Combination therapy based on PD1 inhibitor and IL-17B inhibitor

Abstract

The present invention relates to the combination of a PD1 inhibitor and an IL-17B inhibitor, particularly for the treatment of patients and diseases that are resistant to anti-PD1 therapy.

Description

[Technical Field]

[0001] The present invention relates to combination therapies based on PD1 inhibitors and IL-17B inhibitors. [Background technology]

[0002] Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately.

[0003] Chronic cancer and persistent infections result in constant antigen exposure to antigen-reactive T cells, leading to cell exhaustion and the cessation of effector function. Expression of cell surface binding molecules, such as programmed cell death protein 1 (PD1 / PD-1 / CD279) and cytotoxic T lymphocyte-associated protein 4 (CTLA4 / CTLA-4 / CD152), on antigen-specific T cells is a marker of exposure to immunogenic stimuli. PD1 and CTLA4 are considered immune checkpoints due to their pivotal role in downregulating the magnitude of T cell responses. Other clinically relevant immune checkpoint molecules are T-cell immunoglobulin and mucin domain-containing 3 (TIM3 / TIM-3), with its nominal ligand galectin 9, and, to a lesser extent, lymphocyte-activation gene 3 (LAG3 / LAG-3 / CD223), which binds to major histocompatibility complex (MHC) class II molecules with higher affinity than the CD4 receptor.

[0004] PD1 expression on T cells is rapidly induced following antigen exposure, following engagement between the T cell receptor (TCR) and its cognate epitope-bearing MHC molecule in the draining lymph node. In addition to TCR-dependent regulation, the presence of interleukin-2 (IL-2), IL-7, IL-15, vascular endothelial growth factor (VEGF), IL-6, and transforming growth factor beta (TGF-β) in the local cytokine environment of lymph nodes and diseased tissues further contributes to PD1 upregulation on T cells. PD1 interacts with its ligands, namely, PDL-1 (PDL1 / B7-H1 / CD274) and PDL-2 (PDL2 / B7-DC / CD273). PD1 ligands are expressed on transformed cells, professional antigen-presenting cells (pAPCs), and epithelial cells, as well as T cells. This interaction provides signals that tolerize T cells to their antigen targets and release their effector functions. Type 1 interferon (IFN-α / β) and tumor necrosis factor alpha (TNF-α) can upregulate PDL1 expression on T cells, B cells, natural killer (NK) cells, myeloid cells, and epithelial cells, whereas PDL2 expression is inducible via interferon gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4 signaling.

[0005] For example, by targeting factors that contribute to the development and maintenance of an immunosuppressive microenvironment within tumors, immunotherapy can release the brakes on the host's own immune system and potentially cure the disease.

[0006] Indeed, checkpoint inhibitors (CPi) targeting PD1 or its ligand PDL1 have demonstrated unparalleled clinical efficacy in over 15 cancer types, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's lymphoma. Indeed, therapeutic mAbs targeting either PD1 or PDL1 block the ligand / receptor interaction, liberating T cells from their exhausted phenotype and allowing the reactivation of tumor antigen-specific immunity (for review, see O'Donnell et al., Cancer Treatment Reviews 52 (2017), pp. 71-81).

[0007] Because the phenomenon of T cell exhaustion in chronic infections is similar to that observed in cancer, the same strategy has been applied to chronic infectious diseases such as tuberculosis (TB), human immunodeficiency virus (HIV), hepatitis and malaria (for review see Rao et al., International Journal of Infectious Diseases 56 (2017), pp. 221-228).

[0008] Nevertheless, primary resistance to anti-PD1 therapy is common, affecting up to 60% of patients in some cancer types. Furthermore, it is now becoming clear that the enhanced initial response observed among some patients can be negated by the development of acquired resistance to anti-PD1 therapy (referred to throughout as acquired resistance), leading to disease relapse. To fully elucidate the mechanisms by which anti-PD1 / PDL1 therapies exert their efficacy, significant efforts are currently being focused on understanding the mechanisms of resistance present in some patients that limit their activity and on developing a priori combination therapeutic approaches to sensitize resistant patients. Indeed, as reviewed in O'Donnell et al. (Cancer Treatment Reviews 52 (2017), pp. 71-81), various combination strategies have been proposed or developed to enhance the therapeutic activity of anti-PD1 / PDL1 antibodies, including, but not limited to, anti-CTLA4 therapy, anti-OX40 (CD134) therapy, anti-TIM3, anti-LAG3 and anti-TIGIT therapy, radiation therapy, chemotherapy such as doxorubicin and BRAF / MEK inhibitors, cytokine therapy such as anti-VEGF mAb (bevacizumab), anti-CD40, anti-CD73 or anti-CD137 antibodies, and virotherapy using oncolytic viruses. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2018 / 204303 [Patent Document 2] Chinese Patent No. 108640992 [Patent Document 3] International Publication No. 2018 / 036472 [Patent Document 4] Chinese Patent No. 107384933 [Patent Document 5] International Publication No. 2015 / 035606 [Patent Document 6] Chinese Patent No. 107043425 [Patent Document 7] Chinese Patent No. 106939050 [Patent Document 8] Chinese Patent No. 106749663 [Patent Document 9] International Publication No. 2010 / 116123 [Patent Document 10] International Publication No. 2011 / 044563 [Patent Document 11] International Publication No. 2016 / 004045 [Patent Document 12] U.S. Patent No. 2009 / 0291097 [Patent Document 13] European Patent No. 404,097 [Patent Document 14] International Publication No. 93 / 1 1 161 [Patent Document 15] European Patent No. 0 368 684 [Patent Document 16] International Publication No. 06 / 030220 [Patent Document 17] International Publication No. 06 / 003388 [Patent Document 18] U.S. Patent No. 4,816,567 [Patent Document 19] U.S. Patent No. 5,225,539 [Patent Document 20] U.S. Patent No. 5,585,089 [Patent Document 21] U.S. Patent No. 5,693,761 [Patent Document 22] U.S. Patent No. 5,693,762 [Patent Document 23] U.S. Patent No. 5,859,205 [Patent Document 24] U.S. Patent No. 5,591,669 [Patent Document 25] U.S. Patent No. 5,598,369 [Patent Document 26] U.S. Patent No. 5,545,806 [Patent Document 27] U.S. Patent No. 5,545,807 [Patent Document 28] U.S. Patent No. 6,150,584 [Patent Document 29] U.S. Patent No. 5,565,332 [Patent Document 30] U.S. Patent No. 5,573,905 [Patent Document 31] U.S. Patent No. 5,229,275 [Patent Document 32] U.S. Patent No. 5,567,610 [Patent Document 33] U.S. Patent No. 6,566,135 [Patent Document 34] U.S. Patent No. 6,566,131 [Patent Document 35] U.S. Patent No. 6,365,354 [Patent Document 36] U.S. Patent No. 6,410,323 [Patent Document 37] U.S. Patent No. 6,107,091 [Patent Document 38] U.S. Patent No. 6,046,321 [Patent Document 39] U.S. Patent No. 5,981,732 [Patent Document 40] International Publication No. 2014 / 001368 [Patent Document 41] International Publication No. 2017 / 194554 [Non-patent literature]

[0010] [Non-Patent Document 1] O'Donnell et al., Cancer treatment Reviews 52 (2017), pp. 71-81. [Non-patent document 2] Rao et al., International Journal of Infectious Diseases 56 (2017), pp. 221-228 [Non-patent document 3] Housman et al., Cancer, 2014, 6, pp. 1769-1792 [Non-licensed Document 4] Gaffen, SL (2009) Nature reviews. Immunology 9(8): pages 556~567 [Non-licensed Document 5] Ward et al. (Nature, October 12, 1989; 341(6242): 544-6) [Non-licensed Document 6] Holt et al., Trends Biotechnol., 2003, 21(11): 484-490. [Non-licensed Document 7] Kabat et al. (1991) Sequences of Protein of Immunological Interest, 5th edition [Non-licensed Document 8] Goodman and Gilman's The Pharmaceutical Basis of Therapeutics (7th Edition), (1985), pp. 1277-1280 [Non-licensed Document 9] Goodman and Gilman's The Pharmaceutical Basis of Therapeutics (7th Edition), (1985), pp. 1280-1281 [Non-licensed Document 10] Goodman and Gilman's The Pharmaceutical Basis of Therapeutics (7th Edition), (1985), pp. 1283-1285 [Non-licensed Document 11] Goodman and Gilman's The Pharmaceutical Basis of Therapeutics (7th Edition), (1985), pp. 1281-1283 [Non-licensed Document 12] Goodman and Gilman's The Pharmaceutical Basis of Therapeutics (7th Edition), (1985), pp. 1287-1288 Summary of the Invention [Problem to be solved by the invention]

[0011] However, there remains a need to develop more effective strategies for treating the above types of diseases. [Means for solving the problem]

[0012] The present invention relates to combination therapies, for example for the treatment of cancer or infectious diseases. In particular, the present invention is defined by the claims.

