Stroma / cancer cell crosstalk and / or inhibition of treatment resistance caused by the stroma

Abstract

This disclosure relates to a method for treating abnormally activated (or reactive) stroma, such as cancer stroma, using an antibody or antigen-binding fragment thereof that is an inhibitor of the FBG region of tenascin C, to alter its state, for example, making it less tolerable to cancer cells or other disease cells / tissues, and / or reducing treatment resistance caused by the stroma.

Description

[Technical Field]

[0001] This disclosure relates to methods for treating abnormally activated (or reactive) stroma, such as cancer stroma, to alter its state, for example, making it less tolerant to cancer cells or other disease cells / tissues, and / or reducing the treatment tolerance that the stroma exhibits. [Background technology]

[0002] Cancer is associated with the stromal "tissue," which is composed of invasive immune cells and stromal cells. In the early stages, a large number of immune effector cells typically invade the tumor site, attempting to detect and eliminate tumor cells in a process known as immune surveillance.

[0003] However, as cancer progresses, tumors not only become able to evade the immune system, but also insidiously reprogram the function of immune cells and effectively replenish them to help create a tumor microenvironment (TME) more favorable to tumor growth. For example, sustained activation of the NF-κB pathway in tumor-infiltrating leukocytes leads to increased and continued secretion of pro-inflammatory cytokines, which tumor cells utilize for their own proliferation (i.e., pro-tumor cytokines).

[0004] As will be discussed in more detail below, normal stromal cells are activated to become tumor-associated stromal cells (TASCs). TASCs help create the tumor microenvironment (TME) by forming a stromal "cocoon" that supports cancer cells. Immune cells within the tumor microenvironment, such as cancer-associated fibroblasts (CAFs), play a fundamental role in creating this desmoplasia that drives tumor-promoting properties. TGF-β drives the upregulation of tenascin C, a wound-healing protein, which is found in the extracellular matrix of the stroma and has been correlated with poor prognosis in many cancers.

[0005] Several groups have attempted to target the domain of tenascin C (such as the fibronectin type III repeat) using antibody-drug conjugates as a way to simply guide toxins / radiolabeled substances to locations near cancer cells (see The Journal of Nuclear Medicine Vol. 1 46 No. 6 June 2005, pages 1042 to 1051). However, simply delivering toxins near the stroma offers little therapeutic value in addition to conventional chemotherapy for the following reasons: Traditional cancer treatments have minimal impact on stromal cells; That approach does not address the ability of stromal cells to support cancer cells; and This approach does not fundamentally alter the tumor microenvironment.

[0006] Furthermore, chemotherapy, surgery, and radiotherapy can upregulate tenascin C expression, which may in turn promote cancer recurrence. To date, these tenascin C antibody-drug conjugates have not yet been registered.

[0007] Tenascin C has multiple biological functions and is expressed at low levels in normal tissues. Increased levels are found in abnormal stroma and, as mentioned above, are associated with poor patient prognosis and metastasis. Interestingly, tenascin C may be upregulated in tissues before obvious signs of metastasis appear, for example, by preparing the tissue to accept metastasis.

[0008] In more advanced stages of cancer, the stroma is a heterogeneous matrix that promotes tumor growth by providing energy, nutrients, physical protection, protection from immune cells, immunosuppression, MHC II downregulation, a hypoxic environment (hypoxic state), resistance to radiation and cancer treatments such as chemotherapy agents, signals for primary cancer cells to proliferate, anti-adhesion signals that promote metastasis, increased angiogenesis, a leaky vascular system, and intrastromal pathways that allow tumor cells to escape and enable the metastatic spread of the disease. Many cancer-promoting properties of the TME / stroma can be traced back to the activity of tenascin C.

[0009] Tenascin C has been suggested to play a role in the immune response in tumors, for example, by promoting the M2 state (tolerogenic state) of tumor-associated macrophages and their infiltration into tumors. A therapeutic monoclonal antibody blocking tenascin C activation at Toll-like receptor 4 reversed this phenotypic switch in vitro, reducing tumor growth and lung metastasis in vivo, and, when combined with anti-PD-L1, provided improved benefits compared to either treatment alone.

[0010] Much research in the field of cancer is based on stimulating the immune system to fight cancer cells by activating immune cells within the microenvironment, or by replenishing the microenvironment with active immune cells. This is called cancer immunotherapy. While many checkpoint inhibitors (which block signals that inactivate specific immune cells) are commercially approved, these therapies are only successful in some patients, and it is becoming clear that other factors are at play.

[0011] In addition, cell-based therapies such as CAR-T therapy have been useful in treating blood cancers (liquid cancers), but have not yielded remarkable results in treating solid tumors.

[0012] The inventors believe that the importance of stromal tissue, particularly stromal cells, in cancer has been underestimated. Traditionally, stromal tissue has been considered an inactive matrix, but it is becoming clear that stromal cells / stroma are themselves an integral part of cancer. Furthermore, many mechanisms are at work in the stroma, not just one. Stromal cells appear to be able to provide "protection" to cancer cells. Like a fortified city, if the protection provided by the walls is breached, the castle becomes more vulnerable. Similar to breaching the walls, this disclosure relates to reversing one or more defense mechanisms provided by the stroma and / or reprogramming the tumor microenvironment to be less tolerant / supportive to cancer cells.

[0013] Tumors have been described as wounds that simply do not heal. In the normal wound healing process, local stromal cells change their phenotype and then transform into reactive stroma. However, under certain conditions, tumor cells can further transform these reactive (activated) stromal cells, causing them to transition into tumor-associated stromal cells (TASCs). Crosstalk between host stroma and tumor cells is essential for tumor growth and progression.

[0014] Research is beginning to emerge that suggests cancer cells signal to stromal cells, and vice versa. While we do not wish to be bound by theory, cancer cells, being mutated, may lack all the support systems of normal cells and may not produce all the "nutrients / components" necessary for survival. Therefore, cancer cells may be more dependent on stromal cells for their viability than we realize. The stroma (including stromal cells) can supply cancer cells with nutrients, energy, enzymes, etc. This process is highly complex and not fully understood. By removing this support and protection, cancer cells may become less viable and / or more sensitive to cancer treatment. Therefore, stromal cells have an essential role in the formation and function of the tumor microenvironment. Furthermore, the stroma (including stromal cells) can signal tumor cells to proliferate.

[0015] Furthermore, other cells, such as immune cells like cancer-activated fibroblasts (CAFs) and / or tumor-associated macrophages (TAMs), also appear to interact with stromal cells and / or cancer cells, forming interaction loops.

[0016] Tenascin C is a soluble protein found in stromal tissue and is secreted by one or more of the following: cancer cells, stromal cells, and / or cancer-supporting immune cells.

[0017] The data obtained by the present inventors suggest that tenascin C plays an important role in crosstalk between cancer cells and stromal cells, and may also play an important role in crosstalk between stromal cells and cancer immune cells, and / or between cancer cells and cancer immune cells.

[0018] The inventors have demonstrated that when stromal cells are treated with a functional antibody that is an inhibitor of the FBG region of tenascin C, their viability does not decrease, and that they are not necessarily affected by cancer treatments such as venetoclax.

[0019] Instead, surprisingly, when treated with FBG region inhibitors, these stromal cells undergo a change in state, becoming less supportive (e.g., unsupportive) to associated cancer cells and / or other diseased tissues. Interestingly, when antibodies are used as monotherapy in co-cultures of stromal and cancer cells, the cancer cells appear to have slightly reduced viability after such treatment. Furthermore, when cancer therapy is introduced as a further treatment to the aforementioned co-culture, cancer cells are significantly sensitized to the cancer therapy in the presence of antibodies, but only in the presence of stroma (i.e., the effect is minimal when cancer cells are cultured in the absence of stromal cells).

[0020] Thus, the antibodies of the present disclosure "block / inhibit" the essential crosstalk between stromal cells and cancer cells, and are thus believed to remove the "lifeline" of cancer cells in one or more forms of interaction, energy, nutrients, physical protection, and the like (including the above properties).

[0021] Thus, the antibodies used in the present disclosure are crosstalk inhibitors and are believed to block the signaling (talk) from cancer cells to stromal cells and / or from stromal cells to cancer cells.

[0022] Furthermore, the antibodies according to the present disclosure may also block the crosstalk between cancer cells and immune cells (and / or vice versa), and / or between stromal cells and immune cells (and / or vice versa).

[0023] While not wishing to be bound by theory, this is not only a specific signal for activating a series of immune cells (or inhibition of a blocking signal to immune cells), but also a completely different way of treating stromal cells to change their activation state to a lower activation state (less supportive for cancer cells (and / or other diseased cells / tissues)), and is thus considered not to be an immunotherapeutic effect.

[0024] Alternatively or additionally, the signaling from cancer cells to stromal cells can be blocked.

[0025] This function of the antibody can be utilized for the treatment of cancer as a monotherapy and also as a combination therapy, for example, because the antibody enables the active moiety (including those from natural sources in the body) / cancer therapy to enter the cancer microenvironment and / or promotes the destruction of cancer by immune cells.

[0026] The inventors believe that treatment with the antibodies according to the present disclosure reduces one or more of the following (e.g., in the cancer microenvironment): remodeling / fibrosis, interstitial pressure, active transport of drugs from the cancer microenvironment, autophagy, signal transduction between stromal cells and cancer cells (and / or other cells as described above), nutrient delivery to cancer cells, and secretion of chemokines and / or cytokines that support cancer metabolism and / or proliferation.

[0027] Inhibiting this crosstalk can also result in reduced signal transduction for primary cancer cell proliferation.

[0028] Therefore, the present invention may provide means for reprogramming the tumor microenvironment to be less tumor-promoting, e.g., normalizing the tumor microenvironment.

[0029] The inventors believe that this interrelationship between cancer cells and stromal cells is a fundamental mechanism of most cancers, e.g., based on cancers exploiting the natural wound healing mechanism (Cancer Immunol Res. 2015 January; 3(1): 1-11). Thus, this treatment method is a fundamentally new way to treat cancer, e.g., by inactivating or neutralizing the stroma. It is likely to have broad applications in many cancers, particularly refractory or cancers resistant to existing cancer treatments.

[0030] Therefore, the present invention has broad applications in the treatment of cancers such as solid tumors, and has specific applications in refractory cancers such as pancreatic cancer (currently 5-year survival rate 11.5%), gallbladder cancer (currently 5-year survival rate 19.4%), esophageal cancer (currently 5-year survival rate 20.6%), brain cancer (currently 5-year survival rate 32.5%), liver cancer, biliary tract cancer, cholangiocarcinoma, gastric cancer, colorectal cancer, triple-negative breast cancer, breast cancer with upregulated TGF-β, lung cancer (including mesothelioma (currently 5-year survival rate 12%), bronchial cancer (currently 5-year survival rate 22.9%), and pleural cancer (currently 5-year survival rate 22%)), and their metastatic forms.

[0031] The association between crosstalks in pancreatic cancer is described in Geleta B, Tout FS, Lim SC, Sahni S, Jansson PJ, Apte MV, et al. Targeting Wnt / Tenascin C-Mediated Cross Talk Between Pancreatic Cancer Cells and Stellate Cells Via Activation of the Metastasis Suppressor Ndrg1. J Biol Chem (2022) 298(3):101608.

[0032] Some research groups hypothesize that bone stromal stem cells are recruited and migrate to the tumor microenvironment. While we do not wish to be bound by theory, cancer cells in the local tumor environment may be in a state of interaction with stromal cells from the bone marrow. For example, stromal cells in the bone marrow may be activated or programmed to interact with / support cancer, even before leaving the bone marrow and / or within lymph nodes. This therapy may be able to alter this state. Therefore, this treatment could have a very significant impact on cancer treatment.

[0033] Furthermore, a negative feedback loop may exist, meaning that antibody-mediated inhibition of tenascin C could lead to downregulation of tenascin C expression in diseased tissue, potentially resulting in disease modification, for example.

[0034] In addition, the treatments described herein may reduce or minimize cancer recurrence after treatment and / or prolong remission.

[0035] In an independent embodiment, a method for treating cancer directly derived from stromal cells (e.g., sarcoma) is provided, using an antibody or antigen-binding fragment thereof disclosed herein. [Overview of the project]

[0036] The following will be provided: An antibody or antigen-binding fragment that acts as an inhibitor of the FBG region of tenascin C, which binds to the same epitope as an antibody having VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29 (especially 29), a. Neutralization of cancer-associated stromal cells such that their ability to support cancer viability is reduced, and / or b. Reduction of the activation state of cancer stromal cells (e.g., those within the tumor microenvironment) to make them less tolerant to cancer cells, such as inhibiting crosstalk between stromal cells and / or cancer cells, and / or vice versa; or c. Neutralization of abnormally activated stromal cells in diseased tissue. An antibody or antigen-binding fragment as an inhibitor, characterized in that it is used for the treatment of cancer.

[0037] An antibody or antigen-binding fragment as an inhibitor of the FBG region of tenascin C, which binds to the same epitope as an antibody having VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29, for use in therapy to reprogram the tumor microenvironment (for example, through the treatment of cancer-activated stromal cells) to make it less carcinogenic (tumor-forming), for example, less hypoxic.

[0038] An antibody or antigen-binding fragment as an inhibitor of the FBG region of tenascin C, which binds to the same epitope as an antibody having VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29, for use in the treatment of cancer to reverse / minimize / prevent cancer resistance and / or improve tissue permeability (e.g., resistance to cancer therapies such as chemotherapy, radiotherapy, Bcl-2 inhibitors, DHOH inhibitors, kinase inhibitors, IDO inhibitors, AhR inhibitors, cellular cancer therapies (such as CAR-T therapy), PARP inhibitors, velstine, temozolomide, tamoxifen, oncolytic viruses, corticosteroids, and combinations thereof).

[0039] An antibody or antigen-binding fragment that acts as an inhibitor of the FBG region of tenascin C, which binds to the same epitope as an antibody having VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29, for use in refractory cancers, such as refractory solid tumors, such as pancreatic cancer, gallbladder cancer, esophageal cancer, brain cancer (astrocytoma, glioma, glioblastoma multiforme, medulloblastoma, ependymoma, oligodendroglioma, craniopgaryngioma, pituitary adenoma, germ cell tumor, primitive nerve Antibodies or antigen-binding fragments as inhibitors for use in the treatment of ectodermal tumors, pilocytic astrocytomas, mixed gliomas, chordomas, optic gliomas, diffuse astrocytomas, germ tumors, pineal blastomas, choroid plexus papillomas, especially glioblastoma multiforme), liver cancer, biliary tract / cholangiocarcinoma, gastric cancer, colorectal cancer, kidney cancer, breast cancer (including triple-negative breast cancer and / or breast cancer with upregulated TGF-β), and lung cancer (including mesothelioma, bronchial cancer, and pleural cancer).

