Integrin α10 and aggressive form of cancer

Abstract

To provide a medicine to be used for treating a tumor, a method for detecting a cell of a tumor, a method for diagnosing a tumor, a method for categorizing a specimen of a triple-negative breast cancer tumor, a method for determining prognosis of a tumor having metastasis tendency or the like.SOLUTION: Provided is a medicine to be used for treating a tumor selected from triple-negative breast cancer and inflammatory breast cancer, squamous cell lung carcinoma, pulmonary adenocarcinoma, large cell lung carcinoma and small cell lung carcinoma, small cell neuroendocrine carcinoma (SCNC) of prostate gland, pancreatic carcinoma, or metastatic cancer formed of any one of these cancers, wherein the medicine contains antibody or an antigen-binding fragment thereof, and the antibody or the antigen-binding fragment thereof specifically binds to an integrin α10 polypeptide.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for treating aggressive cancers, including aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer, and metastatic cancer, comprising an antibody or a fragment thereof that specifically binds to an integrin alpha 10 polypeptide. The present invention also relates to methods for diagnosing and treating said aggressive cancer types. The present invention also relates to methods for predicting the survival rate of individuals affected by said aggressive cancer types. [Background technology]

[0002] Cancer is a complex disease that progresses within a dynamically evolving extracellular matrix (ECM), where tumors and tumor-associated cells are regulated in nearly every way. Integrins are the primary cell adhesion receptors for ECM components and are a family of 24 transmembrane heterodimers formed by combinations of 18 α integrin subunits and 8 β integrin subunits. Different types of tissues typically express specific combinations of integrins on their cell surfaces. Different integrin expression patterns are associated with various types of cancer (Moschos et al., 2007). Alterations in integrin signaling are involved in nearly all processes of carcinogenesis, from utilization-dependent switching of integrin αβ heterodimers to aberrant integrin expression and constitutive activation of downstream effectors of integrin signaling and interactions with other signaling pathways.

[0003] Aggressive cancer types are tumors that grow rapidly and / or metastasize rapidly to distant sites and other tissues, and therefore may also be invasive tumors. Furthermore, aggressive cancer types usually have a poor prognosis for life.

[0004] According to the classification of the most common breast cancer subtypes based on histological classification, the most common histological subtype is invasive ductal carcinoma, accounting for 80% of invasive breast cancers, followed by invasive lobular carcinoma, accounting for approximately 10% of invasive breast cancers (Xiaofeng et al., 2015). The expression (or lack of expression) of specific protein markers is associated with breast cancer malignancy, particularly hormone receptor status [estrogen receptor (ER) and progesterone receptor (PR) expression] and human epidermal growth factor receptor 2 (HER2) (Arpino et al., 2015; Hariri et al., 2019). Triple-negative breast cancer (TNBC, ER- / PR- / HER2-) is more likely to exhibit aggressive behavior and therefore often has a poorer prognosis compared to other breast cancer subtypes (Rakha et al., 2007; M (Bianchini et al., 2012). Once TNBC metastasizes, it is likely to reach major visceral organs such as the lungs, liver, and brain, ultimately resulting in a significantly shorter median overall survival compared to other subtypes (Bianchini et al., 2016). TNBC has been classified into six subtypes: basal cell-like (BL1 and BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem cell-like (MSL), and luminal androgen receptor (LAR) subtypes (Ma et al., 2018). Therefore, early detection is crucial. Developing optimal therapeutic strategies for treating stage TNBC is crucial to reducing the burden of TNBC. There is overlap between histological and molecular classifications. For example, invasive ductal carcinomas can have distinct molecular expression profiles and can be triple-negative, HER2-positive, luminal A, or luminal B. Triple-negative basal-like tumors are further characterized by the following: a greater than 50% frequency of mutated TP53, a highly proliferative nature due to RB1 loss, BRCA-1 mutations, high aneuploidy, and distinctive expression of one of cytokeratins 5, 6, or 17. In addition to TNBC, other aggressive breast cancer types also exist. Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer. IBC tends to grow and spread rapidly, and its symptoms worsen within days or even hours. Therefore, developing novel targeted therapies for aggressive breast cancer types is necessary and paramount to improving survival outcomes.

[0005] Prostate cancer is the second most common cancer in men and the fourth most common cancer worldwide. Patients diagnosed with localized or regional cancer have a 5-year survival rate of nearly 100%. However, patients diagnosed with distant metastatic cancer have a 5-year survival rate of only 28%. Healthy prostate epithelium contains luminal epithelial cells, basal cells, and neuroendocrine (NE) cells, small structural cells scattered throughout the prostate. Most prostate cancers are classified as adenocarcinomas, characterized by the absence of basal cells and the uncontrolled proliferation of malignant tumor cells with hallmarks of luminal differentiation (including gland formation and expression of androgen receptor (AR) and prostate-specific antigen (PSA)). Interestingly, every case of prostate adenocarcinoma contains a small population (usually ~1%) of NE tumor cells. NE cells in adenocarcinomas share many important characteristics with those of benign prostates. For example, in contrast to non-NE luminal tumor cells, NE cells in benign prostates and adenocarcinomas do not express AR and PSA (Einstein et al., 2019). A minority of prostate epithelial malignancies are atypical, including ductal adenocarcinoma, mucinous (colloid) carcinoma, signet ring cell carcinoma, and small cell (neuroendocrine) carcinoma (SCNC). Similar to NE cells in benign prostate and prostate adenocarcinoma, SCNC tumor cells do not express AR and PSA; this explains the clinical observation that, unlike adenocarcinoma, these tumors do not respond to hormonal therapies that inhibit AR function by shutting down androgen production. In contrast to most prostate tumors, SCNC are highly aggressive, typically presenting with locally advanced disease or distant metastases, and patients typically die within months of diagnosis (Saad et al., 2019).

[0006] Lung cancer is the leading cause of cancer death worldwide, both in men and women (GLOBOCAN, 2018). The 5-year survival rate for patients with localized tumors in the lung is 56%. However, because most patients are diagnosed at a later stage, the 5-year survival rate for patients with distant tumors is only 5% (SEER Cancer Statistics Review, 2015). Histologically, lung cancer is classified into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The majority of these tumors are classified as NSCLC, accounting for approximately 85% of cases, while the remaining 15% are classified as SCLC. NSCLC comprises a heterogeneous group of tumors and is further subdivided into three major histological subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma and squamous cell carcinoma are the major subtypes of NSCLC. Compared to SCLC, NSCLC is relatively insensitive to chemotherapy and radiation therapy. In recent years, more specific therapies targeting molecular subtypes have shown promising results. However, only a small proportion of patients identified by biomarkers showed a correlation with treatment response (Bombardelli et al., 2016). Therefore, novel biomarkers for early detection of NSCLC and SCLC, as well as novel therapeutic targets, are needed to distinguish them from other lung tumors.

[0007] Pancreatic cancer can be divided into two major groups: exocrine tumors and neuroendocrine tumors. Exocrine tumors account for 94% of all pancreatic cancers and arise from exocrine cells that produce digestive enzymes. This group includes ductal adenocarcinoma (the most common type of pancreatic cancer, accounting for 90% of all cases), acinar cell carcinoma, and intraductal papillary mucinous neoplasm. Neuroendocrine tumors, also known as islet cell tumors, account for 6% of pancreatic cancers. Pancreatic cancer generally develops relatively asymptomatically and is usually advanced at the time of diagnosis. Due to late diagnosis and poor response to chemotherapy and radiation therapy, the 5-year survival rate for pancreatic cancer patients is less than 5% (Milena et al., 2016). Therefore, there is a great need to develop novel methods to diagnose and treat this aggressive disease.

[0008] Sarcomas are a diverse family of cancers that arise from cells of mesenchymal origin and can differentiate into multiple tissue lineages (adipose, muscle, fibrous, cartilaginous, and bony). Sarcomas account for 1% of all cancer diagnoses and cancer-related deaths. Their prevalence is high in children and adolescents, accounting for 19%–21% of cancer-related deaths in these populations. High histological and molecular heterogeneity makes this group of malignancies particularly challenging to diagnose. Compared to carcinomas, these tumors are very rare and typically grow locally, with infiltration of adjacent tissues. While localized, early-stage tumors have favorable long-term survival rates after surgical removal, these tumors carry a high risk of recurrence even 10 to 15 years later. Current treatment strategies for soft tissue sarcomas include surgery, radiation, and chemotherapy, but are limited by toxicity and poor response rates. Currently, the 5-year survival rate is 60%, reflecting age, tumor type, stage, and histological grade, although survival is significantly reduced to 10%-17% in high-risk patients with metastatic tumors. Sarcoma carcinoma subtype classification is explained in the WHO classification of tumors of soft tissue and bone (WHO classification of tumors of soft tissue and bone, 2013).

[0009] Therefore, there is a need for new tools that allow for the early diagnosis of aggressive tumors such as those mentioned hereinabove, as well as new therapeutic targets and methods of treatment, which could improve prognosis and survival rates. Summary of the Invention

[0010] The inventors have unexpectedly found that the most aggressive cancer types are characterized by high expression of integrin alpha 10 on the cell surface. This has led to the inventors finding that it is possible to rapidly detect the presence of aggressive cancer types in an individual based on the expression level of integrin alpha 10 on cells of tissues suspected of being affected by cancer. This allows for earlier and more specific diagnosis than is possible using current diagnostic tools, thereby enabling earlier intervention and improved prognosis for the individual being tested.

[0011] Furthermore, the present inventors have identified integrin alpha 10 as a novel therapeutic target for aggressive cancers and their metastatic forms. Specifically, the present inventors have demonstrated that the proliferation and migration of tumor cells belonging to aggressive cancers can be inhibited by contacting the cells with an antibody or fragment thereof that specifically binds to the integrin alpha 10 polypeptide. Cell death can also be induced by contacting tumor cells with a suitable antibody-drug conjugate containing an antibody or fragment thereof that specifically binds to the integrin alpha 10 polypeptide. Furthermore, the present inventors have demonstrated that tumor growth can be reduced by administering an antibody or fragment thereof that specifically binds to the integrin alpha 10 polypeptide and contacting the tumor cells with the antibody or fragment thereof.

[0012] Thus, one aspect of the present disclosure relates to an antibody or antigen-binding fragment thereof for use in the treatment and / or prevention of an aggressive cancer type selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or metastasis of any of said cancer types, wherein the antibody or antigen-binding fragment thereof specifically binds to an integrin alpha10 polypeptide.

[0013] Another aspect of the present disclosure relates to an antibody or antigen-binding fragment thereof for use in diagnosing an aggressive cancer selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of said aggressive cancer types, wherein the antibody or antigen-binding fragment thereof specifically binds to an integrin alpha 10 polypeptide.

[0014] A further aspect of the present disclosure relates to a method for treating aggressive cancer, comprising administering to a subject in need thereof a pharmaceutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an integrin alphal0 polypeptide, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or the aggressive cancer type is metastatic cancer.

[0015] Yet a further aspect of the present disclosure relates to a method for detecting aggressive cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the tissue; (c) determining the expression level of integrin alpha 10 antigen; and (d) comparing the expression level determined in step (c) with a control level; Including, wherein the control level is the average expression level of the antigen observed in healthy and / or benign cells of the same tissue type as the sample from which it was isolated, and an antigen expression level higher than the control level is indicative of the presence of an aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types.

[0016] A further aspect of the present disclosure relates to a method of detecting aggressive cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) optionally analyzing the presence or absence of one or more cells having a cancerous morphology in the tissue; (c) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the tissue; (d) optionally determining the expression level of integrin alpha 10 antigen; Including, Here, the combination of the presence of one or more cells having a cancerous morphology and expression of the integrin alpha 10 antigen is indicative of the presence of an aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types.

[0017] Another aspect of the present disclosure relates to a method of diagnosing an aggressive cancer type in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the tissue; (c) determining the expression level of integrin alpha 10 antigen; and (d) comparing the expression level determined in step (c) to a control level, wherein the control level is an average of the antigen expression levels; Including, wherein an antigen expression level greater than the control level is indicative of the presence of an aggressive cancer type in the sample, thereby diagnosing the aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types, or is a metastatic cancer of any of the aggressive cancer types.

[0018] A further aspect of the present disclosure relates to a method of diagnosing an aggressive cancer type in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) optionally analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the sample; (d) optionally determining the expression level of integrin alpha 10 antigen; Including, Here, the combination of the presence of one or more cells having a cancerous morphology and expressing the integrin alpha 10 antigen is indicative of the presence of an aggressive cancer type in the sample, thereby diagnosing the aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types.

[0019] A further aspect of the present disclosure relates to a method of classifying a triple-negative breast cancer tumor sample from a subject, the method comprising: (a) providing breast tissue of a subject suspected of containing cancer cells; (b) isolating breast cancer cells characterized as ER-negative, PR-negative and HER2-negative; (c) determining the expression level of an antigen comprising an integrin alphal0 polypeptide or a fragment thereof in the isolated cells; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average antigen expression level observed in healthy and / or benign breast tissue; Including, Here, a breast cancer cell antigen expression level higher than the control level and an expression status that is ER-negative, PR-negative, and HER2-negative are indicative of basal-like triple-negative breast cancer or luminal triple-negative breast cancer, thereby classifying the triple-negative breast cancer tumor sample as belonging to basal-like triple-negative breast cancer tumor or luminal triple-negative breast cancer tumor.

[0020] In one embodiment, the luminal triple-negative breast cancer is luminal androgen receptor triple-negative breast cancer.

[0021] A further aspect of the present disclosure relates to a method of determining a prognosis of an aggressive cancer type in a subject, the method comprising: (a) providing cancer tumor tissue from a subject; (b) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the sample; (c) determining the expression level of integrin alpha 10 antigen; (d) comparing the expression level determined in step (c) to a control level, wherein the control level is the average antigen expression level observed in healthy and / or benign tissue of the same tissue type as the sample; (e) determining that the prognosis of the aggressive cancer type is poor when the expression level of the integrin alpha 10 antigen is higher than the control level; Including, wherein said aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastasis of any of said aggressive cancer types.

[0022] Another aspect of the present disclosure relates to a method of determining a prognosis of an aggressive cancer type in a subject, the method comprising: (a) providing cancer tumor tissue from a subject; (b) optionally analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the sample; (d) optionally determining the expression level of integrin alphal0 antigen and comparing the determined expression level with a control level, wherein the control level is the average antigen expression level observed in healthy and / or benign tissue of the same tissue type as the sample; (e) one or more cells having a cancerous morphology are present in the tissue and express the integrin alpha 10 antigen; and / or determining that the prognosis of the aggressive cancer type is poor when the expression level of the integrin alpha 10 antigen is higher than the control level; Including, wherein said aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastasis of any of said aggressive cancer types.

[0023] A further aspect of the present disclosure relates to a method for preventing metastasis of an aggressive primary cancer selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, and aggressive pancreatic cancer, the method comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof to a patient in need thereof, wherein the antibody is an antibody specific for an integrin alpha 10 polypeptide.

[0024] A further aspect of the present disclosure relates to a method for inhibiting integrin alpha 10-mediated signaling in at least one cancer cell, the method comprising contacting at least one cancer cell with an effective amount of an antibody or antigen-binding fragment thereof specific to an integrin alpha 10 polypeptide, wherein the at least one cancer cell is selected from the group consisting of aggressive breast cancer cells, aggressive lung cancer cells, aggressive prostate cancer cells, aggressive pancreatic cancer cells, and metastatic tumor cells.

[0025] Yet a further aspect of the present disclosure relates to a method for inhibiting a cellular function of at least one cancer cell, the method comprising contacting at least one cancer cell with an effective amount of an antibody or antigen-binding fragment specific to an integrin alpha 10 polypeptide, wherein the at least one cancer cell is selected from the group consisting of aggressive breast cancer cells, aggressive lung cancer cells, aggressive prostate cancer cells, aggressive pancreatic cancer cells, and metastatic tumor cells.

[0026] Yet a further aspect of the present disclosure relates to the use of an antibody or antigen-binding fragment thereof, wherein the antibody is specific for an integrin alpha 10 polypeptide, for use in the manufacture of a medicament for the treatment and / or prevention of an aggressive cancer selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or metastatic cancer of any of said cancer types. [Brief explanation of the drawings]