[0013] Programmed cell death protein 1 (PD1) is an effective therapeutic target for various types of cancer. However, some tumors are resistant to anti-PD1 therapy. In this application, we demonstrate a link between the PD1 immune checkpoint and IL-17B. We found that simultaneous inhibition of PD1 and IL-17B is effective against various types of cancer. Collectively, our data provide the first evidence demonstrating the importance of IL-17B in resistance to anti-PD1 therapy and suggest that blocking IL-17B in combination with anti-PD1 therapy is a novel therapeutic strategy for combating diseases involving the PD1 immune checkpoint.

[0014] Therefore, a first object of the present invention relates to a composition comprising a PD1 inhibitor and an IL-17B inhibitor.

[0015] According to certain embodiments, the compositions according to the invention herein have an amount of PD1 inhibitor that is less than the amount of PD1 inhibitor in a composition that does not include an IL-17B inhibitor.

[0016] According to another aspect, the present invention relates to the use of such compositions in therapy, advantageously for the treatment of cancer or infectious diseases, as detailed below.

[0017] According to a second aspect, and advantageously with respect to the treatment of cancer or infectious diseases, the present invention relates to a composition comprising an IL-17B inhibitor for use in the management of a subject treated with a PD1 inhibitor. According to a particular embodiment, the subject is resistant to treatment with a PD1 inhibitor. In other words, the present invention also relates to a composition comprising an IL-17B inhibitor for use in sensitizing a subject to a PD1 inhibitor.

[0018] As used herein, the expression "resistance to PD1 inhibitors" may refer to the following facts: - a large proportion of patients with a given disease do not respond to these treatments (PD1 inhibitors) and / or have a poor prognosis, in which case the disease is considered to be globally resistant to anti-PD1 treatments, while other diseases are sensitive to said treatments. For example, certain types of cancer are known to be more resistant to PD1 inhibitors than others; and / or - that a given patient with said disease may be resistant to anti-PD1 therapy, even if the disease is comprehensively known to be sensitive to anti-PD1 treatment. This expression encompasses primary resistance to said therapy as well as acquired resistance to said therapy as defined above. According to another embodiment, a resistant patient may be a patient with hyperprogressive disease (HPD) after anti-PD1 treatment, i.e., a patient with accelerated disease upon treatment with a PD1 inhibitor.

[0019] A further aspect of the present invention relates to a method for enhancing the efficacy of a PD1 inhibitor administered to a patient as part of a treatment regimen, the method comprising administering to the subject a pharmaceutically effective amount of an IL-17B inhibitor in combination with the PD1 inhibitor. In other words, the present invention relates to a composition comprising an IL-17B inhibitor for use in enhancing the efficacy of treatment with a PD1 inhibitor in a subject. The present invention also relates to a method of treating a patient in need of treatment, the method comprising administering to the patient a therapeutically effective combination of a PD1 inhibitor and an IL-17B inhibitor, wherein administration of the combination results in enhanced therapeutic efficacy relative to administration of the PD1 inhibitor alone.

[0020] As used herein, the phrase "enhancing the potency or efficacy of a PD1 inhibitor" refers to the ability of an IL-17B inhibitor to increase the ability of a PD1 inhibitor to inhibit disease progression and subsequently improve treatment outcome.

[0021] In the framework of the present invention, the treatment is advantageously dedicated to diseases involving the PD1 immune checkpoint. As previously reported in the literature, said diseases are advantageously selected from the group consisting of cancer and infectious diseases, in particular chronic infections. The infectious diseases are advantageously selected from the following group: severe sepsis, septic shock, viral infections, in particular human immunodeficiency virus (HIV), hepatitis viruses, in particular hepatitis B virus (HBV) and hepatitis C virus (HCV), infections with cytomegalovirus or Epstein-Barr virus, fungal infections such as mucormycosis, mosquito-borne infections such as malaria, and bacterial infections such as tuberculosis (TB).

[0022] As used herein, and in relation to cancer, the phrase "enhanced therapeutic efficacy" refers to a slowing or reduction in the growth of cancer cells or solid tumors, or a reduction in the total number of cancer cells or total tumor burden. Accordingly, "improved therapeutic outcome" or "enhanced therapeutic efficacy" means that there is an improvement in the patient's condition according to any clinically acceptable criteria, including, for example, reduced tumor size, delayed tumor progression, increased progression-free survival, increased overall survival, increased life expectancy, or improved quality of life. In particular, "improved" or "enhanced" refers to a 1%, 5%, 10%, 25%, 50%, 75%, 100%, or greater than 100% improvement or enhancement of any clinically acceptable indicator of therapeutic outcome or efficacy. As used herein, the phrase "relating to," when used in the context of comparing the activity and / or efficacy of a combination composition comprising a PD1 inhibitor and an IL-17B inhibitor with the activity and / or efficacy of the PD1 inhibitor alone, refers to a comparison using amounts known to be comparable according to one skilled in the art.

[0023] As used herein, "cancer" has its common meaning in the art and includes, but is not limited to, solid tumors and blood-borne tumors. The term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term "cancer" further includes both primary and metastatic cancers. Examples of cancers that may be treated by the methods and compositions of the present invention include, but are not limited to, cancer cells originating from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal tract, gums, head, kidney, liver, lung, nasopharynx, cervix, ovary, prostate, skin, stomach, testicle, tongue, or uterus. Furthermore, the cancer may specifically have the following histological types, but is not limited to: malignant tumor; carcinoma; undifferentiated carcinoma; giant cell spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; malignant gastrinoma; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyps; familial polyposis adenocarcinoma; solid tumor; malignant carcinoid tumor; bronchiolo-alveolar adenocarcinoma adenocarcinoma); papillary adenocarcinoma; chromophobe carcinoma; eosinophilic carcinoma; eosinophilic adenocarcinoma; basophilic carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; invasive ductal carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; breast Paget's disease; acinic cell carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous metaplasia; malignant thymoma; malignant ovarian stromal tumor; malignant capsular cell tumor; malignant granulosa cell carcinoma; a);Sertoli cell tumor;Malignant Leydig cell tumor;Malignant lipid cell tumor;Malignant paraganglioma;Extramammary malignant paraganglioma;Pheochromocytoma;Glomus sarcoma;Malignant melanoma;Amelanotic melanoma;Superficial spreading melanoma;Malignant melanoma of giant pigmented nevus;Epithelioid cell melanoma;Malignant blue nevus;Sarcoma;Fibrosarcoma;Malignant fibrous histiocytoma;Myxosarcoma;Liposarcoma;Leiomyosarcoma;Rhabdomyosarcoma;Embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; malignant mixed tumor; mixed Müllerian tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; malignant mesenchymoma; malignant Brenner tumor; malignant phyllodes tumor; synovial sarcoma; malignant mesothelioma; dysgerminoma; embryonal carcinoma; malignant teratoma; malignant ovarian goiter; choriocarcinoma; malignant mesonephroma; angiosarcoma; malignant hemangioendothelioma; Kaposi's sarcoma; malignant hemangiopericytoma; lymphangiosarcoma; Osteosarcoma; Parosteal osteosarcoma; Chondrosarcoma; Malignant chondroblastoma; Mesenchymal chondrosarcoma; Giant cell tumor of bone; Ewing's sarcoma; Malignant odontogenic tumor; Ameloblastic odontosarcoma; Malignant ameloblastoma; Ameloblastic fibrosarcoma; Malignant pinealoma; Chordoma; Malignant glioma; Ependymoma; Astrocytoma; Protoplasmic astrocytoma; Fibrous astrocytoma; Astroblastoma; Glioblastoma; Oligodendroglioma; Oligodendroglioma Glioblastoma; primitive neuroectodermal tumor; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; malignant meningioma; neurofibrosarcoma; malignant neurilemmoma; malignant granular cell tumor; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; small lymphocytic malignant lymphoma; diffuse large cell lymphoma; malignant follicular Lymphoma; Mycosis fungoides; Other specified non-Hodgkin's lymphoma; Malignant histiocytosis; Multiple myeloma; Mast cell sarcoma; Immunoproliferative small intestinal disease; Leukemia; Lymphocytic leukemia; Plasma cell leukemia; Erythroleukemia; Lymphocytic leukemia; Myeloid leukemia; Basophilic leukemia; Eosinophilic leukemia; Monocytic leukemia; Mast cell leukemia; Megakaryoblastic leukemia; Myeloid sarcoma; Hairy cell leukemia.

