Therapeutic regimen of an Anti-PD1 antibody for the treatment of cancer

Abstract

The present invention relates to a novel therapeutic administration regimen of an anti-Programmed Death-1 (PD-1) antibody for treating cancer.

Description

[0001] Therapeutic regimen of an anti-PDl antibody for the treatment of cancer

[0002] Field of the Invention

[0003] The present invention relates to the field of medicine, in particular of oncology, and more particularly the present invention relates to the treatment of cancer.

[0004] Background of the Invention

[0005] T cell-mediated immunity includes multiple sequential steps involving the clonal selection of antigen-specific cells, their activation and proliferation in secondary lymphoid tissues, their trafficking to sites of antigen and inflammation, the execution of direct effector functions and the provision of help (through cytokines and membrane ligands) for a multitude of effector immune cells. The PD-1 (Programmed cell death 1 or cluster of differentiation CD279) which is encoded by the PDCD1 gene in humans and a member of the immunoglobulin superfamily, has a role in regulating the immune system’s response to the cells of the human body by downregulating the immune system and promoting self-tolerance by suppressing T-cell activity (Dong Y et al, Oncotarget 2017;8(2):2171-86. doi: 10.18632 / oncotarget.l3895). The PD-1 ligands are respectively programmed death-ligand 1 and 2 (PD-L1 and PD-L2).

[0006] PD-1 is a protein expressed on the surface of T-cells, B-cells and myeloid cells that has a role in regulating the immune system’s response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T-cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells (Syn NL et al, Lancet Oncol. 2017;18(12):e731-e741. doi: 10.1016 / S1470- 2045(17)30607-1.). PD-1 expression is induced when T cells become activated (Ishida Y et al, EMBO J. 1992;ll(ll):3887-95.). Upon PD-L1 and PD-L2 binding, PD-1 engages the recruitment to the immunoreceptor tyrosine-based switch motif (ITSM) motif of the (SHP)l / 2 phosphatases (Pisibon C et al, Cancers 2021;13(18):4573. doi: 10.3390 / cancersl3184573). The pSHP-1 and pSHP-2 directly inhibits T-cell receptor (TCR) and CD28-mediated signalling, thereby blocking the activation of T-cells, leading to decreased antitumour cytokines such as interferon (IFN)Y, survival proteins like B-cell lymphoma-extra-large (Bcl-xL), proliferation, survival and cytotoxicity as well as expression of transcription factors associated with effector cell function, including GATA-3 and T-bet (Chemnitz JM et al, J Immunol. 2004; 173(2):945- 54. doi: 10.4049 / jimmunol.173.2.945; Nurieva R et al, EMBO J. 2006; 25(ll):2623-33. doi: 10.1038 / sj.emboj.7601146.). This translates into a major immune resistance mechanism within the tumour microenvironment. Therefore, therapeutic approaches aimed at blocking the PD-1 pathway represent an appealing target for cancer therapy.

[0007] Clinical data have shown that blockade of the PD-1 axis of the immune checkpoint program results in reactivation of T cell function and the anti -tumour immune response leading to tumour shrinkage (including some complete responses) in some patients. Treatment of patients with advanced melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma and many other tumour types with Food and Drug Administration (FDA) approved anti-PD-1 (nivolumab or pembrolizumab) or anti-PD-Ll (atezolizumab, durvalumab and avelumab) monoclonal antibodies results in responses in approximately 15-30% of patients (Brahmer J et al, N. Engl. J. Med. 2015; 373(2): 123-35. doi: 10.1056 / NEJMoal 504627; Garon EB et al, N. Engl. J. Med. 2015;372(21):2018-28. doi: 10.1056 / NEJMoal501824.; Patnaik A et al, Clin. Cancer Res. 2015; 21 (19):4286-93. doi: 10.1158 / 1078-0432.CCR-14-2607; Robert C et al, N. Engl. J. Med.2015; 372(4):320-30. doi: 10.1056 / NEJMoal412082; Topalian SL et al, N Engl J Med. 2012;366(26):2443-54. doi: 10.1056 / NEJMoal200690).