[0040] a. An antibody or antigen-binding fragment thereof that inhibits the FBG region of tenascin C and binds to the same epitope as an antibody having VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29; and b. Cancer treatments selected from chemotherapy, radiotherapy, surgery, ablation, photodynamic therapy, periostin inhibitors, Bcl-2 inhibitors, cellular cancer treatments (such as CAR-T therapy), PARP inhibitors, hormone therapy, anti-VEGF, di-2-pyridylketone-4-cyclohexyl-4-methylthiosemicarbazone (thiosenicarbazone), corticosteroids, and combinations of two or more of these (especially corticosteroids). Includes, For example, cancer tissue penetration is improved and / or resistance is minimized. Combination therapy.

[0041] 1. An antibody or antigen-binding fragment thereof that binds to an epitope within the FBG domain of tenascin C, a) VH domains containing sequence number 1 as CDRH1, sequence number 2 as CDRH2, and CDRH3 selected from sequence numbers 3, 9, 12, 14, 16, 18, 20, 22 and 24; and, b) VL domains including sequence number 5 as CDRL1, sequence number 6 as CDRH2, and sequence number 7, Includes, A method for use in cancer treatment, characterized in that stromal cells are neutralized, thereby reducing their ability to support the survival rate of cancer cells associated with stromal cells. The antibody or its antigen-binding fragment. 1A. An antibody or antigen-binding fragment thereof that binds to an epitope within the FBG domain of tenascin C, a) VH domains containing sequence number 1 as CDRH1, sequence number 2 as CDRH2, and CDRH3 selected from sequence numbers 3, 9, 12, 14, 16, 18, 20, 22 and 24; and, b) VL domains including sequence number 5 as CDRL1, sequence number 6 as CDRH2, and sequence number 7, Includes, A method for use in cancer treatment, characterized in that the activation state of stromal cells in the tumor microenvironment is altered to make cancer stromal cells less tolerant to cancer cells, for example, by inhibiting crosstalk between stromal cells and cancer cells and vice versa. The antibody or its antigen-binding fragment. 1B. An antibody or its antigen-binding fragment that binds to an epitope within the FBG domain of tenascin C, a) VH domains containing sequence number 1 as CDRH1, sequence number 2 as CDRH2, and CDRH3 selected from sequence numbers 3, 9, 12, 14, 16, 18, 20, 22 and 24; and, VL domains including sequence number 5 as CDRL1, sequence number 6 as CDRH2, and sequence number 7, Includes, For use in the treatment of cancer-activated stromal cells, such as tumor-associated stromal cells, particularly for modifying their state, The antibody or its antigen-binding fragment. 1C. An antibody or antigen-binding fragment thereof that binds to an epitope within the FBG domain of tenascin C, a. A VH domain containing sequence number 1 as CDRH1, sequence number 2 as CDRH2, and CDRH3 selected from sequence numbers 3, 9, 12, 14, 16, 18, 20, 22 and 24; and, VL domains including sequence number 5 as CDRL1, sequence number 6 as CDRH2, and sequence number 7, Includes, For use in the treatment of cancers originating from stromal cells (especially lymph node stromal cells, bone stromal cells, etc.), such as sarcomas (e.g., Kaposi's sarcoma, childhood rhabdomyosarcoma, child rhabdomysarcoma, pediatric angiomoma, Ewing's sarcoma, osterosarcoma, soft tissue sarcoma, uterine sarcoma, follicular dendritic cell sarcoma; fibroblastic reticular cell sarcoma) and inflammatory myofibroblastic tumors. The antibody or its antigen-binding fragment. 1D. An antibody or antigen-binding fragment thereof that binds to an epitope within the FBG domain of tenascin C, a) VH domains containing sequence number 1 as CDRH1, sequence number 2 as CDRH2, and CDRH3 selected from sequence numbers 3, 9, 12, 14, 16, 18, 20, 22 and 24; and, b) VL domains including sequence number 5 as CDRL1, sequence number 6 as CDRH2, and sequence number 7, Includes, For use in treatments to reverse cancer resistance, such as resistance to cancer treatments like chemotherapy and / or radiation therapy, The antibody or its antigen-binding fragment. 1E. a) VH domains containing sequence number 1 as CDRH1, sequence number 2 as CDRH2, and CDRH3 selected from sequence numbers 3, 9, 12, 14, 16, 18, 20, 22 and 24; and, b) VL domains including sequence number 5 as CDRL1, sequence number 6 as CDRH2, and sequence number 7, An antibody or its antigen-binding fragment that binds to an epitope within the FBG domain of tenascin C; Further cancer treatments, Combination therapies for use in the treatment of cancer, including [mention specific drugs / methods]. 2. The combinations disclosed herein, for example, the six CDRs in the sequence listing described in the family, which are antibodies or antigen-binding fragments for use as described in any of the preceding paragraphs. Any information lost in the sequence listing is incorporated herein by reference to the priority document containing the complete sequence. 3. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VH is selected from SEQ ID NOs: 4, 10, 13, 15, 17, 19, 21, and 23. 4. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein VH is / contains SEQ ID NO: 4. 5. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein VH is / contains SEQ ID NO: 10. 6. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein VH is / contains SEQ ID NO: 13. 7. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein VH is / contains SEQ ID NO: 15. 8. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VH is / contains SEQ ID NO: 17. 9. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VH is / contains SEQ ID NO: 19. 10. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VH is / contains SEQ ID NO: 21. 11. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VH is / contains SEQ ID NO: 23. 12. An antibody or antigen-binding fragment for use as described in the preceding paragraph, wherein the VL is selected from 8, 11, 28, and 29. 13. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VL is / contains SEQ ID NO: 8. 14. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VL is / contains SEQ ID NO: 11. 15. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VL is / contains SEQ ID NO: 28. 16. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the VL is / contains SEQ ID NO: 29. 17. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which lowers the activation state of interstitial cells. 18. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which reduces the viability of cancer cells (such as associated cancer cells) as a result of regulating the activity of stromal cells, for example, by sensitizing cancer cells to cancer treatment. 19. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which, as a result of regulating the activity of stromal cells, has one or more of the following characteristics in cancer cells (such as associated cancer cells): a lower metabolic rate, for example, a reduced replication rate, and / or a reduced ability to repair damage (for example, damage to DNA caused by radiation and / or chemotherapy). 20. An antibody or antigen-binding fragment for use as described in any preceding paragraph, wherein the stromal cells are mesenchymal stromal cells. 21. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the stromal cells are selected from fibroblasts and pericytes. 22. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the stromal cells are bone marrow stromal cells. 23. The antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the stromal cells are located in adipose tissue, endometrium, and / or synovial fluid. 24. The stromal cells are lymph node stromal cells, selected from, for example, fibroblastic reticular cells, follicular dendritic cells, marginal reticular cells, lymphatic endothelial cells, high endothelial cells, and alpha-7 integrin pericytes, and are antibodies or antigen-binding fragments for use as described in any of the preceding paragraphs. 25. The stromal cells are selected from fibroblasts, e.g., cancer-activated fibroblasts, e.g., cancer-associated fibroblasts (CAFs), and the antibody or antigen-binding fragment for use as described in any of the preceding paragraphs. 26. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the stromal cell cancer activity is downregulated, such as by being inhibited by treatment. 27. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, selected from the secretion of nitric oxide, factor-1α, IL-6, IL-8, tenascin C, matrix metalloproteinases, tumorigenic cell supplementation factors, and combinations thereof, which is associated with abnormal stromal cell activity (such as cancer activity). 28. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the abnormal stromal cell activity (such as cancer activity) is the secretion of factors that supplement tumorigenic cells. 29. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the abnormal stromal cell activity (such as cancer activity) is due to the secretion of factor-1α. 30. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the abnormal stromal cell activity (such as cancer activity) is due to IL-6 secretion. 31. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the abnormal stromal cell activity (such as cancer activity) is due to IL-8 secretion. 32. The abnormal stromal cell activity (such as cancer activity) is the secretion of tenascin C (i.e., tenascin C levels are reduced by treatment), an antibody or antigen-binding fragment for use as described in any of the preceding paragraphs. 33. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the abnormal stromal cell activity (such as cancer activity) is due to the secretion of matrix metalloproteinases. 34. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the abnormal stromal cell activity (such as cancer activity) is nitric oxide secretion. 35. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which reduces neovascularization. 36. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which reduces fibroblast infiltration. 37. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which reduces immune cell infiltration. 38. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the mesenchymal properties of the stromal cells are downregulated (normalized) by treatment. 39. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which modulates the tumor microenvironment (e.g., selected from increased permeability, reduced fibrosis, reduced remodeling, reduced metabolic levels, reduced hypoxia, reduced interstitial pressure, reduced secretion of cytokines and / or chemokines that promote cancer survival / growth, reduced energy delivery to cancer cells, reduced "crosstalk", reduced nutrient delivery to cancer cells, reduced autophagy, reduced resistance, and two or more combinations thereof). 40. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39) that increases tumor permeability. 41. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., paragraph 39 or 40) that reduces or halts fibrosis deposition (i.e., the process of fibrosis). 42. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-41) that reduces the amount of deposited fibrosis (i.e., reduces the process of ongoing fibrosis and / or the absolute amount of fibrosis). 43. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-42) in which the process of cancerous remodeling of tissue is reduced or eliminated. 44. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-43) that reduces the rate of cancer metabolism, e.g., the consumption of energy and / or nutrients, and / or the ability to repair DNA damage. 45. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-44), which stabilizes or reduces (e.g., normalizes) the level of hypoxia. 46. ​​An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-45), which stabilizes or reduces (e.g., normalizes) interstitial pressure. 47. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-46) that reduces the secretion of cytokines that support the viability (such as proliferation and / or persistence) of cancer cells. 48. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-47) that reduces the secretion of cytokines that cause cancer-promoting inflammatory conditions. 49. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-48) that increases the secretion of cytokines supporting anti-cancer activity. 50. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-49) that reduces the secretion of one or more chemokines that support the viability (such as proliferation and / or persistence) of cancer cells. 51. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-50) that increases the secretion of one or more chemokines that induce an anti-cancer inflammatory state. 52. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-51) that reduces energy transfer to cancer cells. 53. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-52) that reduces “crosstalk” to cancer cells and / or other cancer-associated immune cells (such as cancer-associated fibroblasts and / or cancer-associated macrophages). 54. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-53) that reduces nutrient delivery to cancer cells. 55. The antibody or antigen-binding fragment for use described in any of the preceding paragraphs (e.g., 39-54) reduces autophagy by the tumor. 56. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-55) that reduces resistance to cancer treatment, such as chemotherapy and / or radiotherapy. 57. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-56) that reduces resistance to chemotherapy. 58. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs (e.g., 39-58) that reduces resistance to radiotherapy. 59. The neutralization of immune cells by the tumor microenvironment is reduced, for example, neutralizing T cells are minimized (endogenous T cells and modified T cells, e.g., CAR-T cells), by the antibody or antigen-binding fragment for use as described in any of the preceding paragraphs. 60. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the upregulation of one or more VEGFA, FGF2, FGFR2, and PDGFRA on stromal cells is minimized. 61. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which minimizes the abnormal expression of PD-L1 by stromal cells. 62. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the adhesion of cancer cells, for example, to stromal cells, is regulated, for example, reduced or increased, and especially increased. 63. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the upregulation of GDNF (e.g., by stromal cells) is minimized, for example, in response to chemotherapy. 64. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which downregulates abnormal CYP3A4 activity. 65. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the upregulation of β1 integrin is minimized, for example, in response to radiotherapy. 66. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the upregulation of β1 integrin is minimized in pancreatic stellate cells, for example, in response to radiotherapy. 67. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the androgen receptor (AR) is not downregulated on stromal cells, particularly in prostate cancer. 68. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein estrogen receptor downregulation is minimized, for example, in breast cancer. 69. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is an epithelial cancer. 70. The antibody or antigen-binding fragment for use as described in paragraph 69, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer (including metastatic brain cancer), liver cancer, prostate cancer, pancreatic cancer, biliary tract cancer, bile duct cancer, colon cancer, intestinal cancer, breast cancer (e.g., triple-negative breast cancer, secondary breast cancer, and locally advanced breast cancer), cervical cancer, gallbladder cancer, esophageal cancer, ovarian cancer, thyroid cancer, kidney cancer, head and neck cancer (such as laryngeal cancer, pharyngeal cancer, and salivary gland cancer), gastric cancer, thyroid cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, inflammatory myofibroblastic tumor, and tracheobronchial tumor), penile cancer, retinoblastoma, testicular cancer, intraocular melanoma, urinary tract cancer, skin cancer (including melanoma), endocrine tumors, neuroendocrine tumors, and two or more combinations thereof. 71. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is a carcinoma, such as ductal carcinoma including basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, adenocarcinoma, transitional cell carcinoma, and pancreatic ductal adenocarcinoma. 72. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is a solid tumor. 73. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is a refractory cancer (e.g., a refractory solid tumor) selected from pancreatic cancer, gallbladder cancer, esophageal cancer, brain cancer (including meningioma, astrocytoma, glioma, glioblastoma multiforme, medulloblastoma, ependymoma, oligodendroglioma, craniopgaryngioma, pituitary adenoma, germ cell tumor, primitive neuroectodermal tumor, pilocytic astrocytoma, mixed glioma, chordoma, optic nerve glioma, diffuse astrocytoma, germ tumor, pineal blastoma, choroid plexus papilloma, especially glioblastoma multiforme), liver cancer, biliary tract / cholangiocarcinoma, gastric cancer, colorectal cancer, breast cancer (including triple-negative breast cancer and / or breast cancer with upregulated TGF-β), lung cancer (including mesothelioma, bronchial cancer, and pleural cancer). 74. The antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is pancreatic cancer. 75. The aforementioned intractable cancers include brain cancer (meningioma, astrocytoma, glioma, glioblastoma multiforme, medulloblastoma, ependymoma, oligodendroglioma, craniopgaryngioma, pituitary adenoma, germ cell tumor, primitive neuroectodermal tumor, pilocytic astrocytoma, mixed glioma, chordoma, optic nerve glioma, diffuse astrocytoma, germ tumor, pineal blastoma, choroid plexus papilloma, especially glioblastoma multiforme), for example, astrocytoma glioma, glioblastoma multiforme, medulloblastoma, ependymoma, oligodendroglioma, craniopgaryngioma, pituitary adenoma, germ cell tumor, primitive neuroectodermal tumor, pilocytic astrocytoma, mixed glioma, chordoma, optic nerve glioma, diffuse astrocytoma, germ tumor, pineal blastoma, choroid plexus papilloma, particularly glioblastoma multiforme, antibody or antigen-binding fragment for use as described in paragraph 73. 76. The antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is biliary tract cancer / cholangiocarcinoma and / or gallbladder cancer. 77. The antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is esophageal cancer. 78. The antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is liver cancer, for example, primary hepatocellular carcinoma (HCC). 79. The antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is gastric cancer. 80. The antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is gastric cancer. 81. The antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is breast cancer (such as triple-negative breast cancer and / or breast cancer with upregulated TGF-β). 82. An antibody or antigen-binding fragment for use as described in paragraph 73, wherein the refractory cancer is lung cancer (including mesothelioma, bronchial cancer, and pleural cancer). 83. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is a liquid tumor. 84. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is not a sarcoma. 85. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is resistant to existing cancer treatments (including resistance to chemotherapy, resistance to radiotherapy, and resistance to tamoxifen). 86. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the cancer is metastatic. 87. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which reduces the risk of metastasis or metastasis. 88. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the number of viable cancer cells is reduced by treatment (e.g., actual number and / or relative number). 89. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the tumor burden is reduced by treatment (e.g., the tumor shrinks). 90. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs that increases the survival of a treated patient, for example, survival in which cancer is in remission, i.e., cancer-free survival. 91. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the patient is human. 92. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the treatment is adjuvant therapy. 93. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the treatment is pre-adjuvant therapy. 94. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, which sensitizes cancer cells to treatment, for example, treatment by cancer therapy such as radiotherapy or chemotherapy. 95. An antibody or antigen-binding fragment for use as described in any of the preceding paragraphs, wherein the antibody or fragment is linked to a payload, for example, conjugated or linked as a fusion protein. 96. An antibody or antigen-binding fragment for use as described in paragraph 95, wherein the payload is for therapeutic purposes. 97. An antibody or antigen-binding fragment for use as described in paragraph 95 or 96, wherein the payload is a detectable label (such as a diagnostic agent), as disclosed herein, for example. 98. The payload is a chemotherapeutic agent, for example, temozolomide, epothilon, melphalan, carmustine, busulfan, lomustine, cyclophosphamide, dacarbazine, polyfeprosan, ifosfamide, chlorambucil, mechloretamine, busulfan, cyclophosphamide, carboplatin, cisplatin, oxaliplatin, thiotepa, capecitabine, streptozocin, bicalutamide, phthalamide, nilutamide, leuprolide acetate, doxorubicin (for example, doxorubicin hydrochloride or liposomal). Doxorubicin hydrochloride, bleomycin sulfate, daunorubicin hydrochloride, dactinomycin, liposomal daunorubicin citrate, epirubicin hydrochloride, idarubicin hydrochloride, mitomycin, barurubicin, anastozole, toremifene citrate, cytarabine, fluorouracil, fludarabine, floxuridine, interferon α-2b, plicamycin, mercaptopurine, methotrexate, interferon α-2a, medroxyprogesterone acetate (acetic acid), estramustine sodium phosphate, estradiol, leuprolide acetate, megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate, testolactone, goserelin acetate, etoposide phosphate, vincristine sulfate, etoposide, vinblastine, etoposide, vincristine sulfate, teniposide, trastuzumab, gemtuzumab ozogamicin, rituximab, exemestane, irinotecan hydrochloride Hydrocholride, asparaginase, gemcitabine hydrochloride, altretamine, topotecan hydrochloride, hydroxyurea, cladribine, mitotane, procarbazine hydrochloride, vinorelbine tartrate, pentostatin sodium, mitoxantrone, pegaspargase, denileukin difutoxAn antibody or antigen-binding fragment for use as described in any one of paragraphs 95-97, selected from diftitix, alitretinoin, porfimer, besarotene, paclitaxel, docetaxel, arsenic trioxide, tretinoin, and two or more combinations thereof, e.g., FOLFOX, Xelox, FOLFIRI, FOLFIRINOX. 99. The payload is an antibody or antigen-binding fragment for use as described in any one of paragraphs 95 to 98, selected from therapeutic proteins (including binding domains such as receptors, ligands, antibodies or their binding fragments); drugs (such as small molecule chemicals); radionuclides; detectable labels, such as fluorescent labels such as Alexa350, DAPI, rhodamine green, or rhodamine green red; radioactive labels such as carbon-14 or tritium; enzymes such as alkaline phosphatase or hydrogen peroxidase; or ligands such as biotin or avidin. 100. An antibody or antigen-binding fragment for use as described in any one of paragraphs 95-99, wherein the payload enhances targeting / selectivity to cancer / strom. 101. An antibody or antigen-binding fragment, which is fully human, for use as described in any of the preceding paragraphs. 102. An antibody or antigen-binding fragment that is chimeric, for use as described in any one of paragraphs 1 to 100. 103. An antibody or antigen-binding fragment for use as described in any one of paragraphs 1-94, 101, or 102, wherein the antibody or fragment is not bound to a payload. 104. A polynucleotide encoding an antibody or antigen-binding fragment as defined in any of the preceding paragraphs, i. The antibody or binding fragment is characterized in that it neutralizes stromal cells (including TASCs), thereby reducing their ability to support the survival of associated cancers, and / or ii. The aforementioned cancers are sarcomas and other cancers that originate from stromal cells. Polynucleotides used in cancer treatment. 105. A vector comprising the polynucleotide described in paragraph 104 for use as described in any one of paragraphs 1 to 103. 106. Cells (e.g., host cells or immune cells, e.g., modified immune cells) comprising the polynucleotide described in paragraph 104 or the vector described in paragraph 105, particularly for use in the treatment according to the present disclosure. 107. Oncolytic viruses encoding an antibody or antigen-binding fragment as described in any one of paragraphs 1 to 103, for use in the treatment described herein, for example. 108. A combination therapy comprising an antibody or antigen-binding fragment as described in any one of paragraphs 1 to 103, a polynucleotide as described in paragraph 104, a vector as described in paragraph 105, a cell as described in paragraph 106, or an oncolytic virus as described in paragraph 107, and at least one further anticancer treatment. 109. The above therapy is chemotherapy, for example, temozolomide, epothilon, melphalan, carmustine, busulfan, lomustine, cyclophosphamide, dacarbazine, polyfeprosan, ifosfamide, chlorambucil, mechloretamine, busulfan, cyclophosphamide, carboplatin, cisplatin, oxaliplatin, thiotepa, capecitabine, streptozocin, bicalutamide, phthalamide, nilutamide, leuprolide acetate, doxorubicin (for example, doxorubicin hydrochloride or liposomal doxorubicin) Sorbicin hydrochloride, bleomycin sulfate, daunorubicin hydrochloride, dactinomycin, liposomal daunorubicin citrate, epirubicin hydrochloride, idarubicin hydrochloride, mitomycin, barurubicin, anastozole, toremifene citrate, cytarabine, fluorouracil, fludarabine, floxuridine, interferon α-2b, plicamycin, mercaptopurine, methotrexate, interferon α-2a, medroxyprogesterone acetate (acetic acid), estramustine sodium phosphate, estradiol, leuprolide acetate, megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate, testolactone, goserelin acetate, etoposide phosphate, vincristine sulfate, etoposide, vinblastine, etoposide, vincristine sulfate, teniposide, trastuzumab, gemtuzumab ozogamicin, rituximab, exemestane, irinotecan hydrochloride Hydrocholride, asparaginase, gemcitabine hydrochloride, altretamine, topotecan hydrochloride, hydroxyurea, cladribine, mitotane, procarbazine hydrochloride, vinorelbine tartrate, pentostatin sodium, mitoxantrone, pegaspargase, denileukin difutoxThe combination therapy described in paragraph 108, which is selected from chemotherapy regimens such as diftitix, alitretinoin, porfimer, besarotene, paclitaxel, docetaxel, arsenic trioxide, tretinoin, and two or more combinations thereof, for example, FOLFOX, Xelox, FOLFIRI, FOLFIRINOX. 110. The combination therapy described in paragraph 108 or 109, wherein the further cancer treatment is a biological agent, selected from, for example, bevacizumab, trastuzumab, PD-1 inhibitor, PD-L1 inhibitor, bevacizumab, cetuximab, gemtuzumab / ozogamicin, ibritumomab / tiuxetan, ofatumumab, panitumumab, rituximab, or tocitumomab. 111. The combination therapy described in paragraph 110, wherein the further cancer treatment is selected from PD-1 inhibitors or PD-L1 inhibitors (inhibitors), such as nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, semiprimab, dostralimab, and retifanlimab. 112. The further cancer treatment is a combination therapy as described in any one of paragraphs 108-111, selected from anti-VEGF therapies, such as axitinib, bevacizumab, cabozantinib, lapatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ranibizumab, regrafenib, sorafenib, sunitinib, and vandetanib. 113. The combination therapy described in any one of paragraphs 108-112, wherein the further cancer treatment is velstine or temozolomide. 114. The combination therapy described in any one of paragraphs 108-113, wherein the further cancer treatment is tamoxifen. 115. The combination therapy described in any one of paragraphs 108-114, wherein the further cancer treatment is selected from venetoclax, navitoclax, and ovatoclax, in particular venetoclax. 116. The combination therapy described in any one of paragraphs 108-115, wherein the further cancer treatment is a periostin inhibitor. 117. The combination therapy described in any one of paragraphs 108 to 116, wherein the further cancer treatment is a modified immune cell, for example, CAR-T therapy, selected from, for example, tisagenlecleucel, axicapbutagen / siloleucel, brexcapbutagen / autolucel, lysocabbutagen / malaloucel, idekabutagen / biculucel, and ciltabtagene / autolucel. 118. The combination therapies described in paragraphs 108, 109 and 112-117, wherein the further cancer treatment is neither a PD-1 inhibitor nor a PD-L1 inhibitor (not a PD-1 inhibitor in particular for the treatment of breast cancer). 119. The combination therapy described in any one of paragraphs 108 to 118, wherein the further cancer treatment is a PARP inhibitor, selected from, for example, talazoparib, veliparib, pamiparib, olaparib, lucaparib, veliparib, CEP9722, E7016, iniparib, and 3-aminobenzamide. 120. The combination therapy described in any one of paragraphs 108 to 119, wherein the further cancer treatment is selected from DHOH inhibitors, kinase inhibitors, IDO inhibitors and / or AhR inhibitors. 121. The combination therapy described in any one of paragraphs 108-120, wherein the therapy is selected from surgical procedures, ablation, and photodynamic therapy. 122. The combination therapy described in any one of paragraphs 108 to 121, wherein the further cancer treatment is radiotherapy. 123. The combination therapy described in any one of paragraphs 108-122, wherein the further cancer treatment is an oncolytic virus, such as an oncolytic adenovirus.