[0024] In some embodiments, the methods and compositions of the present invention are particularly suitable for treating the following cancers: melanoma, sarcoma, cutaneous squamous cell carcinoma (CSCC), primary mediastinal large B-cell lymphoma (PMBCL), microsatellite instability-high (MSI-H), hepatocellular carcinoma (HCC), small cell lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, Merkel cell carcinoma (MCC), head and neck squamous cell carcinoma (HNSCC), cervical cancer, gastric cancer, esophageal cancer, urothelial carcinoma, renal cell carcinoma (RCC), bladder cancer, anal cancer, triple-negative breast cancer (TNBC), mesothelioma, and Hodgkin's lymphoma (cHL).

[0025] In some embodiments, the methods and compositions of the present invention are particularly suitable for treating diseases, particularly cancers, that are resistant to PD1 inhibitors. As used herein, the term "resistant" refers to the repeated outbreaks of a disease or the progression of a disease, regardless of whether the disease was cured before said outbreak or progression.

[0026] "Antineoplastic resistance" refers to drug resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anticancer therapy. There are two general causes for the failure of anticancer therapy: genetic characteristics that confer resistance to cancer cells, which are rooted in the concept of cancer cell heterogeneity, and intrinsic characteristics, such as acquired resistance after drug exposure. Cancer cells can become resistant to drugs through various mechanisms, including protein and pathway mechanisms such as altered membrane trafficking, enhanced DNA repair, defects in apoptotic pathways, altered target molecules, and enzyme inactivation. Because cancer is a genetic disease, two genomic events underlie these mechanisms of acquired drug resistance: genomic alterations (e.g., gene amplification and deletion) and epigenetic modifications (Housman et al., Cancer, 2014, 6, pp. 1769-1792).

[0027] As used herein, the term "treatment" or "treating" refers to both prophylactic or preventative treatment and curative or disease-modifying treatment, including treatment of patients at risk of or suspected of having a disease, as well as patients who are ill or have been diagnosed with a disease or medical condition, and includes the suppression of clinical recurrence. Treatment may be administered to a patient who has a medical disorder or who may ultimately acquire a disorder to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of the disorder or the disorder during recurrence, or to extend the patient's survival beyond that expected in the absence of such treatment. "Therapeutic regimen" refers to a pattern of treatment for a disease, e.g., a pattern of medication used during therapy. Therapeutic regimens can include induction regimens and maintenance regimens. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or portion of a therapeutic regimen) used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to the patient during the initial period of the treatment regimen. The induction regimen may (in part or in whole) use a "loading regimen," which may involve the physician administering a higher dose of drug than used during the maintenance regimen, administering the drug more frequently than the physician administers the drug during the maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or part of a therapeutic regimen) used to maintain a patient during disease treatment, for example, so that the patient remains in remission for an extended period of time (months or years). A maintenance regimen may use continuous therapy (e.g., administering a drug at regular intervals, for example, once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent treatment, treatment upon relapse, or treatment upon achievement of certain predetermined criteria (e.g., pain, disease manifestations, etc.)).

[0028] As used herein, "PD1" has its common meaning in the art and refers to programmed cell death protein 1 (PD1 / PD-1 / CD279). As used herein, the terms "programmed cell death protein 1," "PD1," "PD-1," and "CD279" are used interchangeably. "PD1 ligand" refers to a polypeptide that binds to and / or activates PD1, particularly PDL1 and PDL2.

[0029] As used herein, the term "PD1 inhibitor" refers to an agent that interferes with PD1 activation or function. Examples of PD1 inhibitors include PD1 antibodies (e.g., PD1, PDL1, or PDL2 antibodies); small organic molecule PD1 antagonists; and / or agents that bind to PD1 or interfere with PD1 function. Typically, PD1 inhibitors are antibodies or small organic molecules that bind to the PD1 receptor or its ligands, PDL1 or PDL2.

[0030] In some embodiments, the PD1 inhibitor is a small organic molecule. As used herein, the term "small organic molecule" refers to a molecule of a size comparable to organic molecules commonly used in pharmaceuticals. This term excludes biological macromolecules (e.g., proteins, nucleic acids, etc.), and preferred small organic molecules range in size from 2000 Da to 1000 Da, most preferably from 1000 Da to 2000 Da.

[0031] Patent publications related to PD1 / PDL1 antibodies include WO 2018 / 204303, CN Patent 108640992, WO 2018 / 036472, CN Patent 107384933, WO 2015 / 035606, CN Patent 107043425, CN Patent 106939050, and CN Patent 106749663.

[0032] A non-exhaustive list of PD1 / PDL1 antibodies includes pembrolizumab (Keytruda®), nivolimab (Opdivo®), BMS-936559 (MDX 1105), cemiplimab (REGN2810), cemiplimab-rwlc (LIBTAYO®), avelumab (MSB0010718C or BAVENCIO), durvalumab (MEDI4736 or INFIMZI®), atezolizumab (MPDL3280A or Tecentriq®), spartalizumab (PDR 001), and combinations thereof.

[0033] According to a particular embodiment, atezolizumab or avelumab or durvalumab or pembrolizumab or nivolimab, which can be used to treat bladder cancer; - pembrolizumab or nivolimab can be used to treat colorectal cancer or gastric cancer or head and neck cancer or Hodgkin's lymphoma; - Nivolimab can be used to treat hepatocellular carcinoma, - nivolimab or pembrolizumab or ipilimumab and nivolimab can be used to treat melanoma; - atezolizumab or durvalumab or pembrolizumab or nivolimab, which can be used to treat lung cancer; - avelumab can be used to treat Merkel cell carcinoma; - Pembrolizumab can be used to treat tissue-agnostic cancers.

[0034] The interleukin-17 (IL-17) family includes six interleukins (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F) and their receptors (IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE) (Gaffen, SL (2009) Nature reviews. Immunology 9(8):556-567). IL-17B binds the dimeric IL-17RB receptor, and IL-17E binds the complex of IL-17RA and IL-17RB.