[0008] However, finding the right dosage regimen for checkpoint inhibitor antibodies is challenging due to various factors, including antibody immunogenicity and clearance, target affinity, target baseline levels, target turnovers, anatomical locations, resistance against the drug and mechanisms of action. Additionally, the use of therapeutic drug monitoring (TDM), pharmacokinetic (PK) and pharmacodynamic (PD) properties are essential for individualizing antibody doses. Furthermore, the wide therapeutic window of monoclonal checkpoint inhibitor antibodies in oncology and the need for alternative dosing strategies, such as fixed dosing, are also to be considered. On top of all, therapeutic regimen must be adapted to the patients, to ensure that patients comply with their treatment as fully as possible and to minimise the development of resistance to treatment.

[0009] Accordingly, there continues to be a need for effective therapies to treat patients suffering from cancer. The invention seeks to meet these needs.

[0010] Summary of the Invention

[0011] The object of the present invention relates to a new administration regimen of an anti-PDl antibody, particularly of the antibody OSE-279, such as disclosed in WO2020 / 127366. OSE-279 has a high affinity for the PD-1 protein determined by Biacore assay showing a dissociation constant (KD of 3.78 nM, comparable to the ones of known antibodies such as Pembrolizumab (KD of 3.90 nM) and Nivolumab (KD of 3.80 nM) measured in the same experiment.

[0012] OSE-279 has strict antagonist properties, and is typically devoid of antibody-dependent cell- mediated cytotoxicity (ADCC). OSE-279 is designed to block access of PD-L1 and PD-L2 to the PD-1 receptor, thereby controlling the interaction of these cell surface proteins involved in the negative regulation (ICI) of the immune system.

[0013] OSE-279 particularly displays antagonist activity with an IC50 value of 308 ± 170 ng / mL determined in a PD-1 / PD-L1 and PD-1 / PD-L2 ELISA binding assay. Antagonist properties of OSE-279 was also confirmed in the BLItz method. OSE-279 particularly blocks PD-L1- induced SHIP-1 phosphorylation in a cell-based assay, with an IC50 = 14.19 ng / mL, and promoted reactivation of T cell effector functions leading to interleukin (IL-2) and IFNy secretion.

[0014] In this invention, the inventors surprisingly showed that a fixed dose of 600 mg of OSE-279 monotherapy demonstrates potent efficacy in the treatment of cancer. The use of a flat dose approach instead of a weight normalized dose offers the advantage of less PK drug exposure variability, improved safety resulting from a reduced chance for dosing errors, better compliance, and increased convenience.

[0015] Interestingly, the fixed dose of 600 mg Q6W allows to reach a maintained PD-1 receptor occupancy of more than 75% on T cells, especially CD8+ T cells. This will contribute to an improved therapeutic efficacy and to a decrease of the risk of resistance towards such immunotherapy. By effectively saturating target receptors, it is believed that the administration regimen of the invention can reduce the ability of tumoral cells to evolve resistance mechanisms.

[0016] Finally, the dose of 600 mg Q6W is proposed as an efficient dose regimen that will be convenient for scheduling purposes and patients’ compliance. In addition, with this dosage regimen, the inventors observed an improved efficacy, especially in a rare solid tumor. For instance, it was known that, for Soft tissue sarcoma, the efficacy of anti-PDI antibodies is quite limited (SARC028, NCT0230I039) with an overall response rate (ORR) of less than 20%, often when used in combination with another therapeutic agent such as axitinib or an angiogenesis inhibitor (Lu et al, Cancer Biol Med 2022. doi: 10.20892 / j.issn.2095-3941.2021.0270). Surprisingly, the dose of 600 mg Q6W was associated with more than 30% tumour shrinkage.

[0017] In a first aspect, the invention concerns an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody or a pharmaceutical composition comprising it, for use in the treatment of cancer in a subject in need thereof, wherein said antibody is an antagonist of human PD-1 and comprises:

[0018] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0019] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein said antibody is to be administered periodically at a therapeutically effective dose of at least 550 or 600 mg.