[0042] When we say "any preceding paragraph," we include unnumbered paragraphs. In one embodiment, the brain cancer is a primary or secondary intracranial cancer.

[0043] In one embodiment, the treatment according to this disclosure is used in combination with cancer immunotherapy.

[0044] In one embodiment, inhibition of tenascin C by the present disclosure indirectly inhibits receptors on cancer cells, such as integrins.

[0045] In one embodiment, the cancer is not a meningioma.

[0046] In one embodiment, the patient has a pathology, for example, a cancer in which one or more cell types express tenascin C.

[0047] In one embodiment, the patient is identified to have a pathology expressing tenascin C prior to administration of the treatment according to this disclosure, for the purpose of blood sample testing showing tenascin C, or tenascin C and tenascin W, in the serum.

[0048] In one embodiment, the cancer is not a blood cancer.

[0049] In one embodiment, the antibody or its antigen-binding fragment is used in combination with an approved treatment and / or standard treatment.

[0050] In one embodiment, the present disclosure provides a therapeutic method comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment according to the present disclosure.

[0051] In one embodiment, the present disclosure provides an antibody or antigen-binding fragment for use in the manufacture of a pharmaceutical product disclosed herein. [Modes for carrying out the invention]

[0052] As used herein, the term "identical epitope" refers to an antibody that binds to the same amino acid residue as the bound reference antibody, or whose binding overlaps with that of the bound reference antibody, and in particular, to an antibody whose function (in this case, inhibition) overlaps with that of the reference antibody.

[0053] The epitope conjugated by the aforementioned reference antibody is described in WO2018 / 060462, which is incorporated herein by reference.

[0054] Tumor-associated stromal cells (TASCs) exhibit increased secretion levels of proteins and matrix metalloproteinases (MMPs) compared to non-reactive (inactivated) stromal cells.

[0055] In one embodiment, regulating the state of stromal cells reduces the secretion / expression of pro-inflammatory cytokines.

[0056] In one embodiment, regulating the state of stromal cells reduces the secretion / expression of cancer-promoting cytokines.

[0057] TASCs may secrete one or more of the following: fibroblast-activating protein, α-smooth muscle actin, vascular endothelial growth factor (VEGF), interstitial-derived factor-1α, IL-6, IL-8, and tenascin C.

[0058] In one embodiment, when TASC is regulated, the expression / secretion of one or more of these is reduced, for example, two or more are reduced, for example: fibroblast-activating protein and α-smooth muscle actin; fibroblast-activating protein and VEGF; fibroblast-activating protein and interstitial factor-1α; fibroblast-activating protein and IL-6; fibroblast-activating protein and IL-8; fibroblast-activating protein and tenascin C; α-smooth muscle actin and VEGF; α-smooth muscle actin and interstitial factor-1α; α-smooth muscle actin and IL-6; α-smooth muscle actin and IL-8; α-smooth muscle actin and tenascin C; VEGF and interstitial factor-1α; VEGF and IL-6; VEGF and IL-8; VEGF and tenascin C; interstitial factor-1α and IL-6; interstitial factor-1α and IL-8; interstitial factor-1α and tenascin C; IL-6 and IL-8; IL-6 and tenascin C; IL-8 and tenascin C; VEGF, IL-6 and IL-8; VEGF, IL-6 and tenascin C; VEGF, IL-8 and tenascin C; IL-6, IL-8 and tenascin C; VEGF, IL-6, IL-8 and tenascin C, for example, all of them are reduced / normalized.

