[0350] Two patients received autologous CAR-T cell infusions containing scFvs derived from antibodies of this invention. Unless otherwise stated, all data are derived from samples collected from these patients, referred to as Patient 1 and Patient 2.

[0351] Patient 1

[0352] Patient 1 is a 53-year-old female patient who was diagnosed with primary plasma cell leukemia 4 years ago.

[0353] The patient received multiple cycles of primary androgen deprivation therapy (PADT) and 12 cycles of chemotherapy containing daratumumab. The patient also received autologous stem cell transplantation, autologous BCMA CAR-T cell therapy, and other treatments. The patient received BCMA CAR-T cell therapy one year prior. The best response was VGPR, followed by relapse (within 6 months), and no recommended effective treatment was found based on clinical evaluation.

[0354] Flow cytometry showed that the SRRM2 positivity rate in peripheral plasma cells was >90%.

[0355] ■ PLC: IgG-κ type, refractory / relapsed, 1q21 amplified peripheral plasma cells: CD38++CD138+CD19-CD56-CD45dim~ (increased to 43% before CAR-T therapy).

[0356] ■ Metastasis of extramedullary plasmacytoma: bilateral lungs, left orbit, left arm, left hip, abdominal cavity and pelvis, complicated with pleural effusion, ascites and pelvic effusion, pulmonary infection, gastrointestinal bleeding, incomplete intestinal obstruction.

[0357] ■ The patient was bedridden and unable to eat or speak before the CAR-T infusion. ECOG PS 4.

[0358] After receiving bridging therapy with pomalidomide, dexamethasone, and bortezomib, the patient's condition deteriorated rapidly, and she subsequently received an injection of autologous SRRM2 CAR-T cells / kg (day 0 dose 0.69 × 10⁻⁶). 6 The dose on day 2 was 2.57 × 10⁻⁶. 6 No CRS, no ICANS, and no extratumor-targeted side effects observed in the heart, liver, kidneys, lungs, or CNS.

[0359] Post-treatment:

[0360] ■ The patient's extramedullary tumor softened and shrank, and the symptoms of incomplete intestinal obstruction improved;

[0361] ■ Three weeks after injection (day 16 after infusion), the proportion of peripheral plasma cells decreased from 43% to 6.4%. Figure 9 And blood counts improved;

[0362] ■ Patients can get out of bed and walk after treatment - ECOG PS2;

[0363] ■ No targeted side effects were observed in the heart, liver, kidneys, lungs, or central nervous system;

[0364] ■ From day 0 to day 14, the increase in platelets and reticulocytes indicates an improvement in hematopoietic function.

[0365] Patient 2

[0366] Patient 2 is a 60-year-old male who was diagnosed with relapsed and refractory multiple myeloma 11 years ago.

[0367] The patient was diagnosed with multiple myeloma 11 years ago and has received chemotherapy, autologous hematopoietic stem cell transplantation, and thalidomide maintenance therapy. The patient experienced fatigue and bone pain for one month, which was unresponsive to conventional anti-myeloma drug treatment. The disease continued to progress and was unresponsive to MM therapy. ECOG 2.

[0368] The bone marrow biopsy diagnosed primary plasma cell leukemia (IgGκ type, 1q21 amplification): a large number of diffusely proliferating plasma cells were visible between the bone trabeculae, accounting for approximately 90% of the nucleated cells in the bone marrow. Figure 2 ); IgD-λ type, a rare and difficult-to-cure subtype that is often prone to relapse. Flow cytometry analysis showed that over 73% of bone marrow plasma cells were SRRM2 positive.

[0369] Patient 2 received SRRM2 CAR-T cell infusions (0.7 × 10⁻⁶ / kg) on ​​days 1, 114, and 287. 7 1.1×10 7 2.3×10 7 The CAR-T cell population expanded to 11.1% of the total T cell count within 3 weeks and remained at 7.4% 7 weeks after infusion.

[0370] Sixty-four days after a single dose of SRRM2-specific CAR-T cell infusion, the patient's bone pain symptoms disappeared, hemoglobin and platelet counts rebounded, and no further blood transfusions were needed.

[0371] A restored serum immunoglobulin light chain κ / λ ratio indicates a good treatment response. Partial response (PR) was achieved, and the disease remained stable for 11 months.

[0372] CRS grade 2, no ICANS, and no targeted tumor extra-tumor toxicity (OTOT) observed in the heart, liver, kidney, lung, and central nervous system.

[0373] As is known to those skilled in the art, standard flow cytometry was used. For flow cytometry analysis of SRRM2 expression, cells were stained for 20 minutes in FACS buffer (PBS + 2% FSC) with the inventor's SRRM2-specific antibody EX-02 or with an allotype control antibody, followed by staining with anti-rat Alexa Fluor® 647 secondary antibody (Jackson ImmunoResearch). All staining was performed on ice. For cell identity analysis, a variety of antibodies were used, including anti-CD45 conjugated to PC7, anti-138 conjugated to PE-eFluor™ 610, and anti-CD38 conjugated to allophycocyanin (APC).

[0374] Immunohistochemistry

[0375] Mount paraffin sections onto Superform Plus slides. After fixation with acetone, incubate the slides with primary antibody, then with a suitable biotinylated secondary antibody. Develop the slides using 0.01% 3-amino-9-ethylcarbazole (AEC) as the chromogen. Counterstain with hematoxylin and cover the coverslips with Kaiser glycerol gelatin.