[0020] In a second aspect, the invention concerns a method of treating a cancer in a subject in need thereof, wherein the method comprises administering periodically to said subject a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal antiProgrammed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0021] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0022] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 550 or 600 mg. In a third aspect, the inventions concerns a method for inducing or increasing PD-1 receptor occupancy on T cells in a subject suffering from cancer, wherein the method comprises administering periodically to said subject a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0023] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0024] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 550 or 600 mg, thereby achieving a PD- 1 receptor occupancy of at least 75%, 85% or 95% on T cells.

[0025] Preferably, the at least 75%, 85% or 95% of receptor occupancy of the antibody on T cells is reached within 48 hours of administration of the dose of the antibody and / or is maintained for at least 21 days after administering the dose of the antibody.

[0026] Preferably, the anti-PD-1 antibody comprises: (a) a VH comprising or consisting of an amino acid sequence of SEQ ID NO: 7; and (b) a VL comprising or consisting of an amino acid sequence of SEQ ID NO: 8.

[0027] In particular, the anti-PD-1 antibody comprises an IgG4 with a mutation consisting of S228P.

[0028] Preferably, the anti-PD-1 antibody comprises: (a) a heavy chain comprising or consisting of an amino acid sequence of SEQ ID NO: 9, and (b) a light chain comprising or consisting of an amino acid sequence of SEQ ID NO: 10.

[0029] Preferably, the therapeutically effective dose is comprised between about 550 mg and about 1000 mg, preferably between about 600 and about 1000 mg, even more preferably between about 600 mg and about 800 mg. Even more preferably, the therapeutically effective dose is of about 600 mg. The anti-PD-1 antibody of the invention is or is to be administered typically once every four to twelve weeks, once every four to nine weeks, once every four to eight weeks or once every five to seven weeks.

[0030] In particular, the anti-PD-1 antibody of the invention is or is to be administered once every 4 weeks (Q4W), once every 5 weeks (Q5W), once every 6 weeks (Q6W), once every 7 weeks (Q7W), once every 8 weeks (Q8W), once every 9 weeks (Q9W), once every 10 weeks (Q10W), once every 11 weeks (Q11W) or once every 12 weeks (Q12W).

[0031] More particularly, the anti-PD-1 antibody of the invention is or is to be administered once every 6 weeks (Q6W), preferably at a dose of about 600 mg.

[0032] Typically, the anti-PD-1 antibody of the invention is or is to be administered for 2, 3, 4, 5, 6, or more cycles, preferably 5 cycles.

[0033] In particular, the anti-PD-1 antibody of the invention is or is to be administered during at least 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks or 42 weeks.

[0034] Particularly, the anti-PD-1 antibody of the invention is or is to be administered up to 1 or 2 years or up to complete or partial response.

[0035] The anti-PD-1 antibody of the invention is or is to be administered preferably by intravenous administration or infusion.

[0036] In some instances, the subject has previously been treated with one or more different cancer treatment modalities, such as surgery, chemotherapy, radiotherapy, immunotherapy or any combination thereof.

[0037] The anti-PD-1 antibody of the invention is preferably in the form of a monotherapy. Alternatively, the antibody is used or for use in combination with another anti -cancer treatment, preferably selected from the group consisting of chemotherapy, radiotherapy, anti angiogenic agents, hypomethylating agents, cancer vaccines, peptide vaccine, angiogenesis inhibitors, tyrosine kinase inhibitors, epitopes or neoepitopes from tumour antigens, myeloid checkpoints inhibitors, immunotherapies, cell therapy agents and HDAC inhibitors, a peptide vaccine, a chemotherapy, an immune checkpoint inhibitor other than an anti-PD-1, a tyrosine kinase inhibitor, a VEGF receptor inhibitor and any combination thereof.

[0038] In a fourth aspect, the invention concerns a monotherapy comprising an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody for use in the treatment of cancer in a subject in need thereof, wherein said antibody is an antagonist of human PD-1 and comprises (a) a heavy chain comprising or consisting of an amino acid sequence of SEQ ID NO: 9, and (b) a light chain comprising or consisting of an amino acid sequence of SEQ ID NO: 10, wherein the antibody is to be administered at a flat dose of between about 600 mg and about 1000 mg once every four to twelve weeks, preferably every six weeks, and wherein the cancer is preferably a rare tumour, optionally with a high microsatellite instability (MSI-H) or expressing PD-L1.