[0035] As used herein, the term "IL-17B" has its general meaning in the art and refers to a polypeptide having a sequence according to GenBank Accession No. NP_001304916.1 or NP_055258.1 that is the product of the human IL-17B gene, and encompasses all variants, isoforms, or species homologs of IL-17B. As used herein, the term "IL-17B signaling" refers to the process initiated by IL-17B or a second IL-17B receptor ligand that interacts with the IL-17RB receptor on the cell surface, resulting in a measurable change in cellular function. Typically, IL-17B signaling can be assessed, for example, by measuring the effect of an IL-17B receptor ligand on cell proliferation or differentiation, or by functional assays using reporter genes and reporter gene constructs.

[0036] As used herein, the term "IL17RB" (IL-17RB, CRL4, EVI27, IL17RH1, or MGC5245) refers to "interleukin-17 receptor B," a polypeptide having an amino acid sequence according to GenBank Accession No. NP061195, the product of the human IL17RB receptor gene, and encompasses all variants, isoforms, and species homologs of IL17RB.

[0037] Thus, as used herein, the term "IL-17B inhibitor" refers to any compound capable of inhibiting IL-17B signaling. IL-17B inhibitors to be used in the methods and compositions described herein are molecules that block, suppress, or reduce (including significantly) the biological activity of the IL-17B cytokine, including downstream pathways mediated by IL-17B signaling. Thus, the term "IL-17B inhibitor" does not imply any particular mechanism of biological action, but rather expressly includes and encompasses all possible pharmacological, physiological, and biochemical interactions with IL-17B, whether direct or indirect.

[0038] In some embodiments, the IL-17B inhibitor is selected from the group consisting of an antibody directed against IL-17B and an antibody directed against a receptor for IL-17B (e.g., an antibody that specifically binds IL-17RB or a dimeric complex formed thereby). According to certain embodiments, the IL-17RB inhibitor is an IL-17E inhibitor, e.g., an antibody that specifically binds IL-17E.

[0039] Patent publications related to IL17B / IL17RB antibodies include WO 2010 / 116123, WO 2011 / 044563, WO 2016 / 004045, and U.S. Patent No. 2009 / 0291097.

[0040] IL17B / IL17RB antibodies, such as mouse IL-17B antibody (AF1709; R&D Systems) or human IL-17RB antibody (MAB1207; R&D Systems), are commercially available.

[0041] Thus, as used herein, the term "antibody" is used to refer to any antibody-like molecule having an antigen-binding region, and this term includes Fab', Fab, F(ab')2, single domain antibodies (DAB), TandAbs dimers, Fv, scFv (single-chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibodies, tribodies (scFv-Fab fusions, bispecific or trispecific, respectively); sc-diabodies; kappa (lambda) These include antibody fragments comprising an antigen-binding domain, such as antibodies (scFv-CL fusions); BiTE (bispecific T cell Engager, scFv-scFv tandems for attracting T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immune protein, a type of minibody); SMIP ("small modular immunopharmaceutical" scFv-Fc dimer); DART (ds-stabilized diabody "dual affinity retargeting"); and small antibody mimetics comprising one or more CDRs. Techniques for preparing and using various antibody-based constructs and fragments are well known in the art (see Kabat et al., 1991, specifically incorporated herein by reference). Diabodies, inter alia, are further described in EP 404,097 and WO 93 / 11 161, while linear antibodies are further described in Zapata et al. (1995). Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating an antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can result in the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments, and other fragments can also be synthesized by recombinant techniques or chemically synthesized. Techniques for producing antibody fragments are well known and described in the art.For example, Beckman et al., 2006; Holliger & Hudson, 2005; Le Gall et al., 2004; Reff & Heard, 2001; Reiter et al., 1996; and Young et al., 1995 each further describe and enable the production of effective antibody fragments. In some embodiments, the antibodies of the invention are single-chain antibodies. As used herein, the term "single-domain antibody" has its general meaning in the art and refers to a single heavy-chain variable domain of an antibody of the type that can be found in Camelid mammals, which are naturally devoid of light chains. Such single-domain antibodies are also "Nanobodies®." For a general description of (single) domain antibodies, see the prior art cited above, as well as EP 0 368 684, Ward et al. (Nature 1989 Oct. 12;341(6242):544-6), Holt et al., Trends Biotechnol. 2003, 21(11):484-490, and WO 06 / 030220 and WO 06 / 003388.

[0042] In some embodiments, the antibody is a humanized antibody. As used herein, "humanized" describes an antibody in which some, most, or all of the amino acids outside the CDR regions have been replaced with corresponding amino acids derived from human immunoglobulin molecules. Humanization methods include, but are not limited to, those described in U.S. Patent Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762, and 5,859,205, which are incorporated herein by reference.

[0043] In some embodiments, the antibody is a fully human antibody. Fully human monoclonal antibodies can also be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Patent Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, and 6,150,584, and the references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified so that there is a functional deficiency in endogenous (e.g., murine) antibody production. The animals are further modified to contain all or part of the human germline immunoglobulin loci, such that immunization of these animals results in the production of fully human antibodies against the antigen of interest. After immunization of these mice (e.g., XenoMouse (Abgenix), HuMAb mice (Medarex / GenPharm)), monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies have human immunoglobulin amino acid sequences and therefore will not elicit a human anti-mouse antibody (KAMA) response when administered to humans. In vitro methods for producing human antibodies also exist. These include phage display technology (U.S. Pat. Nos. 5,565,332 and 5,573,905) and in vitro stimulation of human B cells (U.S. Pat. Nos. 5,229,275 and 5,567,610). The contents of these patents are incorporated herein by reference.

[0044] In some embodiments, the antibody does not comprise an Fc portion that induces antibody-dependent cellular cytotoxicity (ADCC). The terms "Fc domain," "Fc portion," and "Fc region" refer to a C-terminal fragment of an antibody heavy chain, e.g., from about amino acid (aa) 230 to about aa 450 of a human gamma heavy chain or its counterpart in other types of antibody heavy chains (e.g., α, δ, ε, and μ for human antibodies), or their naturally occurring allotypes. Unless otherwise specified, the generally accepted Kabat amino acid numbering for immunoglobulins is used throughout this disclosure (see Kabat et al. (1991) Sequences of Protein of Immunological Interest, 5th ed., U.S. Public Health Service, National Institutes of Health, Bethesda, MD). In some embodiments, the antibody of the present invention does not comprise an Fc domain capable of substantially binding to an FcgRIIIA (CD16) polypeptide. In some embodiments, antibodies of the invention lack an Fc domain (e.g., lack a CH2 and / or CH3 domain) or comprise an Fc domain of the IgG2 or IgG4 isotype. In some embodiments, antibodies of the invention consist of or comprise a multispecific antibody, including a Fab, Fab', Fab'-SH, F(ab')2, Fv, diabody, single-chain antibody fragment, or various antibody fragments. In some embodiments, antibodies of the invention are not linked to a toxic moiety. In some embodiments, one or more selected amino acids may be replaced with a different amino acid residue such that the antibody has altered C2q binding and / or reduced or eliminated complement-dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551.

[0045] According to further embodiments, the inhibitory activity against PD1 and IL-17B is possessed by a single molecule, i.e., a bispecific inhibitor. According to certain embodiments, such an inhibitor is a bispecific antibody comprising a first antigen-binding domain that binds to PD1 and a second antigen-binding domain that binds to IL-17B, IL-17RB, or IL-17E.