[0027] [Figure 1] Integrin α10 is expressed in invasive ductal carcinoma (IDC) cells in breast cancer tissue. Immunohistochemical analysis using an antibody against integrin α10 shows that integrin α10 is highly expressed specifically in IDC cells (arrows) in breast cancer tissue, but is expressed in only a few cells in the stroma (asterisk) (A). Integrin α10 expression was weak in morphologically normal benign breast tissue (B). [Figure 2]Integrin α10 is expressed in triple-negative breast cancer tumor tissue. Immunohistochemical analysis using an antibody against integrin α10 shows that integrin α10 is highly expressed specifically in triple-negative breast cancer cells (arrows). [Figure 3] Integrin α10 is expressed in cells of undifferentiated pleomorphic sarcoma tissue. Immunohistochemical analysis using an antibody against integrin α10 shows that integrin α10 is specifically expressed in undifferentiated pleomorphic sarcoma cells (arrows). [Figure 4] Integrin α10 is expressed in aggressive cancer cell lines. Immunofluorescence staining of integrin α10 in T47D and BT549 cells (aggressive breast cancer, monolayer culture) and PC-3 cells (aggressive prostate cancer, sphere culture). Confocal images of T47D cells (A), BT549 cells (B), and PC-3 cells (C) show that integrin α10 is stained on the cell membrane. [Figure 5]Integrin α10 is expressed in aggressive cancer cell lines in monolayer culture, particularly in sphere culture. A-D: Analysis of integrin α10 expression in breast cancer cell monolayers (A and B) and in sphere-like structures (mammospheres) (C and D). (A) As determined by flow cytometry scatter plots, the aggressive breast cancer cell lines BT549 and T47D have a higher number of integrin α10-positive cells compared to the less aggressive cancer cell lines 184A1, HCC1428, and MDA-MB-231 (which show a lower number of integrin α10-positive cells). (B) Summary of the percentage of integrin α10-positive cells in each cell line from five independent experiments (n=5). (C) Flow cytometry scatter plots show that triple-negative cell lines MDA-MB-231 and BT549 grown as mammospheres exhibit highly enhanced integrin α10 expression compared to monolayer culture, whereas 184A1, HCC1428, and T47D cells exhibited little or no increase in integrin α10 expression compared to monolayer culture. (D) Summary of the percentage of integrin α10-positive cells in each cell line from five independent experiments (n=5). E-H: Analysis of integrin α10 expression in monolayer prostate cancer cells (E and F) and in sphere-like structures (prostaspheres) (G and H). Integrin α10 expression was highest in the most aggressive prostate cancer cell line, PC-3. Integrin α10 expression was significantly increased in PC-3 cells under sphere culture conditions, but not in the less aggressive cell lines 22Rv1 or DU145. Representative flow cytometry scatter plots show the percentage of integrin α10-positive cells in each cell line cultured in monolayer (E) and sphere (G) configurations. Summary of the percentage of integrin α10-positive cells across all prostate cancer cell lines cultured in monolayer (F) and sphere (H) configurations, averaged across separate culture experiments. Data are presented as mean ± standard deviation (n≥3). I–J: Analysis of integrin α10 expression in pancreatic cells in monolayer (I) and sphere-like structures (J).In the most highly invasive cell line, MiaPaCa-2 cells (grade III), sphere culture conditions significantly increased the expression level of integrin α10 protein, but not the less invasive cell lines, BxPC-3 and AsPC-1 (grade II). K-L: Analysis of integrin α10 expression in lung cancer cells grown as monolayers (K) and sphere-like structures (L). Compared to monolayer culture conditions (L), aggressive lung cancer cell lines grown as spheres (K) showed significantly increased expression of integrin α10 protein. M: Analysis of integrin α10 expression in sarcoma cells grown as monolayers and sphere-like structures (M). In undifferentiated pleomorphic sarcoma cancer cells, sphere culture conditions significantly increased integrin α10 expression. [Figure 6] Integrin α10 (ITGA10) is expressed in aggressive cancer cell lines in monolayer and, particularly, three-dimensional (3D) culture (spheres) (mRNA analysis). A-B: Increased expression of integrin α10 in breast cancer cells cultured as mammospheres. ITGA10 expression was highest in the most aggressive cancer cell lines, e.g., triple-negative breast cancers (BT549, MDA-MB-231), especially when the cancer cells were cultured as spheres, and lowest in the least aggressive cancer cell line, T47D. C-D: Increased expression of integrin α10 in prostate cancer cells cultured as prostaspheres. ITGA10 expression was highest in the most aggressive cancer cell line, PC-3, especially when the cancer cells were cultured as spheres, and lowest in the least aggressive cancer cell line, 22RV1. E-F: Increased expression of integrin α10 in invasive grade III pancreatic cancer cell lines. Sphere culture conditions significantly increased integrin α10 mRNA levels in the most highly invasive cell lines, MiaPaCa-2 and PANC-1 (grade III), but not in the less invasive cell lines, BxPC-3 and AsPC-1 (grade II). Data are presented as mean ± standard deviation (n ≥ 3). [Figure 7]High expression of ITGA10 is associated with poor overall survival in patients with different aggressive cancer indications. Figure 1. ITGA10 gene expression and overall survival curves in patients with different aggressive cancers. To perform survival analysis and log-rank tests, patients were divided into high ITGA10 expression groups (solid line) and low ITGA10 expression groups (dotted line) based on the median cutoff. P values ​​are for the log-rank test of differences in overall survival. For all cancer types listed, patients with high ITGA10 expression had poorer survival than patients with low ITGA10 expression. [Figure 8] Integrin α10 monoclonal antibody blocks aggressive cancer cell adhesion to collagen. A–D: Triple-negative breast cancer cells. BT549 cells were cultured as monolayers (A and B) and mammospheres (C and D). Cells were preincubated with anti-integrin α10 blocking monoclonal antibody mAb α10 (5 μg / ml) or isotype control antibody IgG2a (5 μg / ml) for 30 minutes. Cells were then allowed to adhere in the presence or absence of antibody to culture dishes coated with type I collagen (A and C), type IV collagen (B and D), or bovine serum albumin (BSA) as a control. Data are the mean of triplicate measurements, and error bars at each data point represent the standard deviation. Cell adhesion is expressed relative to the adhesion of untreated cells (NT), which is defined as 100%. E–F: Aggressive prostate cancer cells. PC-3 cells were preincubated with the function-blocking anti-integrin α10 monoclonal antibody mAbα10 (5 μg / ml) for 30 minutes. Untreated cells served as the control. Cells were then subjected to adhesion assays, adhering to type I collagen (E) and type IV collagen (F) in the presence or absence of the antibody. Data are the average of triplicate measurements, and error bars represent the standard deviation. Cell adhesion is expressed relative to the adhesion of untreated cells (NT), which is set at 100%. [Figure 9]Blocking integrin α10 with monoclonal antibodies reduces migration. A: Breast cancer cells: BT549 breast cancer cells were preincubated with 5 μg / ml of anti-integrin α10 blocking monoclonal antibody mAb α10 (mouse) or Th101 (human) or 5 μg / ml of control antibody IgG2a (mouse) or Th301 (human) for 30 minutes. Cell migration was then assayed using a transwell assay consisting of a chamber coated with type IV collagen. Cell migration is expressed relative to control cell migration (NT = untreated), which is defined as 100%. B: Prostate cancer cells: Blocking integrin α10 reduces prostate cancer cell migration. This figure shows the effect of anti-integrin α10 antibody mAb α10 on PC-3 cell migration in a transwell assay. PC3 cells were seeded into transwell chambers in a 24-well plate coated with type I collagen and incubated with the anti-integrin monoclonal antibody mAb α10 (5 μg / ml). Cell migration (assayed for 24 or 48 hours) is expressed relative to the migration of cells incubated with the isotope control antibody IgG2a, which is set as 100%. C: Lung cancer cells: Lung cancer cells were seeded into transwell chambers attached to a 24-well plate and incubated with the anti-integrin monoclonal antibody mAb α10. Cell migration is expressed relative to the migration of cells incubated with the isotope control antibody IgG2a, which is set as 100%. [Figure 10] Integrin α10 antibody conjugated with the drug MMAE (anti-α10-MMAE) reduces breast cancer cell viability. BT549 cells were incubated with increasing concentrations of the ADC (anti-α10-MMAE) or a negative control (control antibody-MMAE) for 4 days. Cell viability was determined by a WST-1 colorimetric assay. Percent cell viability was calculated relative to the negative control, control antibody-MMAE, which was set at 100%. The results show that anti-α10-MMAE reduces BT549 cell viability. [Figure 11]Integrin α10 antibody reduces cell proliferation in sphere-shaped breast, prostate, pancreatic, and lung cancer cells. (A) Breast cancer cells (BT549), (B) prostate cancer cells (PC-3), and (C and D) pancreatic cancer cells (MiaPaCa-2 and PANC-1) were treated with 5 μg / ml of integrin α10 antibody mAb α10 or control antibody (IgG2a) simultaneously with cell seeding in sphere culture conditions. Additional antibody treatments were added every two days for 14 days. The spheres were then incubated with BrdU for 24 hours and analyzed by flow cytometry to determine proliferation. Data are presented as mean fluorescence intensity. (E) Similarly, breast cancer cells were incubated with anti-integrin α10 monoclonal antibody mAb α10 or Th101, or a negative control antibody (Th301, IgG2a). Proliferation, as determined by BrdU incorporation, is expressed relative to cells incubated in the absence of antibody (NT = untreated), which is set at 100%. (F) In lung cancer, treatment with integrin alpha 10 antibody (mAb alpha 10) inhibits cell proliferation compared to treatment with a control antibody (IgG2a), by arresting the cell cycle at G0 / G1. Lung cancer cells (A549) were seeded as spheres and treated with 5 μg / ml of integrin alpha 10 antibody (mAb 10) or a control antibody (IgG2a). The antibody was added every two days for 14 days. Cells were stained with BrdU and 7-AAD, and the cell cycle was analyzed by flow cytometry. Data are expressed as a percentage of the total cell population. [Figure 12]Treatment with integrin α10 antibodies inhibits breast cancer tumor growth. Total flux readings (equivalent to tumor size) were reduced in mice treated with the integrin α10 antibodies mAb α10 or Th101 compared with mice treated with negative control antibodies (IgG2a and Th301). (A) Box plots showing the progression of tumor growth based on total flux readings (=tumor size) after nine antibody treatments (9X) in different experimental groups (isotype control antibody IgG2a vs. mAb α10, and negative control antibody Th301 vs. Th101). Aggressive breast cancer BT549 cells were infected with luciferase- and GFP-expressing lentivirus (BT549 Luc / GFP). Mice were injected with 2x106 BT549 Luc / GFP cells into the right flank. Tumor growth was measured weekly by bioluminescence imaging using an IVIS-CT Spectrum. The photon flux (photons / s) and their averages for each mouse are shown over a 9-week (9X) period after tumor cell injection. Data are shown as the mean ± standard error of the total photon flux (photons per second). (B) Mouse weights were recorded weekly throughout the experiment. No pathological signs or reduced growth rates were observed before treatment. [Figure 13]The monoclonal antibodies mAb α10 and Th101 bind to different epitopes on integrin α10. A binding competition assay between the antibodies mAb α10 and Th101 was performed using the integrin α10-overexpressing C2C12 cell line, C2C12α10 (A), and the triple-negative breast cancer cell line, BT549 (B), followed by flow cytometry analysis. Cells were incubated with the indicated concentrations (μg / ml) of antibody for 30 minutes, followed by an additional 30 minutes of incubation with the secondary antibody. Data are expressed as mean fluorescence intensity (MFI) per 100,000 cells. Gray bars: fluorescence intensity of donkey anti-human Alexa 488, which determines the binding intensity of antibody TH101 (human anti-integrin α10); black bars: fluorescence intensity of donkey anti-mouse Alexa 647, which determines the binding intensity of antibody mAb α10 (mouse anti-integrin α10). Left part of the figure: The signal representing the antibody mAbα10 (at a constant concentration of 3 μg / ml) remained unchanged (black bars) even when the concentration of antibody Th101 added to the reaction wells increased (0–9 μg / ml) (gray bars). Right part of the figure: The signal representing the antibody Th101 (at a constant concentration of 3 μg / ml) remained unchanged (gray bars) even when the concentration of antibody mAbα10 added to the reaction wells increased (0–9 μg / ml) (black bars).

[0028] definition As used herein, "integrin alpha10" or "integrin alpha10 subunit" or "integrin alpha10 polypeptide" refers to the alpha10 subunit of the heterodimeric protein integrin alpha10beta1. This designation does not exclude the presence of a beta1 subunit that binds to the alpha10 subunit to form the integrin alpha10beta1 heterodimer. "Alpha" and "alpha," as well as "alpha10" and "alpha10," are synonyms.

[0029] As used herein, "integrin alpha 10" may refer to the alpha 10 subunit of the heterodimeric protein integrin alpha 10 beta 1, as well as transcript polynucleotides encoding the alpha 10 subunit of the heterodimeric protein integrin alpha 10 beta 1, and fragments thereof.

[0030] As used herein, "anti-integrin alpha10 antibody" or "integrin alpha10 antibody" or "anti-integrin alpha10 subunit antibody" refers to an antibody capable of recognizing and binding to at least the alpha10 integrin of the heterodimeric protein integrin alpha10beta1. These antibodies may be antibodies that recognize an epitope of the heterodimeric protein integrin alpha10beta1, where the epitope includes amino acid residues of both the alpha10 and beta1 integrin polypeptides. With respect to monoclonal antibodies, "mAba10" and "mAbalpha10" are synonyms.

[0031] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise. Thus, for example, reference to "an antibody" includes a plurality of such antibodies.

[0032] As used herein, "subject" refers to mammals such as rodents, cats, dogs, horses, and primates. Preferably, the subject of the present invention is a human.

[0033] As used herein, the term "sample" includes any subject and various sample types obtained from a subject. Examples of samples useful in the methods of the present disclosure include, but are not limited to, a subject, a liquid tissue sample (such as blood), or a solid tissue sample (such as a biopsy or tissue culture or cells derived therefrom and their progeny). For example, a biological sample includes cells obtained from a tissue sample taken from a subject. Thus, samples include clinical samples, cultured cells, cell supernatants, cell lysates, and tissue samples (e.g., tissue samples from breast tissue, lung tissue, prostate tissue, pancreatic tissue, ovarian tissue, bone tissue, cartilage tissue, adipose tissue, muscle tissue, and connective tissue).

[0034] As used herein, "aggressive cancer type" refers to a tumor that grows rapidly and / or migrates rapidly to distant sites and other tissues. Aggressive cancer types may be invasive tumors and / or tumors that are prone to metastasis and / or high-grade tumors and / or highly proliferative tumors. Aggressive cancer types usually have a poor prognosis for life. Examples of aggressive cancer types include triple-negative breast cancer, inflammatory breast cancer, squamous cell lung cancer, lung adenocarcinoma, small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, and sarcoma. Different types of cancer may be more aggressive than others.

[0035] As used herein, "cancer" refers to a tumor that results from malignant and / or invasive growth or abnormal cell proliferation. As used herein, "cancer" refers to a tumor named based on the type of cells that form the tumor. A cancer or tumor is composed of neoplastic cells or cancer cells. Portions of a cancer or tumor may be stromal cells, e.g., connective tissue cells such as fibroblasts. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. The term "cancer" includes, but is not limited to, primary cancers that begin in a particular part of the body, metastatic cancers that spread from the initial site to other parts of the body, recurrence of the original primary cancer after remission, and second primary cancers, which are new primary cancers of a different type from the previous cancer in people with a history of previous cancer.

[0036] As used herein, "detection," "detect" and "detecting" include qualitative and / or quantitative detection (measuring a value) with or without reference to a control, and further mean identifying the presence, absence or amount of a particular target, specifically a target of integrin alpha 10 subunit.

[0037] As used herein, "inhibition" means that the presence of an antibody of the present invention completely or partially inhibits ligand binding to the receptor and / or neutralizes receptor signaling that can result from ligand binding, including downstream signaling that affects cell behavior and cellular processes. As used herein, "inhibition" and "blocking" are used synonymously.

[0038] As used herein, "ADCC activity" or "antibody-dependent cellular cytotoxicity activity" refers to the activity of effector cells, such as killer cells, natural killer cells, and activated macrophages, activated by binding of the Fc region of the antibody to Fc receptors present on their surfaces, thereby activating the effector cells and thereby damaging target cells (e.g., tumor cells). The activity of the antibodies of the present invention includes ADCC activity. Measurement of ADCC activity and anti-tumor experiments may be performed using any assay known in the art. DETAILED DESCRIPTION OF THE INVENTION

[0039] Surprisingly, the present inventors have demonstrated that the integrin alpha 10 polypeptide (Uniprot: O75578) encoded by the ITGA10 gene is overexpressed in tissues obtained from biopsies of aggressive tumors, particularly in tissues obtained from triple-negative breast cancer, inflammatory breast cancer, squamous cell lung cancer, lung adenocarcinoma, small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, and sarcoma. Furthermore, the present inventors have demonstrated that the integrin alpha 10 polypeptide (Uniprot: O75578) encoded by the ITGA10 gene is overexpressed in metastatic tumors derived from the above cancers.

[0040] Based on this finding, the inventors have developed methods and means for detecting and / or diagnosing and / or treating and / or preventing cancer types, wherein said cancer types are breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or any of said cancer types which are metastatic cancers of the above cancer types.

[0041] In one embodiment, the cancer type is an aggressive cancer type.

[0042] Integrin α10 Polypeptide Integrins are heterodimers consisting of α and β polypeptides. Integrin α10β1 heterodimers can be detected by anti-integrin α10 specific antibodies and integrin α10 binding peptides and proteins.

[0043] In one embodiment of the present disclosure, the integrin alphal0 polypeptide is part of an integrin alphalObetal heterodimer.

[0044] In one embodiment of the present disclosure, the integrin alphal0 polypeptide is expressed on the cell surface.

[0045] Integrin α10β1 was identified in 1998 as a type II collagen-binding receptor on chondrocytes (Camper et al., 1998). Immunohistological analysis of developing and adult tissues has shown that the localization of this marker is restricted to cartilage-containing tissues (Camper et al., 1998; Camper et al., 2001). Knockout mice lacking this marker have disorganized growth plates, reduced collagen in the matrix, and shorter long bones, further supporting the importance of this marker for cellular structure (Bengtsson et al., 2005). Its amino acid sequence, variants, isoforms, and sequence annotation can be found under Uniprot accession number O75578 (ITA10_HUMAN).

[0046] Integrin α10β1 is the most abundant collagen-binding integrin present in cartilage tissue, and its expression pattern differs from that of other collagen-binding integrins. In vitro and in vivo studies have shown that integrin α10β1 is a specific phenotypic marker of chondrocyte differentiation and a critical mediator of cell-matrix interactions required for proper cartilage differentiation (Lundgren Akerlund and Aszodi, 2014).

[0047] Furthermore, integrin α10β1 is present in mesenchymal stem cells (MSCs), and treatment of cultured MSCs with fibroblast growth factor 2 (FGF-2) increases integrin α10β1 expression and improves in vitro chondrogenesis in aggregate cultures. Thus, integrin α10β1 is a cell surface biomarker of mesenchymal stem cells and their chondrogenic potential (Varas et al., 2007).

[0048] Integrin α10 expression has previously been analyzed in several different structures of the mouse brain, including the whole brain, and it was found that integrin α10 expression was low or absent in all healthy brain tissues (WO99 / 51639). However, more recently, it has been shown that integrin α10β1 protein is expressed in tissues obtained from malignant neoplasms of the central nervous system, as well as in the subventricular zone (SVZ), the stem cell niche of the brain (WO2016 / 133449).

[0049] The restricted distribution of integrin alpha10 in healthy tissues makes it an excellent biomarker for disease. Thus, the present disclosure relates to the detection of integrin alpha10 polypeptide as an antigen, for example, using antibodies specific for SEQ ID NO: 1 (integrin alpha10), SEQ ID NO: 2 (extracellular domain of integrin alpha10) or SEQ ID NO: 3 (extracellular I domain of integrin alpha10).

[0050] In one embodiment of the present disclosure, the integrin alphal0 is a naturally occurring variant of an integrin alphal0 polypeptide, an isoform of an integrin alphal0 polypeptide or a splice variant of an integrin alphal0 polypeptide.

[0051] In one embodiment, the variant of the integrin alphal0 antigen is at least 70% identical to SEQ ID NO: 1, 2 or 3, for example, a variant that is at least 75% identical to SEQ ID NO: 1, 2 or 3, such as a variant that is at least 80% identical to SEQ ID NO: 1, 2 or 3, for example, a variant that is at least 85% identical to SEQ ID NO: 1, 2 or 3, such as a variant that is at least 90% identical to SEQ ID NO: 1, 2 or 3, for example, a variant that is at least 95% identical to SEQ ID NO: 1, 2 or 3, such as a variant that is at least 96% identical to SEQ ID NO: 1, 2 or 3, for example, a variant that is at least 97% identical to SEQ ID NO: 1, 2 or 3, for example, a variant that is at least 98% identical to SEQ ID NO: 1, 2 or 3, such as a variant that is at least 99% identical to SEQ ID NO: 1, 2 or 3, such as a variant that is at least 99.5% identical to SEQ ID NO: 1, 2 or 3.

[0052] In one embodiment, the fragment of integrin alpha10 comprises at least 100 contiguous amino acids of SEQ ID NO:1, preferably at least 200 contiguous amino acids of SEQ ID NO:1, preferably at least 300 contiguous amino acids of SEQ ID NO:1, preferably at least 400 contiguous amino acids of SEQ ID NO:1, preferably at least 500 contiguous amino acids of SEQ ID NO:1, preferably at least 600 contiguous amino acids of SEQ ID NO:1, preferably at least 700 contiguous amino acids of SEQ ID NO:1, preferably at least 800 contiguous amino acids of SEQ ID NO:1, preferably at least 900 contiguous amino acids of SEQ ID NO:1, preferably at least 1000 contiguous amino acids of SEQ ID NO:1.

[0053] Integrin alpha 10 can also be detected at the nucleotide level, for example by analyzing a sample for the presence or absence of mRNA transcripts that, upon translation, generate the integrin alpha 10 antigen, as described herein above.

[0054] Pharmaceutical Compositions and Their Administration In one embodiment, the present disclosure relates to a composition, such as a pharmaceutical composition, comprising: (a) an antibody or fragment thereof that specifically binds to an integrin alpha 10 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; Including, wherein said composition is for use in the diagnosis and / or treatment of cancer types as defined herein.

[0055] In one embodiment of the present disclosure, the composition for use in the diagnosis and / or treatment of an aggressive cancer type as defined herein comprises a pharmaceutically effective amount of an antibody or fragment thereof that specifically binds to an integrin alphal0 polypeptide.

[0056] In one embodiment of the present disclosure, the composition for use in the diagnosis and / or treatment of an aggressive cancer type as defined herein comprises a pharmaceutically effective amount of a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a mutant (variant) thereof.

[0057] As used herein, a pharmaceutically effective amount is typically an amount of anti-integrin alpha10 antibody or an amount of polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha10 polypeptide that induces a desired response in an individual receiving the pharmaceutical composition.

[0058] Antibodies or fragments thereof that specifically bind to integrin alpha10 polypeptides, as well as polynucleotides and fragments and mutants (variants) thereof that specifically bind to transcript polynucleotides encoding integrin alpha10 polypeptides, are described in detail herein.

[0059] In one embodiment of the present disclosure, the composition for use in the diagnosis and / or treatment of a cancer type as defined herein comprises a pharmaceutically effective amount of an antibody or fragment thereof that specifically binds to an integrin alphal0 polypeptide, wherein the antibody or fragment thereof is conjugated to an additional moiety.