[0376] The presence of morphologically abnormal plasma cells (indicators of cancer-associated plasma cells) in bone marrow smears was quantified using Wright-Giemsa staining.

[0377] Patient 3

[0378] Patient 3 is a 55-year-old female patient diagnosed with plasma cell leukemia (PCL). She had multiple myeloma for 5 years and achieved complete remission (CR) after 10 cycles of chemotherapy. Three years prior, she progressed to PCL. After 7 cycles of chemotherapy, she achieved CR again. In 2024, her PCL relapsed, accompanied by worsening anemia, kidney damage, disease progression, and unresponsiveness to treatment (ECOG 2).

[0379] Flow cytometry showed that >42% of peripheral plasma cells were SRRM2 positive.

[0380] Patient 3 received SRRM2 CAR-T cells (0.54 × 10⁻⁶ cells) on days 0, 1, and 18, respectively. 7 2.34×10 7 1.06×10 7 Intravenous infusion of cells / kg. 28 days post-infusion: Peripheral blood plasma cell percentage decreased from 29.0% before CAR-T infusion (day 0) to 0.55% on day 28, indicating a very good partial response (VGPR) to CAR-T therapy. Figure 18Grade 3 CRS occurred, which resolved after tocilizumab treatment. No ICANS was observed, and no extratumor-targeted side effects were observed in the heart, liver, kidneys, lungs, or central nervous system.

[0381] AML research

[0382] This study included 65 AML patients admitted to the Second Affiliated Hospital of Anhui Medical University between January 2022 and June 2023. Peripheral blood and bone marrow samples were also collected and analyzed from an additional subgroup of 20 patients. Peripheral blood samples from all 65 AML patients were collected and analyzed.

[0383] Online database search

[0384] The gene expression profile of SRRM2 in all tumor samples and paired normal tissues was assessed using the GEPIA database (http: / / gepia.cancer-pku.cn / ). SRRM2 expression in AML patients was assessed using the BloodSpot database (https: / / servers.binf.ku.dk / bloodspot / ). Survival analysis data were obtained from the Cancer Genome Atlas database (TCGA, https: / / www.cancer.gov / ccg / ).

[0385] Flow cytometry analysis of SRRM2 expression

[0386] PB samples from AML patients were collected using Ficoll (Cytiva, 17544602) and divided into two tubes. Cells were counted, and each 100,000 cells was stained with either SRRM2 mAb EX-02 or an allotype control antibody. Cells were then washed twice with phosphate-buffered saline (PBS) and stained for 15 minutes at room temperature in the dark with CD34-PE or CD117-PE, CD33-APC, CD45-PC7 (Beckman Coulter, USA), and FITC-labeled goat anti-rat IgG (Abcam, 150165, UK). Samples were analyzed using flow cytometry (Cytoflex, Beckman Coulter, USA). The gating of the target cell population was stepwise using CytExpert for DxFLEX flow cytometry software to facilitate quantitative analysis of SRRM2 expression.

[0387] Bone marrow and PB samples from newly diagnosed and previously diagnosed MM patients were collected using Ficoll (Cytiva, 17544602) and separated into two tubes. Cells were counted and stained per 100,000 cells with either SRRM2 mAb EX-02 or an allotype control antibody. Cells were then washed twice with phosphate-buffered saline (PBS) and stained for 15 minutes at room temperature in the dark with CD34-PE or CD117-PE, CD33-APC, CD45-PC7 (Beckman Coulter, USA), and FITC-labeled goat anti-rat IgG (Abcam, 150165, UK). Samples were analyzed by flow cytometry (Cytoflex, Beckman Coulter, USA). The gating of the target cell population was stepwise using CytExpert for DxFLEX flow cytometry software to facilitate quantitative analysis of SRRM2 expression.

[0388] Cell culture

[0389] Myeloid leukemia cell lines HL-60 and MOLM-13 were purchased from Nanjing Saihongrui Biotechnology Co., Ltd. Myeloid leukemia cell line KG-1a was purchased from Guangzhou Saiku Biotechnology Co., Ltd. Myeloid leukemia cell lines MV4-11, SKM-1, and K562 were obtained from the Hematology Laboratory of the Second Affiliated Hospital of Anhui Medical University. All experiments were performed using mycoplasma-free cells. Except for HL-60 and MV4-11 cell lines, which were cultured in Iskov Modified Durbeco Medium (IMDM, Cytiva, USA), all other cell lines were cultured in Roswell Park Memorial Institute Medium (RPMI, Cytiva, USA) supplemented with 10% fetal bovine serum (FBS, Excell, Uruguay). All cell lines were maintained in a humid environment at 37°C and 5% CO2.

[0390] CAR construction and viral vector generation

[0391] A single-chain variable region fragment (scFv) of a rat-derived antibody targeting SRRM2 was cloned in-frame with a transmembrane domain (TMD), a 4-1BB co-stimulatory domain, and a CD3ζ signaling domain via a short hinge to achieve CAR expression on T cells. A third-generation lentiviral packaging system was used for the preparation of transient functional lentiviral vector (LV) particles. Specifically, four LV production plasmids (including a transfer plasmid encoding CAR and a plasmid produced by GenScript ProBio (LentiHelper)) were used. TMThree helper plasmids (VSV-G, Rev, and GagPol) were transfected into HEK293T packaging cells for LV production and purification according to standard techniques. The eluted LV particles were stored at -80°C.