[0046] In some embodiments, the PD1 or IL-17B inhibitor is an inhibitor of PD1, PDL1, PDL2, IL-17B, or IL-17RB expression. An "inhibitor of expression" refers to a natural or synthetic compound that has the biological effect of inhibiting gene expression. In a preferred embodiment of the present invention, the inhibitor of gene expression is an siRNA, antisense oligonucleotide, or ribozyme. For example, antisense oligonucleotides, including antisense RNA molecules and antisense DNA molecules, directly block the translation of PD1 or IL-17B mRNA by binding to PD1 or IL-17B mRNA, thereby preventing protein translation or increasing mRNA degradation, thereby reducing the level and, therefore, activity of PD1 or IL-17B in cells. For example, antisense oligonucleotides having at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding PD1 or IL-17B can be synthesized, for example, by conventional phosphodiester techniques. Methods for using antisense technology to specifically inhibit gene expression of genes whose sequences are known are well known in the art (see, e.g., U.S. Patent Nos. 6,566,135, 6,566,131, 6,365,354, 6,410,323, 6,107,091, 6,046,321, and 5,981,732). Small inhibitory RNAs (siRNAs) can also function as inhibitors of expression for use in the present invention. PD1 or IL-17B gene expression can be reduced by contacting a patient or cells with small double-stranded RNA (dsRNA) or a vector or construct that causes the production of small double-stranded RNA (i.e., RNA interference or RNAi), such that PD1 or IL-17B gene expression is specifically inhibited. The antisense oligonucleotides, siRNAs, shRNAs, and ribozymes of the present invention can be delivered in vivo alone or in association with a vector. In its broadest sense, a "vector" is any vehicle capable of facilitating the introduction of an antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid into a cell, typically a cell that expresses PD1 or IL-17B.Typically, vectors deliver nucleic acids to cells with reduced degradation relative to the extent of degradation that would occur in the absence of the vector. Generally, vectors useful in the present invention include, but are not limited to, plasmids, phagemids, viruses, and other vehicles derived from viruses or bacterial sources engineered by the insertion or incorporation of antisense oligonucleotides, siRNA, shRNA, or ribozyme nucleic acid sequences. Viral vectors are a preferred type of vector, including, but not limited to, retroviruses such as Moloney murine leukemia virus, Harvey murine sarcoma virus, mouse mammary tumor virus, and Rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyomavirus; Epstein-Barr virus; papillomavirus; herpesvirus; vaccinia virus; poliovirus; and nucleic acid sequences derived from RNA viruses such as retroviruses. Although not specified, other vectors known in the art can readily be used.

[0047] As used herein, the term "co-administering" refers to the process in which a combination of an IL-17B inhibitor and a PD1 inhibitor is administered to the same patient. The IL-17B inhibitor and the PD1 inhibitor can be administered simultaneously, essentially simultaneously, or sequentially. The IL-17B inhibitor and the PD1 inhibitor need not be administered using the same vehicle. The IL-17B inhibitor and the PD1 inhibitor may be administered once or multiple times, and the number of doses of each component of the combination may be the same or different. Furthermore, the IL-17B inhibitor and the PD1 inhibitor need not be administered at the same site.

[0048] As used herein, the term "therapeutically effective combination" refers to an amount or dose of an IL-17B inhibitor together with an amount or dose of a PD1 inhibitor sufficient to treat a disease, particularly cancer. The amount of an IL-17B inhibitor in a given therapeutically effective combination may vary for different individuals and different tumor types, depending on the one or more additional agents or treatments included in the combination. A "therapeutically effective amount" is determined using procedures routinely used by those skilled in the art to produce an "improved therapeutic outcome." However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concomitantly with the specific polypeptide used, and other factors well known in the medical arts. For example, it is well within the skill of the art to start a dose of the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the product can vary over a wide range, from 0.01 mg to 1,000 mg per adult per day. Typically, the composition contains 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 50.0 mg, 100 mg, 250 mg, or 500 mg of the active ingredient, with the symptomatic adjustment of the dosage to the patient being treated. The medicament usually contains about 0.01 mg to about 500 mg of the active ingredient, preferably 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg / kg to about 20 mg / kg of body weight per day, especially from about 0.001 mg / kg to 7 mg / kg of body weight per day.

[0049] According to the present invention, the IL-17B inhibitor and the PD1 inhibitor are administered to a patient in the form of a pharmaceutical composition. Typically, the IL-17B inhibitor and the PD1 inhibitor can be combined with a pharmaceutically acceptable excipient and, optionally, a sustained-release matrix, such as a biodegradable polymer, to form a therapeutic composition. "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to mammals, particularly humans, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation auxiliary. In pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, topical, or rectal administration, the active ingredient can be administered to animals and humans alone or in combination with another active ingredient, in unit dosage forms, or in admixture with conventional pharmaceutical adjuvants. Suitable unit dosage forms include oral route forms such as tablets, gel capsules, powders, granules, and oral suspensions or solutions, sublingual and buccal dosage forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal, and intranasal dosage forms, and rectal dosage forms. Typically, pharmaceutical compositions contain a pharmaceutically acceptable vehicle for injectable formulations. These may be, in particular, isotonic, sterile saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium, or magnesium chloride, etc., or mixtures of such salts), or dried, especially lyophilized, compositions that, upon addition of sterile water or saline, allow for the constitution of an injectable solution. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Solutions of the compounds of the invention as free base or pharmaceutically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms. The IL-17B inhibitors and PD1 inhibitors can be formulated into compositions in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of the protein) formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, and the like. Salts formed with free carboxyl groups can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. For example, in the case of dispersions, proper fluidity can be maintained by maintaining the required particle size using a coating such as lecithin, and by the use of surfactants. Prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active ingredient in the required amount in an appropriate solvent with some of the other ingredients enumerated above, as needed, followed by sterile filtration. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.The preparation of more or very concentrated solutions for direct injection is also contemplated, where the use of DMSO as a solvent is envisioned to provide extremely rapid penetration, delivering high concentrations of the active agent to small tumor areas. Upon formulation, the solution will be administered in a manner compatible with the dosage formulation and in an amount that is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the injectable solution types described above, although drug-release capsules and the like may also be used. For example, for parenteral administration in aqueous solution, the solution should be suitably buffered, if necessary, and the liquid diluent should first be rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intrathecal administration. In this regard, sterile aqueous media that can be used will be known to those skilled in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the patient being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual patient.

[0050] According to another embodiment, the administration of the PD1 and IL-17B inhibitor is combined with another treatment dedicated to the same disease. If the further treatment also corresponds to the administration of a given molecule, said molecule may be present in the same composition as that containing the PD1 inhibitor and / or the IL-17B inhibitor, or may be administered separately.

[0051] For cancer, other treatments include, for example: - local surgery; - surgery; - Radiation or radiotherapy; - Chemotherapy; - Immunotherapy; - Targeted therapy, for example, with BRAF / MEK inhibitors; - hormone therapy; - Stem cell transplant; - Precision medicine; - antitumor antibodies; - Gene therapy; - vaccine; - Cell therapy; - CAR (chimeric antigen receptor)-T cell therapy; - TCR (T cell receptor) therapy; - induction therapy; - Consolidation therapy; - Maintenance therapy; - Differentiation inducers; - Angiogenesis inhibitors It could be.

[0052] Additional immunotherapies include, for example, other checkpoint inhibitors (CPi) that target CTL-4 (e.g., the antibody ipilimumab (YERVOY®)), LAG3, TIM3, and / or TIGIT.

[0053] Other immuno-oncology (IO) agents include those that target OX40, GITR, ICOS, VISTA, CD39, CD40, CD47, CD70 (e.g., anti-mAbs ARGX-110 and MDX-1203), CD73, or CD137.

[0054] Vaccines, especially vaccines with PRR (pattern recognition receptors such as Toll-like receptors or TLRs) agonistic properties, such as vaccines based on attenuated rotavirus, reovirus or Newcastle disease virus (NDV), are also further possible treatments.