[0039] In a fifth aspect, the invention concerns a kit for treating a subject suffering from cancer, wherein the kit comprises:

[0040] (a) a dosage ranging from 600 mg to 1000 mg of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0041] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0042] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, and

[0043] (b) instructions for using the antibody in a periodic regimen of any one of claims 10-15.

[0044] In a sixth aspect, the invention concerns the use of a composition comprising an immunoglobulin G4 (IgG4) humanized monoclonal anti-Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, for the manufacture of a medicament for treating a cancer in a subject in need thereof, wherein said antibody is or is to be administered periodically at a therapeutically effective dose of at least 600 mg.

[0045] In a seventh aspect, the invention concerns the use of a flat dose of between about 600 mg and about 1000 mg of an anti PD-1 antibody in the manufacture of a medicament for the treatment of cancer; wherein said antibody is an immunoglobulin G4 (IgG4) humanized monoclonal antiProgrammed Death-1 (PD-1) antibody, said antibody being an antagonist of t human PD-1 and comprising (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the treatment comprises a periodic regimen.

[0046] Particularly, the cancer to be treated is an advanced solid cancer or a lymphoma.

[0047] In particular, the cancer is a solid rare tumour, optionally with a high microsatellite instability (MSI-H) or expressing PD-L1. Particularly, the solid rare tumour is selected from the group consisting of sarcoma, preferably soft tissue sarcoma, squamous cell carcinoma, neuroendocrinal tumour and oncocytic carcinoma.

[0048] The solid rare tumour can particularly be a neuroendocrinal tumour selected from the group consisting of Well differentiated not functioning endocrine carcinoma of pancreas and digestive tract, Well differentiated functioning endocrine carcinoma of pancreas and digestive tract, Poorly differentiated endocrine carcinoma of pancreas and digestive tract, Mixed endocrine- exocrine carcinoma of pancreas and digestive tract Endocrine carcinoma of thyroid gland, neuroendocrine carcinoma of the parathyroid gland, Neuroendocrine carcinoma of skin, Typical and atypical carcinoid of the lung, Pheochromocytoma, and Paraganglioma.

[0049] Alternatively, the solid rare tumour can be a soft tissue sarcoma selected from the group consisting of soft tissue sarcoma of head and neck (such as Sarcoma NOS, Epithelioid sarcoma, Desmoplastic small round cell tumour, Fibrosarcoma, Fibromyxosarcoma, Infantile fibrosarcoma, Myxoinflammatory fibroblastic sarcoma, Malignant fibrous histiocytoma, DFSP, Well differentiated liposarcoma, Myxoid liposarcoma, Pleomorphic liposarcoma, Mixed type liposarcoma, Dedifferentiated liposarcoma, Leiomyosarcoma, Pleomorphic rhabdomyosarcoma, Extrarenal rhabdoid tumour, Synovial sarcoma, Clear cell sarcoma of soft tissue, Epithelioid angiosarcoma, Epithelioid haemangioendothelioma, Extraskeletal osteosarcoma, Extraskeletal myxoid chondrosarcoma, Malignant peripheral nerve sheath tumours, Malignant glomus tumours (glomangiosarcoma), Intimal Sarcoma, Low grade fibromyxoid sarcoma, Low grade myofibroblastic sarcoma, PEComas, Sclerosing epithelioid fibrosarcoma or Undifferentiated pleomorphic sarcoma (UPS)); Soft tissue sarcoma of limbs, Soft tissue sarcoma of superficial trunk, Soft tissue sarcoma of mediastinum, Soft tissue sarcoma of heart, Soft tissue sarcoma of breast, Soft tissue sarcoma of uterus, Soft tissue sarcoma of paratestis, Soft tissue sarcomas of other genitourinary tract (such as vulva, vagina, ovary, penis, prostate, testis, kidney, renal pelvis, ureter, bladder, urethra), Clear cell sarcoma of kidney, Malignant rhabdoid tumour of kidney, Soft tissue sarcoma of viscera, Soft tissue sarcoma of retroperitoneum and peritoneum, Soft tissue sarcoma of pelvis, Soft tissue sarcoma of skin (such as dermatofibrosarcoma protuberans (DFSP)), Soft tissue sarcoma of paraorbit, Soft tissue sarcoma of brain and other parts of the nervous system, Embryonal rhabdomyosarcoma of soft tissue, Alveolar rhabdomyosarcoma of soft tissue, alveolar soft part sarcoma (ASPS), Ewing’s sarcoma of soft tissue (such as Ewing Sarcoma, Peripheral neuroectodermal tumour, Primitive neuroectodermal tumour), preferably is UPS or ASPS .