[0392] Production of CAR-T cells

[0393] Peripheral blood mononuclear cells (PBMCs) were isolated from PB cells in healthy volunteers using Ficoll isolation. The cells were then cultured at a concentration of 2 × 10⁻⁶ cells / mL. 6 T cells were seeded at a density of [number] cells / ml and stimulated for 24 hours with CD3 / CD28 monoclonal antibody (mAb) (100 IU / ml or 300 IU / ml, Miltenyi, Germany). T cells were transduced with lentivirus at a multiplicity of infection (MOI) of 5. Human serum albumin (HSA, 10 ng / ml, Baxalat, USA) was added simultaneously to optimize transfection efficiency. Cells were washed 24 hours after transduction to remove LV particles. Conversely, CAR-T cells in the uninfected group were cultured according to a similar procedure to CAR-T cells, but without any viral infection. T cells were expanded for 4–7 days in PRIME-XV T cell chemistry-defined medium (CDM, Santa Ana, USA) in the presence of IL-2 (300 IU / ml or 600 IU / ml, Quangang, China) or IL-7 and IL-15 (10 ng / ml, SinoBio, China). The cell products were washed twice with PBS (Cytiva, USA) for subsequent experiments.

[0394] Quality control of SRRM2-specific CAR-T cells

[0395] CAR-T cells cultured for 4–7 days were collected, centrifuged to remove the culture medium, and resuspended in 100 μl PBS. Cells were stained with Alexa647-labeled AffiniPure F(ab')2 fragment donkey anti-rat IgG (H+L) (Jackson ImmunoResearch, USA) and CD3 (FITC, Beckman Coulter, USA) to measure the number of CAR-positive CD3+ T cells, thereby determining the transduction rate. Mycoplasma and endotoxin contamination were assessed using specific detection kits according to established protocols. CAR gene expression in mice was detected using a PCR-based CAR gene detection kit (Hillgene, PX-CA001, according to manufacturer's instructions).

[0396] In vitro functional testing

[0397] After co-culturing with target cells at specified E:T ratios (1:1; 2.5:1; 5:1) for 24 hours, the cytotoxicity of SRRM2 CAR-T cells was determined by measuring lactate dehydrogenase (LDH) release using the CytoTox 96® Non-Radioactive Cytotoxicity Assay Kit (Dojindo Molecular Technologies, Inc, Japan). Assays were performed according to the manufacturer's instructions. Control groups were set up to measure (i) background medium (no cells added), (ii) spontaneous release (target cells only), and (iii) maximum release (target cells treated with 10 ml lysis buffer). Killing efficiency was calculated using the following formula: %cytotoxicity = [target cells plus effector cells (OD 490nm) - effector cells spontaneous (OD 490nm)] / [target cells maximum (OD 490nm) - target cells spontaneous (OD 490nm)] × 100.

[0398] Constructing an AML tumor-bearing mouse model

[0399] Immunodeficient NSG mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. 4×10⁶ mice were used to induce phosphoprotein metabolism in mice. 6 A human AML tumor-bearing mouse model was established by injecting SKM-1 cells into the tail vein of 4-6 week old mice. After 14 days, the tumor-bearing mice were randomly divided into two groups (n=5) and intravenously administered either simulated T cells (untransduced T cells) or CAR-T cells (1×10⁻⁶ cells). 7 When euthanizing mice, isolate the BM or tumor tissue.

[0400] Wright-Giemsa staining

[0401] After the BM smear has air-dried, fix it immediately using the Wright-Giemsa staining kit (BASO, BA4107). Add approximately 0.5–0.8 ml of solution A to the smear and incubate for 1 minute for staining. Then, add solution B (2–3 times the volume of solution A) to solution A. Gently blow air onto the surface of the solution using a bulb syringe to create ripples, ensuring thorough mixing of solutions A and B. Incubate for 4–10 minutes. Rinse with tap water and allow the slide to air-dry. Examine under a microscope using an oil immersion microscope.

[0402] A mouse model was established to analyze the in vivo efficacy of SRRM2-specific EX-02 CAR-T cells. For this purpose, 3.3 × 10⁻⁶ cells were administered on day -5. 6Kawasaki Medical School (KMS)-11 multiple myeloma cells were intravenously (iv) injected into immunodeficient NSG mice. These cells carried a luciferase transgene to allow for bioluminescent imaging. Five days later (day 0), mice (n=5 / group) received 1.3 × 10⁻⁶ cells. 6 EX-02 CAR-T cells or the same number of T cells previously isolated from peripheral blood of healthy volunteers were used to generate T-mimicking cells. Tumor progression was monitored by bioluminescence imaging at different time points (days 7, 15, 24, 24, and 50). Simultaneously, human CD4+ in peripheral blood was analyzed by flow cytometry. + and CD8 + The number of CAR-T cells was also analyzed at the end of the experiment (day 50).