[0059] In one embodiment, the treatment downregulates the expression of tenascin C.

[0060] In one embodiment, regulating the state of stromal cells reduces the secretion / expression of CCL21 and / or CXCL12.

[0061] In one embodiment, this treatment is used as monotherapy.

[0062] In one embodiment, this treatment is used as a combination therapy with further cancer treatment, such as a treatment selected from those described herein.

[0063] In one embodiment, this treatment is performed using pre-adjuvant therapy.

[0064] In one embodiment, this treatment is used as adjuvant therapy.

[0065] In one independent embodiment, the use of antibodies according to this disclosure is provided for the treatment of hard-to-treat cancers characterized by the presence of stroma, e.g., solid tumors, e.g., pancreatic cancer, gallbladder cancer (esophageal cancer, brain cancer, liver cancer, biliary tract cancer, bile duct cancer, gastric cancer, colorectal cancer, triple-negative breast cancer, TGF-β upregulated breast cancer, lung cancer, bronchial cancer, and pleural cancer, and their metastatic forms), and / or

[0066] This disclosure is also useful in treating breast cancer (including triple-negative breast cancer, TGFβ1 upregulated breast cancer, BRCA breast cancer, and tamoxifen-resistant breast cancer), brain cancer (such as glioma and glioblastoma), head and neck cancer, lung cancer (such as non-small cell lung cancer and mesothelioma, and pleural cancer), uterine cancer, ovarian cancer, prostate cancer, pancreatic, colorectal, kidney, liver, biliary tract cancer, bile duct cancer, gallbladder cancer, prostate cancer, stomach cancer, gastric cancer, osteosarcoma, oral cancer (such as oral squamous cell carcinoma), pharyngeal, laryngeal, urinary tract, and skin cancer (such as melanoma), as well as their metastatic forms.

[0067] In one embodiment, a method / use is provided for treating cancer-related activated stromal cells, particularly TASCs, using an antibody or an antigen-binding fragment thereof.

[0068] In one embodiment, an antibody or an antigen-binding fragment thereof is provided for the manufacture of a pharmaceutical product for the treatment of activated stromal cells associated with cancer cells, particularly TASCs.

[0069] In one embodiment, antibody therapy according to this disclosure blocks / inhibits crosstalk between stromal cells and immune cells in the TME, for example, between cancer-associated fibroblasts and / or cancer-associated macrophages.

[0070] In one embodiment, antibody therapy according to this disclosure blocks / inhibits crosstalk between cancer cells and immune cells in the TME, for example, between cancer-associated fibroblasts and / or cancer-associated macrophages.

[0071] In one embodiment, treatment with antibodies also blocks / inhibits / reduces metastasis.

[0072] In one embodiment, this method / use is useful for treating treatment-resistant cancers, such as cancers resistant to chemotherapy and / or radiotherapy.

[0073] In one embodiment, the treatment according to this disclosure is useful in combination therapy, for example, in combination with further anticancer agents.

[0074] In one embodiment, the stromal cells are cancer stromal cells, which co-localize with, for example, cancer cells and are in particular under the control of / activated by cancer cells. This may be evident by one or more of the following: a pro-inflammatory profile, high levels of cytokines (such as growth factors), MMPs, fibroblast-activating proteins, and α-smooth muscle actin secretion.

[0075] In one embodiment, cancer reduced viability in the context of this disclosure is not due to the activation of immune cells, i.e., it is not an immunotherapeutic effect in itself, but rather a change in the state of the stroma (such as TASCs) may allow the immune system and immune cells to better access and eliminate cancer cells.

[0076] In one embodiment, after treatment, cancer cells show increased sensitivity to apoptosis.

[0077] In one embodiment, the viability of stromal cells remains unchanged after treatment.

[0078] In one embodiment of this disclosure, abnormal integrin signaling is downregulated, particularly in stromal cells.

[0079] In one embodiment, desmoplasia of stromal cells is downregulated by treatment.

[0080] In one embodiment, fibrosis is downregulated by treatment, particularly within and / or around the TME.

[0081] In one embodiment, stromal cells do not refer to cells such as immune cells that have infiltrated the stroma.

[0082] In one embodiment, the treatment reduces the division of cancer cells.

[0083] In one embodiment, the treatment reduces the rate of cancer metabolism. In another embodiment, cytokines secreted from stromal cells are reduced.

[0084] In one embodiment, stromal cell activation does not affect the state of tumor-associated macrophages.

[0085] In one embodiment, the stromal cells are cancer-activated fibroblasts, and for example, signal transduction between mesenchymal stromal cells and cancer-activated fibroblasts is blocked / inhibited.

[0086] In one embodiment, the stromal cells are cancer-activated myofibroblasts.

[0087] In one embodiment, the stromal cells are activated fibroblasts.

[0088] In one embodiment, the interstitial cells are activated myofibroblasts.

[0089] In one embodiment, the phenotype of cancer-associated fibroblasts is downregulated by treatment.

[0090] In one embodiment, the stromal cells are not cancer-activated fibroblasts and / or activated fibroblasts.

[0091] In one embodiment, the stromal cells are not cancer-activated myofibroblasts and / or activated myofibroblasts.

[0092] In one embodiment, stromal cells refer to any cells within the cancer stroma, and include immune cells that have infiltrated the cancer stroma, particularly cancer-supporting cells.

[0093] In one embodiment, stromal cells do not include immune cells and other cells that have infiltrated the stroma, but refer only to, for example, mesenchymal stromal cells and cells having stromal components (such as red blood cells), and in particular refer only to mesenchymal stromal cells.

[0094] In one embodiment, the stroma is associated with blood cancer cells, such as red blood cells.

[0095] In one embodiment, epithelial cancer is a carcinoma.

[0096] In one embodiment, the cancer is an ovarian stromal tumor, for example, one disclosed herein.

[0097] In one embodiment, the cancer treatment of this disclosure is used in combination with a PARP inhibitor.

[0098] In one embodiment, the treatment according to the present disclosure is used in combination with further inhibitors of cancer stroma, for example, the target being a stromal antigen selected from CD163, CD206, CD68, CD11c, CD11b, CD14, CSF1 receptor, CD15, CD33 and CD66b, fibroblast-activating protein (FAP), TREM1, IGFBP7, FSP-1, platelet-derived growth factor α receptor (PDGFR-α), platelet-derived growth factor β receptor (PDGFR-β), and vimentin.

[0099] Tenascin C activity in cancer appears to have at least nine aspects: 1) it is found at the invasive margins of primary tumors; 2) it has anti-adhesion properties and is involved in metastasis; 3) it promotes angiogenesis; 4) it is an immunomodulator; 5) it helps create immunosuppression in the TME, including hypoxia, stiffness, pressure, and secretion of cancer-promoting cytokines by the leaky vascular system; 6) it is involved in maintaining the TME; 7) it mediates intercellular crosstalk, making cells tumorigenic; 8) it is involved in creating resistance to cancer treatment; and 9) it may promote the proliferation of cancer cells.

[0100] The treatments described herein may improve one or more of these, for example, all of the above.

[0101] The C-terminal fibrinogen-like globe (FBG) domain of tenascin C (TNC) can activate TLR4 on either macrophages or fibroblasts. TLR4 is an important component of the innate immune system, and when activated, it stimulates the secretion of pro-inflammatory cytokines such as IL-6, IL-8, or TNFα.

[0102] Activation of latent TGFβ by tenascin C suggests a potential involvement of tenascin in tumor immunomodulation.

[0103] Tenascin C is important for conferring resistance to doxorubicin-based and docetaxel-based neoadjuvant chemotherapy integrin b1 / to cancer cells by activating the mTOR pathway. Furthermore, a correlation between high tenascin C expression and tamoxifen resistance was identified in a clinical study analyzing 1286 primary breast tumors by qPCR.

[0104] Unless otherwise specified in the context, stroma and cancer stroma are used interchangeably herein to refer to the network of connective tissue that accumulates around cancer cells, particularly the tissue surrounding the tumor microenvironment (TME).

[0105] Therefore, as used herein, stromal cells refer to mesenchymal stromal cells, and also to cells that have stromal components such as red blood cells.

[0106] Mesenchymal stromal cells (MSCs) are a type of non-hematopoietic adult stem cell found in various tissues throughout the body, including bone marrow and umbilical cord tissue. Stromal cells are pluripotent and can differentiate into a variety of cell types, particularly osteoblasts, chondrocytes, adipocytes, and muscle cells.

[0107] The International Society for Cellular Therapy defines MSCs as cells that meet the following criteria: 1) Cells must adhere to a plastic surface under standard tissue culture conditions; 2) Cells must express specific surface markers, including CD105, CD73, and CD90, while lacking the expression of hematopoietic markers such as CD45, CD34, CD14, or CD11b, CD79α, or CD19, and HLA-DR; 3) Cells must have the ability to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro.

[0108] These criteria are widely adopted in this field and are used to identify and characterize stromal cells in research and clinical applications.

[0109] Normally, stromal cells are produced in the bone marrow and stored there until they mature and differentiate. Located in the stroma, stromal cells help hematopoietic cells form the components of blood. While most are found in the bone marrow, stromal cells can also be found in a variety of other tissues. These tissues may include adipose tissue, endometrium, synovial fluid, and dental tissue.

[0110] MSCs are generally low immunogenic and possess the ability to differentiate into three cell lines; therefore, MSCs can adapt to osteoblasts, chondrocytes, and adipocytes.

[0111] As used herein, activated cancer cells refer to cancer cells that exhibit one or more functions that promote tumorigenesis, for example, by inducing the replacement of regulatory CD4+ T cells (Tregs) that help counteract other anti-tumor immune cells.

[0112] As used herein, activated stromal cells (also referred to herein as cancer-activated stromal cells) refer to stromal cells that exhibit one or more functions that promote tumor formation, for example, by forming a scaffold to support tumor growth. In one embodiment, the stromal cells are associated with cancer cells (also referred to herein as tumor-associated stromal cells (TASCs)).

[0113] Compared to non-reactive stromal cells, TASCs exhibit increased secretion levels of proteins and matrix metalloproteinases (MMPs). These proteins include fibroblast-activating protein and α-smooth muscle actin. Furthermore, TASCs secrete numerous pro-tumorogenic factors, including vascular endothelial growth factor (VEGF), stromal-derived factor-1α, IL-6, IL-8, tenascin C, and others.

[0114] As used herein, the activated state of stromal cells refers to whether the stromal cells are activated (cancer-activated) or in a "normal" healthy state (also referred to herein as unresponsive).

[0115] As used herein, "relevant cancer cells" refers to cancer cells that interact with one or more activated stromal cells, for example, those from which the cancer obtains benefits, particularly improved viability.

[0116] Factors secreted by activated stromal cells such as TASCs replenish further tumor cells and tumorigenic cells. Crosstalk between host stroma and tumor cells is essential for tumor growth and progression. Tumor stroma production exhibits qualities similar to normal wound repair, including neovascularization, infiltration of immune cells and fibroblasts, and substantial remodeling of the extracellular matrix.

[0117] Furthermore, supplementation of local normal host stromal cells, such as bone marrow mesenchymal stromal cells, endothelial cells, and adipocytes, helps create a remarkably heterogeneous composition. Additionally, these cells secrete abundant factors that aid in regulating tumor development. Potential targets for tumor-associated stromal cell supplementation have been identified in the following host tissues: bone marrow, connective tissue, adipose tissue, and blood vessels. Furthermore, evidence suggests that tumor-associated stroma is a prerequisite for metastasis and tumor cell invasion. Tumor-associated stromal cells are known to arise from at least six different origins: immune cells, macrophages, adipocytes, fibroblasts, pericytes, and bone marrow mesenchymal stromal cells. Moreover, tumor stroma is primarily composed of the basement membrane, fibroblasts, extracellular matrix, immune cells, and blood vessels. Typically, most host cells within the stroma are characterized by their tumor-suppressing capacity. However, during malignant transformation, the stroma undergoes changes, resulting in proliferation, invasion, and metastasis. These changes include the formation of cancer-associated fibroblasts (CAFs), which make up a large portion of the reactive tissue stroma and play a crucial role in regulating tumor progression.

[0118] Because cancer cells require nearby stromal cells to continue their division, certain types of skin cancer (basal cell carcinoma) cannot spread throughout the body. The loss of these stromal growth factors as cancer travels throughout the body prevents it from invading other organs.

[0119] The cancer stroma (sometimes simply called the stroma depending on the context) is composed of non-malignant cells, but can provide an extracellular matrix on which tumor cells can proliferate. Stromal cells may also restrict T cell proliferation through nitric oxide production and impair immune function.

[0120] Lymph node stromal cells include several types, including fibroblastic reticular cells (FRCs), lymphatic endothelial cells (LECs), and vascular endothelial cells (BECs). FRCs are the most abundant type of stromal cells in lymph nodes and are involved in the organization of lymphoid tissue. FRCs form a network of reticular fibers that provide a physical scaffold for immune cells to interact with each other and with antigen-presenting cells.

[0121] In addition to their structural roles, lymph node stromal cells also play a crucial role in regulating the immune response. They replenish the lymph nodes with immune cells and express various cytokines and chemokines that help regulate the function of immune cells. Lymph node stromal cells are also involved in the development of lymphoid tissue and the maintenance of immune cell populations.

[0122] Lymph node stromal cells are a group of non-hematopoietic cells that constitute the structural framework of lymph nodes. Lymph node stromal cells are an important component of lymphoid tissue and play a crucial role in regulating the immune response.

[0123] Lymph node stromal cells include several types, including fibroblastic reticular cells (FRCs), lymphatic endothelial cells (LECs), and vascular endothelial cells (BECs). FRCs are the most abundant type of stromal cells in lymph nodes and are involved in the organization of lymphoid tissue. FRCs form a network of reticular fibers that provide a physical scaffold for immune cells to interact with each other and with antigen-presenting cells.

[0124] In addition to their structural roles, lymph node stromal cells also play a crucial role in regulating the immune response. They replenish the lymph nodes with immune cells and express various cytokines and chemokines that help regulate the function of immune cells. Lymph node stromal cells are also involved in the development of lymphoid tissue and the maintenance of immune cell populations.