[0055] Chemotherapeutic agents to be used with the combinations according to the invention include vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel (Taxol™, Bristol Myers Squibb), colchicine, cytochalasin B, emetine, maytansine, and amsacrine (or "mAMSA"). Vinca alkaloid species are described in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (7th ed.), (1985), pp. 1277-1280. Exemplary vinca alkaloids are vincristine, vinblastine, and vindesine. Epipodophyllotoxin species are described, for example, in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (7th ed.), (1985), pp. 1280-1281. Exemplary epipodophyllotoxins are etoposide, etoposide orthoquinone, and teniposide. Anthracycline antibiotic species are described in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (7th ed.), (1985), pp. 1283-1285. Exemplary anthracycline antibiotics are daunorubicin, doxorubicin, mitoxantrone, and bisanthrene. Actinomycin D, also known as dactinomycin, is described, for example, in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (7th ed.), (1985), pp. 1281-1283. Plicamycin, also known as mithramycin, is described, for example, in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (7th ed.), (1985), pp. 1287-1288.Additional chemotherapeutic agents include cisplatin (Platinol™, Bristol Myers Squibb), carboplatin (Paraplatin™, Bristol Myers Squibb), mitomycin (Mutamycin™, Bristol Myers Squibb), altretamine (Hexalen™, US Bioscience), cyclophosphamide (Cytoxan™, Bristol Myers Squibb), lomustine (CCNU) (CeeNU™, Bristol Myers Squibb), and carmustine (BCNU) (BiCNU™, Bristol Myers Squibb).

[0056] Also exemplary chemotherapeutic agents include aclacinomycin A, aclarubicin, acronin, acronysin, adriamycin, aldesleukin (interleukin-2), altretamine (hexamiethylmelamine), aminoglutethimide, aminoglutethimide (cytadren), aminoimidazole carboxamide, amsacrine (m-AMSA; amsidine), anastrazole (arimidex), ancitabine, anthracycline, thiazolinone ... Cyclin, anthramycin, asparaginase (elspar), azacitdin, azacitidine (ladakamycin), azaguanine, azaserine, azauridine, 1,1',1"-phosphinothioiridine trisaziridine, azirino(2',3':3,4)pyrrolo(1,2-a)indole-4,7-dione, BCG (Terracys), BCNU, BCNU chloroethylnitrosourea, benzamide, 4-(bis(2-chloroethyl)amino)benzenebutanoic acid, bicalutamide , bischloroethylnitrosourea, bleomycin (blenozane), bromodeoxyuridine, broxuridine, busulfan (myleran), carbamic acid ethyl ester, chlorambucil (leukeran), chloroethylnitrosourea, chlorozotocin (DCNU), chloromycin A3, cis-retinoic acid, cladribine (2-chlorodeoxyadenosine; 2cda; leustatin), coformycin, cycloleucine, cyclophosphamide anhydrous chlorambucil, cytarabine, cytarabine HCl (cytosar-u), 2-deoxy-2-(((methylnitrosamino)carbonyl)amino)-D-glucose, dacarbazine, decarbazine (DTIC-dome), demecolcine, dexamethasone, dianhydrogalactitol, diazooxonorleucine, diethylstilbestrol, docetaxel (taxotere), eflornithine, estramustine,Estramustine phosphate sodium (Emcyt), ethiodized oil, etoglucide, ethyl carbamate, ethyl methanesulfonate, fenretinide, floxuridine, floxuridine (Fudr), fludarabine (Fludara), fluorouracil (5-FU), fluoxymesterone (Halotestin), flutamide, flutamide (Eulexi) n), fluxuridine, gallium nitrate (granite), gemcitabine (gemzar), genistein, 2-deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose, goserelin (zoladex), hexestrol, hydroxyurea (hydra), idarubicin (idamycin), ifosfagemcitabine , ifosfamide (iflex), ifosfamide with mesna (MAID), interferon, interferon alpha, interferon alpha-2a, alpha-2b, alpha-n3, interleukin-2, iobenguane, iobenguane, irinotecan (camptosar), isotretinoin (accutane), ketoconazole, 4-(bis(2-chloroethyl)amino)-L-phenylalanine, L-serine diazoacetate, lentinan, leucovorin, leuprolide acetate (LHRH analog), levamisole (ergamisol), mannomustine, maytansine, mechlorethamine, mechlorethamine HCl (nitrogen mustard), medroxyprogesterone acetate (Provera, Depo-Provera) provera), megestrol acetate (menace), melengestrol acetate, melphalan (alkeran), menogaril, mercaptopurine, mercaptopurine (purinethol), mercaptopurine anhydride, MESNA, mesna (mesne), methanesulfonic acid, ethyl ester, methotrexate (mtx; methotrexate), methyl-ccnu, mimosine, misonidazole,Mithramycin, mitoantrone, mitobronitol, mitoguazone, mitolactol, mitomycin (mutamycin), mitomycin C, mitotane (o,p'-DDD; lysodren), mitoxantrone HCl (novantrone), mopidamol, N,N-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide, N-(1-methylethyl)-4-((2-methylhydrazino)methyl)benzamide, N-methyl-bis( 2-chloroethylamine, nicardipine, nilutamide (nilandron), nimustine, nitracrine, nitrogen mustard, nocodazole, nogalamycin, octreotide (sandostatin), pactamycin, pegaspargase (PEGx-1), pentostatin (2'-deoxycoformycin), peplomycin, peptichemio, photophoresis, picibanil, pipobroman, podofiloxin, podophyllotoxin, porfiromycin, prednisone, procarbazine, pro Carbazine HCl (matulane), prospidium, puromycin aminonucleoside, PUVA (psoralen + ultraviolet a), pyran copolymer, rapamycin, s-azacytidine, 2,4,6-tris(1-aziridinyl)-s-triazine, semustine, showdomycin, sirolimus, streptozocin (zanosar), suramin, tamoxifen citrate (nolvadex), taxon, tegafur, tenuazonic acid, TEPA, testolactone, thio-tepa, thioguanine, thiotepa (thio thioplex), tilorone, topotecan, tretinoin (vesanoid), triaziquone, trichodermin, triethylene glycol diglycidyl ether, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimetrexate (neutrexin), tris(1-aziridinyl)phosphine oxide, tris(1-aziridinyl)phosphine sulfide, tris(aziridinyl)-p-benzoquinone, tris(aziridinyl)phosphine sulfide,Uracil mustard, vidarabine, vidarabine phosphate, vinorelbine, vinorelbine tartrate (navelbine), (1)-mimosine, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, (8S-cis)-10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione, 131-meta-iodobenzylguanidine (I-131 MIBG), 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide, 5-(bis(2-chloroethyl)amino)-2,4(1H,3H)-pyrimidinedione, 2,4,6-tris(1-aziridinyl)-s-thiazine, 2,3,5-tris(1-aziridinyl)-2,5-cyclohexadiene-1,4-dione, 2-chloro-N-(2-chloroethyl)-N-methylethanamine, N,N-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine Indole-2-oxide, 3-deazauridine, 3-iodobenzylguanidine, 5,12-naphthalenedione, 5-azacytidine, 5-fluorouracil, (1aS,8S,8aR,8bS)-6-amino-8-(((aminocarbonyl)oxy)methyl)-1,1a,2,8,8a,8b-hexahydro-8a-methoxy-5-methylazirino(2',3':3,4)pyrrolo(1,2-a)indole-4,7-dione, 6-azauridine, 6-mercaptopurine, 8-azaguanine, and mixtures thereof.

[0057] Preferred chemotherapeutic agents include, for example, doxorubicin, pemetrexed, platinum-based drugs such as oxaliplatin, cisplatin, or carboplatin, paclitaxel, tamoxifen, vincristine, and vinblastine.

[0058] Cytokine therapy, e.g., bevacizumab, anti-VEGF mAbs such as anti-TNFα, anti-IL-6, or anti-TGF-β, can also be used. Antibodies directed against other isoforms of IL-17, e.g., IL-17A as taught in WO 2014 / 001368, or against EGFR / HER2 as taught in WO 2017 / 194554, are also of interest.

[0059] Infectious diseases are typically treated with antiviral or antibacterial (e.g., antibiotic) agents. By way of example, and simply to illustrate the gist of the present invention, fungal sepsis, e.g., mucormycosis, is treated by administering an antifungal agent, such as posaconazole and / or ampholytensin, and optionally, the further administration of an immune adjuvant, such as interferon-γ.