[0403] Statistical analysis

[0404] Statistical analysis was performed using IBM SPSS Statistics 25 and GraphPad Prism 8.0. Continuous data are expressed as mean ± standard deviation. For comparisons between two groups, if the data were normally distributed, a t-test was used to assess differences; otherwise, data were expressed as median and interquartile range, and a nonparametric rank-sum test was used for analysis. Survival time was defined as the time from initial diagnosis to death (all-cause mortality). A p-value less than 0.05 was considered statistically significant.

[0405] result

[0406] Figure 1A The figure shows that most abnormal plasma cells are positive for SRRM2 on the surface. An example of an immunophenotypic analysis strategy using white blood cells (WBCs) or bone marrow cells from patients with plasma cell leukemia is illustrated in the figure. Figure 1A (A) 75.2% of all cells were CD38+CD138+ and were identified as abnormal plasma cells (located in the upper right quadrant; Q1-UR). Figure 1A (B) and (C) show that the majority of these plasma cells were positive for SRRM2 antibody staining (in the phylum = 59.6% of all leukocytes and 90.02% of all CD38+CD138+ plasma cells). Normal lymphocytes, monocytes, and granulocytes were SRRM2 negative (in Figure 1A (B) Below the middle door). Figure 1A (D) and (E) show isotype control staining.

[0407] Figure 1B The immunophenotypic analysis of WBCs as described above showed that 92.94% of the abnormal plasma cells in patient 1 were positive for SRRM2 staining.

[0408] Figure 2 The CD138 level was observed after SRRM2 CAR-T cell therapy. + Cell reduction. CD138 immunohistochemistry was performed on bone marrow extracted from patient 2. Figure 2 A showed that before CAR-T cell therapy, more than 90% of nucleated cells were positive for CD138 staining (dark gray). Figure 2 B shows that on day 50 after CAR-T cell infusion, less than 10% of nucleated cells were positive for CD138 staining (black arrow). Magnification: 10×20.

[0409] Figure 3 The image shows that abnormal plasma cells were eliminated through SRRM2 CAR-T cell therapy. The figure shows bone marrow smears of Patient 2 before and 50 days after SRRM2 CAR-T cell infusion. Figure 3 A shows plasma cells before treatment: primitive and immature plasma cells (black arrows) account for 5% of all nucleated cells. Figure 3 B shows plasma cells on day 50 after SRRM2 CAR-T cell infusion. No abnormal plasma cells can be detected. Cells were stained with Wright-Giemsa stain.

[0410] Figure 4 A shows that in vivo expansion of the SRRM2-specific CAR T cell population (quantified as a proportion of the total number of T cells present in each sample) peaked at week 3 post-infusion. This was achieved with a single dose of 5 × 10⁻⁶. 7 The amount of cells was determined by infusing SRRM2-targeted CAR-T cells into patient 2 (=day 0), and blood samples were collected periodically to assess CAR-T cell proliferation. The percentage of SRRM2 CAR T cells is shown on days 1, 3, 6, 16, 23, and 50. This data is presented in... Figure 4 Quantification was performed in B.

[0411] Figure 5 The figure shows that CAR-T cell therapy targeting SRRM2 restored the κ / λ light chain ratio in the blood. The figure illustrates the measurement of serum free immunoglobulin (Ig) light chains in the blood of Patient 2, as measured by an automated immunoassay. Total concentration (top inset) and κ / λ ratio (bottom inset) are shown. The patient's tumor cells produced antibodies containing Igλ light chains. Therefore, the decrease in λ concentration and the resulting increase in κ concentration (and the resulting ratio) indicate the clinical efficacy of SRRM2 CAR-T cells.

[0412] Figure 6It showed a reduction in cancer-associated plasma cells, quantified by counting the number of abnormal plasma cells (gated), which are characterized by the marker CD138. + CD19 – CD56 – CD45 dim The figure shows the bone marrow FACS of patient 1 before SRRM2CAR-T cell infusion (left) and on day 50 after infusion (right).

[0413] Figure 7 Clinical data from patient 1 are shown, demonstrating the antitumor activity of the infused SRRM2 CAR-T cells.

[0414] - ECOG decreased from 4 to 2 (for more information on the ECOG performance status scale, see, for example, https: / / ecog-acrin.org / resources / ecog-performance-status / ).

[0415] - Reduced minimal residual disease (MRD) in the blood

[0416] - Mildly elevated hemoglobin (HB)

[0417] - Significantly increased platelet (PIT) count

[0418] - A significant decrease in creatinine (Cr) concentration indicates improved renal function.

[0419] Figure 8 The workflow (gating strategy) for detecting SRRM2-positive abnormal plasma cells in the blood of myeloma patients is shown. In this example, 90.02% of myeloma plasma cells were membrane-positive for SRRM2, while normal cells were membrane-negative for SRRM2 (not shown). Figure 8 B shows according to Figure 8 The workflow shown in A tests the percentage of SRRM2-positive plasma cells in the bone marrow of a total of 67 patients.

[0420] Figure 9 The results showed that in patient 1, the percentage of plasma cells (CD38+ + CD138+ CD19-CD56-CD45dim) in peripheral blood decreased from 43% (before) to 6.4% of the total white blood cell count on day 16 post-infusion. SRRM2 CAR-T cells were infused twice (indicated by arrows): 3.4 × 10⁻⁶ cells on day 0. 7 The values ​​for (first) and day 2 were 1.18 × 10⁻⁶. 8 .