[0125] Therefore, the functions of lymph node stromal cells include: creating an internal tissue scaffold to support hematopoietic cells; releasing small molecular chemical messengers that facilitate interactions between hematopoietic cells; promoting hematopoietic cell migration; presenting antigens to immune cells at the onset of the adaptive immune system; and maintaining lymphocyte homeostasis.

[0126] Interactions between stromal cells and hematopoietic cells are crucial for lymph node development. Crosstalk between LECs, lymphoid tissue-inducing cells, and mesenchymal stromal organizer cells initiates lymph node formation.

[0127] The stroma on red blood cells can be activated to serve / support cancer cells. Minimizing and / or blocking the activation of the stroma on red blood cells may help limit the cancer's ability to signal and transmit information beyond local areas.

[0128] The stroma of hematopoietic tissue contains several diverse cell types, namely endosteal cells and associated capsular and columnar structures, epithelial reticular cells and other epithelial cells, reticular cells, macrophages, and antigen-presenting cells. These stromal cells have a variety of mechanical and metabolic functions. Stromal cells support and surround hematopoietic tissue and its vascular system. Stromal cells regulate the migration of blood cells and hematopoietic cells. Stromal cells contribute to the microenvironment that induces the differentiation of stem cells into several blood cell lines. The nature of the interaction between stromal cells and hematopoietic cells depends on long-range and short-range humoral factors, as well as cell surface compounds such as immunoglobulins and major histocompatibility antigens. Blood cells themselves, such as neutrophils and lymphocytes, play a regulatory role in hematopoiesis together with stromal cells. Furthermore, certain stromal cells, such as macrophages, develop as blood cells and have a migratory phase. Therefore, distinguishing between blood cells, their derivatives, and stromal cells can be difficult. Considering the above, the inventors believe that the stroma of hematopoietic tissue is closely involved in the development of hematological cancers (Am J Anat 1984 Jul;170(3):447-63).

[0129] While we do not wish to be bound by theory, it may be possible to treat, minimize, and / or block the invasion of lymph nodes, such as peritumoral lymph nodes, by cancer cells by altering the activation state of stromal cells using antibodies or their binding fragments as described herein. Furthermore, lymph nodes may also be strategically important for replenishing bone marrow stromal cells to support cancer.

[0130] In one embodiment, a method / use of the present disclosure is provided for minimizing and / or blocking the infiltration of lymph nodes and / or its initial stages by cancer cells.

[0131] In one embodiment, a method / use of the present disclosure is provided for minimizing and / or blocking the support of cancer by bone stromal cells.

[0132] Lymph node stromal cells can be classified into six subpopulations known by the expression of surface markers. These subpopulations include fibroblastic reticular cells (FRCs); follicle dendritic cells (FDCs); lymphatic endothelial cells (LECs); vascular endothelial cells (BECs); α7 integrin pericytes (AIPs); and double-negative cells (DNCs).

[0133] Surface markers include the glycoprotein CD31 and the glycoprotein podoplanin GP38. Different subpopulations are also known by the production of their small molecules; where they are located; and their functions. Most also express common markers such as desmin, laminin, various subunits of integrins, vascular cell adhesion molecule 1 (VCAM-1), and mucosal vascular addressing cell adhesion molecule 1 (MAdCAM-1).

[0134] Fibroblastic reticular cells (FRCs) are located in the T cell zone of the cortex. FRCs produce collagen α-1(III)-rich reticular fibers that form a dense network within lymphoid tissue. These reticular fibers are connected by type XIV collagen, small leucine-rich proteoglycans, and lysyl oxidase. The fiber network supports and guides the movement of dendritic cells (DCs), T lymphocytes, and B lymphocytes. [1] This network also constructs a porous molecular sieve within the lymph node.

[0135] Lymphocytes transport chemokines (chemical messenger molecules) and antigens to lymph nodes. Within the lymph nodes, lymphocytes rapidly pass through a reticular network to the T cell zone and high endothelial venules. FRCs express chemokines such as CCL21 and CCL19, which assist the movement of T cells and dendritic cells that possess the CCR7 receptor.

[0136] FRCs also produce extracellular matrix components such as ER-TR7, fibrillin, laminin, and fibronectin, as well as intracellular components such as desmin and α-actin smooth muscle, which can influence the formation of reticular fiber networks. For example, the chemokine CCL21 adheres to the surface of FRCs via collagen and glycosaminoglycan molecules.

[0137] FRCs express the cytokine IL-7, which is a regulator of the survival of quiescent T lymphocytes.

[0138] Follicular dendritic cells (FDCs) are found at the center of B lymphocyte follicles. FDCs form a dense network of cellular filaments. FDCs also express Fc receptors, CD16, CD23, and CD32; complement receptors CD21 and CD35, and complement components. The network of cellular filaments and receptors helps FDCs capture antigens as immune complexes and present them to other immune cells.

[0139] FDCs assist in germinal center development through interactions with B lymphocytes and helper T lymphocytes. B lymphocytes proliferate and differentiate into plasma cells and memory cells. FDCs produce the chemokine CXCL13, which promotes the migration of B lymphocytes to primary B cell follicles. B lymphocytes require a factor called B cell activating factor (BAFF) for their survival, which is also produced by FDCs.

[0140] Marginal reticular cells (MRCs) form a cell layer beneath the subcapsular sinus. Through the reticular network, MRCs deliver antigens from the subcapsular sinus to B-cell follicles. MRCs express the TRANCE molecule (also known as RANKL), a type of tumor necrosis factor. MRCs are one of the organizer cells involved in the structural formation of lymph nodes during organogenesis. MRCs express CXCL13 at the margins of B-cell follicles.

[0141] Lymphatic endothelial cells (LECs) line the inside of lymphatic vessels. LECs express adhesion molecules, the chemokine CCL21, and lymphatic endothelial hyaluronic acid receptor-1 (LYVE1), a homolog of CD44. These molecules allow hematopoietic cells to enter lymphatic vessels. During inflammatory states, the number of adhesion molecules on the surface of LECs increases.

[0142] High endothelial cells (HECs) are a specialized type of vascular endothelial cell. In the thymus, HECs line the inside of high endothelial venules (HEVs) where lymphocytes originate. HEVs in lymph nodes express adhesion molecules such as peripheral lymph node adresin (PNAd), which is essential for the migration of naive T cells from peripheral blood to lymph nodes. In mouse lymph nodes, HECs also express the chemokine CCL21, which binds to its receptor CCR7 on naive T cells, enhancing migration.

[0143] α7 integrin pericytes (AIPs) express several types of integrin chains that generate heterodimers. These integrin chains enable integrin pericytes to interact with hematopoietic cells and promote their migration.

[0144] The fibroblasts used herein include myofibroblasts.

[0145] Cancer-associated fibroblasts (CAFs), also known as tumor-associated fibroblasts, oncogenicity-associated fibroblasts, or activated fibroblasts, are a type of stromal cell found in the tumor microenvironment. CAFs are activated fibroblasts that have been reprogrammed by cancer cells to promote tumor growth and progression, for example, by initiating extracellular matrix remodeling or by secreting cytokines, thereby promoting oncogenetic features.

[0146] CAFs are heterogeneous and can originate from a variety of sources, including tissue fibroblasts, bone marrow-derived mesenchymal stem cells, and mesenchymal metastatic epithelial cells. CAFs are characterized by the expression of specific markers such as alpha-smooth muscle actin (α-SMA), fibroblast-activating protein (FAP), and platelet-derived growth factor receptor β (PDGFRβ).

[0147] CAFs play a crucial role in tumor progression by secreting extracellular matrix components, growth factors, and cytokines that promote tumor cell survival, proliferation, and invasion. CAFs also contribute to the tumor's immunosuppressive environment by inhibiting immune cell function and promoting regulatory T cell replenishment.

[0148] These CAFs are known to stimulate angiogenesis, supporting tumor formation, and consequently, the proliferation and metastasis of cancer cells.

[0149] These CAFs then support tumor growth by secreting growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), as well as other chemokines, thereby stimulating angiogenesis and ultimately tumor growth.

[0150] In addition to their role in tumor progression, CAFs are also involved in resistance to cancer treatment. CAFs can interact with cancer cells and other stromal cells, potentially promoting drug resistance through various mechanisms.

[0151] CAFs are a complex and diverse cell type that contributes to resistance to apoptosis.

[0152] In contrast, normal fibroblasts help produce extracellular matrix components such as collagen, fibers, glycosaminoglycans, and glycoproteins, and are therefore essential for tissue repair in wound healing. However, CAFs are derived from any of normal fibroblasts, pericytes, smooth muscle cells, fibrous cells, or mesenchymal stem cells.

[0153] Unless otherwise specified, the term "stromal antigen" as used herein refers to "antigens" present only within stromal tissue or on stromal cells, and does not include "antigens" present on cancer cells. Therefore, antigens expressed on cancer cells and stromal cells are considered cancer antigens in the context of this specification. Accordingly, stromal antigens may be presented on the surface of stromal cells (cells located in the stroma) and / or on soluble molecules located in the stromal matrix.

[0154] In one embodiment, this therapy is used in combination with an antibody used to target cancer.

[0155] Antibodies that target cancer include avelumab, bevacizumab, brentuximab, semiprimab, cetuximab, daratumumab, dinutuximab, elotuzumab, enfortumab, gemtuzumab, ibritumomab, inotuzumab, ipilimumab, isatuximab, mogamulizumab, moxetumomab, necitumumab, nivolumab, obinutuzumab, ofatumumab, olaratumumab, panitumumab, pembrolizumab, pertuzumab, polatuzumab, ramucirumab, rituximab, sacituzumab, tocitumomab, trastuzumab, Fab-G8 and Fab-Hyb3 (MAGE). Targeting EADPTGHSY in A1); G2D12 and G3G4 (targeting KTWGQYWQV in GP100); 1A9, 1C8, 1A11, 1A7 and G1 (targeting IMDQVPFSV in GP100); 2F1, 2B2, 2C5 and 2D1 (targeting YLEPGPVTV / A in GP100); GPA7 (targeting ITDQVPFSV); 4A9 and 4G9 (targeting ILAFLHWL in hTERT); 3H2 and 3G3 (targeting RLVDDFLLV in hTERT); 3M4E5 (NY-ES Targeting SLIMWITQC in O-1); 7D4, 8A11, 2G12 and 9E6 (targeting FLWGPRALV in MAGE3); RL4B / 3.2G1 and 1B10 (targeting GVLPALPQV in hCGβ); 3F9 (targeting TMTRVLQGV in hCGβ); 1B8 (targeting KIFGSLAFL in Her2 / Neu); CAG10 and CLA12 (targeting EAAGIGILTV in Melan-A / MARR-1); Fab-D2 (targeting FLRNFSLML in TARP); I3.Examples include M3-2A6 (targeting LLGRNSFEV in p53); T1-116C, T1-29D, and T1-84C (targeting RMPEAAPPV in p53); T2-108A, T2-2A, and T2-116A (targeting GLAPPQHLIRV in p53); T2A (specific to YMDGTMSQV in tyrosinase); RL6A (specific to YLLPAIVHI in p68); RL21A (specific to FLSELTQQL in MIF); 8FA (specific to VLQELNVTV in proteinase 3); ESK1 F2, F3, and Clone45 (specific to RMFPNAPYL in WT1); #131 (specific to VLHDDLLEA in HA-1H); and Pr20 (specific to ALYVDSLFFL).

[0156] As used herein, "in combination with" refers to administration in a combination therapy protocol in which each component is administered separately, and also includes administration of the combination in a mixture.

[0157] The methods / uses described herein may also limit the effects of cancer cachexia and other factors.

[0158] cancer This invention is useful for treating cancer, including solid tumors and liquid tumors.

[0159] In one embodiment, the cancer is colorectal cancer.

[0160] In one embodiment, the cancer is a gastrointestinal stromal tumor.

[0161] Common Epithelial Tumors - Epithelial ovarian tumors arise from the cells that line the outer surface of the ovary. Most epithelial ovarian tumors are benign (non-cancerous). There are several types of benign epithelial tumors, including serous adenomas, mucinous adenomas, and Brenner tumors. Cancerous epithelial tumors are carcinomas - that is, they begin in the tissue lining the ovary. These tumors are the most common and dangerous of all types of ovarian cancer. Unfortunately, nearly 70 percent of women with common epithelial ovarian cancer are not diagnosed until the disease has progressed to an advanced stage.

[0162] There are several epithelial ovarian tumors that cannot be clearly identified as cancerous based on their appearance under a microscope. These are called borderline malignant tumors or low-grade malignant tumors (LMP tumors). The methods described herein include treatment for the latter.

[0163] Germ cell tumors – Ovarian germ cell tumors originate from oocytes, or eggs. Most germ cell tumors are benign (non-cancerous), but some are cancerous and can be life-threatening. The most common germ cell malignancies are mature teratomas, undifferentiated germ cell tumors, and endodermal sinus tumors. Germ cell malignancies occur most frequently in teenagers and women in their 20s. Today, 90 percent of patients with ovarian germ cell malignancies are cured and can preserve their fertility.

[0164] Stromal tumors – Ovarian stromal tumors are a rare class of tumors that arise from the connective tissue cells that make up the ovaries, and the cells that produce the female hormones estrogen and progesterone. The most common types are granulosa-theca tumors and Sertoli-Leydig cell tumors. These tumors are very rare and are usually considered low-grade cancers, with about 70 percent presenting as stage I disease (cancer confined to one or both ovaries).

[0165] Primary peritoneal cancer – While oophorectomy eliminates the risk of ovarian cancer, it does not eliminate the risk of an even rarer cancer called primary peritoneal cancer. Primary peritoneal cancer is closely related to epithelial ovarian cancer (the most common type). Primary peritoneal cancer originates in cells derived from the peritoneum (endometrium) and looks identical under a microscope. Primary peritoneal cancer is also similar in terms of symptoms, extent, and treatment.

[0166] Stages of ovarian cancer When ovarian cancer is diagnosed, the stage of the tumor can be determined during surgery, at which time the doctor can determine whether the cancer has spread outside the ovary. Ovarian cancer has four stages: Stage I (early stage) to Stage IV (advanced stage). The treatment plan and prognosis (the possible course and outcome of the disease) are determined by the stage of the cancer.