[0060] In one embodiment of the present disclosure, the composition for use in the diagnosis and / or treatment of an aggressive cancer type as defined herein comprises a pharmaceutically effective amount of a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof, wherein the polynucleotide or fragment or variant (variant) thereof is complexed with an additional moiety.

[0061] For example, the additional moiety may be a detectable moiety. An antibody that specifically binds to an integrin alphal0 polypeptide or a fragment thereof and that is conjugated to a detectable moiety may be useful for detecting integrin alphal0 expression on a cell and may be useful for determining whether the cell is a malignant cell and / or a tumor-associated cell. For example, the additional moiety may be a cytotoxic moiety. An antibody that specifically binds to an integrin alphal0 polypeptide or a fragment thereof and that is conjugated to a cytotoxic moiety (such as an antibody-drug conjugate (ADC) comprising an antibody that specifically binds to an integrin alphal0 polypeptide or a fragment thereof) may be useful for specifically targeting a particular cytotoxic moiety and / or drug to a cell that expresses integrin alphal0 and that is a malignant cell and / or a tumor-associated cell.

[0062] For example, the additional moiety may include a biological response modifier. A biological response modifier is a substance that modifies the immune response by either enhancing or suppressing the immune response. The biological response modifier may be endogenous (such as a moiety normally produced naturally in the body) or exogenous.

[0063] In one embodiment, the additional moiety may comprise a biological response modifier, such as a cytokine, lymphokine, interferon, or a combination thereof.

[0064] Detectable Part The composition for use in the present disclosure may comprise a detectable moiety, for example, an antibody or fragment thereof that specifically binds to an integrin alphal0 polypeptide and / or a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a mutant (variant) thereof may be covalently linked to a detectable moiety.

[0065] In one embodiment, the detectable moiety is selected from the group consisting of a fluorophore, an enzyme, or a radioactive tracer or radioisotope. In one embodiment, the detectable moiety is a radioactive tracer selected from a positron emitter and a gamma emitter. In one embodiment, the radioisotope is 99mTc, 111 In, 67 Ga, 68 Ga, 72 As, 89 Zr, 123 I and 201 Tl.

[0066] In one embodiment, the antibody comprises: 86 Y / 90 Y or 124 I / 211 It includes pairs of detectable and cytotoxic radionuclides such as At.

[0067] In one embodiment, the radioisotope can simultaneously act as both a detectable moiety and a cytotoxic moiety.

[0068] In one embodiment, the detectable moiety is: 157 Gd, 55 Mn, 162 Dy, 52 Cr and 56The detectable moiety comprises or consists of a paramagnetic isotope, such as selected from the group consisting of Fe. In one embodiment, the detectable moiety is detectable by imaging techniques such as SPECT, PET, MRI, optical imaging, or ultrasound imaging.

[0069] In one embodiment, the cytotoxic moiety and / or detectable moiety is indirectly linked to the antibody or antigen-binding fragment thereof via a linking moiety.

[0070] cytotoxic moiety The compositions for use in the present disclosure may comprise a cytotoxic moiety, for example, an antibody or fragment thereof that specifically binds to an integrin alphal0 polypeptide and / or a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a mutant (variant) thereof may be covalently linked to a cytotoxic moiety.

[0071] In one embodiment, the cytotoxic moiety is selected from the group consisting of a toxin, a chemotherapeutic agent, and a radioactive agent, or a combination thereof.

[0072] In one embodiment, the cytotoxic moiety is a toxin, for example, in one embodiment, the cytotoxic moiety is a toxin selected from the group selected from microtubule toxins, DNA toxins, and transcription toxins.

[0073] In one embodiment, the cytotoxic moiety is a microtubule toxin selected from the group consisting of auristatin-based toxins, maytansinoid-based toxins, tubulysin-based toxins, and eribulin.

[0074] In one embodiment, the cytotoxic moiety is a DNA toxin selected from the group consisting of DNA minor groove binding agents, DNA minor groove binding alkylating agents, DNA alkylating agents, and DNA cleaving agents. For example, in one embodiment, the cytotoxic moiety is a DNA toxin selected from the group consisting of pyrrolobenzodiazepines (PBDs), duocarmycins, duocarmycin analogs, indolino-benzodiazepines, calicheamicins, irinotecan, and exatecan derivatives.

[0075] In one embodiment, the cytotoxic moiety is a transcription toxin, such as a ribosome-inactivating protein (eg, an RNA polymerase II inhibitor).

[0076] In one embodiment, the cytotoxic moiety is a transcription toxin selected from the group consisting of doxorubicin, doxorubicin derivatives, and amanitin.

[0077] In one embodiment, the cytotoxic moiety is a transcriptional toxin selected from the group consisting of Shiga toxins and Shiga-like toxins; type I ribosome-inactivating proteins, type II ribosome-inactivating proteins, and saporins, or combinations thereof. For example, the type I ribosome-inactivating proteins can be trichosanthin and / or ruffin. For example, the type II ribosome-inactivating proteins can be ricin, agglutinin, and / or abrin.

[0078] In one embodiment, the cytotoxic moiety is a chemotherapeutic agent. For example, in one embodiment, the chemotherapeutic agent may be an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic. For example, in one embodiment, the chemotherapeutic agent may be selected from the group consisting of anthracyclines, taxanes, and platinum agents. For example, in one embodiment, the chemotherapeutic agent may be selected from the group consisting of cisplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, cyclophosphamide, eribulin, epirubicin, doxorubicin, carboplatin, gemcitabine, bleomycin, fluorouracil, cyclophosphamide, vinorelbine, capecitabine, ixabepilone, and ixabepilone, or a combination thereof.

[0079] formulation The composition for use in the present disclosure may be a pharmaceutical composition suitable for parenteral administration. Such compositions preferably include aqueous and non-aqueous sterile injection solutions, which may contain wetting or emulsifying agents, antioxidants, pH buffers, bacteriostatic compounds, and solutes that make the formulation isotonic with the individual's body fluids, preferably blood; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents or thickening agents. The pharmaceutical compositions may be in the form of unit-dose or multi-dose containers (e.g., sealed ampoules and vials), and can be stored in a freeze-dried state, the only condition being the addition of a sterile liquid medium immediately before use.

[0080] In one embodiment, the composition for use according to the present disclosure further comprises at least one pharmaceutically acceptable diluent, carrier or excipient.

[0081] Preferably, the composition of the present invention comprises one or more suitable pharmaceutical excipients, which can be non-sterile or sterile, and the pharmaceutical excipient is a pharmaceutical excipient for use in cells, tissues or living organisms (such as a pharmaceutical excipient suitable for administration to an individual).Such excipients can include, but are not limited to, saline, buffered saline, glucose, water, glycerol, ethanol and combinations containing these excipients in various amounts.The formulation should be adapted to the method of administration.

[0082] Preferably, the pharmaceutical compositions of the present invention are prepared in injectable form, either as liquid solutions or suspensions; solid forms suitable for solution in or suspension in liquid prior to injection are also within the scope of the present invention. The preparations may also be emulsified or encapsulated in liposomes.

[0083] The anti-integrin alphal0 polypeptide antibody or the polynucleotide that specifically binds to the transcript polynucleotide encoding the integrin alphal0 polypeptide may be administered alone or in combination with other compounds, simultaneously or sequentially in any order.

[0084] Administration may be parenteral, for example by injection or infusion. Parenteral administration may be, for example, intracerebroventricular, intrathecal, intratumoral, intravenous, intramuscular, intradermal, or subcutaneous injection. Preferably, the administration is parenteral, for example by injection or infusion.

[0085] Pathological condition In one embodiment of the present disclosure, the cancer type to be treated and / or prevented and / or detected and / or diagnosed and / or classified and / or prognosed and / or prevented from metastasis is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer, ovarian cancer and sarcoma.

[0086] In another embodiment of the present disclosure, the cancer type to be treated and / or prevented and / or detected and / or diagnosed and / or classified and / or prognosed and / or prevented from metastasis is an aggressive cancer type selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer, ovarian cancer and aggressive sarcoma.

[0087] As used herein, "aggressive cancer type" refers to a tumor that grows rapidly and / or migrates rapidly to distant sites and other tissues. Aggressive cancer types may be invasive tumors and / or tumors that are prone to metastasis and / or high-grade tumors and / or highly proliferative tumors. Aggressive cancer types usually have a poor prognosis for life. Examples of aggressive cancer types include triple-negative breast cancer, inflammatory breast cancer, squamous cell lung cancer, lung adenocarcinoma, small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, and sarcoma. Different types of cancer may be more aggressive than others.

[0088] In one embodiment of the present disclosure, the aggressive breast cancer is selected from the group consisting of triple-negative breast cancer and inflammatory breast cancer.

[0089] In one embodiment of the present disclosure, the aggressive cancer type is a triple-negative breast cancer type, and the triple-negative breast cancer is selected from the group consisting of basal-like type 1 breast cancer, basal-like type 2 breast cancer, claudin-low breast cancer, metaplastic breast cancer (MBC), interferon-high breast cancer, immunomodulatory breast cancer, mesenchymal breast cancer, mesenchymal stem cell-like breast cancer, luminal androgen receptor breast cancer, and unstable breast cancer.

[0090] Characteristics of aggressive breast cancer are known to those of skill in the art (see, e.g., Arpino et al., 2015; Dai et al., 2016; and Ma et al., 2018).

[0091] In one embodiment of the present disclosure, the aggressive breast cancer type is a triple-negative breast cancer type, which has the morphological characteristics of invasive ductal carcinoma.

[0092] In one embodiment of the present disclosure, the aggressive breast cancer type is a triple-negative breast cancer type, having the morphology characteristic of basal-like triple-negative breast cancer.

[0093] In one embodiment of the present disclosure, the aggressive breast cancer type is a basal-like breast cancer type, which has the morphology characteristic of invasive ductal carcinoma.

[0094] In one embodiment of the present disclosure, the aggressive cancer type is prostate cancer, and the prostate cancer is small cell (neuroendocrine) carcinoma (SCNC).

[0095] In one embodiment of the present disclosure, the aggressive cancer type is lung cancer, and the lung cancer is squamous cell lung cancer, lung adenocarcinoma, small cell lung cancer, or large cell lung cancer.

[0096] In one embodiment of the present disclosure, the aggressive cancer type is lung cancer, and the lung cancer is squamous cell lung cancer.

[0097] In one embodiment of the present disclosure, the aggressive cancer type is pancreatic cancer, and the aggressive pancreatic cancer is a neuroendocrine tumor.

[0098] In one embodiment of the present disclosure, the aggressive cancer type is pancreatic cancer, and the aggressive pancreatic cancer is grade I, grade II, or grade III pancreatic cancer.

[0099] In one embodiment of the present disclosure, the aggressive sarcoma is selected from the group consisting of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, atypical lipoma-like tumor, myxoinflammatory fibroblastic sarcoma, low-grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma, pseudomyogenic hemangioendothelioma, and mesenchymal chondrosarcoma.

[0100] In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, the aggressive cancer type may be a metastatic cancer of any of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer, ovarian cancer, and aggressive sarcoma.

[0101] In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, a metastatic cancer of either triple-negative breast cancer or inflammatory breast cancer.

[0102] In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, a metastatic cancer of a triple-negative breast cancer (such as a triple-negative breast cancer selected from the group consisting of basal-like type 1 breast cancer, basal-like type 2 breast cancer, claudin-low breast cancer, metaplastic breast cancer (MBC), interferon-high breast cancer, immunomodulatory breast cancer, mesenchymal breast cancer, mesenchymal stem cell-like breast cancer, luminal androgen receptor breast cancer, and unstable breast cancer).

[0103] In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, a metastatic cancer of an aggressive lung cancer. In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, a metastatic cancer of squamous cell lung cancer, lung adenocarcinoma, small cell lung cancer, or large cell lung cancer.

[0104] In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, a metastatic cancer of an aggressive pancreatic cancer.

[0105] In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, a metastatic cancer of an aggressive prostate cancer.

[0106] In one embodiment of the present disclosure, the aggressive cancer type is a metastatic cancer, for example, a metastatic cancer of an aggressive sarcoma.

[0107] Treatment of aggressive cancer types In one aspect, the present invention relates to the use of a composition, wherein the composition comprises: (a) an antibody that specifically binds to an integrin alpha10 polypeptide or a fragment thereof; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, a fragment thereof, or a variant (modified) thereof; wherein the composition is for use in the manufacture of a medicament for the treatment of an aggressive cancer type, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer, and aggressive sarcoma, or the aggressive cancer type is a metastatic cancer.

[0108] One aspect of the present disclosure relates to a method of treating an aggressive type of cancer, wherein the aggressive type of cancer is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer, and aggressive sarcoma, or wherein the aggressive type of cancer is metastatic cancer, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising: (a) an antibody or fragment thereof that specifically binds to an integrin alpha 10 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; Includes.

[0109] One aspect of the present disclosure relates to a method of inhibiting integrin alphal0-mediated signaling in at least one cancer cell, the method comprising contacting the at least one cancer cell with a composition, the composition comprising an effective amount of: (a) an antibody or antigen-binding fragment specific for an integrin alpha10 polypeptide; and / or (b) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; Including, wherein the at least one cancer cell is selected from the group consisting of aggressive breast cancer cells, aggressive lung cancer cells, aggressive prostate cancer cells, aggressive pancreatic cancer cells, aggressive sarcoma cells, and metastatic tumor cells.

[0110] Those skilled in the art will appreciate that cell signaling includes the molecular mechanisms by which cells detect and respond to external stimuli. Cell signaling also includes signal transduction mechanisms as well as transcriptional and translational control and mechanisms.

[0111] One aspect of the disclosure relates to a method of inhibiting a cellular function of at least one cancer cell, the method comprising contacting the at least one cancer cell with a composition comprising an effective amount of: (a) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (b) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; Including, wherein the at least one cancer cell is selected from the group consisting of aggressive breast cancer cells, aggressive lung cancer cells, aggressive prostate cancer cells, aggressive pancreatic cancer cells, aggressive sarcoma cells, and metastatic tumor cells.

[0112] In one embodiment, the present invention relates to a method for inhibiting the proliferation and / or hyperplasia of integrin alphal0 expressing cells, the method comprising administering a composition comprising an effective amount of: (a) an antibody or fragment thereof that specifically binds to an integrin alpha 10 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; Includes.

[0113] In one embodiment of the present disclosure, inhibiting at least one cancer cell comprises: (a) inhibiting the growth of at least one cancer cell; (b) inhibiting the self-renewal of at least one cancer cell; (c) inhibiting anchorage-independent growth of at least one cancer cell; (d) inhibiting the migration of at least one cancer cell; (e) inhibiting the invasion of at least one cancer cell; (f) inhibiting adhesion of at least one cancer cell; and / or combinations of them; is selected from the group consisting of:

[0114] In another embodiment, anchorage-dependent growth of at least one cancer cell is inhibited by inhibiting the at least one cancer cell using (i) an antibody that specifically binds to an integrin alpha 10 polypeptide or (ii) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a mutant (variant) thereof.

[0115] In one embodiment, the present disclosure relates to a method of inhibiting at least one cancer cell, wherein the cancer cell is present in an aggressive and / or metastatic tumor, and the inhibition comprises: (a) inhibition of aggressive and / or metastatic tumor growth; (b) inhibition of aggressive and / or metastatic tumor growth; (c) inhibition of aggressive and / or metastatic tumor migration; (d) inhibition of aggressive and / or metastatic tumor invasion; (e) inhibition of the development of new aggressive and / or metastatic tumors; (f) inhibition of invasion of new aggressive and / or metastatic tumors; and combinations of them; At least one of the following is true:

[0116] The cells may further express one or more markers as defined herein. In one embodiment, the cells are malignant cells and / or tumor-associated cells. In another embodiment, the cells are cancer-associated fibroblasts (CAFs), stromal cells, stem cells and / or stem cell-like cells. The method may be performed in vitro or in vivo.

[0117] In one embodiment of the present disclosure, the composition comprises an effective amount of: (a) an antibody or fragment thereof that specifically binds to an integrin alpha 10 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; The composition comprising is capable of inducing cell death and / or inhibiting proliferation and / or inhibiting hyperplasia and / or inhibiting migration of integrin alpha 10 expressing cells.

[0118] In one embodiment of the present disclosure, the treatment is initiated if integrin alphal0 polypeptide and / or transcript polynucleotide is detected in cancer cells of the subject's tumor.

[0119] In one embodiment of the present disclosure, the composition of the present disclosure for the treatment of aggressive cancer types is administered to an individual in need thereof in combination with radiotherapy and / or surgical removal of cancer.For example, in one embodiment, the composition of the present disclosure for the treatment of aggressive cancer types is administered to an individual in need thereof prior to radiotherapy and / or surgical removal of cancer.Alternatively or in addition, in one embodiment, the composition of the present disclosure for the treatment of aggressive cancer types is administered to an individual in need thereof after radiotherapy and / or surgical removal of cancer.

[0120] In one embodiment of the present disclosure, the treatment is prophylactic, ameliorative or curative.

[0121] In one embodiment of the present disclosure, the method of the present disclosure targets an antigen comprising an integrin alphal0 polypeptide or a fragment thereof expressed on a cell surface.

[0122] Those skilled in the art will appreciate the potential for preventing metastases from aggressive cancers.

[0123] One aspect of the present disclosure relates to a method of preventing metastasis of a primary cancer, wherein the primary cancer is a cancer type selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer, and sarcoma, wherein the method comprises administering a therapeutically effective amount of: (a) an antibody or antigen-binding fragment thereof specific for an integrin alphal0 polypeptide; and / or (b) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; to a patient in need thereof.

[0124] Those skilled in the art will appreciate that methods for preventing metastasis of a primary cancer can be performed once the primary cancer is detected.

[0125] Detection and diagnosis of aggressive cancer types One aspect of the present disclosure relates to a substance comprising or consisting of an antibody or fragment thereof having specificity for an integrin alpha 10 polypeptide, which is used to detect cells associated with an aggressive cancer type in a mammal, wherein the cells express the integrin alpha 10 polypeptide, and the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer and aggressive sarcoma, or a metastatic cancer of any of the aggressive cancer types.

[0126] One aspect of the present disclosure relates to a composition comprising: (a) an antibody or antigen-binding fragment thereof that specifically binds to an integrin alphal0 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; Including, The composition is for use in diagnosing a cancer type selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer, and sarcoma, or metastasis of any of said cancer types.

[0127] Those skilled in the art will understand that the process of detecting a biological marker of disease (for example, integrin alpha 10 as in the present invention) or diagnosing a disease (for example, by analyzing the expression of integrin alpha 10 as in the present invention) can include comparing the analyzed tissue with healthy tissue, non-malignant tissue or non-diseased tissue. For example, a breast cancer sample can be compared with a sample of non-diseased or healthy breast tissue from the same tissue sample. A lung cancer sample can be compared with a sample of non-diseased or healthy lung tissue from the same tissue sample. A prostate cancer sample can be compared with a sample of non-diseased or healthy prostate tissue from the same tissue sample. A pancreatic cancer sample can be compared with a sample of non-diseased or healthy pancreatic tissue from the same tissue sample. A sarcoma sample can be compared with a sample of non-diseased or healthy connective tissue from the same tissue sample.

[0128] Those skilled in the art will appreciate that in the process of diagnosing cancer it may be useful to compare the levels of integrin alphal0 polypeptide or polynucleotide in cancer cells with control cells.

[0129] In one embodiment, the cancer being diagnosed comprises cells that exhibit the same or higher levels of (i) integrin alpha 10 antigen or (ii) transcript polynucleotide observed in healthy and / or benign tissue of the same type.

[0130] In another embodiment, the diagnosed cancer comprises cells that exhibit the same or higher levels of (i) integrin alpha 10 antigen or (ii) transcript polynucleotide observed in a cancer type of the same tissue type but a less aggressive cancer type compared to the diagnosed cancer type.

[0131] In another embodiment, the cancer to be diagnosed comprises cells that exhibit expression levels of (i) the integrin alphal0 antigen or (ii) the transcript polynucleotide that are the same as or higher than those in a control cell line.