[0421] Figure 10The results showed that SRRM2 CAR-T cell infusion led to the recovery of hematopoietic function 50 days post-infusion. Patient 2 received only SRRM2 CAR-T cell infusion without blood transfusion to assist hematopoietic recovery. Platelet levels increased from only 36 g / L on the day of infusion to 62 g / L on day 50. Thrombocytopenia is a common symptom of multiple myeloma (29%) and can lead to altered coagulation phenotypes.

[0422] Figure 11 This study illustrates the correlation between SRRM2 expression and clinical data in AML patients. (A) Survival analysis based on the Center for Cancer Genomics-NCI database showed that patients with high SRRM2 expression had shorter median survival than those with low SRRM2 expression. (B) SRRM2 expression in AML cells with cytogenetic abnormalities and in normal HSCs. (C) Surface SRRM2 expression on leukemia blasts derived from bone marrow (BM) and peripheral blood (PB). (DE) SRRM2 expression in patient groups of different ages and sexes. (F) Surface SRRM2 expression in newly diagnosed (ND) and relapsed / refractory (RR) AML cases. (G) Surface SRRM2 expression in patients with chromosomal karyotype abnormalities and patients with normal chromosomal karyotypes. (H) Surface SRRM2 expression in patients with and without gene mutations. (IJ) Surface SRRM2 expression on tumor cell membranes in AML patients carrying different gene mutations. SRRM2 levels were highest in patients carrying the FLT3 mutation. ISO: Isotype control. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ns: no significant difference.

[0423] Survival analysis showed that AML patients with high SRRM2 expression had a significantly shorter median survival compared to AML patients with low SRRM2 expression. Figure 11 A). Compared with normal hematopoietic stem cells (HSCs), SRRM2 was significantly elevated in various types of AML blast cells with different cytogenetic abnormalities ( Figure 11 B). Flow cytometry was performed to evaluate cell surface SRRM2 expression in 65 AML patients and various myeloid leukemia cell lines. There were no statistically significant differences in SRRM2 expression among the groups grouped by sample type, age, and sex. Figure 11 C-11E). However, a significant correlation was observed between disease status and chromosomal abnormalities and SRRM2 expression in AML patients (C-11E). Figure 11 F and 11G). Compared with patients without gene mutations, AML patients carrying gene mutations showed increased SRRM2 expression (F and 11G). Figure 11H). It is worth noting that, compared with the wild-type FLT3 (FLT3... WT Compared to patients carrying other gene mutations, those carrying the FLT3 mutation (FLT3) are more likely to have higher rates of FLT3 mutation. mut AML patients showed significantly higher SRRM2 expression ( Figure 11 I and 11J).

[0424] Figure 12 The expression of SRRM2 in AML patients and healthy donors is shown. (AB) SRRM2 expression on the membrane surface of leukemia blasts, lymphocytes, monocytes, and neutrophils from two AML patients was assessed by flow cytometry. (C) SRRM2 expression on lymphocytes, monocytes, and neutrophils in the PB of a healthy donor. (D) SRRM2 expression on lymphocytes, monocytes, neutrophils, and hematopoietic stem cells in the bone marrow of a healthy donor.

[0425] In some cases, SRRM2 is significantly and specifically expressed in leukemia blast cells, but not in normal blood cells. Figure 12 A and 12B). In healthy donors, SRRM2 is barely expressed or negligibly expressed on lymphocytes, monocytes, neutrophils, and HSCs. Figure 12 C: PB sample, Figure 12 D: BM sample). SRRM2 expression was significantly elevated on the surface of AML cell membranes, suggesting it is a promising target for CAR-T therapy in AML.

[0426] Figure 13 The expression and localization of SRRM2 on different AML cell lines are shown. Surface SRRM2 expression on six AML cell lines was measured by flow cytometry using the SRRM2 antibody of this invention. ISO: Isotype control. ***p<0.001, ****p<0.0001. SRRM2 expression was identified using anti-SRRM2 and goat anti-rabbit IgG (H+L) / AF647 antibody (Bioss, catalog number: bs-0295G-AF647).

[0427] Six AML cell lines were selected for subsequent experiments to verify the relationship between surface SRRM2 expression and FLT3. mut The relationships between AMLs; where MOLM-13 and MV-4-11 represent FLT3. mut Cell lines. Increased SRRM2 expression was observed in several AML cell lines. FLT3 mut The MOLM-13 cell line showed better performance than other FLT3 cells. 野生型 The cell line had higher surface SRRM2 levels.

[0428] Figure 14 The optimization of SRRM2-CAR-T cell preparation conditions is shown. (A) Schematic diagram of the LV construct expressing SRRM2 CAR. Wherein, scFv: single-stranded variable fragment (SRRM2); hinge (CD8); TMD: transmembrane domain; intracellular domains: 4-1BB and CD3ζ. (B) CAR-T cell preparation workflow. (CG) Transfection rate of CAR-T cells under different culture conditions. For all relevant groups, data are expressed as mean standard deviation, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ns: no significant difference.