[0050] Alternatively the solid rare tumour can be a squamous cell carcinoma (SCC) selected from the group consisting of Squamous cell carcinoma of nasal cavity and sinuses, nasopharynx, hypopharynx, larynx, oropharynx, oral cavity, lips, oesophagus, stomach, small intestine, colon, rectum, anal canal, pancreas, liver, gallbladder, trachea, lung, thymus, thyroid, lungs, corpus uteri, cervix uteri, vulva, vagina, prostate, penis, kidney, pelvis, ureter, bladder, eye, ear and skin, preferably is anal SCC.

[0051] Alternatively, the solid rare tumour can be an oncocytic carcinoma affecting an organ or tissue selected from the group consisting of thyroid gland, salivary glands, kidney, nasal cavity, paranasal sinuses, bronchus, parathyroid, ovary, upper mediastinum, lung and breast, preferably is an oncocytic carcinoma of the thyroid (OCA).

[0052] In some instances, the cancer is a stage III or IV cancer. Particularly, the cancer is a stage IV cancer with lung metastasis.

[0053] The cancer can be an advanced hepatocellular carcinoma. Very particularly, the solid rare tumour has a high microsatellite instability (MSI-H), preferably is a UPS with MSI-H or an ASPS with MSI-H and / or expresses PD-L1, preferably is an anal SCC expressing PD-L1.

[0054] The subject suffering from cancer is particularly is a human of at least 30 years old.

[0055] Detailed description of the Invention

[0056] Definitions

[0057] In order that the present invention may be more readily understood, certain terms are defined hereafter. Additional definitions are set forth throughout the detailed description.

[0058] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art

[0059] As used herein, the term "antibody" describes a type of immunoglobulin molecule and is used in its broadest sense. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen binding site. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass. The heavychain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. Unless specifically noted otherwise, the term "antibody" includes intact immunoglobulins and "antibody fragment" or "antigen binding fragment" (such as Fab, Fab', F(ab')2, Fv), single chain (scFv), mutants thereof, molecules comprising an antibody portion, diabodies, linear antibodies, single chain antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies. Preferably, the term “antibody” refers to a humanized antibody. In terms of structure, an antibody may have heavy (H) chains and light (L) chains interconnected by disulfide bonds. There are two types of light chain, lambda (X) and kappa (K). Each heavy and light chain contains a constant region and a variable region (or "domain"). Light and heavy chain variable regions contain a "framework" region interrupted by three hypervariable regions, also called "complementarity-determining regions" or "CDRs". The extent of the framework region and CDRs have been defined (see, Kabat et al., Sequences of Proteins of Immunological Interest, and U.S. Department of Health and Human Services, 1991, which is hereby incorporated by reference). “Complementarity determining regions” or “CDRs” are known in the art as referring to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and binding affinity. The precise amino acid sequence boundaries of a given CDR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al., (Sequences of Proteins of Immunological Interest 5th ed. (1991) "Kabat" numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol, 273:927-948 ("Chothia" numbering scheme); MacCallum et al, 1996, J. Mol. Biol. 262:732-745 ("Contact" numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 ("IMGT" numbering scheme); and Honegge and Pluckthun, J. Mol. Biol, 2001, 309:657-70 ("AHo" numbering scheme). Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat numbering scheme. In addition to the CDR, the “framework regions” act to form a scaffold that provides, for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions. The CDRs are primarily responsible for binding to an epitope of an antigen. The CDRs of each chain are typically referred to as "Complementarity Determining Region 1" or “CDR1”, “CDR2”, and “CDR3”, numbered sequentially starting from the N-terminus. The VL and VH domain of the antibody according to the invention may comprise four framework regions or "FR's", which are referred to in the art and herein as "Framework region 1 " or "FR1", "FR2", "FR3", and "FR4", respectively. These framework regions and complementary determining regions are preferably operably linked in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (from amino terminus to carboxy terminus).