[0132] Those skilled in the art will understand that these cell lines have genotypic and phenotypic stability compared to primary cells, and therefore can be used as control cell lines in standardized diagnostic methods. Control cell lines can be established from healthy tissue or cancer tissue, where the cancer can be a highly aggressive or a less aggressive type of cancer depending on its proliferation and metastasis tendency. The established cell line needs to be immortalized so that it can be subcultured in cell culture. In this specification, a non-malignant cell line is understood to be an established cell line that does not show signs of malignancy and is phenotypically similar to healthy tissue cells.

[0133] The control cell line can be, for example, a cell line shown in Table 1.

[0134] [Table 1]

[0135] In one embodiment, the control cell line used for diagnosis is derived from healthy tissue (such as a control cell line selected from the group consisting of a control cell line derived from healthy breast tissue, a control cell line derived from healthy prostate tissue, a control cell line derived from healthy lung tissue, a control cell line derived from healthy pancreatic tissue, and a control cell line derived from healthy connective tissue).

[0136] In one embodiment, the control cell line used for breast cancer diagnosis is derived from healthy tissue (such as control cell line 184A1 derived from healthy breast cancer tissue).

[0137] In another embodiment, the control cell line used for diagnosis is derived from a cancer type of the same tissue type, but one that is less aggressive than the cancer type being diagnosed (e.g., a control cell line selected from the group consisting of a control cell line derived from a less aggressive breast cancer, a control cell line derived from a less aggressive prostate cancer, a control cell line derived from a less aggressive lung cancer, a control cell line derived from a less aggressive pancreatic cancer, and a control cell line derived from a less aggressive sarcoma).

[0138] In one embodiment, the control cell line used to diagnose aggressive cancer is selected from the group consisting of cell line HCC1428 derived from low-aggressive breast cancer, cell line T47D derived from low-aggressive breast cancer, cell line 22Rv1 derived from low-aggressive prostate cancer, cell line DU145 derived from low-aggressive prostate cancer, cell line BxPC-3 derived from low-aggressive pancreatic cancer, and cell line AsPC-1 derived from low-aggressive pancreatic cancer.

[0139] One aspect of the disclosure relates to a method of detecting aggressive cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of the (i) antigen and / or (ii) transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level; Including, wherein the control level is the average level observed in healthy and / or benign cells of the same tissue type as the isolated sample; wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is higher than the control level is indicative of the presence of an aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer and aggressive sarcoma, or a metastatic cancer of any of the aggressive cancer types.

[0140] Another aspect of the present disclosure relates to a method of diagnosing a type of cancer in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) to a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign tissue of the same tissue type; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is higher than the control level is indicative of the presence of the cancer type in the sample, thereby diagnosing the cancer type in the subject, wherein the cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastatic cancer of any of the cancer types.

[0141] Yet another aspect of the present disclosure relates to a method of diagnosing a type of cancer in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not Optionally, determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide; Including, Here, the presence of one or more cells having a cancerous morphology in combination with expression of (i) integrin alpha10 antigen and / or (ii) integrin alpha10 transcript polynucleotide is indicative of the presence of a cancer type in the sample, thereby diagnosing a cancer type in the subject, wherein the cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastatic cancer of any of the cancer types.

[0142] In one embodiment of the present disclosure, analyzing the presence or absence of an antigen comprising an integrin alphal0 polypeptide or a fragment thereof in step (b) comprises contacting a tissue suspected of containing aggressive cancer cells with a composition of the present disclosure. For example, in one embodiment of the present disclosure, the tissue suspected of containing cancer cells may be contacted with a composition comprising or consisting of an antibody having specificity for an integrin alphal0 polypeptide.

[0143] In addition to analyzing whether an antigen comprising an integrin alpha 10 polypeptide or a fragment thereof; and / or a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a mutant (variant) thereof is present in a sample, and determining whether the integrin alpha 10 expression level is higher than the control level, the method for diagnosing an aggressive cancer type in a subject and / or the method for detecting aggressive cancer cells in a subject may further comprise a step of morphologically characterizing a sample containing cancer cells belonging to an aggressive cancer type, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer and aggressive sarcoma, or metastatic cancer of any of the aggressive cancer types.

[0144] The morphological characterization of cancer tissue or suspected cancerous tissue is known to those skilled in the art, and is currently used to detect cancer cell and diagnose whether cancer exists.However, morphological characterization alone can only be useful in distinguishing cancer cell from the healthy and / or benign cell of the same tissue type, but is not sufficient to determine whether cancer cell belongs to aggressive cancer type (such as to diagnose whether aggressive cancer type exists in subject).

[0145] Accordingly, in one aspect, the present disclosure relates to a method of detecting aggressive cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) In the organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (d) optionally determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the expression level of the transcript polynucleotide; Including, wherein the presence of one or more cells having a cancerous morphology in combination with expression of (i) integrin alpha10 antigen and / or (ii) integrin alpha10 transcript polynucleotide is indicative of the presence of an aggressive cancer type in the subject, wherein said aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer and aggressive sarcoma, or a metastatic cancer of any of said aggressive cancer types.

[0146] In one embodiment, the disclosure relates to a method of detecting the presence of breast cancer cells in a subject or diagnosing breast cancer in a subject, wherein the breast cancer is an aggressive type of breast cancer selected from the group consisting of triple-negative breast cancer and inflammatory breast cancer, the method comprising: (a) providing breast tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of (i) the antigen or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign breast tissue; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is higher than the control level is indicative of the presence of breast cancer, thereby detecting the presence of breast cancer cells and / or diagnosing breast cancer in the subject.

[0147] In one embodiment, the present disclosure relates to a method of detecting the presence of lung cancer in a subject or diagnosing lung cancer in a subject, the method comprising: (a) providing lung tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of (i) the antigen or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign lung tissue; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is higher than the control level is indicative of the presence of lung cancer, thereby detecting and / or diagnosing squamous cell lung cancer in the subject.

[0148] In one embodiment, the disclosure relates to a method of detecting the presence of squamous cell lung carcinoma in a subject or diagnosing squamous cell lung carcinoma in a subject, the method comprising: (a) providing lung tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of (i) the antigen or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign lung tissue; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is higher than the control level is indicative of the presence of squamous cell lung cancer, thereby detecting and / or diagnosing squamous cell lung cancer in the subject.

[0149] In one embodiment, the present disclosure relates to a method of detecting the presence of lung adenocarcinoma in a subject or diagnosing lung adenocarcinoma in a subject, the method comprising: (a) providing lung tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of (i) the antigen or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign lung tissue; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is higher than the control level is indicative of the presence of lung adenocarcinoma, thereby detecting and / or diagnosing lung adenocarcinoma in the subject.

[0150] In one embodiment, the disclosure relates to a method of detecting the presence of prostate cancer cells in a subject or diagnosing prostate cancer in a subject, the method comprising: (a) providing prostate tissue suspected of containing cancer cells in a subject; (b) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; analyzing whether or not (c) determining the expression level of (i) the antigen or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign prostate tissue; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is greater than the control level is indicative of the presence of prostate cancer, thereby detecting and / or diagnosing prostate cancer in the subject.

[0151] In one embodiment, the disclosure relates to a method of detecting the presence of pancreatic cancer cells in a subject or diagnosing pancreatic cancer in a subject, the method comprising: (a) providing pancreatic tissue suspected of containing cancer in a subject; (b) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; analyzing whether or not (c) determining the expression level of (i) the antigen or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign pancreatic tissue; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is greater than the control level is indicative of the presence of pancreatic cancer, thereby detecting and / or diagnosing pancreatic cancer in the subject.

[0152] In one embodiment, the disclosure relates to a method of detecting the presence of sarcoma cells in a subject or diagnosing sarcoma in a subject, the method comprising: (a) providing connective tissue suspected of containing cancer in a subject; (b) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; analyzing whether or not (c) determining the expression level of (i) the antigen or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign connective tissue; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide that is greater than the control level is indicative of the presence of sarcoma, thereby detecting and / or diagnosing sarcoma in the subject.

[0153] The present inventors have demonstrated that the expression level of integrin alpha 10 is useful for distinguishing between subtypes of aggressive breast cancer (such as between subtypes of triple-negative breast cancer).

[0154] Accordingly, one aspect of the present disclosure relates to a method of classifying a triple-negative breast cancer tumor sample from a subject, the method comprising: (a) providing a breast tissue sample from a subject; (b) isolating breast cancer cells characterized as ER-negative, PR-negative and HER2-negative; (c) In isolated cells: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; determining the expression level of and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of an antigen comprising integrin alphal0 polypeptide observed in healthy and / or benign breast tissue; Including, Here, (i) antigen expression levels and / or (ii) transcript polynucleotide expression levels in breast cancer cells that are higher than control levels, and an expression status that is ER-negative, PR-negative, and HER2-negative, are indicative of basal-like triple-negative breast cancer or luminal triple-negative breast cancer, thereby classifying the triple-negative breast cancer tumor sample as belonging to basal-like triple-negative breast cancer tumor or luminal triple-negative breast cancer tumor.

[0155] In another embodiment, the luminal triple-negative breast cancer is luminal androgen receptor triple-negative breast cancer.

[0156] In one embodiment, the disclosed method of classifying a triple-negative breast cancer tumor sample further comprises analyzing the expression levels of claudins in the sample, wherein a higher expression level of (i) antigen and / or (ii) transcript polynucleotide in breast cancer cells than a control level, and an ER-negative, PR-negative, HER2-negative expression status, and a lower level of claudins are indicative of basal-like triple-negative breast cancer, thereby classifying the triple-negative breast cancer tumor sample as belonging to a basal-like triple-negative breast cancer tumor.

[0157] Claudin-low breast tumors are a subtype of triple-negative breast tumors. These tumors exhibit low expression of many claudin genes, including claudin 3, claudin 4, and claudin 7. Other key features of claudin-low tumors include almost always being heavily infiltrated by immune cells and possessing stem cell features and features of epithelial-mesenchymal transition (EMT).

[0158] In one embodiment, (i) the expression level of the integrin α10 antigen; and / or (ii) the expression level of the transcript polynucleotide is higher than the control level, The disclosed method of classifying a triple-negative breast cancer tumor sample further comprises classifying the triple-negative breast cancer tumor sample as belonging to a basal-like type 2 triple-negative breast cancer tumor.

[0159] In one embodiment, the disclosed method of classifying a triple-negative breast cancer tumor sample further comprises determining the presence or absence of expression of one or more polypeptides selected from the group consisting of cytokeratin 7, cytokeratin 8, cytokeratin 18 and cytokeratin 19, wherein expression of integrin alpha 10 and expression of one or more polypeptides selected from the group consisting of cytokeratin 7, cytokeratin 8, cytokeratin 18 and cytokeratin 19 are indicative of luminal triple-negative breast cancer.

[0160] In one embodiment, the disclosed method of classifying a triple-negative breast cancer tumor sample further comprises determining the presence or absence of expression of one or more polypeptides selected from the group consisting of cytokeratin 5 / 6, cytokeratin 14, cytokeratin 17, p63, EGFR, and c-kit / CD117, wherein expression of integrin alpha 10 and expression of one or more polypeptides selected from the group consisting of cytokeratin 5 / 6, cytokeratin 14, cytokeratin 17, p63, EGFR, 34BE12, and c-kit / CD117 are indicative of basal-like triple-negative breast cancer.

[0161] Surprisingly, the inventors have discovered that high expression levels of integrin alpha 10 in cells belonging to aggressive cancer types as defined herein directly correlate with and are indicative of poor prognosis.

[0162] Accordingly, one aspect of the present disclosure relates to a method of determining the prognosis of an aggressive cancer type in a subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer and aggressive sarcoma, or a metastatic cancer of any of the aggressive cancer types, the method comprising: (a) providing cancer tumor tissue from a subject; (b) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; analyzing whether or not (c) determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the expression level of the transcript polynucleotide; (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of (i) integrin alphal0 antigen and / or (ii) integrin alphal0 transcript polynucleotide observed in healthy and / or benign tissue of the same tissue type as the sample; (e) determining that the aggressive cancer type has a poor prognosis if the expression level of the (i) antigen and / or (ii) transcript polynucleotide is higher than the control level; Includes.

[0163] Another aspect of the present disclosure relates to a method of determining a prognosis of an aggressive cancer type in a subject, the method comprising: (a) providing cancer tumor tissue from a subject; (b) analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) in the sample (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (d) optionally determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the expression level of the transcript polynucleotide; (e) determining that the aggressive cancer type has a poor prognosis when (i) integrin alpha 10 antigen and / or (ii) integrin alpha 10 transcript polynucleotide are expressed and one or more cells having a cancerous morphology are present in the tissue; Including, wherein said aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer and aggressive sarcoma, or a metastasis of any of said aggressive cancer types.

[0164] The method of determining the prognosis of an aggressive cancer type in a subject can be used for any of the aggressive cancer types described herein (see, eg, the "Pathologies" section).

[0165] In one embodiment, the present disclosure relates to a method of determining the prognosis of an aggressive cancer type in a subject, wherein the prognosis is overall survival or recurrence-free survival.

[0166] In one embodiment of the present disclosure, the method of the present disclosure targets an antigen comprising an integrin alphal0 polypeptide or a fragment thereof expressed on a cell surface.

[0167] The methods of the present disclosure may be performed in vivo or in vitro.

[0168] In one embodiment, the method of detecting aggressive cancer cells in a subject as disclosed herein is performed in vivo. In one embodiment, the method of diagnosing an aggressive cancer type in a subject as disclosed herein is performed in vitro, and the tissue is a tissue sample obtained from the subject.

[0169] In one embodiment, the method of diagnosing an aggressive cancer type in a subject as disclosed herein is performed in vivo. In one embodiment, the method of diagnosing an aggressive cancer type in a subject as disclosed herein is performed in vitro and the tissue is a tissue sample obtained from the subject.

[0170] In one embodiment, the method for determining the prognosis of an aggressive cancer in a subject as disclosed herein is performed in vivo. In one embodiment, the method for determining the prognosis of an aggressive cancer in a subject as disclosed herein is performed in vitro, and the tissue is a tissue sample obtained from the subject.

[0171] In one embodiment of the present disclosure, the sample comprises: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; The step of analyzing for the presence of includes imaging the tissue and / or tissue sample.

[0172] In one embodiment of the present disclosure, the step of determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide comprises imaging of the tissue and / or tissue sample.

[0173] Imaging may be performed, for example, by administering to the subject and / or tissue sample a labeled moiety capable of binding to an antigen comprising an integrin alphal0 polypeptide or a fragment thereof. For example, imaging may be performed by administering to the subject and / or tissue sample a labeled anti-integrin alphal0 antibody as defined herein.

[0174] Antibodies against integrin alpha 10 polypeptide In one embodiment, the composition of the present disclosure used for the diagnosis and / or treatment and / or prevention of aggressive cancer types comprises an anti-integrin alphal0 specific antibody, wherein the antibody binds to integrin alphal0 polypeptide in an immune reaction. Preferably, the antibody binds to the extracellular domain of integrin alphal0 polypeptide, but in a particular embodiment, the anti-integrin alphal0 antibody has overlapping specificity to the heterodimeric integrin alphal0beta1 complex itself. This can mean, for example, that the antibody of the present invention binds to an epitope spanning both the alphal0 polypeptide and the beta1 polypeptide.

[0175] The antibodies and functional equivalents thereof can be produced by any suitable method known to those skilled in the art.

[0176] In one embodiment, the antibodies of the invention are produced by a hybridoma cell line (e.g., hybridoma cell line mAb 365, deposited with Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under accession number DSM ACC2583), which produces antibodies that bind to the extracellular integrin alpha 10 domain. Gene knockout mice for integrin alpha 10 beta 1 may be used to generate the hybridomas. Such knockout mice are described in WO 03 / 101497, which is incorporated herein by reference.

[0177] In one embodiment, an antibody of the invention comprises: (a) the monoclonal antibody produced by the hybridoma cell line deposited at Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under accession number DSM ACC2583; or (b) an antibody that competes for binding to the same epitope as the monoclonal antibody produced by the hybridoma deposited with Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under accession number DSM ACC2583; or (c) a fragment of (a) or (b) capable of specifically binding to the extracellular I domain of the integrin α10 polypeptide chain. is.

[0178] In another embodiment, the anti-integrin alpha 10 antibody of the present invention is identified by antibody panning.

[0179] The antibodies of the present invention, identified by the amino acid sequences of SEQ ID NOS: 4 to 11, are referred to herein as Th101. The six CDRs (complementarity determining regions) (SEQ ID NOS: 4 to 9), heavy chain variable region (SEQ ID NOS: 10), and light chain variable region (SEQ ID NOS: 11) of antibody Th101 are disclosed herein. The identification and construction of antibody Th101, as used in the Examples, are described in WO08 / 075038, which is incorporated herein by reference.

[0180] In one embodiment, the anti-integrin alphal0 antibody of the invention comprises: (a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; (b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and (c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising: and / or (d) CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; (e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and (f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; a light chain variable region comprising: or A mutant (modified form) of any one of SEQ ID NOs: 4 to 9, Including, Here, the variant has any one amino acid substituted with another amino acid, provided that such changes are no more than three amino acids, for example, where two or one amino acid are substituted.

[0181] In another embodiment, the anti-integrin alphal0 antibody of the invention comprises a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:10.

[0182] In another embodiment, the anti-integrin alphal0 antibody of the invention comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:11.

[0183] The integrin α10 antibody may be administered to the mammal two or more times (twice, for example, three times, 3 to 5 times, for example, 5 to 10 times, 10 to 20 times, for example, 20 to 50 times, more than 50 times, etc.). It is also possible to administer different integrin α10 antigens to the same mammal simultaneously or sequentially in any order.

[0184] Usually, the integrin alpha10 antibody is made into an aqueous solution or suspension before administration.In addition, the integrin alpha10 antigen may be mixed with one or more other compounds.For example, the integrin alpha10 antigen may be mixed with one or more suitable adjuvants and / or one or more carriers.

[0185] An adjuvant is a substance that, when mixed with an administered antigen, enhances or modifies the immune response to that antigen. Suitable adjuvants are well known to those skilled in the art.

[0186] A carrier is a backbone structure (e.g., a polypeptide or polysaccharide to which an antigen can be attached). A carrier may exist independently of an adjuvant. Suitable carriers are well known to those skilled in the art.

[0187] Methods for preparing monoclonal antibodies, mixtures of monoclonal or polyclonal antibodies are known in the art and are described, for example, in Antibodies: A Laboratory Manual (By Ed Harlow and David Lane, Cold Spring Harbor Laboratory Press, 1988).

[0188] In one embodiment, the anti-integrin alphal0 antibody of the present invention is an antibody capable of inhibiting the biological and functional activity of an integrin alphal0 polypeptide.

[0189] In another embodiment, the anti-integrin alphal0 antibody is administered as part of an antibody-drug conjugate (ADC), in which the antibody is linked to a moiety (e.g., a disease-modifying drug or toxin). Upon specific binding to the integrin alphal0 polypeptide, the ADC is internalized within the cell, delivering the moiety into the cell.

[0190] In one embodiment, the antibody contained in a composition of the present disclosure for use in diagnosing and / or treating an aggressive cancer type is an isotype selected from the group consisting of IgA, IgD, IgG, IgE, and IgM. In a further embodiment, the antibody is an IgG isotype, such as an IgG isotype selected from the group consisting of IgG1, IgG2 (e.g., IgG2a), IgG3, and IgG4.

[0191] In one embodiment, the antibody of the present disclosure that specifically binds to an integrin alphal0 polypeptide is a single chain antibody.

[0192] The present disclosure contemplates both monoclonal and polyclonal antibodies capable of binding to integrin alphal0 polypeptides, as well as fragments thereof, antigen-binding fragments and recombinant proteins thereof.

[0193] In one embodiment, the antibody of the present disclosure that specifically binds to an integrin alphal0 polypeptide and that is used for diagnosis and / or therapy is a polyclonal antibody.