[0429] CAR-T cells specifically targeting SRRM2 were designed and constructed to achieve targeted therapy for SRRM2 in AML. Figure 14 (A and 14B). The effects of CD3 and CD28 stimulation on SRRM2CAR-T cell survival and expansion during transduction were assessed using 100 ng / ml or 300 ng / ml. Figure 14 C). The effect of IL-2 concentration on transduction efficiency was investigated by culturing SRRM2 CAR-T cells with different concentrations (300 IU / ml or 600 IU / ml). Changing the IL-2 concentration had little effect on the transduction rate of SRRM2 CAR-T cells. Figure 14 C) indicates that under the experimental conditions of this invention, IL-2 concentration did not significantly affect transduction efficiency. The effects of different proliferation factors (IL-2 alone, or a combination of IL-7 and IL-15) on SRRM2 CAR-T cell transduction were compared. Compared with IL-2 alone, the combination of IL-7 and IL-15 significantly improved the transduction rate. Figure 14 C). Adding HSA during viral transduction significantly improved the transduction success rate; compared to the group without HSA, SRRM2 CAR expression was significantly increased. Figure 14 C). Based on these findings, repeat experiments were conducted to determine the optimal transduction conditions: CD3 and CD28 at 100 ng / ml, with IL-7 and IL-15 as proliferation factors, and 10 ng / ml of HSA added. Figure 14 D). Under these optimized conditions, subsequent experiments successfully achieved stable and high-proportion SRRM2 CAR-T cell production.

[0430] Figure 15The in vitro efficacy of SRRM2 CAR-T cells was demonstrated. (AD) In ​​vitro cytotoxicity of SRRM2 CAR against four AML cell lines was measured using an LDH-based cytotoxicity assay. Untransduced T cells (simulated T) were used as controls. Three effector-target (E:T) ratios were set (1:1, 2.5:1, and 5:1), with triplicate for each condition. (E) At an effector-target ratio of 1:1, CAR-T cells showed significantly higher killing efficacy against MOLM-13 cells than against the other three cell lines.

[0431] LDH release assays were performed to evaluate the cell lysis activity of CAR-T cells prepared by the inventors against different tumor cell types at different effector-to-target ratios, thereby examining the cytotoxicity of these CAR-T cells against SRRM2-positive AML cells. The results showed that with increasing effector-to-target ratio, the cell lysis capacity of SRRM2 CAR-T cells was significantly enhanced, significantly exceeding that of untransduced viral-simulated T cells (SSTCs). Figure 15 A-15D). At a 1:1 effector-to-target ratio, over 50% target cell death was observed, and the killing efficiency of SRRM2 CAR-T cells increased with increasing effector-to-target ratio. At a 1:1 balanced E:T ratio, four different cells with or without FLT3 were compared. mut A comparative analysis of cytotoxicity was performed on AML cell lines. The results showed that, compared with FLT3... WT Compared to other cells, SRRM2 CAR-T cells showed better performance against FLT3. mut The cells exhibit a significantly superior cell lysis effect. Figure 15 E).

[0432] Figure 16This study demonstrates the potent antitumor activity of SRRM2 CAR-T cells in vivo. (A) Schematic diagram of in vivo experiments using SRRM2 CAR-T cells in an NCG mouse AML model. An AML model was constructed using six-week-old immunodeficient NCG mice via injection of SKM-1 cells. (B) Wright-Giemsa staining in the AML mouse model. The images shown in the insets are magnified at ×10 and ×100. (C) Cardiac blood samples were collected for PCR analysis, and CAR gene expression was assessed using a CAR gene copy number assay kit. (D) Continuous monitoring of mouse body weight showed no difference between groups before administration of CAR-T or mimic-T cells. However, over time, the body weight difference between the two groups increased and became statistically significant after CAR-T injection. (E) Mice in the CAR-T group showed a statistically significant prolonged survival compared to the MOCK-T group (p=0.0044). Data are presented as mean standard deviation across all relevant groups. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ns: no significant difference.

[0433] The efficacy and safety of SRRM2 CAR-T in mice carrying AML tumors were evaluated in vivo. A xenograft mouse model was established in NSG mice using SKM-1 cells (not shown) expressing SRRM2. Figure 16 A). Successful modeling was confirmed by Wright-Giemsa staining 14 days after AML cell injection. Figure 16 A). Subsequent administration included a single injection of 1×10⁻⁶ cells on day 15 following AML cell injection. 7 One simulated T or CAR-T cell. CAR-T cell expansion was detected in PB. Figure 16 C). Mouse body weight was continuously monitored. No significant difference in body weight was observed between the two groups before administration of either the mimic-T or CAR-T cell therapy. However, over time, the body weight difference between the mimic-T and CAR-T groups increased after CAR-T cell injection. Figure 16 D). Notably, compared to the CAR-T group mice, tumor-bearing mice in the CAR-T group exhibited a significantly prolonged survival. Figure 16 D). Treatment of mice with SRRM2 CAR-T cells did not result in cytokine release syndrome or other common related adverse reactions, and led to a significant increase in leukemia blast clearance and survival rates. Figure 16 (B and 16E). These findings demonstrate the significant efficacy and safety of SRRM2 CAR-T therapy in vivo for AML.

[0434] Figure 17The images show staining of the surface of live cells with different SRRM2 antibodies. Commercial antibodies cannot bind to SRRM2 on the cell surface of live cells, while the SRRM2-specific antibody (EX-02) of this invention binds to SRRM2 on the cell surface of live cells. The binding of human A549 cells to the antibody shown in each corresponding histogram was analyzed by flow cytometry. The antibody application (black line) was compared with a suitable isotype control antibody (gray line), followed by incubation with a suitable Alexa-647-labeled secondary antibody. Only antibody EX-02 was able to bind to SRRM2 located on the cell surface of live human cells.