[0167] The following is a description of the various stages of ovarian cancer: Stage I cancer growth is limited to the ovary or both ovaries. Stage IA - Growth is limited to one ovary, and the tumor is confined to the inside of the ovary. There is no cancer on the outside of the ovary. Ascites containing malignant cells is not present. The capsule is preserved. Stage IB - Proliferation is limited to both ovaries, and there are no tumors on their external surfaces. Ascites containing malignant cells is absent. The capsule is preserved. Stage IC - The tumor is classified as either Stage IA or Stage IB and has one or more of the following: (1) the tumor is located on the outer surface of one or both ovaries; (2) the capsule is ruptured; and (3) ascites containing malignant cells is present, or intraperitoneal lavage fluid is positive. Stage II - Cancer growth has spread to one or both ovaries and into the pelvic cavity. Stage IIA cancer has progressed to and / or invaded the uterus, fallopian tubes, or both. Stage IIB cancer has spread to other pelvic organs. Stage IIC - The tumor is classified as either Stage IIA or Stage IIB and has one or more of the following: (1) the tumor is located on the outer surface of one or both ovaries; (2) the capsule is ruptured; and (3) ascites containing malignant cells is present, or intraperitoneal lavage fluid is positive. Stage III - Cancerous growth involves one or both ovaries, and one or more of the following are present: (1) the cancer has spread beyond the pelvis into the abdominal endometrium; and (2) the cancer has spread to the lymph nodes. The tumor is confined to the true pelvis but with histologically demonstrated malignant extension into the small intestine or greater omentum. Stage IIIA - During surgery for staging, the surgeon can see cancer extending to one or both ovaries, but there is no macroscopically visible cancer in the abdomen and it has not spread to the lymph nodes. However, microscopic examination of the biopsy reveals a very small cancerous deposit on the surface of the abdominal peritoneum. Stage IIIB - The tumor is located in one or both ovaries, and the cancerous deposit is present in the abdomen, large enough to be seen by a surgeon but not exceeding 2 cm in diameter. The cancer has not spread to the lymph nodes. Stage IIIC - The tumor is located in one or both ovaries and one or more of the following are present: (1) the cancer has spread to the lymph nodes; and / or (2) a tumorous deposit greater than 2 cm in diameter is found in the abdomen. Stage IV – This is the most advanced stage of ovarian cancer. Cancer growth has spread to one or both ovaries, and distant metastasis (spread of cancer to organs located outside the peritoneal cavity) has occurred. The presence of ovarian cancer cells in pleural effusion (fluid from the cavity surrounding the lungs) is also evidence of stage IV disease.

[0168] In one embodiment, ovarian cancer is type I, e.g., IA, IB, or IC; type II, e.g., IIA, IIB, or IIC; type III, e.g., IIIA, IIIB, or IIIC; or type IV.

[0169] This disclosure relates in particular to the treatment of any stage of ovarian cancer as described herein.

[0170] Lung cancer is classified according to its histological type, determined by the size and appearance of malignant cells as seen by a histopathologist under a microscope. For therapeutic purposes, two broad classes are distinguished: non-small cell lung cancer and small cell lung cancer.

[0171] In one embodiment, epithelial cancer is lung cancer, such as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0172] The three main subtypes of non-small cell lung cancer (NSCLC) are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.

[0173] Nearly 40% of lung cancers are adenocarcinomas, which typically occur in peripheral lung tissue. Bronchioloalveolar carcinoma, a subtype of adenocarcinoma, is more common in non-smoking women and may have a better long-term survival rate.

[0174] Squamous cell carcinoma accounts for about 30% of lung cancers. Squamous cell carcinomas usually develop near the airways. Cavities and associated cell death are commonly found in the center of the tumor. About 9% of lung cancers are large cell carcinomas. Large cell carcinomas are so named because the cancer cells are large and have excess cytoplasm, large nuclei, and prominent nucleoli.

[0175] Small cell lung cancer (SCLC) is characterized by cells containing a high density of neurosecretory granules (vesicles containing neuroendocrine hormones), which gives this tumor its endocrine / paraneoplastic syndrome association. Most cases originate in the airways (primary and secondary bronchi). These cancers grow rapidly and spread early in the disease. 60–70 percent of patients have metastatic disease at the time of diagnosis.

[0176] In one embodiment, the cancer is non-small cell lung carcinoma.

[0177] In one embodiment, a treatment for kidney cancer, such as renal cell carcinoma and / or urothelial cell carcinoma, using the oncolytic adenovirus disclosed herein is provided. Other examples of kidney cancer include squamous cell carcinoma, juxtaglomerular cell neoplasm (reninma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma, mesenchymal nephroma, Wilms' tumor, mixed epithelial-stromal tumor, clear cell adenocarcinoma, transitional cell carcinoma, inverted papilloma, renal lymphoma, teratoma, carcinosarcoma, and carcinoid tumor of the renal pelvis.

[0178] In one embodiment, the cancer is bladder cancer, which is, for example, one of several types of malignant tumors arising from the inner lining of the bladder (i.e., urothelium). Approximately 90% of bladder cancers are transitional cell carcinomas. The remaining 10% are squamous cell carcinomas, adenocarcinomas, sarcomas, small cell carcinomas, and secondary deposits from cancers elsewhere in the body. The staging is shown below.

[0179] T (Primary Tumor) TX Primary tumor unassessable; T0 No evidence of primary tumor; Ta Non-invasive papillary carcinoma; Tis Carcinoma in situ ("squamous tumor"); T1 Tumor invading subepithelial connective tissue; T2a Tumor invading superficial muscular layer (inner half); T2b Tumor invading deep muscular layer (outer half); T3 Tumor invading perivelabial tissue: T3a Microscopically visible; T3b Macroscopically visible (extravesical mass); T4a Tumor invading prostate, uterus, or vagina; T4b Tumor invading pelvic wall or abdominal wall

[0180] N (lymph node) NX: Regional lymph node evaluation impossible; N0: No regional lymph node metastasis; N1: Metastasis to a single lymph node with a maximum diameter of 2 cm or less; N2: Metastasis to a single lymph node with a maximum diameter greater than 2 cm but 5 cm or less, or metastasis to multiple lymph nodes (all with a maximum diameter of 5 cm or less); N3: Metastasis to lymph nodes with a maximum diameter greater than 5 cm.

[0181] M (Distant Metastasis) MX: Distant metastasis cannot be assessed; M0: No distant metastasis; M1: Distant metastasis present.

[0182] As used herein, thyroid cancer refers to cancer of the thyroid gland originating from follicular or parafollicular thyroid cells, and includes papillary thyroid carcinoma (75-85% of cases); follicular thyroid carcinoma (10-20% of cases); medullary thyroid carcinoma (5-8% of cases) - cancer of parafollicular cells, often part of multiple endocrine neoplasia type 2; poorly differentiated thyroid carcinoma; undifferentiated thyroid carcinoma (less than 5% of cases), which may not respond to treatment and may cause compression symptoms; thyroid lymphoma, squamous cell thyroid carcinoma, and thyroid sarcoma.

[0183] As used herein, kidney cancer refers to cancer of the kidney, such as renal cell carcinoma and transitional cell carcinoma of the renal pelvis, such as squamous cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, renal clear cell sarcoma, mesenchymal nephroma, Wilms' tumor, mixed epithelial-stromal tumor, clear cell adenocarcinoma, transitional cell carcinoma, inverted papilloma, renal lymphoma, teratoma, carcinosarcoma; and carcinoid tumor of the renal pelvis.

[0184] As used herein, bladder cancer refers to cancer of the bladder, including transitional cell bladder cancer, carcinoma in situ, papillary carcinoma, and rare types of bladder cancer such as squamous cell carcinoma and adenocarcinoma.

[0185] In one embodiment, a treatment for breast cancer, such as triple breast cancer, is provided.

[0186] In one embodiment, a treatment for prostate cancer is provided.

[0187] In one embodiment, a treatment for liver cancer is provided.

[0188] In one embodiment, the cancer is cholangiocarcinoma, and is located in a site selected from, for example, the intrahepatic bile duct, left hepatic duct, right hepatic duct, common hepatic duct, cystic duct, common bile duct, ampulla of Vater, and combinations thereof.

[0189] As used herein, esophageal cancer refers to cancer of the esophagus, including squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, and subtypes of squamous cell carcinoma, as well as non-epithelial tumors such as leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

[0190] As used herein, head and neck cancer refers to cancer of the neck and / or head, and includes oral cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus cancer, and salivary cancer.

[0191] In one embodiment, the treatment according to this disclosure is used in combination with cancer treatments such as chemotherapy, and optionally with other cancer treatments.

[0192] In one embodiment, the treatment according to the present disclosure is used in combination with at least a kinase inhibitor, selected from, for example, sorafenib and baritinib, for the treatment of cancer, such as liver cancer and / or biliary tract cancer, particularly biliary tract cancer.

[0193] In one embodiment, the treatment according to the present disclosure is used in combination with at least a tyrosine kinase inhibitor, such as axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib, or sunitinib.

[0194] In one embodiment, the treatment according to this disclosure is used in combination with at least a PI3K inhibitor.

[0195] In one embodiment, the treatment according to this disclosure is used in combination with at least an AhR inhibitor.

[0196] In one embodiment, the treatment according to this disclosure is used in combination with at least an IDO inhibitor, for example, an IDO-1 inhibitor.

[0197] In one embodiment, the treatments according to the Disclosure are used in combination with PD-1 or PD-L1 inhibitors, such as atezolizumab and / or bevacizumab, in the treatment of cancers disclosed herein, such as liver cancer, biliary tract cancer and / or pancreatic cancer, particularly liver cancer.

[0198] Chemotherapy agents and chemotherapy or cytotoxic agents are used interchangeably in this specification unless otherwise specified in the context.

[0199] As used herein, chemotherapy refers to certain antitumor chemical agents or drugs that "selectively" destroy malignant cells and tissues, such as alkylating agents, antimetabolites (including thymidylate synthase inhibitors), anthracyclines, antimicrotubule agents (including plant alkaloids), topoisomerase inhibitors, PARP inhibitors, and other antitumor agents. The term "selective" in this context is not strictly used, as, of course, many of these drugs have serious side effects.

[0200] The preferred dose may be selected by the practitioner based on the nature of the cancer being treated.

[0201] Examples of alkylating agents that may be used in the methods of this disclosure include alkylating agents such as nitrogen mustard, nitrosourea, tetrazine, aziridine, platin and its derivatives, as well as non-classical alkylating agents.

[0202] Examples include platinum-containing chemotherapeutic agents (also called platins), such as cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, and lipoplatin (liposomal versions of cisplatin), especially cisplatin, carboplatin, and oxaliplatin.

[0203] The dosage of cisplatin varies depending on the specific type of cancer, ranging from approximately 20 to 270 mg / m². 2 The range is as follows. In most cases, the dose is approximately 70 to 100 mg / m². 2 It is within the range.

[0204] Nitrogen mustard contains mechloretamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, and busulfan.

[0205] Nitrosoureas include N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, and streptozocin. Tetrazine includes dacarbazine, mitozolomid, and temozolomid.

[0206] Aziridines include thiotepa, mitomycin, and diaziquane (AZQ).

[0207] Examples of antimetabolites that may be used in the methods of this disclosure include antifolic acid agents (e.g., methotrexate and pemetrexed), purine analogs (e.g., thiopurines, e.g., azathioprine, mercaptopurine, thiopurines, fludarabine (including phosphate form), pentostatin and cladribine), pyrimidine analogs (e.g., fluoropyrimidines, e.g., 5-fluorouracil and their prodrugs such as capecitabine [Xeloda®]), flucusuridine, gemcitabine, cytarabine, decitabine, larcitrexed (tomdex) hydrochloride, cladribine and 6-azauracil.

[0208] Examples of anthracyclines that may be used in the methods of this disclosure include daunorubicin (daunomycin), daunorubicin (liposomal), doxorubicin (adriamycin), doxorubicin (liposomal), epirubicin, idarubicin, barurubicin (currently used only for the treatment of bladder cancer), and anthracycline analogs such as mitoxantrone, particularly doxorubicin.

[0209] Examples of antimicrotubule agents that may be used in the methods of this disclosure include vinca alkaloids and taxanes.

[0210] Vinca alkaloids include entirely natural chemicals such as vincristine and vinblastine, as well as semi-synthetic vinca alkaloids such as vinorelbine, vindesine, and vinflunin.

[0211] Taxanes include paclitaxel, docetaxel, abraxane, cabazitaxel, and their derivatives. Derivatives of taxanes as used herein include taxane reformulations such as taxol, e.g., micelle formulations (formulaitons), and derivatives also include chemical derivatives in which synthetic chemistry is used to modify the taxane starting material.

[0212] Examples of topoisomerase inhibitors that may be used in the methods of this disclosure include type I topoisomerase inhibitors, type II topoisomerase inhibitors, and type II topoisomerase toxins. Type I inhibitors include topotecan, irinotecan, indothecan, and indimitecan. Type II inhibitors include genistein and ICRF193 having the following structure:

[0213] [ka]

[0214] Type II toxins include amsacrin, etoposide, etoposide phosphate, teniposide, doxorubicin, and fluoroquinolones.

[0215] In one embodiment, the chemotherapeutic agent is a PARP inhibitor, such as olaparib, niraparib, pamiparib, rucaparib, talazoparib, veliparib, CEP9722, E7016, iniparib, and 3-aminobenzamide (which may be particularly useful for the treatment of pancreatic cancer), particularly olaparib, niraparib, rucaparib, and talazoparib.

[0216] In one embodiment, the combination of chemotherapeutic agents used is, for example, platinum and 5-FU or its prodrug, such as cisplatin or oxaliplatin, and capecitabine or gemcitabine, such as FOLFOX.

[0217] In one embodiment, chemotherapy includes a combination of chemotherapeutic agents, particularly cytotoxic chemotherapeutic agents.

[0218] In one embodiment, the chemotherapy combination includes platinum, such as cisplatin, and fluorouracil or capecitabine.

[0219] In one embodiment, the chemotherapy combination is capecitabine and oxaliplatin (Xelox).

[0220] In one embodiment, the chemotherapy is a combination of folinic acid and 5-FU, optionally combined with oxaliplatin.

[0221] In one embodiment, chemotherapy is a combination of folinic acid, 5-FU, and irinotecan (FOLFIRI), optionally combined with oxaliplatin (FOLFIRINOX). This regimen consists of: irinotecan (180 mg / m²). 2 , taking IV over 90 minutes, simultaneously with folinic acid (400 mg / m³). 2 [or 2 x 250 mg / m²] 2 ], followed by IV over 120 minutes; then fluorouracil (400-500 mg / m²) 2 (IV bolus), followed by fluorouracil (2400-3000 mg / m²) 2 (Intravenous infusion over 46 hours). This cycle is usually repeated every two weeks. The dosage shown above may vary from cycle to cycle.