[0194] In one embodiment, the antibody of the present disclosure that specifically binds to an integrin alphal0 polypeptide is a humanized or human antibody.

[0195] In one embodiment, the antibody of the present disclosure that specifically binds to an integrin alphal0 polypeptide is a murine antibody.

[0196] In one embodiment, the antibody of the present disclosure that specifically binds to an integrin alphal0 polypeptide is a monoclonal antibody.

[0197] In one embodiment, the antibody of the present disclosure that specifically binds to an integrin alphal0 polypeptide is a polyclonal antibody.

[0198] In one embodiment, the antibody comprised in the composition of the present disclosure for use in the diagnosis and / or treatment of aggressive cancer types is an antibody fragment. An antigen-binding fragment of an antibody is an antibody fragment that retains the ability to specifically bind to an antigen. Examples of antibody fragments of the present invention include antibody fragments selected from the group consisting of Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments (such as single-chain variable fragments (scFv)) and single-domain antibodies.

[0199] The antibodies contained in the compositions of the present disclosure for use in diagnosing and / or treating aggressive cancer types may be chimeric antibodies (i.e., antibodies containing regions derived from different species). The chimeric antibodies may, for example, contain variable regions derived from one animal species and constant regions derived from another animal species. For example, a chimeric antibody may have variable regions derived from a mouse monoclonal antibody and human constant regions. Such antibodies are sometimes referred to as humanized antibodies. For example, a chimeric humanized antibody may be fully human.

[0200] In one embodiment, the antibody comprised in the composition of the present disclosure for use in the diagnosis and / or treatment of aggressive cancer types is a heterospecific antibody (e.g., a bispecific antibody, which is a protein or polypeptide comprising two different antigen-binding sites with different specificities). For example, the bispecific antibody may recognize and bind to (a) one epitope on integrin alpha10 and (b) another epitope on integrin alpha10. Thus, the antibody may recognize and bind to two different epitopes within the same antigen. The term "heterospecific antibody" is intended to include proteins or polypeptides with three or more antigen-binding sites with different specificities. Thus, the present invention includes, but is not limited to, bispecific, trispecific, tetraspecific, and other multispecific antibodies directed against integrin alpha10 polypeptides.

[0201] In some embodiments, the antibodies or fragments thereof of the present disclosure that specifically bind to integrin alphal0 polypeptide may be conjugated to a moiety, such as an additional moiety, which can improve and enhance both the treatment and diagnosis of aggressive cancer types.

[0202] In one embodiment, the antibody is covalently linked to a detectable moiety, such as a detectable moiety selected from the group consisting of a fluorophore, an enzyme, a radioactive tracer, or a radioisotope. The integrin alphal0 antigen may be detected by detecting other peptides, proteins, or polypeptides other than the integrin alphal0 polypeptide, where the other peptides, proteins, or polypeptides are capable of specifically binding to the integrin alphal0 antigen. In one embodiment, the peptide, protein, or polypeptide is linked to an enzyme, a fluorophore, or a radioactive tracer. The radioactive tracer may be selected, for example, from a positron emitter or a gamma emitter. Conjugating the antibody to a detectable moiety can enhance or improve the detection of the antibody, thereby facilitating the detection of integrin alphal0-expressing cells in a sample, and may also improve the diagnosis of aggressive cancer types.

[0203] Those skilled in the art can select standard experimental equipment for detecting anti-integrin alphal0 antibodies depending on the circumstances and physical state of the sample.

[0204] In one embodiment, one skilled in the art would perform the detection step using flow cytometry, such as fluorescence activated cell sorting (FACS).

[0205] Common immunological methods well known in the art include, but are not limited to, Western blotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunohistochemistry (IHC), immunofluorescence assay (IF), and fluorescence in situ hybridization (FISH).

[0206] Detection of integrin alpha 10 can be performed using detection methods well known in the art and imaging methods such as clinical imaging (conventional fluorescence microscopy, confocal microscopy, two-photon microscopy, stimulated emission depletion microscopy (STED) etc.).

[0207] In one embodiment, the anti-integrin alphal0 antibody is a function-blocking antibody, such as an antibody capable of inhibiting and / or blocking the migration and / or proliferation of integrin alphal0-expressing cells.

[0208] Molecular probes for detecting integrin α10 Analysis of biological samples for the presence of integrin alpha10 antigen or polynucleotides encoding integrin alpha10 can also be carried out by utilizing molecular probes (protein or polynucleotide) capable of binding to or hybridizing to integrin alpha10 mRNA, cDNA or protein to detect expression in the biological sample, or by using PCR, preferably Q-PCR.

[0209] In one embodiment, the integrin alpha10 specific polynucleotide probe is linked to a detectable moiety, and the detectable moiety can optionally emit photons.When using this embodiment, the light source that can excite the detectable moiety (for example, a fluorescent dye molecule) can be used to irradiate the object to be diagnosed or examined with light.Methods for detecting photons include, but are not limited to, PET scan and SPECT scan.

[0210] In certain embodiments, the detectable moiety is selected from the group consisting of a fluorophore, an enzyme, or a radioactive tracer.

[0211] Transcript polynucleotides may be detected using PCR, preferably Q-PCR.

[0212] In a further embodiment, the presence or absence of integrin alpha 10 in a biological sample is detected using an integrin alpha 10 nucleic acid probe that binds to integrin alpha 10 RNA or cDNA by a hybridization reaction.

[0213] Examples of nucleic acid components that specifically target integrin alpha10 include DNA probes, antisense RNA or RNAi (such as microRNA, small interfering RNA (siRNA) and short hairpin RNA (shRNA)).

[0214] Exemplary nucleic acid detection methods well known in the art include, but are not limited to, Northern blotting, Southern blotting, polymerase chain reaction (PCR), microarrays, in situ hybridization, and the like.

[0215] In a further embodiment, the presence or absence of integrin alpha 10 in a biological sample is detected using integrin alpha 10 binding peptides or proteins, which can be produced recombinantly, chemically synthesized, or purified from natural sources.

[0216] In a further embodiment, the presence of integrin alpha 10 in a biological sample is detected in vivo by using an integrin alpha 10-specific antibody, or an integrin alpha 10-binding peptide or protein, or an integrin alpha 10 nucleic acid probe that binds to integrin alpha 10 RNA or cDNA in a hybridization reaction.

[0217] Exemplary in vivo detection methods for cell surface antigens and polynucleotides are well known in the art and include, but are not limited to, positron emission tomography, X-ray computed tomography (CT), magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI), ultrasonography, and single-photon emission computed tomography (SPECT). In particular, cell surface antigens can be imaged in vivo using immunolabeling with radioactive tracers linked to antibodies or other specific binding proteins.

[0218] Preferably, antibodies used for in vivo imaging are antibody fragments (such as Fab fragments) and single chain antibodies because of their small size and lack of effector functions.

[0219] item Item 1: A composition comprising: (a) an antibody or antigen-binding fragment thereof that specifically binds to an integrin alpha10 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; Including, A composition for use in the treatment and / or prevention of a cancer type selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastases of any of said cancer types.

[0220] Item 2: A composition for use according to any one of the above items, wherein the breast cancer is selected from the group consisting of triple-negative breast cancer and inflammatory breast cancer.

[0221] Item 3: A composition for use according to any one of the preceding items, wherein the triple negative breast cancer is selected from the group consisting of basal-like type 1 breast cancer, basal-like type 2 breast cancer, claudin-low breast cancer, metaplastic breast cancer (MBC), interferon-high breast cancer, immunomodulatory breast cancer, mesenchymal breast cancer, mesenchymal stem cell-like breast cancer, luminal androgen receptor breast cancer, and unstable breast cancer.

[0222] Item 4: A composition for use according to any one of the above items, wherein the lung cancer is selected from the group consisting of squamous cell lung cancer, lung adenocarcinoma, large cell lung cancer and small cell lung cancer.

[0223] Item 5: A composition for use according to any one of the above items, wherein the prostate cancer is small cell neuroendocrine carcinoma (SCNC).

[0224] Item 6: A composition for use according to any one of the above items, wherein the pancreatic cancer is a neuroendocrine tumor.

[0225] Item 7: A composition for use according to any one of the preceding items, wherein the pancreatic cancer and / or neuroendocrine tumor is grade I, grade II or grade III pancreatic cancer.

[0226] Item 8: A composition for use according to any one of the preceding items, wherein the sarcoma is selected from the group consisting of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, atypical lipomatous tumor, myxoinflammatory fibroblastic sarcoma, low-grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma, pseudomyogenic hemangioendothelioma, and mesenchymal chondrosarcoma.

[0227] Item 9: A composition for use according to any one of the preceding items, wherein the integrin alphal0 polypeptide is expressed on the surface of malignant cells and / or tumor-associated cells.

[0228] Item 10: A composition for use according to any one of the preceding items, wherein the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody or a fragment thereof.

[0229] Item 11: A composition for use according to any one of the preceding items, wherein the antibody is a non-human antibody, a chimeric antibody, a bispecific antibody, a humanized antibody or a human antibody.

[0230] Item 12: A composition for use according to any one of the preceding items, wherein the antibody is a mouse monoclonal antibody.

[0231] Item 13: A composition for use according to any one of the preceding items, wherein the antibody is a human monoclonal antibody.

[0232] Item 14: A composition for use according to any one of the preceding items, wherein the antibody is an isotype selected from the group consisting of IgA, IgD, IgG, IgE and IgM.

[0233] Item 15: A composition for use according to any one of the preceding items, wherein the antibody is: (a) the monoclonal antibody produced by the hybridoma cell line deposited at Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under accession number DSM ACC2583; or (b) an antibody that competes for binding to the same epitope as the monoclonal antibody produced by the hybridoma deposited with Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under accession number DSM ACC2583; or (c) a fragment of (a) or (b) capable of specifically binding to the extracellular I domain of the integrin α10 polypeptide chain. That is, composition.

[0234] Item 16: A composition for use according to any one of the preceding items, wherein the antibody or antigen-binding fragment thereof is: (a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; (b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and (c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising: and / or (d) CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; (e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and (f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; a light chain variable region comprising: or A mutant (modified form) of any one of SEQ ID NOs: 4 to 9, Including, wherein the variant is a composition in which any one amino acid is substituted with another amino acid, provided that such changes are no more than three amino acids, for example, in which two amino acids or one amino acid are substituted.

[0235] Item 17: A composition for use according to any one of the preceding items, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 10.

[0236] Item 18: A composition for use according to any one of the preceding items, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 11.

[0237] Item 19: A composition for use according to any one of the preceding items, wherein the antibody or antigen-binding fragment thereof and / or the polynucleotide or fragment thereof or variant (variant) thereof is complexed with an additional moiety.

[0238] Item 20: A composition for use according to any one of the preceding items, wherein the additional moiety comprises a detectable moiety, such as a detectable moiety selected from the group consisting of a fluorophore, an enzyme and a radioactive tracer or a radioisotope.

[0239] Item 21: A composition for use according to any one of the preceding items, wherein the additional moiety comprises a cytotoxic moiety.

[0240] Item 22: A composition for use according to any one of the preceding items, wherein the cytotoxic moiety is selected from the group consisting of a toxin, a chemotherapeutic agent and a radioactive substance, or a combination thereof.

[0241] Item 23: A composition for use according to any one of the preceding items, wherein the cytotoxic moiety is a toxin.

[0242] Item 24: A composition for use according to any one of the preceding items, wherein the toxin is selected from the group consisting of microtubule toxins, DNA toxins and transcription toxins.

[0243] Item 25: A composition for use according to any one of the preceding items, wherein the microtubule toxins are selected from the group consisting of auristatin-based toxins, maytansinoid-based toxins, tubulysin-based toxins and eribulin.

[0244] Item 26: A composition for use according to any one of the preceding items, wherein the DNA toxins are selected from the group consisting of agents that bind to the major groove of DNA, alkylating agents that bind to the minor groove of DNA, DNA alkylating agents and DNA cleaving agents.

[0245] Item 27: A composition for use according to any one of the preceding items, wherein the DNA toxins are selected from the group consisting of pyrrolobenzodiazepines (PBDs), duocarmycins, duocarmycin analogs, indolinobenzodiazepines, calicheamicins, irinotecan and exatecan derivatives.

[0246] Item 28: A composition for use according to any one of the preceding items, wherein the transcription toxin is an RNA polymerase II inhibitor.

[0247] Item 29: A composition for use according to any one of the preceding items, wherein the transcriptional toxin is selected from the group consisting of doxorubicin, doxorubicin derivatives and amanitin.

[0248] Item 30: A composition for use according to any one of the preceding items, wherein the transcriptional toxin is selected from the group consisting of Shiga toxins and Shiga-like toxins; type I ribosome-inactivating proteins, type II ribosome-inactivating proteins and saporins, or combinations thereof.

[0249] Item 31: A composition for use according to any one of the preceding items, wherein the type I ribosome-inactivating protein is trichosanthin and / or ruffin.

[0250] Item 32: A composition for use according to any one of the preceding items, wherein the type II ribosome-inactivating protein is ricin, agglutinin and / or abrin.

[0251] Item 33: A composition for use according to any one of the preceding items, wherein the additional moiety comprises a biological response modifier.

[0252] Item 34: A composition for use according to any one of the preceding items, wherein the biological response modifier is a cytokine, lymphokine, interferon or a combination thereof.

[0253] Item 35: A composition for use according to any one of the preceding items, wherein the chemotherapeutic agent is an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor or a cytotoxic antibiotic.

[0254] Item 36: A composition for use according to any one of the preceding items, wherein the chemotherapeutic agent is selected from the group consisting of anthracyclines, taxanes and platinum agents.

[0255] Item 37: A composition for use according to any one of the preceding items, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, cyclophosphamide, eribulin, epirubicin, doxorubicin, carboplatin, gemcitabine, bleomycin, fluorouracil, cyclophosphamide, vinorelbine, capecitabine, ixabepilone, and ixabepilone, or a combination thereof.

[0256] Item 38: A composition for use according to any one of the preceding items, wherein the composition further comprises at least one pharmaceutically acceptable diluent, carrier or excipient.

[0257] Item 39: A composition for use according to any one of the preceding items, wherein the integrin alphal0 polypeptide is a naturally occurring variant of an integrin alphal0 polypeptide, an isoform of an integrin alphal0 polypeptide or a splice variant of an integrin alphal0 polypeptide.

[0258] Item 40: A composition for use according to any of the preceding items, wherein the antibody and / or polynucleotide is capable of inducing cell death and / or inhibiting proliferation and / or inhibiting hyperplasia and / or inhibiting migration of cells expressing the integrin alphal0 polypeptide and / or transcript polynucleotide.

[0259] Item 41: A composition for use according to any of the preceding items, wherein the cells are malignant cells and / or tumor-associated cells.

[0260] Item 42: A composition for use according to any of the preceding items, wherein the malignant or tumor-associated cells are cancer-associated fibroblasts (CAFs), stromal cells, stem cells and / or stem cell-like cells.

[0261] Item 43: A composition for use according to any one of the preceding items, wherein the integrin alphal0 polypeptide is part of an integrin alphal0beta1 heterodimer.

[0262] Item 44: A composition for use according to any of the preceding items, wherein the treatment is preventative, ameliorative or curative.

[0263] Item 45: A composition for use according to any of the preceding items, wherein the treatment is initiated upon detection of integrin alphal0 polypeptide and / or transcript polynucleotide in cancer cells of a tumor in the subject.

[0264] Item 46: A composition for use according to any of the preceding items, wherein the composition is administered to an individual in need thereof in combination with radiotherapy and / or surgical removal of cancer.

[0265] Item 47: A composition for use according to any of the preceding items, wherein the composition is administered to an individual in need thereof prior to radiotherapy and / or surgical removal of cancer.

[0266] Item 48: A composition for use according to any of the preceding items, wherein the composition is administered to an individual in need thereof after radiotherapy and / or surgical removal of cancer.

[0267] Item 49: A composition, wherein the composition comprises: (a) an antibody or antigen-binding fragment thereof that specifically binds to an integrin alpha10 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; Including, A composition for use in diagnosing a cancer type selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer, and sarcoma, or metastases of any of said cancer types.

[0268] Item 50: The composition of Item 49, wherein the cancer comprises cells that exhibit the same or higher levels of (i) integrin alpha 10 antigen or (ii) transcript polynucleotide observed in healthy and / or benign tissue of the same type.

[0269] Item 51: The composition of Item 49, wherein the cancer comprises cells that exhibit the same or higher levels of (i) integrin alpha 10 antigen or (ii) transcript polynucleotide observed in a cancer type of the same tissue type but that is less aggressive compared to the diagnosed cancer type.

[0270] Item 52: The composition of Item 49, wherein the cancer comprises cells that exhibit the same or higher expression level of (i) integrin alpha 10 antigen or (ii) transcript polynucleotide as in a control cell line.

[0271] Item 53: The composition of Item 52, wherein the control cell line is derived from healthy tissue.

[0272] Item 54: The composition of any one of Items 52-53, wherein the control cell line is selected from the group consisting of a control cell line derived from healthy breast tissue, a control cell line derived from healthy prostate tissue, a control cell line derived from healthy lung tissue, a control cell line derived from healthy pancreatic tissue, and a control cell line derived from healthy connective tissue.

[0273] Item 55: The composition according to any one of Items 52 to 54, wherein the control cell line is cell line 184A1 derived from healthy breast cancer tissue.

[0274] Item 56: The composition of item 52, wherein the control cell line is derived from a cancer type of the same tissue type, but a less aggressive cancer type compared to the diagnosed cancer type.

[0275] Item 57: The composition of item 56, wherein the control cell line is selected from the group consisting of a control cell line derived from a less aggressive breast cancer, a control cell line derived from a less aggressive prostate cancer, a control cell line derived from a less aggressive lung cancer, a control cell line derived from a less aggressive pancreatic cancer, and a control cell line derived from a less aggressive sarcoma.

[0276] Item 58: The composition of any one of Items 56 to 57, wherein the control cell line is selected from the group consisting of cell line HCC1428 derived from a minimally aggressive breast cancer, cell line T47D derived from a minimally aggressive breast cancer, cell line 22Rv1 derived from a minimally aggressive prostate cancer, cell line DU145 derived from a minimally aggressive prostate cancer, cell line BxPC-3 derived from a minimally aggressive pancreatic cancer, and cell line AsPC-1 derived from a minimally aggressive pancreatic cancer.

[0277] Item 59: A method of treating a type of cancer, wherein the type of cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or the type of cancer is metastatic cancer, the method comprising: (a) an antibody or fragment thereof that specifically binds to an integrin alpha 10 polypeptide; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, or a fragment thereof, or a mutant (variant) thereof; to a subject in need thereof.

[0278] Item 60: A method for detecting cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) to a control level; Including, wherein the control level is the average expression level of (i) the antigen or (ii) the transcript polynucleotide observed in healthy and / or benign cells of the same tissue type as the isolated sample; wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide higher than the control level is indicative of the presence of a cancer type in the subject, wherein the cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastatic cancer of any of the cancer types.

[0279] Item 61: A method for detecting cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) In the organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (d) optionally determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide; Including, wherein the presence of one or more cells having a cancerous morphology in combination with expression of (i) integrin alpha10 antigen and / or (ii) integrin alpha10 transcript polynucleotide is indicative of the presence of a cancer type in the subject, wherein the cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastatic cancer of any of the cancer types.

[0280] Item 62: A method for diagnosing a cancer type in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) In that organization: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; analyzing whether or not (c) determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide; and (d) comparing the expression level determined in step (c) to a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign tissue of the same tissue type; Including, wherein an expression level of (i) the antigen and / or (ii) the transcript polynucleotide higher than the control level is indicative of the presence of a cancer type in the sample, thereby diagnosing a cancer type in the subject, wherein the cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or a metastatic cancer of any of the cancer types.

[0281] Item 63: A method for diagnosing a cancer type in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; analyzing whether or not (d) optionally determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the expression level of the transcript polynucleotide; Including, wherein the presence of one or more cells having a cancerous morphology in combination with expression of (i) integrin alpha10 antigen and / or (ii) integrin alpha10 transcript polynucleotide is indicative of the presence of a cancer type in the sample, thereby diagnosing a cancer type in the subject, wherein the cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastatic cancer of any of the cancer types.