[0060] By way of further example, drugs that may be used with the combinations of the present invention, particularly to treat tuberculosis, are isoniazid (INH), rifampin / rifampicin (RIF), ethambutol (EMB) and pyrazinamide (PZA), either alone or in combination.

[0061] By way of further example, drugs that can be used in conjunction with the combinations of the present invention to treat HIV infection in particular include: - Nucleoside reverse transcriptase inhibitors (NRTIs) such as abacavir (abacavir sulfate), emtricitabine (FTC), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and zidovudine (azidothymidine, AZT or ZDV); - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as doravirine (DOR), efavirenz (EFV), etravirine (ETR), nevirapine (NVP), and rilpivirine (rilpivirine hydrochloride or RPV); - Protease inhibitors (PIs) such as atazanavir (atazanavir sulfate or ATV), darunavir (darunavir ethanolate or DRV), fosamprenavir (fosamprenavir calcium or DRV), ritonavir (RTV), sequinavir (sequinavir mesylate or SQV), and tipranavir (TPV); - fusion inhibitors such as enfuvirtide (T-20); - CCR5 antagonists such as maraviroc (MVC); - Integrase inhibitors such as dolutegravir (dolutegravir sodium or DTG) and raltegravir (raltegravir potassium or RAL); - Post-attachment inhibitors such as ipalizumab; - Pharmacokinetic enhancers such as colbicistat (COBI) Antiretroviral therapy includes:

[0062] Such drugs include, for example, the following combinations: - abacavir and lamivudine; - abacavir, dolutegravir and lamivudine; - Abacavir, lamivudine and zidovudine; - Atazanavir and cobicistat; - Bictegravir, emtricitabine and tenofovir alafenamide fumarate; - Darunavir and cobicistat; - Darunavir, cobicistat, emtricitabine and tenofovir alafenamide fumarate; - dolutegravir and rilpivirine; - Doravirine, lamivudine and tenofovir disoproxil fumarate; - Efavirenz, emtricitabine and tenofovir disoproxil fumarate; - Efavirenz, lamivudine and tenofovir disoproxil fumarate; - Elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide; - Elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate; - emtricitabine, rilpivirine and tenofovir alafenamide; - emtricitabine, rilpivirine and tenofovir disoproxil fumarate; - emtricitabine and tenofovir alafenamide; - emtricitabine and tenofovir disoproxil fumarate; - Lamivudine and tenofovir disoproxil fumarate; - Lamivudine and Zidovudine; - Lopinavir and Ritonavir It can be used in.

[0063] By way of further example, drugs that can be used in conjunction with the combinations of the present invention, particularly for treating HBV / HCV infection, include: - For HBV: entecavir, lamivudine (3TC), adefobicil dipivoxil, interferon alfa-2b, pegylated interferon, telbivudine, tenofovir alafenamide, tenofovir; - For HCV: Ribavirin, Daclatasvir, Sofosbuvir and Velpatasvir, Ledipasvir and Velpatasvir, Teleprevir, Interferon alfacon-1, Interferon alfa-2b, Glecaprevir and Vibrentasvir, Simeprevir, Pegylated Interferon, Pegylated Interferon alfa-2b, Interferon alfa-2a, Sofosbuvir, Ambitasvir and Paritaprevir and Ritonavir, Boceprevir, Ambitasvir and Paritaprevir and Ritonavir and Dasabuvir, Elbasvir and Grazoprevir is.

[0064] References Throughout this application, various references describe the state of the art to which this invention pertains, the disclosures of which are incorporated by reference into this disclosure.

[0065] The present invention is further illustrated by the following figures and examples, which, however, should not be construed as limiting the scope of the present invention in any way. [Brief explanation of the drawings]

[0066] [Figure 1] In vivo study of anti-PD1 therapy in IL-17B WT vs. KO mice in the MCA205 fibrosarcoma model. Tumor growth (top) and percent survival (bottom) in WT and KO mice treated with control antibody (IC; A and C) or anti-PD1 antibody (α-PD1; B and D). [Figure 2] In vivo study of anti-PD1 and oxaliplatin therapy in IL-17B WT vs. KO mice in the MCA205 fibrosarcoma model. Tumor growth (top) and percent survival (bottom) in WT and KO mice treated with oxaliplatin (OXA) alone (A and C) or in combination with an anti-PD1 antibody (α-PD1; B and D). [Figure 3] In vivo study of anti-PD1 and anti-IL-17B therapy in the MCA205 fibrosarcoma mouse model. Tumor growth (top; A and B) and percent survival (bottom; C) in mice treated with: anti-PD1 antibody (α-PD1) or the corresponding control antibody (2A3); and anti-IL-17B antibody (α-IL-17B) or the corresponding control antibody (IC). [Figure 4] In vivo study of anti-PD1 therapy in IL-17B WT vs. KO mice in the B16K1 melanoma model. Tumor growth (top) and percent survival (bottom) in WT and KO mice treated with control antibody (IC; A and C) or anti-PD1 antibody (α-PD1_D6; B and C). DETAILED DESCRIPTION OF THE INVENTION [Example]

[0067] Example 1 / Efficacy of anti-PD1 immunotherapy in the MCA205 fibrosarcoma model in the presence (WT mice) or absence (IL-17B KO mice) of IL-17B: 1-1 Materials and Methods Eight 6- to 8-week-old C57BL6 WT mice and seven 8- to 11-week-old C57BL6 IL-17B KO mice were injected with 10 6 MCA205 cells were implanted subcutaneously. Tumor growth was monitored using a caliper. On day 6, mice were treated with anti-PD1 antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, RMP1-14, BP0146, batch: 695318A1) or control monoclonal rat IgG2a antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, 2A3, batch: 686318F1B) twice weekly on days 9, 12, 16, 19, 23, 26, and 30. When tumors reached 1500 mm 3 The animals were sacrificed when the stool mass reached 0.1 mg / kg or in case of ulceration.

[0068] 1-2 Results and Conclusions Figure 1 shows the results obtained in terms of tumor growth (top) and percent survival (bottom).

[0069] Significant tumor growth delay was observed in IL-17B KO mice treated with anti-PD1 antibody monotherapy compared to WT mice (Figure 1B). Complete tumor regression was observed only in the IL-17B KO background.

[0070] After anti-PD1 treatment, the survival rate of KO mice was significantly increased compared with that of the WT group ( Figure 1 D).

[0071] In this experiment, anti-PD1 therapy was largely ineffective in WT animals, whereas anti-PD1 therapy induced partial and complete responses in IL-17B KO animals, thus confirming the higher efficacy of anti-PD1 monotherapy treatment in the IL-17B KO background, i.e., in the absence of IL-17B.

[0072] Example 2 / Efficacy of anti-PD1 and oxaliplatin therapy in the MCA205 fibrosarcoma model in the presence (WT mice) or absence (IL-17B KO mice) of IL-17B: 2-1 Materials and Methods Eight 6- to 8-week-old C57BL6 WT mice and seven 8- to 11-week-old C57BL6 IL-17B KO mice were injected with 10 6 MCA205 cells were implanted subcutaneously. Tumor growth was monitored using a caliper. On day 5, mice were treated with oxaliplatin (intraperitoneal injection, 10 mg / kg, Accord PX00494, exp. 01 / 2020) or PBS for the control group. The following day (D6), mice were treated with anti-PD1 antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, RMP1-14, BP0146, batch: 695318A1) or control monoclonal rat IgG2a antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, 2A3, batch: 686318F1B), followed by treatment twice weekly on days 9, 12, 16, 19, 23, 26, and 30. When tumors reached 1500 mm 3 The animals were sacrificed when the stool mass reached 0.1 mg / kg or in case of ulceration.