[0222] In one embodiment, the chemotherapy combination uses a microtubule inhibitor, such as vincristine sulfate, epotilon A, N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide (ABT-751), a taxol-derived chemotherapeutic agent, such as paclitaxel, abraxane, or docetaxel, or a combination thereof.

[0223] In one embodiment, the chemotherapy combination uses an mTor inhibitor. Examples of mTor inhibitors include everolimus (RAD001), WYE-354, KU-0063794, papamycin (sirolimus), temsirolimus, defololimus (MK-8669), AZD8055, and BEZ235 (NVP-BEZ235).

[0224] In one embodiment, the chemotherapy combination uses a MEK inhibitor. Examples of MEK inhibitors include AS703026, CI-1040 (PD184352), AZD6244 (selumetinib), PD318088, PD0325901, AZD8330, PD98059, U0126-EtOH, BIX02189, or BIX02188.

[0225] In one embodiment, the chemotherapy combination uses an AKT inhibitor. Examples of AKT inhibitors include MK-2206 and AT7867.

[0226] In one embodiment, the combination uses an aurora kinase inhibitor. Examples of aurora kinase inhibitors include aurora A inhibitor I, VX-680, AZD1152-HQPA (valasertib), SNS-314 mesylate, PHA-680632, ZM-447439, CCT129202, and hesperazine.

[0227] In one embodiment, the combination chemotherapy uses a p38 inhibitor, such as those disclosed in WO2010 / 038086, such as N-[4-({4-[3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido]naphthalen-1-yloxy}methyl)pyridin-2-yl]-2-methoxyacetamide.

[0228] In one embodiment, the combination uses a Bcl-2 inhibitor. Examples of Bcl-2 inhibitors include obatoclax mesylate, ABT-737, ABT-263 (navitoclax), and TW-37.

[0229] In one embodiment, the combination chemotherapy includes antimetabolites such as capecitabine (Xeloda), fludarabine phosphate, fludarabine (Fludara), decitabine, raltitrexed (Tomudex), gemcitabine hydrochloride, and cladribine. In one embodiment, the combination chemotherapy includes ganciclovir, which may help control the immune response and / or tumor vascularization.

[0230] Approved therapies for use in combination with the treatments herein Currently approved bladder cancer therapies for use in combination with the present invention include atezolizumab, avelumab, enfortumab, erdafitinib, nivolumab, pembrolizumab, and sacitumab govitecan-hziy.

[0231] Currently approved brain cancer therapies for use in combination with the present invention include belzutifan, bevacizumab, dabrafenib, everolimus, trametinib.

[0232] Currently approved breast cancer therapies for use in combination with the present invention include abemaciclib, ad-trastuzumab, alpelicib, elastrant dihydrochloride, everolimus, exemestane, fam-trastuzumab deruxtecan-NXKI, fluvestrant, lapatinib nitrate, letrozole, margetuximab-cmkb, neratinib maleate, olaparib, palbociclib, perbrozumab-trastuzumab and hyaluronidase-zzxf, ribociclib, sacituzumab, talazoparib tosylate, tamoxifen, toremifene, toremifene, trastuzumab and tucatinib.

[0233] Currently approved coloreactal cancer treatments for use in combination with the present invention include bevacizumab, cetuximab, encorafenib, ipilimumab, nivolumab, panitumumab, pembrolizumab, ramucirumab, regorafenib, tucatinib, and zib-aflibercept.

[0234] Imatinib is one of the currently approved treatments for ermatofibrosarcoma protuberans that is suitable for use in combination with the present invention.

[0235] Approved therapies for endocrine tumors and neuroendocrine tumors for use in combination with the present invention include avelumab, iobenguan I 131, lanreotide acetate and lutetium ( 177 Lu)-dotate is included.

[0236] Currently approved therapies for esophageal cancer to be used in combination with the present invention include fam-trastuzumab deruxtecan-nxki, ipilimumab, nivolumab, pembrolizumab, ramucirumab, and trastuzumab.

[0237] Head and neck cancer therapies for use in combination with the present invention include cetuximab, nivolumab, pembrolizumab, and ONYX-15.

[0238] Currently approved therapies for gastrointestinal stromal tumors for use in combination with the present invention include avapritinib, imatinib, regorafenib, lipretinib, and sunitinib maleate.

[0239] Currently approved therapies for giant cell tumors to be used in combination with the present invention include denosumab and pexidartinib hydrochloride.

[0240] Currently approved therapies for kidney cancer to be used in combination with the present invention include avelumab, axitinib, verzutifan, bevacizumab, cabozantinib-S-maleate, everolimus, ipilimumab, lenvatinib, nivolumab, pazopanib, pembrolizumab, sorafenib tosylate, sunitinib, tesirolimus, and tivozanib.

[0241] Approved therapies for liver cancer and cholangiocarcinoma for use in combination with the present invention include atezolizumab, bevacizumab, cabozantinib-S-maleate, durvalumab, futivatinib, infiglatinibrate, ipilimumab, ivosidenib, nivolumab, pembrolizumab, pemigatinib, ramucircumab, regorafenib, sorafenib, and tremelimumab-actl.

[0242] Currently approved therapies for lung cancer to be used in combination with the present invention include adaglacib, afatinib, alectinib, amivantamab-vmjw, atezolizumab, bevacizumab, brigatinib, capmatinib hydrochloride, semiprimab-rwlc, ceritinib, crizotinib, dabrafenib mesylate, dacomitinib, durvalumab, entrectinib, erlotinib hydrochloride, and fam-tras. This includes tuzumab deruxtecan-nxki, gefitinib, ipilimumab, lorlatinib, mobocertinib (succinate), necitumumab, nivolumab, osimertinib (mesylate), pembrolizumab, ramucircumab, serpercatinib, sotrasib, tepotinib, trametinib dimethyl sulfoxide, and tremelimumab.

[0243] Currently approved therapies for lymphoma to be used in combination with the present invention include acalabrutinib, axicabutagen siroylosel, bellinostat, bexarotene, bortezomib, brentuximab vedotin, brexucabtahene autolucel, copanlisib hydrochloride, crizotinib, denileukin difutitox, duvelisib, epcolitamab-bysp, grofitamab-gxbm, and This includes britumomab / tiuxetan, ibrutinib, loscabragene / malaloicel, loncatuximab / tecilin-lpyl, mogamulizumab-kpkc, mosmetuzumab-axgb, nivolumab, obinutuzumab, pembrolizumab, pemigatinib, piltobrutinib, polatuzumab / vedotin-piiq, pralatrexate, rituximab, rituximab / human hyaluronidase, romidepsin, selinexor, siltuximab, tafacitamab CXIX, tazemetostat hydrobromide, tisagenlecleucel, venetoclax, vorinostat, and zanubrutinib.

[0244] Currently approved treatments for malignant mesothelioma for use in combination with the present invention include ipilimumab and nivolumab.

[0245] Currently approved treatments for neuroblastoma for use in combination with the present invention include dinutuximab and naxitamab-gqgk.

[0246] Currently approved treatments for ovarian epithelial cancer, fallopian tube cancer, and primary peritoneal cancer for use in combination with the present invention include bevacizumab, mirvetuximab, niraparib tosylate monohydrate, olaparib, and rucaparib camsylate.

[0247] Currently approved treatments for pancreatic cancer for use in combination with the present invention include belzutifan, erlotinib, everolimus, olaparib, and sunitinib.

[0248] Currently approved treatments for plexiform neurofibroma for use in combination with the present invention include selumetinib sulfate .

[0249] Currently approved treatments for prostate cancer for use in combination with the present invention include abiraterone acetate, apalutamide, cabazitaxel, darolutamide, enzalutamide, lutetium ( 177 Lu) vipivotide tetraxetan, niraparib tosylate monohydrate, and abiraterone acetate, olaparib, talazoparib tosylate, radium 223 dichloride, rucaparib camsylate.

[0250] Currently approved therapies for skin cancer for use in combination with the present invention include alitretinoin, atezolizumab, avelumab, binimetinib, semaprimab-rwlc, cobimetinib fumarate, dabrafenib, encorafenib, ipilimumab, nivolumab and relatlimab-rmbw, pembrolizumab, retifanlimab-dlwr, sonidegib, tebentafusp-tebn, trametinib dimethyl sulfoxide, visimodegib, bemrafenib.

[0251] Currently approved therapies for soft tissue sarcoma for use in combination with the present invention include alitretinoin, atezolizumab, crizotinib, pazopanib hydrochloride, sirolimus protein-bound particles, tazemetostat hydrobromide.

[0252] Currently approved therapies for solid tumors (anywhere in the body) for use in combination with the present invention include dabrafenib mesylate, dostarlimab-gxly, entrectinib, larotrectinib, pembrolizumab, selpercatinib, trametinib dimethyl sulfoxide.

[0253] Currently approved therapies for gastric cancer for use in combination with the present invention include fam-trastuzumab deruxtecan-nxki, nivolumab, pembrolizumab, ramucirumab, trastuzumab.

[0254] Currently approved therapies for systemic mastocytosis for use in combination with the present invention include avapritinib, imatinib mesylate, midostaurin.

[0255] Currently approved therapies for thyroid cancer to be used in combination with the present invention include cabozantinib malate, dabrafenib mesylate, lenvatinib mesylate, pralcetinib, selprecatinib, sorafenib tosylate, trametinib dimethyl sulfoxide, and vandetanib.

[0256] sign Labeling as described herein is defined as any portion that can be detected using an assay. Non-limiting examples of reporter molecules include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, photoaffinity molecules, colored particles, or ligands, such as biotin.

[0257] Labeled conjugates are generally preferred for use as diagnostic agents. Diagnostic agents are generally classified into two classes: those for use in in vitro diagnostics and those for use in in vivo diagnostic protocols, commonly known as “directed imaging.” Many suitable imaging agents are known in the art, as are methods for conjugating them to peptides and polypeptides (see, for example, U.S. Patents 5,021,236, 4,938,948, and 4,472,509). Possible imaging moieties include paramagnetic ions, radioisotopes, fluorochromes, NMR-detectable substances, and X-ray imaging agents.

[0258] Examples of paramagnetic ions include chromium(III), manganese(II), iron(III), iron(II), cobalt(II), nickel(II), copper(II), neodymium(III), samarium(III), ytterbium(III), gadolinium(III), vanadium(II), terbium(III), dysprosium(III), holmium(III), and / or erbium(III), with gadolinium being particularly preferred. Ions useful in other contexts such as X-ray imaging include, but are not limited to, lanthanum(III), gold(III), lead(II), and especially bismuth(III).

[0259] Examples of radioisotopes for therapeutic and / or diagnostic use include astatine 211, carbon 14, chromium 51, chlorine 36, cobalt 57, cobalt 58, copper 67, europium 152, gallium 67, hydrogen 3, iodine 123, iodine 125, iodine 131, indium 111, iron 59, phosphorus 32, rhenium 186, rhenium 188, selenium 75, sulfur 35, technetium 99m, and / or yttrium 90. Iodine 125 is often preferred for use in certain embodiments, and technetium 99m and / or indium 111 are also often preferred due to their suitability for low-energy and long-range detection. Radiolabeled peptides and polypeptides can be produced according to methods well known in the art. For example, polypeptides such as antibodies can be iodized by contact with sodium iodide and / or potassium iodide, and a chemical oxidizing agent such as sodium hypochlorite, or an enzymatic oxidizing agent such as lactoperoxidase. Polypeptides can be labeled with technetium-99m by a ligand exchange process, for example, by reducing pertechnate with a stannous solution, chelating the reduced technetium onto a Sephadex column, and applying the peptide to this column. Alternatively, direct labeling techniques may be used, for example, by incubating pertechnate, a reducing agent such as SNCl2, a buffer solution such as a sodium-potassium phthalate solution, and the peptide. Intermediate functional groups often used to bind radioactive isotopes existing as metal ions to peptides are diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).

[0260] Fluorescent labels intended for use as conjugates include Alexa350, Alexa 430, AMCA, BODIPY 630 / 650, BODIPY 650 / 665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, Cascade Blue, Cy3, Cy5, 6-FAM, Fluorescein Isothiocyanate, HEX, 6-JOE, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, REG, Rhodamine Green, Rhodamine Red, Renographin, ROX, TAMRA, TET, Tetramethylrhodamine, and / or Texas Red.

[0261] Another type of conjugate intended for use primarily in vitro involves a polypeptide being linked to a secondary ligand and / or an enzyme (enzyme tag) that produces a colored product upon contact with a chromogenic substrate. Examples of suitable enzymes include urease, alkaline phosphatase, (horseradish) hydrogen peroxidase, or glucose oxidase. Preferred secondary ligands are biotin and avidin and streptavidin compounds. The use of such labels is well known to those skilled in the art and is described, for example, in U.S. Patents 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149, and 4,366,241.

[0262] Other methods for conjugating or linking peptides to a conjugate portion of the peptide are known in the art. Some conjugation methods include the use of metal chelate complexes with organic chelating agents such as diethylenetriaminepentaacetic anhydride (DTPA); ethylenetriaminetetraacetic acid; N-chloro-p-toluenesulfonamide; and / or tetrachloro-3α,6α-diphenylglycoluryl, conjugated to antibodies (U.S. Patents 4,472,509 and 4,938,948). Peptides or polypeptides may also be reacted with enzymes in the presence of coupling agents such as glutaraldehyde or periodates. Conjugates with fluorescein markers are prepared in the presence of these coupling agents or by reaction with isothiocyanates.

[0263] As used herein, "is" means "comprising".

[0264] In the context of this specification, "comprising" should be interpreted as "including."

[0265] Embodiments of the present invention that include certain features / elements are also intended to extend to alternative embodiments that "consist" or "consist essentially" of the relevant elements / elements.

[0266] Where technically appropriate, embodiments of the present invention can be combined.

[0267] Technical documents such as patents and applications are incorporated herein by reference.

[0268] The technical background is part of the technical disclosure of this specification, and the discussions therein are not limited to discussing the prior art, as they include discussions of the technical problems encountered in the art and the application of this technology, and may be used as a basis for amendments. Any embodiment specifically and expressly described herein may form the basis for a disclaimer, either alone or in combination with one or more further embodiments.