[0282] Item 64: The method according to any one of Items 60 to 63, wherein step (b) further comprises administering to the subject a composition or a fragment thereof according to any one of Items 1 to 58.

[0283] Item 65: The method of any one of Items 60 to 64, further comprising morphologically characterizing the sample as containing cancer cells belonging to a cancer type, wherein the cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer, and sarcoma, or metastatic cancer of any of the cancer types.

[0284] Item 66: The method of any one of Items 60 to 65, wherein the method is a method for detecting the presence of breast cancer in a subject or a method for diagnosing breast cancer in a subject, wherein the breast cancer is selected from the group consisting of breast cancer-type triple negative breast cancer and inflammatory breast cancer, and wherein the method comprises comparing the expression level of integrin alpha 10 polypeptide determined in step (b) with a control level, wherein the control level is an average value of the expression levels of (i) the antigen or (ii) the transcript polynucleotide observed in healthy and / or benign breast tissue cells, and wherein a higher level of the antigen comprising integrin alpha 10 polypeptide than the control level is indicative of the presence of breast cancer in the subject.

[0285] Item 67: The method of any one of Items 60 to 65, wherein the method is a method for detecting the presence of lung cancer in a subject or a method for diagnosing lung cancer in a subject, wherein the method comprises comparing the expression level of integrin alphal0 polypeptide determined in step (b) with a control level, wherein the control level is an average value of the expression levels of (i) the antigen or (ii) the transcript polynucleotide observed in non-cancerous lung cells, and wherein a higher level of the antigen comprising integrin alphal0 polypeptide than the control level is indicative of the presence of lung cancer in the subject.

[0286] Item 68: The method of any one of Items 60 to 65, wherein the method is a method for detecting the presence of squamous cell lung cell carcinoma in a subject or a method for diagnosing squamous cell lung cell carcinoma in a subject, wherein the method comprises comparing the expression level of integrin alpha 10 polypeptide determined in step (b) with a control level, wherein the control level is an average value of the expression levels of (i) the antigen or (ii) the transcript polynucleotide observed in non-cancerous lung cells, and wherein a higher level of the antigen comprising integrin alpha 10 polypeptide than the control level is indicative of the presence of squamous cell lung cell carcinoma in the subject.

[0287] Item 69: The method of any one of Items 60 to 65, wherein the method is a method for detecting the presence of lung adenocarcinoma in a subject or a method for diagnosing lung adenocarcinoma in a subject, wherein the method comprises comparing the expression level of integrin alpha 10 polypeptide determined in step (b) with a control level, wherein the control level is an average value of the expression levels of (i) the antigen or (ii) the transcript polynucleotide observed in non-cancerous lung cells, and wherein a higher level of the antigen comprising integrin alpha 10 polypeptide than the control level is indicative of the presence of lung adenocarcinoma in the subject.

[0288] Item 70: The method according to any one of Items 60 to 65, wherein the method is a method for detecting the presence of prostate cancer cells in a subject or a method for diagnosing prostate cancer in a subject, wherein the method comprises comparing the expression level of integrin alphal0 polypeptide determined in step (b) with a control level, wherein the control level is an average value of the expression levels of (i) the antigen or (ii) the transcript polynucleotide observed in non-cancerous prostate cells, and wherein a higher level of the antigen comprising integrin alphal0 polypeptide than the control level is indicative of the presence of a cancer type of prostate cancer in the subject.

[0289] Item 71: The method according to any one of Items 60 to 65, wherein the method is a method for detecting the presence of pancreatic cancer cells in a subject or a method for diagnosing pancreatic cancer in a subject, wherein the method comprises comparing the expression level of integrin alphal0 polypeptide determined in step (b) with a control level, wherein the control level is an average value of the expression levels of (i) the antigen or (ii) the transcript polynucleotide observed in non-cancerous pancreatic cells, and wherein a higher expression level of integrin alphal0 polypeptide than the control level is indicative of the presence of a cancer type of pancreatic cancer in the subject.

[0290] Item 72: The method of any one of Items 60 to 65, wherein the method is a method for detecting the presence of a sarcoma in a subject or a method for diagnosing a sarcoma in a subject, wherein the method comprises comparing the expression level of integrin alpha 10 polypeptide determined in step (b) with a control level, wherein the control level is an average value of the expression levels of (i) the antigen or (ii) the transcript polynucleotide observed in non-cancerous sarcoma cells, and wherein a higher level of the antigen comprising the integrin alpha 10 polypeptide than the control level is indicative of the presence of a sarcoma in the subject.

[0291] Item 73: A method for classifying a triple-negative breast cancer tumor sample from a subject, the method comprising: (a) providing breast tissue of a subject suspected of containing cancer cells; (b) isolating breast cancer cells characterized as ER-negative, PR-negative and HER2-negative; (c) In isolated cells: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; determining the expression level of and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average expression level of the (i) antigen or (ii) transcript polynucleotide observed in healthy and / or benign breast tissue; Including, wherein (i) antigen expression levels and / or (ii) transcript polynucleotide expression levels in breast cancer cells that are higher than control levels, and an expression status that is ER-negative, PR-negative, and HER2-negative, are indicative of basal-like triple-negative breast cancer or luminal triple-negative breast cancer, thereby classifying the triple-negative breast cancer tumor sample as belonging to a basal-like triple-negative breast cancer tumor or a luminal triple-negative breast cancer tumor.

[0292] Item 74: The method according to Item 73, wherein expression of integrin alpha 10 and expression of one or more polypeptides selected from the group consisting of cytokeratin 7, cytokeratin 8, cytokeratin 18 and cytokeratin 19 are indicative of luminal triple-negative breast cancer.

[0293] Item 75: The method of Item 73, wherein expression of integrin alpha 10 and expression of one or more polypeptides selected from the group consisting of cytokeratin 5 / 6, cytokeratin 14, cytokeratin 17, p63, EGFR, 34BE12 and c-kit / CD117 are indicative of basal-like triple-negative breast cancer.

[0294] Item 76: A method for determining the prognosis of a cancer type in a subject, the method comprising: (a) providing cancer tumor tissue from a subject; (b) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; analyzing whether or not (c) determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide; (d) comparing the expression level determined in step (c) to a control level, wherein the control level is the average expression level of the (i) antigen and / or (ii) transcript polynucleotide observed in healthy and / or benign tissue of the same tissue type as the sample; (e) determining that the prognosis of the cancer type is poor if the expression level of (i) the integrin alphal0 antigen and / or (ii) the integrin alphal0 transcript polynucleotide is higher than the control level; Including, wherein said cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastasis of any of said cancer types.

[0295] Item 77: A method for determining the prognosis of a cancer type in a subject, the method comprising: (a) providing cancer tumor tissue from a subject; (b) optionally analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) In the sample: (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; analyzing whether or not (d) optionally determining the expression level of (i) the integrin alphal0 antigen and / or (ii) the transcript polynucleotide and comparing the determined expression level to a control level, wherein the control level is the average of the expression levels of (i) the antigen and / or (ii) the transcript polynucleotide observed in healthy and / or benign tissue of the same tissue type as the sample; (e) one or more cells having a cancerous morphology are present in the tissue, and (i) an integrin alpha 10 antigen and / or (ii) an integrin alpha 10 transcript polynucleotide are expressed; and / or (i) the expression level of the integrin alpha 10 antigen and / or (ii) the expression level of the integrin alpha 10 transcript polynucleotide is higher than the control level; determining that the prognosis of the cancer type is poor; Including, wherein said cancer type is selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, or metastasis of any of said cancer types.

[0296] Item 78: The method according to any one of Items 76 to 77, wherein the prognosis is overall survival rate or recurrence-free survival rate.

[0297] Item 79: The method according to any one of Items 60 to 78, wherein the sample (i) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (ii) a transcript polynucleotide encoding an integrin alphal0 polypeptide or a fragment thereof or a variant (variant) thereof; wherein said step of analyzing for the presence of comprises imaging of the tissue and / or tissue sample.

[0298] Item 80: The method of any one of items 60 to 79, wherein the step of determining the expression level of (i) integrin alpha 10 antigen and / or (ii) transcript polynucleotide comprises imaging of the tissue and / or tissue sample.

[0299] Item 81: A method for preventing metastasis of a primary cancer, the primary cancer being a cancer type selected from the group consisting of breast cancer, lung cancer, prostate cancer, pancreatic cancer and sarcoma, wherein the method comprises: (a) an antibody or antigen-binding fragment thereof specific for an integrin alpha10 polypeptide; and / or (b) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; to a patient in need thereof in a therapeutically effective amount.

[0300] Item 82: The method of Item 81, wherein if primary cancer is detected, (a) an antibody or antigen-binding fragment and / or (b) a transcript polynucleotide is administered.

[0301] Item 83: A method for inhibiting integrin alpha 10-mediated signaling in at least one cancer cell, the method comprising treating at least one cancer cell with an effective amount of: (a) an antibody or antigen-binding fragment specific for an integrin alpha10 polypeptide; and / or (b) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; contacting the composition comprising wherein the at least one cancer cell is selected from the group consisting of a breast cancer cell, a lung cancer cell, a prostate cancer cell, a pancreatic cancer cell, a sarcoma cell, and a metastatic tumor cell.

[0302] Item 84: A method for inhibiting cellular function of at least one cancer cell, comprising administering an effective amount of: (a) an antibody or antigen-binding fragment specific for an integrin alpha10 polypeptide; and / or (b) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; the method comprising contacting at least one cancer cell with a composition comprising wherein the at least one cancer cell is selected from the group consisting of a breast cancer cell, a lung cancer cell, a prostate cancer cell, a pancreatic cancer cell, a sarcoma cell, and a metastatic tumor cell.

[0303] Item 85: The method according to any one of Items 60 to 84, wherein the antigen comprising the integrin alphal0 polypeptide or a fragment thereof is expressed on the cell surface.

[0304] Item 86: The method of any one of Items 84 to 85, wherein the cellular function of at least one cancer cell is inhibited, wherein the at least one cancer cell is present in a tumor and / or a metastatic tumor, and the inhibiting comprises: (a) inhibiting the growth of at least one cancer cell; (b) inhibiting the self-renewal of at least one cancer cell; (c) inhibiting anchorage-independent growth of at least one cancer cell; (d) inhibiting the migration of at least one cancer cell; (e) inhibiting the invasion of at least one cancer cell; (f) inhibiting the survival of at least one cancer cell; (g) inhibiting adhesion of at least one cancer cell; and / or Combinations of these, The method is selected from the group consisting of:

[0305] Item 87: The method of any one of Items 84 to 86, wherein the cellular function of at least one cancer cell is inhibited, wherein the at least one cancer cell is present in a tumor and / or a metastatic tumor, and inhibiting the cellular function of the at least one cancer cell comprises: (a) inhibiting tumor and / or metastatic tumor growth; (b) inhibiting tumor and / or metastatic tumor growth; (c) inhibiting tumor and / or metastatic tumor migration; (d) inhibiting tumor and / or metastatic tumor invasion; (e) inhibiting the spread of new and / or metastatic tumors; (f) inhibiting the development of new tumors and / or metastatic tumors; (g) inhibiting the invasion of new and / or metastatic tumors; and / or Combinations of these, The method is at least one of:

[0306] Item 88: The method according to any one of Items 83 to 87, wherein the at least one cancer cell is: (a) an antigen comprising an integrin alpha10 polypeptide or a fragment thereof; and / or (b) a transcript polynucleotide encoding an integrin alpha 10 polypeptide or a fragment thereof or a variant (modification) thereof; is characterized by a higher expression level than a control level of wherein the control level is the average expression level of (a) the antigen and / or (b) the polynucleotide observed in healthy and / or benign cells of the same tissue type as the cancer cells.

[0307] Item 89: The method and / or composition according to any one of items 49 to 88, wherein the composition is a composition according to any one of items 1 to 48.

[0308] Item 90: The method according to any one of items 59 to 89, wherein the method further comprises administering to the subject the composition according to any one of items 1 to 48, or a fragment thereof.

[0309] Item 91: The method according to any one of Items 60 to 90, wherein the method is an in vitro method and the tissue is a tissue sample obtained from a subject.

[0310] Item 92: The composition of claim 49, wherein the diagnosis is an in vitro diagnosis.

[0311] Item 93: Use of a composition, wherein the composition comprises: (a) an antibody that specifically binds to an integrin alpha 10 polypeptide or a fragment thereof; or (b) a polynucleotide that specifically binds to a transcript polynucleotide encoding an integrin alpha 10 polypeptide, a fragment thereof, or a variant (modified) thereof; wherein the composition is used in the manufacture of a medicament for the treatment and / or prevention of a cancer type selected from the group consisting of breast cancer, lung cancer, prostate cancer and pancreatic cancer, or metastasis of any of said cancer types.

[0312] Item 94: The composition, use or method according to any one of Items 1 to 93, wherein the cancer type is an aggressive cancer type selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer, aggressive pancreatic cancer and aggressive sarcoma.

[0313] Example Example 1: Protein expression of integrin alpha 10 visualized by immunohistochemistry in tissues of aggressive tumors, including breast tumors, lung tumors, pancreatic tumors and sarcomas, compared to expression in non-affected tissue areas Materials and Methods Human tissue samples consisted of breast, lung, pancreas, and sarcoma tissues. A standard immunohistochemistry protocol (see Renshaw 2007, ISBN 10:1 904842 038, Scion Publishing Ltd, UK) was optimized (see below) using an HRP polymer-conjugated secondary antibody (DAKO Envision anti-rabbit, DK), followed by diaminobenzidine and hydrogen peroxide reaction.

[0314] For breast and pancreatic tissues: Paraffin sections (4 or 8 μm) were used. Sections were deparaffinized by immersion in xylene and rehydrated in a series of ethanol and water solutions according to standard protocols. Procedures performed to optimize the labeling protocol included processing paraffin sections for antigen retrieval, which involved immersion in an acidic buffer solution (citrate buffer: 10 mM sodium citrate, 0.05% Tween 20, pH 6.0) followed by heat treatment (92–95°C).

[0315] For lung and sarcoma tissue: Cryosections (8 μm) and the same protocol as above were used. The procedures performed to optimize the labeling protocol included post-fixation of the cryosections with acetone (100%) at -20°C and quenching with 0.3% hydrogen peroxide before blocking (PBS containing 1% BSA and 0.05% Triton-X100). Between pretreatment and incubation steps, three 3-minute rinses with PBS were performed.

[0316] Triton-X100 (0.05%) was added to the primary antibody dilution buffer. Between pretreatment and incubation steps, three 3-minute rinses with PBS were performed. Nuclei were visualized by counterstaining the sections with Mayer's hematoxylin solution.

[0317] The primary antibody used was a rabbit anti-integrin α10 polyclonal antibody at a concentration of 3 μg / ml.

[0318] result Integrin α10 is specifically and highly expressed in multiple aggressive cancer types, including invasive ductal carcinoma (Figure 1A), and in triple-negative breast cancer tissue (Figure 2), whereas integrin α10 expression is negligible in morphologically normal breast tissue (Figure 1B). As expected, integrin α10 was localized to the cell membrane (arrow).

[0319] Furthermore, integrin α10 was significantly expressed in squamous lung cancer cells (data not shown), pancreatic cancer cells, and proliferating islet cells in pancreatic ductal adenocarcinoma tissue (data not shown), but not in surrounding morphologically healthy tissue. Integrin α10 was significantly expressed in undifferentiated pleomorphic sarcoma cells (Figure 3).

[0320] conclusion The results show that integrin alpha10 is significantly expressed in patient tissues obtained in several different cancer types that are considered to be the most aggressive.

[0321] Example 2: Expression of integrin alpha10 visualized by immunofluorescence in breast and prostate cancer cell lines Materials and Methods Triple-negative breast cancer cell line BT549 and luminal A breast cancer cell line T47D cells (originally obtained from the American Type Culture Collection (ATCC)) were grown in monolayers, while prostate cancer cell line PC-3 cells were grown as spheres on Ibidi microslide 8-well microscope slides (Ibidi Labware, Germany). Immunofluorescence was performed according to the protocol described in Example 2 of PCT / EP2017 / 070838. The primary antibody used was a mouse monoclonal surrogate antibody against integrin α10 at 1.7 μg / ml. The secondary antibodies were fluorophore-conjugated antibodies (anti-mouse AF488 or AF647 conjugate and / or anti-rabbit AF488 or RodRX, both raised in donkeys and obtained from Jackson Immunoresearch, USA). All secondary antibodies were diluted 1:200 in PBS containing 1% BSA, and incubation was performed for 30 minutes.

[0322] result Immunofluorescence observation by confocal microscopy revealed that integrin α10 was highly expressed specifically on the cell membrane in two different breast cancer cell lines (Figure 4A-B) and a prostate cancer cell line (Figure 4C).

[0323] conclusion The results demonstrate that integrin alpha10 is significantly expressed in cell lines derived from different aggressive cancers.

[0324] Example 3: Monolayer culture of human non-malignant and cancer cell lines and flow cytometry analysis of integrin alpha10 protein expression Materials and Methods The following cancer cell lines were originally obtained from the American Type Culture Collection (ATCC): breast cancer cell lines 184A1, HCC1428, T47D, MDA-MB-231, and BT549; lung cancer cell lines A549 (adenocarcinoma) and U-1752 (squamous lung carcinoma); prostate cancer cell lines 22Rv1, Du145, and PC-3; and pancreatic cancer cell lines BxPC-3, AsPC-1, PANC-1, and MiaPaCa-2.

[0325] Cell line 184A1 was established from healthy breast tissue obtained during reduction mammoplasty. Cells derived from this tissue were exposed to benzo(a)pyrene to establish a transformed line. In this cell line, the cells appear to be immortalized but not malignant. All other cell lines are malignant cells derived from malignant tumors (see table below).

[0326] Cells were immunostained by incubating them with a mouse anti-integrin 10 monoclonal surrogate antibody (Alexa Fluor 647 conjugate) at a concentration of 1.0 μg / ml for 30 min in the dark at 4° C. After 30 min of incubation with the primary antibody, cells were washed twice with DPBS containing 1% FBS and 0.1% sodium azide (Hyclone, SH3002802) before being analyzed by flow cytometry using a BD Accuri C6 flow cytometer.

[0327] [Table 2]

[0328] result The results for breast cancer cells show that integrin α10 is moderately expressed in monolayer-cultured T47D cells, whereas it is highly expressed in the triple-negative cell line BT549 (Figures 5A and 5B). In monolayer culture, aggressive prostate cancer cells PC-3 showed the highest integrin α10 expression (Figures 5E and 5F). Furthermore, the most invasive high-grade pancreatic cancer cell lines (grade III), MiaPaCa-2 and PANC-1, also showed the highest integrin α10 expression (Figure 5I). In contrast, the less aggressive pancreatic cancer cell lines BxPC-3 and AsPC-1 either did not express integrin α10 or expressed it at lower levels, which was particularly evident in sphere cultures (see Example 4, Figure 5J). Expression was significantly lower in monolayer-cultured lung cancer cells (Figure 5K), but increased when the same cells were cultured as spheres (Figure 5L and Experiment 4).

[0329] conclusion These results indicate that integrin α10 expression is highest in the most aggressive cancer types. This suggests a correlation between the malignant potential of different cancers and integrin α10, and therefore likely also with cell migration and invasiveness. This finding is readily apparent in monoculture systems and is even more evident in three-dimensional (3D) culture systems (see Example 4). 3D cell culture models offer improved cell-cell interactions, cell-ECM interactions, and cell populations, as well as a structure that resembles in vivo architecture, making them a better model than traditional 2D monolayer cultures.