[0060] An "antibody heavy chain" as used herein, refers to the larger of the two types of polypeptide chains present in antibody conformations. The CDRs of the antibody heavy chain are typically referred to as “HCDR1”, “HCDR2” and “HCDR3”. The framework regions of the antibody heavy chain are typically referred to as “HFR1”, “HFR2”, “HFR3” and “HFR4”. An "antibody light chain," as used herein, refers to the smaller of the two types of polypeptide chains present in antibody conformations, K and X light chains refer to the two major antibody light chain isotypes. The CDRs of the antibody light chain are typically referred to as “LCDR1”, “LCDR2” and “LCDR3”. The framework regions of the antibody light chain are typically referred to as “LFR1”, “LFR2”, “LFR3” and “LFR4”.

[0061] The term “monoclonal antibody,” as used herein, refers to an antibody that displays a single binding specificity and affinity for a particular epitope or a composition of antibodies in which all antibodies display a single binding specificity and affinity for a particular epitope. Typically, such monoclonal antibodies will be derived from a single cell or nucleic acid encoding the antibody, and will be propagated without intentionally introducing any sequence alterations. Accordingly, the term “humanized monoclonal antibody” refers to a monoclonal antibody that has variable and optionally constant regions derived from human germline immunoglobulin sequences, in particular to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins.

[0062] As used herein, "isotype" refers to the antibody class (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE antibody) that is encoded by the heavy chain constant region genes.

[0063] With regard to the binding of an antibody to a target molecule, the terms "bind" or "binding" refer to peptides, polypeptides, proteins, fusion proteins and antibodies (including antibody fragments) that recognize and contact an antigen. Preferably, it refers to an antigen-antibody type interaction. The terms "specific binding", "specifically binds to," "specific for," "selectively binds" and "selective for" a particular antigen (e.g., PD-1) or an epitope on a particular antigen (e.g., PD-1) mean that the antibody recognizes and binds a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically (or preferentially) binds to PD-1 or to a PD-1 epitope is an antibody that binds this PD-1 epitope for example with greater affinity, avidity, more readily, and / or with greater duration than it binds to other PD-1 epitopes or non-PD-1 epitopes.

[0064] As used herein, the term "humanized antibody" is intended to refer to antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences (e.g. chimeric antibodies that contain minimal sequence derived from a non-human antibody). A "humanized form" of an antibody, e.g., a non- human antibody, also refers to an antibody that has undergone humanization. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from at least one CDR of a non-human antibody (donor antibody) while maintaining the desired specificity, affinity, and capacity of the original antibody. The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect.

[0065] As used herein, the terms "Programmed Death 1", "Programmed Cell Death 1", “PD1”, “PDF’, "PDCD1", “PD-1 antigen”, “human PD-1”, "hPD-1" and "hPDl" are used interchangeably and refer to the Programmed Death- 1 receptor, also known as CD279, and include variants and isoforms of human PD-1, and analogues having at least one common epitope with PD-1. PD-1 is a key regulator of the threshold of immune response and peripheral immune tolerance. It is expressed on activated T cells, B cells, monocytes, and dendritic cells and binds to its ligands PD-L1 and PD-L2. Human PD-1 is encoded by the PDCD1 gene. As an example, the amino acid sequence of a human PD-1 is disclosed under GenBank accession number NP 005009 or UniProt accession number QI 5116. PD1 has four splice variants expressed on human Peripheral blood mononuclear cells (PBMC). Accordingly, PD-1 proteins include full-length PD-1, as well as alternative splice variants of PD-1, such as PD-lAex2, PD-lAex3, PD-lAex2,3 and PD- lAex2,3,4. Unless specified otherwise, the terms include any variant and, isoform of human PD-1 that are naturally expressed by PBMC, or that are expressed by cells transfected with a PD-1 gene.