[0269] Certain values ​​in the examples may be extracted from the examples and used separately from other features present therein as the basis for correction.

[0270] This application claims priority from SG10202301006Y filed April 11, 2023, SG10202302846W filed October 5, 2023, and SG10202302916W filed October 13, 2023 (each incorporated by reference). Their disclosures can be used as the basis for amendments herein. The background section, which contains technically relevant details, can be used as the basis for amendments. [Brief explanation of the drawing]

[0271] [Figure 1] Figure 1 shows a graph comparing the viability of CLL tumor cells when bone marrow stromal cells are cultured alone or co-cultured with CLL cells, in the presence of C3*, and optionally in the presence of venetoclax. [Figure 2] Figure 2 shows a graph of the viability of CLL tumor cells when co-cultured with bone marrow stromal cells in the presence of C3* as a monotherapy agent. [Figure 3A] Figure 3A shows a graph of the viability of CLL tumor cells when co-cultured with bone marrow stromal cells in the presence of various concentrations of C3* and venetoclax. [Figure 3B] Figure 3B shows a graph of the viability of CLL tumor cells when co-cultured with bone marrow stromal cells in the presence of 2.5 nM or 5 nM venetoclax and C3* or a control. [Examples]

[0272] Example 1: Solitary culture of bone stromal cells or co-culture with CLL cells (optionally in the presence of venetoclax) Bone marrow stromal cells (commercially available from Lonza) were seeded, and chronic lymphocytic leukemia (CLL) cells were added 24 hours later. C3* SEQ ID NOs. 30 and 31 were added at specific concentrations, incubated for 2 hours, and then patient primary CLL cells were added.

[0273] CLL cells were seeded under co-culture conditions and incubated with a specific concentration of C3* for 24 hours.

[0274] Venetoclax was added under specific conditions 24 hours later and incubated for 48 hours.

[0275] Survival capacity was evaluated using flow cytometry analysis with annexin V and DAPI staining. The results are shown in Figure 1.

[0276] Example 2: Single-agent experiment Bone marrow stromal cells were seeded, and CLL cells were added 24 hours later. C3* was added at a specific concentration and incubated for 2 hours, after which patient primary CLL cells were added. CLL cells were seeded under co-culture conditions and incubated with a specific concentration of C3* for 72 hours. Viability was evaluated using flow cytometry analysis with annexin V and DAPI staining.

[0277] The results are shown in Figure 2.

[0278] Example 3: Long-term experiment Bone marrow stromal cells were seeded, and CLL cells were added 24 hours later. C3* was added at 10 μg / ml and incubated for 2 hours, after which patient primary CLL cells were added. CLL cells were seeded under co-culture conditions and incubated with a specific concentration of C3* for 24 hours. After 24 hours, venetoclax was added under specific conditions and incubated for 120 hours. Viability was evaluated using flow cytometry analysis with annexin V and DAPI staining.

[0279] The results are shown in Figure 3.

[0280] The sequences are found in the sequence listings that constitute part of this specification.

Claims

1. An antibody or antigen-binding fragment as an inhibitor of the FBG region of tenascin C, The antibody having VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29 (especially 29) binds to the same epitope, a. Neutralization of cancer-associated stromal cells such that their ability to support cancer viability is reduced, and / or b. A reduction in the activation state of cancer stromal cells (e.g., in the tumor microenvironment) that makes cancer stromal cells less tolerant to cancer cells, for example, inhibiting crosstalk between stromal cells and / or cancer cells, and / or vice versa; or c. Neutralization of abnormally activated stromal cells in diseased tissue, Features, for use in cancer treatment, The aforementioned inhibitor is an antibody or antigen-binding fragment.

2. An antibody or antigen-binding fragment as an inhibitor of the FBG region of tenascin C, The antibody has VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29, and binds to the same epitope. For use in the treatment of cancer-activated stromal cells to reprogram the tumor microenvironment to make it less carcinogenic (tumor-forming), The aforementioned inhibitor is an antibody or antigen-binding fragment.

3. An antibody or antigen-binding fragment as an inhibitor of the FBG region of tenascin C, The antibody has VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29, and binds to the same epitope. For use in the treatment of cancer to reverse / prevent cancer resistance, such as resistance to chemotherapy, radiotherapy, Bcl-2 inhibitors, DHOH inhibitors, kinase inhibitors, IDO inhibitors, AhR inhibitors, cellular cancer therapies (such as CAR-T therapy), PARP inhibitors, velstine, temozolomide, tamoxifen, oncolytic viruses, corticosteroids, and combinations of two or more thereof. The aforementioned inhibitor is an antibody or antigen-binding fragment.

4. An antibody or antigen-binding fragment as an inhibitor of the FBG region of tenascin C, The antibody has VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29, and binds to the same epitope. For use in the treatment of refractory cancers, such as refractory solid tumors, pancreatic cancer, gallbladder cancer, esophageal cancer, brain cancer (including astrocytoma, glioma, glioblastoma multiforme, medulloblastoma, ependymoma, oligodendroglioma, craniopharyngioma, pituitary adenoma, germ cell tumor, primitive neuroectodermal tumor, pilocytic astrocytoma, mixed glioma, chordoma, optic nerve glioma, diffuse astrocytoma, germ tumor, pineal blastoma, choroid plexus papilloma, especially glioblastoma multiforme), liver cancer, biliary tract / cholangiocarcinoma, gastric cancer, colorectal cancer, breast cancer (including triple-negative breast cancer and / or breast cancer with upregulated TGF-β), and lung cancer (including mesothelioma, bronchial cancer, and pleural cancer), The aforementioned inhibitor is an antibody or antigen-binding fragment.

5. a. An antibody or antigen-binding fragment thereof that inhibits the FBG region of tenascin C, and which binds to the same epitope as an antibody having VH of SEQ ID NO: 17 and VL selected from SEQ ID NOs: 8, 11, 28, or 29; and b. Cancer treatments selected from chemotherapy, radiotherapy, surgery, ablation, photodynamic therapy, periostin inhibitors, Bcl-2 inhibitors, cellular cancer treatments (such as CAR-T therapy), PARP inhibitors, hormone therapy, anti-VEGF, di-2-pyridylketone-4-cyclohexyl-4-methyl-thiosemicarbazone, corticosteroids, and combinations of two or more thereof (especially corticosteroids). Combination therapy including, For example, tissue penetration is improved and / or tolerance is minimized. The aforementioned combination therapy.

6. a. The treated cancer has a lower survival rate, for example, as a result of the regulation of the activity of cancer stromal cells, and / or b. The treated cancer cells are sensitized to cancer treatment, and / or c. The treated cancer cells have a lower metabolic rate, for example, a reduced proliferation rate. An antibody or antigen-binding fragment for use according to any one of claims 1 to 5.

7. The antibody or antigen-binding fragment for use according to any one of claims 1 to 6, wherein the stromal cells are mesenchymal stromal cells, selected from, for example, fibroblasts and pericytes.

8. The aforementioned stromal cells, a. Bone marrow stromal cells, b. Lymph node stromal cells, selected from, for example, fibroblastic reticular cells, follicular dendritic cells, marginal reticular cells, lymphatic endothelial cells, hyperendothelial cells, and α7 integrin-positive pericytes. An antibody or antigen-binding fragment for use according to any one of claims 1 to 7, selected from the above.

9. The antibody or antigen-binding fragment for use according to any one of claims 1 to 8, wherein the stromal cells are selected from fibroblasts, for example, cancer-activated fibroblasts, for example, cancer-associated fibroblasts (CAFs).

10. An antibody or antigen-binding fragment for use according to any one of claims 1 to 9, wherein the cancer activity of the stromal cells is downregulated, for example, inhibited by treatment, for example, inhibition of the secretion of nitric oxide, factor-1α, IL-6, IL-8, tenascin C, matrix metalloproteinases, factors that supplement tumorigenic cells, matrix metalloproteinases, and combinations thereof.

11. An antibody or antigen-binding fragment for use according to any one of claims 1 to 10, wherein neovascularization is reduced.

12. An antibody or antigen-binding fragment for use according to any one of claims 1 to 11, wherein the mesenchymal properties of the stromal cells are downregulated (normalized) by treatment.

13. An antibody or antigen-binding fragment for use according to any one of claims 1 to 12, wherein the tumor microenvironment is regulated, for example, by increasing permeability, reducing fibrosis, reducing remodeling, reducing metabolic levels, reducing hypoxia, reducing interstitial pressure, reducing the secretion of cytokines and / or chemokines that promote cancer survival / growth, reducing energy delivery to cancer cells, reducing "crosstalk", reducing nutrient delivery to cancer cells, reducing autophagy, reducing resistance, and a selection of two or more combinations thereof.

14. An antibody or antigen-binding fragment for use according to any one of claims 1 to 13, wherein the secretion of chemokines that support the viability (such as proliferation and / or persistence) of cancer cells is reduced.

15. An antibody or antigen-binding fragment for use according to any one of claims 1 to 14, wherein the secretion of chemokines that produce an anti-cancer inflammatory state is increased.

16. An antibody or antigen-binding fragment for use according to any one of claims 1 to 15, wherein tumor-induced autophagy is reduced.

17. An antibody or antigen-binding fragment for use according to any one of claims 1 to 16, wherein the neutralization of immune cells by the tumor microenvironment is reduced, for example, the neutralization of T cells is minimized (including endogenous T cells and modified T cells, such as CAR-T cells).

18. An antibody or antigen-binding fragment for use according to any one of claims 1 to 17, wherein the upregulation of β1 integrin is minimized, for example, in response to radiotherapy.

19. An antibody or antigen-binding fragment for use according to any one of claims 1 to 18, wherein the androgen receptor (AR) is not downregulated on stromal cells, particularly in prostate cancer.

20. An antibody or antigen-binding fragment for use according to any one of claims 1 to 19, wherein estrogen receptor downregulation is minimized, for example, in breast cancer.

21. An antibody or antigen-binding fragment for use according to any one of claims 1 to 20, wherein the cancer is an epithelial cancer and / or solid tumor selected from bladder cancer, bone cancer, brain cancer (including metastatic brain cancer), liver cancer, prostate cancer, pancreatic cancer, biliary tract cancer, bile duct cancer, colon cancer, intestinal cancer, breast cancer (e.g., triple-negative breast cancer, secondary breast cancer, and locally advanced breast cancer), cervical cancer, gallbladder cancer, esophageal cancer, ovarian cancer, thyroid cancer, kidney cancer, head and neck cancer (such as laryngeal cancer, pharyngeal cancer, and salivary gland cancer), gastric cancer, thyroid cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, inflammatory myofibroblastic tumor, and tracheobronchial tumor), penile cancer, retinoblastoma, testicular cancer, intraocular melanoma, urinary tract cancer, skin cancer (including melanoma), endocrine tumors, neuroendocrine tumors, and two or more combinations thereof (including their metastatic forms).

22. An antibody or antigen-binding fragment for use according to any one of claims 1 to 21, wherein the aforementioned refractory cancer is brain cancer (including astrocytoma, glioma, glioblastoma multiforme, medulloblastoma, ependymoma, oligodendroglioma, craniopgaryngioma, pituitary adenoma, germ cell tumor, primitive neuroectodermal tumor, pilocytic astrocytoma, mixed glioma, chordoma, optic nerve glioma, diffuse astrocytoma, germ tumor, pineal blastoma, choroid plexus papilloma, and especially glioblastoma multiforme) (including their metastatic forms).

23. An antibody or antigen-binding fragment for use according to any one of claims 1 to 22, which increases the survival of treated patients, for example, survival in remission of cancer, i.e., cancer-free survival.

24. The aforementioned treatment method, a. Chemotherapy, for example, temozolomide, epothilon, melphalan, carmustine, busulfan, lomustine, cyclophosphamide, dacarbazine, polyfeprosan, ifosfamide, chlorambucil, mechloretamine, busulfan, cyclophosphamide, carboplatin, cisplatin, oxaplatin, thiotepa, capecitabine, streptozocin, bicalutamide, phthalamide, nilutamide, leuprolide acetate, doxorubicin (e.g., doxorubicin hydrochloride or liposomal doxorubicin hydrochloride), bleomycin sulfate, daunorubicin hydrochloride, dactinomycin, liposomal daunorubicin citrate, epirubicin hydrochloride, idarubicin hydrochloride, mitomycin, barurubicin, anastrozole, toremifene citrate, cytarabine, fluorouracil, fludarabine, floxuridine, interferon α-2b, plicamycin, mercaptopurine, methotrexate, interferon α-2a, medroxyprogesterone acetate, estramustine sodium phosphate, estradiol, leuprolide acetate, megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate, testolactone, goserelin acetate, etoposide phosphate, vincristine sulfate, etoposide, vinblastine, etoposide, vincri A chemotherapy regimen selected from stine sulfate, teniposide, trastuzumab, gemtuzumab ozogamicin, rituximab, exemestane, irinotecan hydrochloride, asparaginase, gemcitabine hydrochloride, altretamine, topotecan hydrochloride, hydroxyurea, cladribine, mitotane, procarbazine hydrochloride, vinorelbine tartrate, pentostatin sodium, mitoxantrone, pegaspargase, denileukin diftitix, alitretinoin, porfimer, bexarotene, paclitaxel, docetaxel, arsenic trioxide, tretinoin, and combinations of two or more thereof, such as FOLFOX, Xelox, FOLFIRI, FOLFIRINOX; b. Anti-VEGF therapies, e.g., axitinib, bevacizumab, cabozantinib, lapatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ranibizumab, regrafenib, sorafenib, sunitinib, vandetanib; c. Modified immune cells, for example, selected from CAR-T therapy, particularly tisagenlecleucel, axicapbutagen siroleucel, brexcapbutagen autoceucel, lysokabutagen malaroucel, idekabutagen bicleucel, and siltabtagene autoceucel. The combination therapy according to any one of claims 1 to 23.

25. a. A VH domain comprising sequence number 1 as CDRH1, sequence number 2 as CDRH2, and CDRH3 selected from sequence numbers 3, 9, 12, 14, 16, 18, 20, 22 and 24; and b. A VL domain containing sequence number 5 as CDRL1, sequence number 6 as CDRH2, and sequence number 7. An antibody or antigen-binding fragment for use according to any one of claims 1 to 24, comprising:

26. The antibody or antigen-binding fragment for use according to any one of claims 1 to 25, wherein the VH comprises sequence number 17 and the VL comprises a sequence selected from sequence numbers 8, 11, 28, or 29.

Images