[0435] Figure 18 The results showed that the percentage of plasma cells (CD38+ + CD138+ CD19-CD56-CD45dim) in the peripheral blood of patient 3 decreased from 29.0% before SRRM2 CAR-T cell infusion (day 0) to 0.55% of the total peripheral plasma cell count on day 28 post-infusion. SRRM2 CAR-T cells were infused three times intravenously: 0.54 × 10⁻⁶ cells on days 0, 1, and 18. 7 2.34×10 7 1.06×10 7 Cells per kg of body weight.

[0436] Figure 19 The surface SRRM2 was shown to be expressed on plasma cells in newly diagnosed MM patients (A) and in plasma cells in patients previously diagnosed with plasma cell diseases (including relapsed and refractory MM, PCL, reactive plasmacytosis and other plasma cell diseases) during or after routine treatment (B).

[0437] Figure 20 The significant tumor-suppressive effect of SRRM2 CAR-T cells was demonstrated in an in vivo MM model. The efficacy and safety of SRRM2 CAR-T cells in mice carrying MM tumors were evaluated in vivo. A xenograft mouse model was established in NSG mice using KMS-11 cells (not shown) expressing surface SRRM2 (A). (B) A single dose of CAR-T cells (1.3 × 10⁻⁶) was administered. 6 Following intravenous injection of CAR-T cell therapy, the bioluminescent signal of Luc+ KMS-11 cells in NSG mice was longitudinally monitored. The results showed that CAR-T therapy significantly reduced tumor burden in the mouse model. Forty days after KMS-11-luc transplantation, in ID CAR-6 mice (symbol...) Tumor recurrence was found in (C) CAR-T therapy led to significant CD8+ T cell expansion and a higher CD8 / CD4 ratio in the blood samples of four mice, indicating a positive response to treatment. In mice, CAR-6 (symbol) (D) Bioluminescence imaging of NSG mice transplanted with KMS-11 tumors expressing luciferase showed that SRRM2 CAR-T cells inhibited tumor growth. Significant differences in tumor burden were discernible from day 24 post-CAR-T infusion. Four out of five mice in the CAR-T group were tumor-free by day 50, but CAR-6 mice relapsed, while the control group experiment was discontinued on day 34 due to high tumor burden.

[0438] Figure 21 This study demonstrates in vivo proliferation of CAR-T cells in the KMS-11 xenograft model and the absence of observed toxicity. CAR-T cell counts / mL blood (A) and CAR-T cell counts / spleen (B) were examined using samples from day 50, showing CAR-T cell proliferation in the CAR-T treatment group. The median counts in the mimic-T group and the CAR-T group were 100 vs. 3140 counts / mL in blood and 404 vs. 9476 counts / mL in spleen. (C) Monitoring of body weight changes in tumor-bearing mice in both the CAR-T and mimic-T groups revealed no significant difference between the two groups after administration of mimic-T and CAR-T cells. No treatment-related toxicity was observed in the animals.

[0439] References

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[0455] Zoller, MJ and Smith, M. (1983) Methods Enzymol. 100, 468-500.64.

Claims

1. An antibody that binds to human serine / arginine repeat matrix protein 2 (SRRM2) present on the cell surface of target cells, used in a method for treating blood cancers in human patients.

2. The antibody for the stated purpose according to claim 1, wherein the weight of the patient to be treated is 16 to 150 kg, preferably 18 to 140 kg, more preferably 20 to 130 kg, and even more preferably 22 to 120 kg.

3. The antibody for the purpose according to any one of the preceding claims, wherein the patient to be treated is at least 1 year old, preferably 2 years old, more preferably 2 to 80 years old.

4. The antibody for the purpose according to any one of the preceding claims, wherein the height of the patient to be treated is 70 to 220 cm, preferably 80 to 200 cm, more preferably 90 to 200 cm.

5. An antibody for the purpose according to any one of the preceding claims, wherein the antibody has cytotoxic activity, preferably antigen-dependent cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).

6. An antibody for the purpose according to any one of the preceding claims, wherein the antibody is part of a chimeric antigen receptor (CAR).

7. The antibody according to claim 6, wherein the CAR is expressed by T cells, NK cells, NK-T cells or macrophages.

8. An antibody for the purpose according to any one of the preceding claims, wherein the antibody is expressed by an autologous cell population.

9. An antibody for the purpose according to any one of the preceding claims, wherein the antibody is expressed by an allogeneic cell population.

10. An antibody for the purpose according to any one of the preceding claims, wherein the SRRM2 present on the cell surface of the target cell is externalized.

11. An antibody for the purpose according to any one of the preceding claims, wherein the antibody is not an intracellular antibody.

12. An antibody for the purpose according to any one of the preceding claims, wherein the blood cancer to be treated is characterized by cells expressing human SRRM2 on their cell surface.

13. The antibody for the purpose according to any one of claims 1 to 12, wherein the blood cancer to be treated is multiple myeloma.

14. The antibody for the purpose according to any one of claims 1 to 12, wherein the blood cancer to be treated is leukemia, including acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), mast cell leukemia (MCL), or plasma cell leukemia (PCL).