[0330] Example 4: Detection and analysis of integrin alpha 10 protein in a sphere-forming assay Materials and Methods Breast cell lines 184A1, HCC1428, T47D, MDA-MB-231, and BT549, lung cancer cell lines A549 and U-1752, prostate cancer cell lines 22Rv1, DU145, and PC-3, pancreatic cancer cell lines BxPC-3, AsPC-1, PANC-1, and MiaPACa-2, and sarcoma cell line MFH152 were seeded in serum-free medium in ultra-low attachment plates (CLS3471, Corning) to form self-renewing, nonadherent spheres (called mammospheres for breast cancer and prostaspheres for prostate cancer). Scaffold-free cultures are formed by cell aggregates commonly known as spheroids or spheres. The plating medium for sphere formation consisted of DMEM / F12 (1:1) w / Glutamax (31331-08, Gibco) medium supplemented with B27 (12587-010, Gibco), 20 ng / ml human basic fibroblast growth factor (Miltenyi Biotec), 20 ng / ml human epidermal growth factor (Miltenyi Biotec), and 100 U / ml penicillin and 100 U / ml streptomycin. Cells were incubated in an incubator for approximately 10 days, with the first 5 days being particularly stable. Immunostaining and flow cytometry analysis were performed as described in Example 3 using a mouse anti-integrin α10 monoclonal surrogate antibody. The 3D culture system provides an excellent in vitro model, allowing for the study of cellular responses in a context similar to the in vivo environment.

[0331] result Experimental results from breast cancer demonstrated that integrin α10 expression was significantly increased when aggressive triple-negative breast cancer cells MDA-MB-231 and BT549 were cultured under three-dimensional (sphere) conditions that mimic tumor growth in vitro (Figure 5C-D). In the non-malignant or minimally aggressive breast cell lines 184A1 and HCC1428, sphere culture did not increase integrin α10 expression. In the aggressive prostate cancer cell line PC-3, integrin α10 protein expression was also upregulated when cells were grown into spheres (Figure 5G-H) compared to monolayer culture (Figure 5E-F). Similarly, aggressive pancreatic cancer cells PANC-1 and MiaPaCa-2 readily formed spheres, and integrin α10 protein expression was significantly increased compared to monolayer culture (Figure 5I-J). In contrast, increased expression of integrin α10 was not observed in the cell lines BxPC-3 and AsPC-1, and furthermore, spheres did not form in AsPC-1 cultures. In lung cancer cells A549 and U-1752, which grew into spheres, the level of integrin α10 protein was significantly increased (Figure 5K-L). Similarly, the aggressive sarcoma cell line MFH152 readily formed spheres and showed significantly increased expression of integrin α10 protein compared to monolayer cultures (Figure 5M).

[0332] conclusion Our results demonstrate that integrin α10 expression is highest in the most aggressive cancer types. In sphere culture (three-dimensional cell culture), an excellent method for mimicking in vivo tumor growth, integrin α10 expression in aggressive cancer cells is further increased. This further supports the correlation between integrin α10 and aggressive cancer.

[0333] Example 5: Detection and analysis of integrin alpha 10 mRNA (ITGA10) expression in human breast, prostate, and pancreatic cancer cell lines cultured in monolayers or spheres Materials and Methods RNA extraction and quantitative PCR were performed on different cell lines cultured either in monolayers or in spheres to mimic tumor growth. Total RNA was extracted from cells using the RNeasy Plus Mini Kit (Qiagen) and converted to cDNA by reverse transcription using the SuperScript cDNA Synthesis Kit (Life Technologies). Quantitative PCR was performed using TaqMan Gene Expression Master Mix (Life Technologies) and TaqMan probes (Thermo Fisher Scientific): GAPDH (Mm99999915_g1) and ITGA10 (Mm01265767_m1). The cycles at which the target genes reached threshold were normalized to the geometric mean of the housekeeping gene GAPDH to obtain ΔCt. In the final analysis, 2 to the power of -ΔCt (2 -ΔCt ) was calculated.

[0334] result As shown in the respective figures, the levels of integrin α10 mRNA (ITGA10) were higher in highly invasive and aggressive cancer cells, i.e., triple-negative breast cancer cells MDA-MB-231 and BT549 (Figure 6A-B), prostate cancer cell PC-3 (Figure 6C-D), and pancreatic cancer cells PANC-1 and MiaPaCa-2 (Figure 6E-F), compared with the less invasive and aggressive cell lines, i.e., non-malignant breast cancer cell 184A1, breast cancer cells HCC1428 and T47D, prostate cancer cells 22RV1 and DU145, and pancreatic cancer cells BxPC-3 and AsPC-1. Furthermore, the level of integrin α10 mRNA (ITGA10) was significantly increased when cells were cultured in sphere conditions compared with monolayer conditions (see Figure 6A vs. 6B, Figure 6C vs. 6D, and Figure 6E vs. 6F).

[0335] conclusion Our results demonstrate that integrin α10 mRNA expression is highest in the most aggressive cancer types. Spheroid culture (three-dimensional cell culture), an excellent method for mimicking in vivo tumor growth, further increases integrin α10 expression in aggressive cancer cells. This further supports the correlation between integrin α10 and aggressive cancer.

[0336] Example 6: Overall survival curves and ITGA10 gene expression in different cancers Materials and Methods Overall survival curves and ITGA10 gene expression (A) were analyzed for 255 patients with triple-negative breast cancer (Gyorffy B et al., 2010). Patients were divided into ITGA10 low-expressing and ITGA10 high-expressing cohorts based on a median cutoff. Kaplan-Meier plots were generated, and the log-rank test was used to determine differences in recurrence-free survival rates. The cutoff value used for the analysis was 224.

[0337] Overall survival curves for squamous cell lung cancer (database GSE4573, 88 samples), prostate adenocarcinoma (database TCGA-Prostate Adenocarcinoma, 413 samples), localized pancreatic ductal adenocarcinoma (database GSE211501, 102 samples), and sarcoma (database TCGA-Sarcoma, 234 samples) were analyzed using the PROGgeneV2 tool for ITGA10 high and ITGA10 low expression groups separated by the median. This analysis allowed us to examine how ITGA10 gene expression correlates with prognosis in the corresponding microarray datasets (Goswami CP et al., 2013).

[0338] result The survival curves show the difference in overall survival between patients with high ITGA10 expression (solid line) and low ITGA10 expression (dotted line) (Figure 7). For survival analysis and log-rank tests, patients were divided into high and low ITGA10 expression groups based on the median cutoff. P values ​​are for the log-rank test of the difference in overall survival. For all cancer types listed, patients with high ITGA10 expression had a lower survival rate than patients with low ITGA10 expression.

[0339] conclusion In the cancer types described, high expression of ITGA10 correlates with poor overall survival.

[0340] Example 7: Cell adhesion inhibition after blocking integrin alpha10 with antibodies Materials and Methods The day before the adhesion assay, 48-well plates were coated with type I collagen (Sigma, C7661-5MG), type IV collagen (Sigma, C5533-5MG), or bovine serum albumin (BSA). On the day of the experiment, the plates were incubated with 0.25% BSA at 37°C for 30 minutes to block nonspecific binding. Simultaneously, cancer cells (BT549 breast cancer cells and PC-3 prostate cancer cells) were harvested and suspended in HBSS to form a single cell suspension. The cells were preincubated for 30 minutes with or without a 10 μg / ml concentration of mouse monoclonal antibody mAbα against the integrin α10 polypeptide. An isotopic mouse control monoclonal antibody IgG2a was used as a negative control. Cells were then allowed to adhere for 60 minutes, and nonadherent cells were removed by washing with HBSS. Adherent cells were fixed with 96% ethanol and stained with 0.1% crystal violet. The absorbance was measured at a wavelength of 590 nm using a plate reader.

[0341] result Treatment of breast cells BT549 with a function-blocking monoclonal antibody against the integrin α10 polypeptide significantly increased cell adhesion of BT549 cells to type I and type IV collagen (Figure 8). This effect was observed in both monolayer (Figure 8A-B) and mammosphere (Figure 8C-D) cultures compared with untreated or IgG2a-treated cells. Similarly, treatment with a function-blocking monoclonal antibody against integrin α10 significantly decreased cell adhesion of PC-3 cells cultured in spheres to type I and type IV collagen compared with untreated control cells (Figure 8E-F). BSA-coated wells were used as a negative control because integrin receptors mediate cell adhesion to the extracellular matrix (ECM), and cells do not adhere to BSA-coated wells.

[0342] conclusion These results revealed that integrin α10 function-blocking antibodies can block adhesion, thereby potentially affecting key functions of tumor cells (such as proliferation, migration, and growth).

[0343] Example 8: Decreased cell migration after blocking integrin α10 with monoclonal antibodies Materials and Methods Cell migration assays were performed using a Boyden chamber (Corning) with an 8 μm pore size polycarbonate filter for breast cancer cells BT549, lung cancer cells A549, and prostate cancer cells PC-3. The filter was coated with type IV collagen (Sigma, C5533-5MG) for breast cancer cells BT549, type I collagen (Sigma, C7661-5MG) for prostate cancer cells PC-3, and uncoated for lung cancer cells A549. A collagen working solution (0.01 mg / ml) for the cell migration assay was prepared from the stock solution (1 mg / ml) in PBS. The lower chamber was filled with medium containing 10% FBS as a chemoattractant, and a monoclonal antibody against integrin α10 was also added. The cancer cells were incubated with 5 μg / ml of antibody for 30 minutes before adding the cells to the upper chamber of the Boyden chamber. After 24 or 48 hours, the cells in the inferior cisterna were fixed and stained with crystal violet, and the OD590nm was measured using a plate reader (SpectraMax ABS, Molecular Devices).

[0344] Cell migration assay of breast cancer cells: Cells were incubated with either a mouse anti-integrin alpha 10 monoclonal antibody (mAb alpha 10) or the human anti-integrin alpha 10 antibody Th101, which bind to different epitopes of integrin alpha 10 (see Example 12). As negative controls, cells were incubated with the negative control antibody Th301 (human IgG1 VH / lambda) or the negative / isotope control antibody IgG2a (mouse monoclonal IgG2a, kappa), or antibody treatment was omitted completely (NT = no treatment).

[0345] Cell migration assay of prostate cancer cells: Cells were incubated with mouse anti-integrin α10 monoclonal antibody (mAb α10) and allowed to migrate for 24 or 48 hours. As a negative control, cells were incubated with isotope control antibody IgG2a.

[0346] Lung cancer cell migration assay: Cells were incubated with mouse anti-integrin α10 monoclonal antibody (mAb α10) for 24 or 48 hours. As a negative control, cells were incubated with isotope control antibody IgG2a.

[0347] result Breast cancer cells: Incubation with either the anti-integrin α10 monoclonal antibody mAb α10 or Th101 reduced cell migration compared to untreated cells or cells incubated with a control antibody (Figure 9A). Both anti-integrin α10 antibodies exerted similar effects.

[0348] Prostate cancer cells: Incubation with the anti-integrin α10 antibody mAb α10 reduced cell migration compared to cells incubated with a control antibody (Figure 9B). This effect was enhanced when cells were assayed for 48 hours compared to 24 hours.

[0349] Lung cancer cells: Similarly, incubation with anti-integrin α10 monoclonal antibody mAbα10 reduced cell migration compared to cells incubated with a control antibody (FIG. 9C).

[0350] conclusion The present results demonstrate that integrin alpha 10 monoclonal antibodies can block integrin alpha 10 and inhibit the migration of breast and prostate cancer cells (FIGS. 9A and 9B, respectively) and lung cancer cells (FIG. 9C).

[0351] Example 9: Decreased viability of breast cancer cells treated with integrin alpha 10 antibody drug conjugates Materials and Methods BT549 breast cancer cells were cultured in monolayers in 96-well plates and treated with anti-integrin α10-MMAE ADCs (antibody-drug conjugates or anti-control MMAE ADCs). The ADCs were conjugated with a mouse monoclonal surrogate antibody against integrin α10 (IgG1 (kappa)) or an isotype control antibody (IgG1 (anti-ctrl)) conjugated with the microtubule inhibitor monomethyl auristatin E (MMAE). Cells were incubated with 23 nM, 69 nM, or 207 nM ADCs at 37°C for 4 days. Cell viability was assessed using the WST-1 assay (Roche, Mannheim, Germany) according to the manufacturer's recommendations.

[0352] result An antibody-drug conjugate (ADC) consisting of an integrin α10 antibody conjugated to the potent cytotoxin MMAE (anti-α10-MMAE) induced cell death in breast cancer cells (Figure 10). In contrast, no cell death was observed when cells were treated with an isotype control antibody IgG1 conjugated to MMAE (control antibody-MMAE). Breast cancer cell viability decreased with increasing concentrations of the antibody-drug conjugate.

[0353] conclusion The present results demonstrate the specific cytotoxic effect of the integrin alpha 10 antibody conjugate.

[0354] Example 10: Anti-alpha10 monoclonal antibody treatment inhibits in vitro cell proliferation of aggressive breast, pancreatic, and lung cancer cells Materials and Methods Sphere assay (Figures 11A-D and F): Breast cancer cells (BT549), prostate cancer cells (PC-3), pancreatic cancer cells (MiaPaCa-2 and PANC-1), and lung cancer cells (A549) were seeded in serum-free medium in ultra-low attachment 6-well plates (CLS3471, Corning) to form non-adherent spheres. Simultaneously with seeding, cells were treated with 10 μg / ml of either anti-integrin α10 monoclonal antibody mAbα10 or control antibody (IgG2a). The antibody was added every 2 days for 14 days. After 14 days of treatment, BrdU (final concentration 10 μM) was added to the spheres, and the cells were incubated for 24 hours. Cells were then harvested for BrdU analysis using flow cytometry according to the instructions in the BD Pharmigen APC BrdU Flow Kit (Cat. No. 552598). The mean fluorescence intensity of BrdU staining was calculated. For lung cancer cells (A549), in addition to BrdU staining, 7-aminoactinomycin D (7-AAD) was added to stain total DNA. Cell cycle analysis was performed based on both BrdU and 7-AAD staining.

[0355] Monolayer assay (Figure ​(Figure6E): BT549 adherent breast cancer cells were seeded onto type IV collagen-coated 96-well plates and treated with anti-integrin α10 monoclonal antibody (mAbα10 or Th101) at a final concentration of 5 μg / ml immediately after cell seeding. After 24 hours of antibody treatment, BrdU was added 2.5 hours later, and proliferation was determined using the Cell Proliferation ELISA BrdU kit (Roche Diagnostics GmbH) according to the manufacturer's instructions.

[0356] Cell cycle analysis (Figure 11F): The proportion and nature of individual cells synthesizing DNA were determined by immunofluorescent staining for incorporated bromodeoxyuridine (BrdU) and flow cytometric analysis. In this method, BrdU (an analog of the DNA precursor thymidine) is incorporated into newly synthesized DNA by cells entering and progressing through the S (DNA synthesis) phase of the cell cycle. A specific anti-BrdU fluorescent antibody is used to stain for incorporated BrdU. Cellular BrdU levels are then measured by flow cytometry. Staining with a dye that binds to total DNA, such as 7-aminoactinomycin D (7-AAD), is often combined with immunofluorescent BrdU staining. This combination allows for the enumeration of cells actively synthesizing DNA (BrdU incorporation) and characterization of their cell cycle position (i.e., G0 / G1, S, or G2+M, as determined by 7-AAD staining intensity) using dual-stain flow cytometric analysis.

[0357] result Sphere assay: The results demonstrate that function-blocking α10 monoclonal antibody reduces the proliferation of aggressive breast cancer (Figure 11A), aggressive prostate cancer (Figure 11B), and aggressive pancreatic cancer cells (Figures 11C-D). This was compared to proliferation after treatment with the control antibody IgG2a, which did not reduce proliferation at all. In the lung cancer cell line A549, cell cycle analysis showed that α10 monoclonal antibody treatment arrested cells in the G0 / G1 phase, thereby inhibiting cell proliferation, compared to treatment with the control antibody IgG2a (Figure 11F).

[0358] Monolayer assay: Figure 11E shows that anti-integrin alpha 10 antibodies (mAb alpha 10 and Th101) blocked cell proliferation of monolayer cultured breast cancer cells compared to incubation in the presence of control antibody or in the absence of antibody.

[0359] conclusion The present results confirm that integrin alpha 10 is involved in the cell proliferation process, indicating that anti-integrin alpha 10 antibodies have potential as therapeutic agents to suppress cancer growth.

[0360] Example 11: Treatment with integrin alpha 10 antibody inhibits the progression of breast tumor growth in vivo Materials and Methods All in vivo experiments were performed using 6-8 week-old female NMRI-nu immunodeficient mice (n = 5 per group) purchased from Janvier Labs (France). Animal welfare and experimental procedures were performed in accordance with international standards, and animals were maintained under specific pathogen-free conditions (SPF). All experimental methods were approved by the Malmö and Lund Animal Ethics Committee (Sweden). For tumor induction, 2 x 10 6Matrigel containing 1000 BT549 aggressive breast cancer cells was inoculated subcutaneously into the right flank region of mice. Two to three weeks after injection, tumor growth was tracked by noninvasive two-dimensional bioluminescence (BLI) imaging using an IVIS-CT Spectrum (PerkinElmer, MA, USA). Mice showing signs of tumor growth were randomly divided into two groups (control and treatment) based on the mean BLI signal intensity recorded in a defined region of interest (ROI) along with the mean total flux value (photons / s). Several different antibodies against integrin α10 were used in this experiment: mouse monoclonal antibody mAb α10 and human monoclonal antibody Th101. The concentration of each antibody injected into mice was calculated to be 5 mg / kg, and the antibodies were administered to the animals via intraperitoneal injection until the endpoint. Tumor growth was tracked using bioluminescence 2D and 3D microCT imaging. Briefly, before imaging, mice were anesthetized with 3% isoflurane gas and intraperitoneally injected with 150 mg / kg body weight of D-luciferin dissolved in PBS. 2D images were acquired by sequentially imaging five intervals between different exposure segments (emission: open filter, f / stop: 1, binding: 8). After estimating the average background signal (Bkg) from region of interest (ROI) measurements using bioimage analysis software (PerkinElmer, MA, USA), BLI signal intensity was quantified as total flux (photons / s). Mouse weights were recorded weekly before antibody treatment. No pathological signs or reduced growth rates were observed.

[0361] result The results show that mice treated with the integrin alpha 10 antibody mAb alpha 10 or Th101 had reduced total flux readings compared to mice treated with negative control antibodies (IgG2a and Th301) (Figure 12A), indicating reduced tumor growth. Animal weights were followed from the start of treatment, and no signs of pathology or weight loss were observed in animals treated with each antibody (Figure 12B).

[0362] conclusion The present results show that different antibodies against integrin alpha 10 (here, mAb alpha 10 (=Ab365) or Th101) reduce tumor growth in vivo, which may suggest the usefulness of anti-integrin alpha 10 antibodies as therapeutic agents to suppress cancer growth.

[0363] Example 12: Monoclonal antibodies mAb alpha10 and Th101 bind to different epitopes on integrin alpha10 Materials and Methods A binding competition assay was performed between mouse monoclonal antibody mAb α10 and human monoclonal antibody Th101 in C2C12α10 cells overexpressing integrin α10 and triple-negative breast cancer BT549 cells. Cells were incubated with the indicated concentrations (μg / ml) of single or mixed antibodies for 30 minutes, washed twice, and then stained with secondary antibodies for 30 minutes. Donkey anti-human Alexa 488 was used as the secondary antibody for human monoclonal antibody Th101. Donkey anti-mouse Alexa 647 was used as the secondary antibody for mouse monoclonal antibody mAb mAb10. Antibody binding was analyzed by flow cytometry, and the fluorescent signal of the secondary antibody was detected.

[0364] Data are expressed as the mean fluorescence intensity of 100,000 cells.

[0365] result Flow cytometry data show that increasing the concentration of Th101 antibody does not significantly change the binding intensity of antibody mAbα10 (Figure 13A-B). The signal corresponding to antibody mAbα10 (at a constant concentration of 3 μg / ml) remained stable (black bars) even when increasing concentrations of antibody Th101 (0-9 μg / ml) were added to the reaction wells (gray bars) (left part of each figure).