[0073] 2-2 Results and Conclusions As already observed in Figure 1A, the animals were given a large number (10 6 When MCA205 fibrosarcoma cells (1000 cells / mL) were implanted, no difference in tumor growth was observed in IL-17B KO compared to WT mice.

[0074] Oxaliplatin treatment alone induced a transient response in both WT and IL-17B KO mice. As shown in Figure 2A, its antitumor effect was more pronounced in the IL-17B KO background, with 1 out of 7 mice experiencing complete tumor regression.

[0075] As already shown in Figure 1B, the MCA205 fibrosarcoma model is highly resistant to anti-PD1 therapy. Although anti-PD1 treatment slightly delayed tumor progression in WT mice, it did not induce any complete tumor regression (0%). This is in stark contrast to the results obtained in the IL-17B KO background, where anti-PD1 therapy induced complete tumor regression in four of seven IL-17B KO mice (57%) at the end of the study and near-complete regression of one additional tumor that did not re-grow. At the end of the study, the survival rate of IL-17B KO mice treated with anti-PD1 antibody was significantly improved (72%) compared with that of WT mice treated with anti-PD1 antibody (0%) (Figure 1D).

[0076] As can be seen in Figure 2B, the combination of oxaliplatin and anti-PD-1 was more effective in inducing complete tumor regression in all IL-17B KO mice (7 of 7, 100%) compared to 5 of 8 (63%) WT mice.

[0077] In a PD-1-resistant fibrosarcoma model, high efficacy of anti-PD1 monotherapy treatment was demonstrated only in the IL-17B KO background (Figure 1D). Furthermore, and as evidenced by Figure 2D, combination with oxaliplatin was able to induce 100% survival in IL-17B KO animals, whereas combination with oxaliplatin showed some efficacy (63% survival) in WT mice.

[0078] This example clearly demonstrates the benefit of combining the approach according to the invention (inhibition of PD1 and IL-17B) with further therapeutic approaches, such as chemotherapy.

[0079] Example 3 / Efficacy of anti-PD1 and anti-IL-17B immunotherapy in the MCA205 fibrosarcoma model: Absence of IL-17B is Obtained To confirm the results obtained in Example 1 using IL-17B KO mice, the experiment was repeated in WT mice treated with anti-IL-17B antibodies.

[0080] 3-1 Materials and Methods Eight-week-old C57BL6 mice were inoculated with 5.10 mg of 10 mAb per group (9 animals for the IC group). 4 MCA205 cells were implanted subcutaneously. Tumor growth was monitored using a caliper. On day 5, mice were treated with anti-IL-17B antibody (subcutaneous injection, 200 μg / mouse) or control antibody (subcutaneous injection, 200 μg / mouse) + / - anti-PD-1 antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, RMP1-14, BP0146, batch: 640517M2B) or control monoclonal rat IgG2a antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, 2A3, batch: 627416N1), followed by twice-weekly treatments on days 9, 12, 16, 19, 23, 26, 30, 33, 37, 40, 44, 47, 51, 54, 58, 62, 65, 68, and 72 for the anti-IL-17B / IC antibody, and twice-weekly treatments on days 9, 12, and 16 for the anti-PD1 / IC antibody. 3 The animals were sacrificed when the stool mass reached 0.1 mg / kg or in case of ulceration.

[0081] 3-2 Results and Conclusions As previously shown, the MCA205 model is highly resistant to anti-PD1 therapy. Accordingly, anti-PD1 treatment alone had a modest but significant effect on tumor growth (Figure 3A) and no effect on survival (0% at the end of the study; Figure 3C). In this experiment, definitive treatment with anti-IL-17B antibody did not significantly affect MCA205 tumor growth (Figure 3B). However, anti-IL-17B antibody significantly increased the response to anti-PD1 therapy, including complete regression in 1 of 10 mice (10%) and an additional long-term control of near-complete response in 1 mouse (10%) (Figure 3B).

[0082] Consistent with the data obtained using IL-17B KO mice, anti-IL-17B antibodies increased the response to anti-PD-1 therapy and induced long-term responses (complete and long-term near-complete responses). The combination of anti-IL-17B and anti-PD-1 antibodies significantly improved mouse survival, whereas anti-PD-1 therapy alone did not (Figure 3C).

[0083] Example 4 / Efficacy of anti-PD1 immunotherapy in the B16K1 melanoma model in the presence (WT mice) or absence (IL-17B KO mice) of IL-17B: To confirm the results obtained in Example 1 in a fibrosarcoma model, the experiment was repeated in a melanoma model.

[0084] 4-1 Materials and Methods Ten 10-week-old C57BL6 WT mice (n = 10) and seven or eight 10-week-old C57BL6 IL-17B KO mice (n = 7 or 8) were injected with 10 5 B16K1 melanoma cells were implanted subcutaneously. Tumor growth was monitored using a caliper. On day 6, mice were treated with anti-PD1 antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, RMP1-14, BP0146, batch: 695318A1) or control monoclonal rat IgG2a antibody (intraperitoneal injection, 200 μg / mouse, BioXCell, 2A3, batch: 686318F1B), followed by treatment twice weekly on days 6, 10, and 13. When tumors reached 1500 mm 3 The animals were sacrificed when the stool mass reached 0.1 mg / kg or in case of ulceration.

[0085] 4-2 Results and Conclusions As previously observed, the data shown in Figure 4 demonstrate that the efficacy of anti-PD1 antibodies is improved in KO background animals.

[0086] This example validates that the PD1 / IL-17B inhibitory approach according to the present invention can be applied to other types of cancer or even to other diseases.

Claims

1. 1. A composition for use in treating a cancer that is a sarcoma, comprising an inhibitor of PD1 or its ligand and an inhibitor of IL-17B or its receptor, the inhibitor of PD1 or its ligand is an antibody or an antigen-binding fragment thereof that specifically binds to PD1 or its ligand and inhibits the activity of PD1 or its ligand; the inhibitor of IL-17B or its receptor is an antibody or an antigen-binding fragment thereof that specifically binds to IL-17B or its receptor and inhibits the activity of IL-17B or its receptor; A composition wherein the inhibitor of PD1 or its ligand is an inhibitor of PD1, PDL1, or PDL2.

2. The composition of claim 1, wherein the inhibitor of PD1 or its ligand and the inhibitor of IL-17B or its receptor are bispecific antibodies.

3. 3. The composition of claim 1 or 2, wherein the sarcoma is a fibrosarcoma.

4. 1. A composition for use in treating cancer that is a sarcoma in a subject being treated with an inhibitor of PD1 or its ligand, comprising an inhibitor of IL-17B or its receptor, wherein the inhibitor of IL-17B or its receptor is an antibody or antigen-binding fragment thereof that specifically binds to IL-17B or its receptor and inhibits the activity of IL-17B or its receptor; A composition wherein the inhibitor of PD1 or its ligand is an inhibitor of PD1, PDL1, or PDL2.

5. The composition of claim 4, wherein the treatment is for increasing the sensitivity of the subject to an inhibitor of PD1 or its ligand.

6. The composition of claim 4 or 5, wherein the subject is resistant to the treatment with an inhibitor of PD1 or its ligand.

7. 7. The composition of claim 1, wherein the cancer is resistant to an inhibitor of PD1 or its ligand.

8. 8. The composition of claim 4, wherein the sarcoma is a fibrosarcoma.

9. The composition of any one of claims 1 to 8, wherein the inhibitor of PD1 or its ligand is an anti-PD1 antibody or an anti-PDL1 antibody.

10. 10. The composition of any one of claims 1 to 9, wherein the inhibitor of PD1 or its ligand is selected from the group consisting of pembrolizumab, nivolimab, BMS-936559, cemiplimab, avelumab, durvalumab, atezolizumab, spartalizumab, or a combination thereof.

11. 11. The composition according to any one of claims 1 to 10 as a combined preparation for simultaneous, separate or sequential use.

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