15. The antibody for the purpose according to any one of claims 1 to 12, wherein the blood cancer to be treated is acute myeloid leukemia (AML).

16. The antibody for the said use according to claim 15, wherein the AML is further characterized by having a genetically mutated cell, preferably an FMS-like tyrosine kinase-3 (FLT3) mutation.

17. The antibody for the purpose according to any one of claims 1 to 12, wherein the blood cancer to be treated is plasma cell leukemia (PCL).

18. The antibody for the stated purpose according to claim 17, wherein the PCL is primary or secondary PCL.

19. The antibody for the purpose according to any one of claims 1 to 12, wherein the hematologic malignancy to be treated is a lymphoma, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), post-transplant lymphoproliferative disorder (PTLD), or Waldenström macroglobulinemia (WM).

20. The antibody for the purpose according to any one of claims 1 to 12, wherein the hematologic cancer to be treated is myelodysplastic syndrome, myeloproliferative neoplasm (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

21. An antibody for the purpose according to any one of the preceding claims, wherein the patient to be treated is refractory to previous cancer therapies and / or has relapsed after previous cancer therapies.

22. The antibody for the stated purpose according to any one of the preceding claims, wherein the antibody is administered via a parenteral route, including but not limited to intravenous, intradermal, intramuscular, intrathecal, or intraperitoneal administration.

23. An antibody for the purpose according to any one of the preceding claims, wherein the antibody is conjugated with a cytotoxic substance.

24. An antibody for the purpose according to any one of the preceding claims, wherein the antibody binds to non-permeable cells.

25. An antibody for the purpose according to any one of the preceding claims, wherein the antibody binds to a living cell.

26. An antibody for the said use according to any one of the preceding claims, wherein the antibody comprises an antibody that, (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 9, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 10, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 11, and The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:

14. (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 15, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 16, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 17, and The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:

20. (c) Heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and A light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 24, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 25, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 26; or (d) Heavy chain variable region, said heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and 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.

27. An antibody for the said use according to any one of the preceding claims, wherein said antibody comprises an antibody that, (a) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:

2. (b) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:

4. (c) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 6, or (d) A heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:

7.

28. An antibody for the purpose according to any one of the preceding claims, wherein the antibody is contained in a composition containing a buffer solution.

29. The antibody for the said use according to claim 28, wherein the antibody is contained in a composition comprising a buffer solution and sodium chloride.

30. A method for determining whether a patient may have a blood cancer, the method comprising determining, in a sample obtained from the patient, whether SRRM2 is present on the cell surface of cells contained in the sample and / or on the surface of extracellular vesicles.

31. The method of claim 30, wherein an increase in the amount of SRRM2 present on the cell surface of the cells and / or on the surface of extracellular vesicles of the samples contained in the sample, compared to the amount of SRRM2 present on the cell surface of the cells and / or on the surface of extracellular vesicles of the samples obtained from healthy subjects, indicates that the patient may have blood cancer.

32. The method of claim 30, wherein if there is no difference in the amount of SRRM2 on the cell surface and / or on the surface of extracellular vesicles of cells contained in a sample obtained from the patient compared with the amount of SRRM2 on the cell surface and / or on the surface of extracellular vesicles in a sample obtained from a healthy subject, it indicates that the patient may not have blood cancer.

33. The method according to any one of claims 30 to 32, wherein the antibody comprises an antibody that, (a) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 9, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 10, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 11, and The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:

14. (b) A heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 15, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 16, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 17, and The light chain variable region comprises a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 18, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO:

20. (c) Heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and A light chain variable region comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 24, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 25, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 26; or (d) Heavy chain variable region, said heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 21, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 22, and heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 23, and 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.

34. The method according to any one of claims 30 to 33, wherein the antibody comprises an antibody that, (a) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:

2. (b) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:

4. (c) A heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 5, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 6, or (d) A heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 5, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:

7.

35. The method according to any one of claims 30 to 34, wherein the cell is a non-permeable cell.

36. The method according to any one of claims 30 to 35, wherein the cell is a living cell.

37. The method according to any one of claims 30 to 36, wherein the hematologic cancer is multiple myeloma.

38. The method according to any one of claims 30 to 36, wherein the hematologic cancer is leukemia, including acute erythroid leukemia, acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), childhood leukemia, hairy cell leukemia (HCL), large granular lymphoblastic leukemia (LGLL), mast cell leukemia (MCL), or plasma cell leukemia (PCL).

39. The method according to any one of claims 30 to 36, wherein the blood cancer is acute myeloid leukemia (AML).

40. The method according to any one of claims 30 to 36, wherein the blood cancer is plasma cell leukemia (PCL).

41. The antibody for the said use according to claim 40, wherein the PCL is primary or secondary PCL.

42. The method according to any one of claims 30 to 36, wherein the hematologic malignancy is a lymphoma, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, MALT lymphoma, mantle cell lymphoma, small lymphocytic lymphoma (SLL), post-transplant lymphoproliferative disorder (PTLD), or Waldenström macroglobulinemia (WM).

43. The method according to any one of claims 30 to 36, wherein the hematologic cancer is myelodysplastic syndrome, myeloproliferative neoplasm (including polycythemia vera, essential thrombocythemia, or myelofibrosis), Erdheim-Chester disease, Langerhans cell histiocytosis, mast cell polycythemia, or mast cell leukemia.

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