[0366] Conversely, the binding intensity of Th101 was not affected by increasing concentrations of mAbα10 (Figure 13A-B). The signal corresponding to antibody Th101 (at a constant concentration of 3 μg / ml) remained stable (gray bars) even with increasing concentrations (0-9 μg / ml) of antibody mAbα10 added to the reaction wells (black bars) (right part of each figure).

[0367] Similar results were obtained for the C2C12α10 cell line (FIG. 13A) and the BT549 cell line (FIG. 13B), respectively.

[0368] conclusion If the antibodies bind to the same epitope, increasing the concentration of one antibody should decrease the binding of the other antibody due to competition for the same binding site. This ruled out, so our results suggest that the two integrin α10 monoclonal antibodies, mAb α10 and Th101, bind to different epitopes on the integrin α10 antigen.

[0369] Example 13: Sequences Human integrin α10 polypeptide sequence information SEQ ID NO: 1 Full-length polypeptide of human integrin α10 See sequence listing. SEQ ID NO: 2 The extracellular domain of human integrin α10 See sequence listing. SEQ ID NO: 3 Human integrin α10 I domain See sequence listing.

[0370] Sequence information of anti-integrin α10 antibody Th101 SEQ ID NO:4: Complementarity-determining region 1 of the heavy chain variable region (CDR-H1) FTFSDYGMN SEQ ID NO:5: Complementarity-determining region 2 of the heavy chain variable region (CDR-H2) VISYDGSNKYYADSVKG SEQ ID NO:6: Complementarity-determining region 3 of the heavy chain variable region (CDR-H3) GGNWGVFDY SEQ ID NO:7: Complementarity-determining region 4 of the light chain variable region (CDR-L1) SGSSSNIGSNPVH SEQ ID NO:8: Complementarity-determining region 5 of the light chain variable region (CDR-L2) ENNKRPS SEQ ID NO:9: Complementarity-determining region 6 of the light chain variable region (CDR-L3) AAWDDSLSGQGV SEQ ID NO:10: Heavy chain variable region EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYGMNWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGNWGVFDYWGQGTLVTVSS SEQ ID NO:11: Light chain variable region QSVLTQPPSASGTPGQRVTISSCSGSSSNIGSNPVHWYQQLPGTAPKLLIYENNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGQGVFGGGTKLTVLG

[0371] References Arpino G, Milano M, De Placido S. Features of aggressive breast cancer, The Breast. 2015;24(5): 594-600. Bengtsson T, Aszodi A, Nicolae C, Hunziker EB, Lundgren-Akerlund E, Fassler R. Loss of alpha10beta1 integrin expression leads to moderate dysfunction of growth plate chondrocytes, J Cell Sci. 2005;118(Pt 5):929-36. Bianchini G, Balko JM, Mayer IA, et al. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 2016;13:674-90. Bombardelli L and Berns A. The steady progress of targeted therapies, promising advances for lung cancer, Ecancermedicalscience 2016;10:638. Camper L, Hellman U, Lundgren-Akerlund. Isolation, Cloning, and Sequence Analysis of the Integrin Subunit α10, a β1-associated Collagen Binding Integrin, Expressed on Chondrocytes, J Biol Chem 1998; 273(32):20383-9. Camper L, Holmvall K, Wangnerud C, Aszodi A, Lundgren-Akerlund E. Distribution of the collagen-binding integrin alpha10beta1 during mouse development, Cell Tissue Res. 2001;306(1):107-16. Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, Shi B. Breast cancer intrinsic subtype classification, clinical use and future trends, Am J Cancer Res. 2015;5(10):2929-2943. Dai X, Xiang L, Li T, Bai Z. Cancer Hallmarks, Biomarkers and Breast Cancer Molecular Subtypes, Journal of Cancer. 2016;7(10):1281-94. Einstein DJ, Arai S, Balk SP. Targeting the androgen receptor and overcoming resistance in prostate cancer, Curr Opin Oncol. 2019; 31(3):175-18. Goswami CP and Nakshatri H. PROGgene: gene expression based survival analysis web application for multiple cancers. J Clin Bioinforma. 2013 Oct 28;3(1):22. Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients, Breast Cancer Res Treatment, 2010 Oct;123(3):725-31. Hariri N, Hasteh F, Walavalkar V, Roma AA, and Fadare, O. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 testing in breast cancer: assessing the value of repeated centralized testing in excision specimens, Appl Immunohistochem Mol Morphol. 2019; 27(1):1-7. Ilic M, Ilic I. Epidemiology of pancreatic cancer. World Journal of Gastroenterology 2016; 44:9694-9705. Lundgren-Akerlund E, Aszodi A. α10β1: a collagen receptor critical in skeletal development, Adv Exp Med Biol. 2014; 819:61-71. Ma L, Liang Z, Zhou H, Qu L. Applications of RNA Indexes for Precision Oncology in Breast Cancer, Genomics Proteomics Bioinformatics. 2018;16(2):108-119. Malorni L, Shetty PB, De Angelis C, et al. Clinical and biologic features of triple-negative breast cancers in a large cohort of patients with long-term follow-up. Breast Cancer Res Treat 2012;136:795-804. Moschos SJ, Drogowski LM, Reppert SL, Kirkwood JM. Integrins and Cancer, Oncology. 2007 Aug;21(9 Suppl 3):13-20. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO Prognostic markers in triple-negative breast cancer. Cancer. 2007 1; 109(1):25-32 Saad F, Shore N, Zhang T, Sharma S, Cho HK, Jacobs IA. Emerging therapeutic targets for patients with advanced prostate cancer. Cancer Treat Rev. 2019;19;76:1-9. U.S. National Institute of Health, National Cancer Institute. SEER Cancer Statistics Review, 1975-2015. Varas L, Ohlsson LB, Honeth G, Olsson A, Bengtsson T, Wiberg C, Bockermann R, Jarnum S, Richter J, Pennington D, Johnstone B, Lundgren-Akerlund E, Kjellman C. Alpha10 integrin expression is up-regulated on fibroblast growth factor-2-treated mesenchymal stem cells with improved chondrogenic differentiation potential, Stem Cells Dev. 2007;16(6):965-78. WHO classification of tumors of soft tissue and bone (2013).

Claims

1. An antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof specifically binds to an integrin alpha 10 polypeptide, and is used in the treatment and / or prevention of an aggressive cancer type selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or metastatic cancer of any of said cancer types.

2. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the aggressive breast cancer is selected from the group consisting of triple-negative breast cancer and inflammatory breast cancer.

3. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the triple-negative breast cancer is selected from the group consisting of basal-like type 1 breast cancer, basal-like type 2 breast cancer, claudin-low breast cancer, metaplastic breast cancer (MBC), interferon-high breast cancer, immunomodulatory breast cancer, mesenchymal breast cancer, mesenchymal stem cell-like breast cancer, luminal androgen receptor breast cancer and unstable breast cancer.

4. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the aggressive lung cancer is selected from the group consisting of squamous cell lung carcinoma, lung adenocarcinoma, large cell lung carcinoma and small cell lung carcinoma.

5. 10. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the aggressive prostate cancer is small cell neuroendocrine carcinoma (SCNC).

6. 10. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the aggressive pancreatic cancer is a neuroendocrine tumor.

7. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the aggressive pancreatic cancer and / or neuroendocrine tumor is grade I, grade II or grade III pancreatic cancer.

8. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein said integrin alphal0 polypeptide is expressed on the surface of malignant cells and / or on the surface of tumor-associated cells.

9. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody or a fragment thereof.

10. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is a non-human antibody, a chimeric antibody, a bispecific antibody, a humanized antibody or a human antibody.

11. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is a murine monoclonal antibody.

12. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is a human monoclonal antibody.

13. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is of an isotype selected from the group consisting of IgA, IgD, IgG, IgE and IgM.

14. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody comprises: (a) a monoclonal antibody produced by the hybridoma cell line deposited at Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under accession number DSM ACC2583; or (b) an antibody that competes for binding to the same epitope as the monoclonal antibody produced by the hybridoma deposited with Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under accession number DSM ACC2583; or (c) a fragment of (a) or (b) capable of specifically binding to the extracellular I domain of the integrin α10 polypeptide chain; An antibody or antigen-binding fragment thereof,

15. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment comprises: (a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; (b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and (c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising: and / or (d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; (e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and (f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; a light chain variable region comprising: or A mutant (modified form) of any one of SEQ ID NOs: 4 to 9; Including, wherein the variant is an antibody or antigen-binding fragment thereof in which any one amino acid has been substituted with another amino acid, provided that such changes are no more than three amino acids, for example, in which two amino acids or one amino acid has been substituted.

16. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:

10.

17. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:

11.

18. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is conjugated to an additional moiety.

19. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein said additional moiety comprises a detectable moiety such as a detectable moiety selected from the group consisting of a fluorophore, an enzyme and a radioactive tracer or radioisotope.

20. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the additional moiety comprises a cytotoxic moiety.

21. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the cytotoxic moiety is selected from the group consisting of a toxin, a chemotherapeutic agent and a radioactive substance, or a combination thereof.

22. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the cytotoxic moiety is a toxin.

23. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the toxin is selected from the group selected from microtubule toxins, DNA toxins and transcription toxins.

24. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the microtubule toxins are selected from the group consisting of auristatin-based toxins, maytansinoid-based toxins, tubulysin-based toxins and eribulin.

25. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the transcription toxin is an RNA polymerase II inhibitor.

26. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the transcription toxin is selected from the group consisting of doxorubicin, doxorubicin derivatives and amanitin.

27. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the transcriptional toxin is selected from the group consisting of Shiga toxins and Shiga-like toxins; type I ribosome-inactivating proteins, type II ribosome-inactivating proteins and saporins, or combinations thereof.

28. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein said type I ribosome-inactivating protein is trichosanthin and / or ruffin.

29. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein said type II ribosome-inactivating protein is ricin, agglutinin and / or abrin.

30. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the integrin alphal0 polypeptide is a naturally occurring variant (variant) of an integrin alphal0 polypeptide or an isoform of an integrin alphal0 polypeptide.

31. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is capable of inducing cell death and / or inhibiting proliferation and / or inhibiting hyperplasia and / or inhibiting migration of cells expressing an integrin alphal0 polypeptide.

32. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the cells are malignant cells and / or tumor-associated cells.

33. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the malignant or tumor-associated cells are cancer-associated fibroblasts (CAFs), stromal cells, stem cells and / or stem-like cells.

34. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein said integrin alphalO polypeptide is part of an integrin alphalObetal heterodimer.

35. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the treatment is prophylactic, ameliorative or curative.

36. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the treatment is initiated upon detection of integrin alpha 10 polypeptide in aggressive cancer cells of a tumor in the subject.

37. 10. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered to an individual in need thereof in combination with radiotherapy and / or surgical removal of cancer.

38. 10. An antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered to an individual in need thereof prior to radiotherapy and / or surgical removal of cancer.

39. 10. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered to an individual in need thereof after radiotherapy and / or surgical removal of cancer.

40. An antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof specifically binds to an integrin alpha 10 polypeptide and is used in the diagnosis of an aggressive cancer selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or metastatic cancer of any of the aggressive cancer types.

41. The antibody or antigen-binding fragment thereof described in claim 40, wherein the cancer comprises cells that exhibit the same or higher levels of integrin alpha 10 antigen as observed in healthy and / or benign tissue of the same type.

42. The antibody or antigen-binding fragment thereof of claim 40, wherein the cancer comprises cells that exhibit the same or higher levels of integrin alpha 10 antigen as observed in a cancer type of the same tissue type but a less aggressive cancer type compared to the diagnosed cancer type.

43. A method for treating an aggressive cancer, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or the aggressive cancer type is metastatic cancer, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an integrin alpha 10 polypeptide.

44. 1. A method for detecting aggressive cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether an antigen comprising an integrin alpha 10 polypeptide or a fragment thereof is present in the tissue; (c) determining the expression level of integrin alpha 10 antigen; and (d) comparing the expression level determined in step (c) with a control level; Including, wherein the control level is the average expression level of the antigen observed in healthy and / or benign cells of the same tissue type as the isolated sample; wherein an expression level of the antigen higher than the control level is indicative of the presence of an aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types.

45. 1. A method for detecting aggressive cancer cells in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) optionally analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) analyzing whether an antigen comprising an integrin alpha 10 polypeptide or a fragment thereof is present in the tissue; (d) optionally determining the expression level of the integrin alpha 10 antigen; Including, wherein the combination of the presence of one or more cells having a cancerous morphology and expressing the integrin alpha 10 antigen is indicative of the presence of an aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types.

46. 1. A method of diagnosing an aggressive cancer type in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) analyzing whether an antigen comprising an integrin alpha 10 polypeptide or a fragment thereof is present in the tissue; (c) determining the expression level of integrin alpha 10 antigen; and (d) comparing the expression level determined in step (c) with a control level, wherein the control level is an average antigen expression level; Including, wherein an antigen expression level higher than the control level is indicative of the presence of an aggressive cancer type in the sample, thereby diagnosing the aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types, or is a metastatic cancer of any of the aggressive cancer types.

47. 1. A method for diagnosing an aggressive cancer type in a subject, the method comprising: (a) providing tissue suspected of containing cancer cells in a subject; (b) optionally analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the sample; (d) optionally determining the expression level of the integrin alpha 10 antigen; Including, wherein the combination of the presence of one or more cells having a cancerous morphology and expressing the integrin alpha 10 antigen is indicative of the presence of an aggressive cancer type in the sample, thereby diagnosing the aggressive cancer type in the subject, wherein the aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of the aggressive cancer types.

48. 1. A method of classifying a triple-negative breast cancer tumor sample from a subject, the method comprising: (a) providing breast tissue of a subject suspected of containing cancer cells; (b) isolating breast cancer cells characterized as being ER-negative, PR-negative and HER2-negative; (c) determining the expression level of an antigen comprising an integrin alphal0 polypeptide or a fragment thereof in the isolated cells; and (d) comparing the expression level determined in step (c) with a control level, wherein said control level is the average antigen expression level observed in healthy and / or benign breast tissue; Including, wherein a breast cancer cell antigen expression level higher than the control level and an expression status that is ER negative, PR negative and HER2 negative are indicative of basal-like triple-negative breast cancer or luminal triple-negative breast cancer, thereby classifying the triple-negative breast cancer tumor sample as belonging to a basal-like triple-negative breast cancer tumor or a luminal triple-negative breast cancer tumor.

49. 1. A method for determining a prognosis of an aggressive cancer type in a subject, the method comprising: (a) providing cancer tumor tissue from a subject; (b) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the sample; (c) determining the expression level of integrin alpha 10 antigen; (d) comparing the expression level determined in step (c) with a control level, wherein the control level is the average antigen expression level observed in healthy and / or benign tissue of the same tissue type as the sample; (e) determining that the prognosis of the aggressive cancer type is poor when the expression level of the integrin α10 antigen is higher than the control level; Including, wherein said aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of said aggressive cancer types.

50. 1. A method for determining a prognosis of an aggressive cancer type in a subject, the method comprising: (a) providing cancer tumor tissue from a subject; (b) optionally analyzing whether one or more cells having a cancerous morphology are present in the tissue; (c) analyzing whether an antigen comprising an integrin alphal0 polypeptide or a fragment thereof is present in the sample; (d) optionally, determining the expression level of the integrin alphal0 antigen and comparing the determined expression level with a control level, wherein the control level is the average antigen expression level observed in healthy and / or benign tissue of the same tissue type as the sample; (e) one or more cells having a cancerous morphology are present in the tissue and express the integrin alpha 10 antigen; and / or determining that the prognosis of the aggressive cancer type is poor when the expression level of the integrin α10 antigen is higher than the control level; Including, wherein said aggressive cancer type is selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or a metastatic cancer of any of said aggressive cancer types.

51. 51. The method of any one of claims 49 to 50, wherein the prognosis is overall survival or recurrence-free survival.

52. 52. The method according to any one of claims 44 to 51, wherein the step of analyzing whether an antigen comprising an integrin alpha 10 polypeptide or a fragment thereof is present in a sample comprises imaging of the tissue and / or tissue sample.

53. The method of any one of claims 44 to 52, wherein the step of determining the expression level of the integrin alphal0 antigen comprises imaging of the tissue and / or tissue sample.

54. A method for preventing metastasis of an aggressive primary cancer selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, the method comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof to a patient in need thereof, wherein the antibody is specific for an integrin alpha 10 polypeptide.

55. 55. The method of claim 54, wherein the antibody or antigen-binding fragment is administered if a primary cancer is detected.

56. A method for inhibiting integrin alpha 10-mediated signaling in at least one cancer cell, the method comprising contacting at least one cancer cell with an effective amount of an antibody or antigen-binding fragment thereof specific to an integrin alpha 10 polypeptide, wherein the at least one cancer cell is selected from the group consisting of aggressive breast cancer cells, aggressive lung cancer cells, aggressive prostate cancer cells, aggressive pancreatic cancer cells, and metastatic tumor cells.

57. A method for inhibiting a cellular function of at least one cancer cell, the method comprising contacting at least one cancer cell with an effective amount of an antibody or antigen-binding fragment specific to an integrin alpha 10 polypeptide, wherein the at least one cancer cell is selected from the group consisting of an aggressive breast cancer cell, an aggressive lung cancer cell, an aggressive prostate cancer cell, an aggressive pancreatic cancer cell, and a metastatic tumor cell.

58. The method of any one of claims 44 to 57, wherein said antigen comprising an integrin alphal0 polypeptide or a fragment thereof is expressed on the cell surface.

59. 59. The method of any one of claims 57 to 58, wherein the cellular function of at least one cancer cell is inhibited, wherein the at least one cancer cell is present in an aggressive and / or metastatic tumor, and the inhibiting comprises: (a) inhibiting the growth of at least one cancer cell; (b) inhibiting self-renewal of at least one cancer cell; (c) inhibiting anchorage-independent growth of at least one cancer cell; (d) inhibiting the migration of at least one cancer cell; (e) inhibiting the invasion of at least one cancer cell; (f) inhibiting survival of at least one cancer cell; (g) inhibiting adhesion of at least one cancer cell; and / or Combinations of these, The method is selected from the group consisting of:

60. 60. The method of any one of claims 57 to 59, wherein the at least one cancer cell is present in an aggressive and / or metastatic tumor, and wherein inhibiting the cellular function of the at least one cancer cell comprises: (a) inhibiting aggressive and / or metastatic tumor growth; (b) inhibiting aggressive and / or metastatic tumor growth; (c) inhibiting the migration of aggressive and / or metastatic tumors; (d) inhibiting the invasion of aggressive and / or metastatic tumors; (e) inhibiting the spread of new aggressive and / or metastatic tumors; (f) inhibiting the development of new aggressive and / or metastatic tumors; (g) inhibiting the invasion of new aggressive and / or metastatic tumors; and / or Combinations of these, The method is at least one of:

61. 61. The method of any one of claims 56 to 60, wherein the at least one cancer cell is characterized by an expression level of an antigen comprising an integrin alpha 10 polypeptide or a fragment thereof that is higher than a control level; wherein said control level is the average expression level of said antigen observed in healthy and / or benign cells of the same tissue type as said cancer cells.

62. 62. The method or antibody of any one of claims 40 to 61, wherein the antibody or antigen-binding fragment thereof is as defined in any one of claims 1 to 39.

63. 63. The method of any one of claims 43 to 62, wherein the method further comprises administering to the subject an antibody or antigen-binding fragment thereof according to any one of claims 1 to 39.

64. 64. The method of any one of claims 44 to 63, wherein the method is an in vitro method and the tissue is a tissue sample obtained from a subject.

65. 41. The antibody or antigen-binding fragment thereof of claim 40, wherein the diagnosis is an in vitro diagnosis.

66. Use of an antibody or antigen-binding fragment thereof, wherein the antibody is specific for an integrin alpha 10 polypeptide, for use in the manufacture of a medicament for the treatment and / or prevention of aggressive cancer selected from the group consisting of aggressive breast cancer, aggressive lung cancer, aggressive prostate cancer and aggressive pancreatic cancer, or metastatic cancer of any of said cancer types.

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