[0066] As used herein "PD-1 antibody," "anti-PD-1 antibody," "PD-1 Ab," "PD-1 -specific antibody" or "anti-PD-1 Ab" or “humanized anti-PD-1 antibody” are used interchangeably and refer to an antibody, as described herein, which specifically binds to PD-1, preferably human PD-1. In some embodiments, the antibody binds to the extracellular domain of PD-1. Particularly, an anti-PD-1 antibody is an antibody capable of binding to a PD-1 antigen and inhibits the PD-1- mediated signalling pathway (i.e., antagonist of PD-1), thereby enhancing immune responses such as T cell activation.

[0067] As used herein, the term "isolated" indicates that the recited material (e.g., antibody, polypeptide, nucleic acid, etc.) is substantially separated from, or enriched relative to, other materials with which it occurs in nature. Particularly, an "isolated" antibody is one which has been identified and separated and / or recovered from a component of its natural environment. For example, the isolated antibody is purified (1) to greater than 75% by weight of antibody as determined by the Lowry method, or (2) to homogeneity by SDS-PAGE under reducing or non- reducing conditions. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. Particularly, an "isolated antibody" is an antibody that has been separated and / or recovered from a component of its natural environment. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment is not present. In some embodiments, an antibody is purified to homogeneity and / or to greater than 90%, 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) under reducing or non-reducing conditions.

[0068] The terms “derive from” and “derived from” as used herein refers to a compound having a structure derived from the structure of a parent compound or protein and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar properties, activities and utilities as the claimed compounds. For example, a humanized antibody derived from a murine antibody refers to an antibody or antibody fragment that shares similar properties with the murine antibody, e.g. recognizes the same epitope, shares similar VH and VL with modified residues that participate and / or increased the humanization of the antibody.

[0069] The term “and / or” as used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually.

[0070] The term “a” or “an” can refer to one of or a plurality of the elements it modifies (e.g., “a reagent” can mean one or more reagents) unless it is contextually clear either one of the elements or more than one of the elements is described.

[0071] The term “about” as used herein in connection with any and all values (including lower and upper ends of numerical ranges) means any value having an acceptable range of deviation of up to + / - 10% (e.g., + / - 0.5%, + / -1 %, + / -1 .5%, + / - 2%, + / - 2.5%, + / - 3%, + / - 3.5%, + / - 4%, + / - 4.5%, + / - 5%, + / - 5.5%, + / - 6%, + / - 6.5%, + / - 7%, + / - 7.5%, + / - 8%, + / - 8.5%, + / - 9%, + / - 9.5%). The use of the term “about” at the beginning of a string of values modifies each of the values (i.e. “about 1, 2 and 3” refers to about 1, about 2 and about 3). Further, when a listing of values is described herein (e.g. about 50%, 60%, 70%, 80%, 85% or 86%) the listing includes all intermediate and fractional values thereof (e.g., 54%, 85.4%). The term “at least one” means “one or more” or “one or several” can be used interchangeably.

[0072] For instance, it refers to one, two, three or more.

[0073] UniProt and GenBank Accession numbers are herein incorporated by reference in their entirely, as if each individual reference were specifically and individually indicated to be incorporated by reference.

[0074] Administration regimen

[0075] In a first aspect, the invention concerns a novel administration regimen of an IGg4 humanized antibody against human PD-1, in particular OSE-279, such as described here below.

[0076] The “administration regimen” or “treatment regimen” refers to the way a drug (e.g., an anti- PD-1 antibody) is given to a patient and typically includes the dose, the frequency of administration and / or the route of administration.

[0077] Preferably, the administration regimen of the anti -PD-1 antibody according to the invention comprises a flat or fixed dose of the anti -PD-1 antibody.

[0078] As used herein, the term “dose” or “amount” are used interchangeably and refers to a measured quantity or amount of a drug (e.g., an anti-PD-1 antibody or composition comprising it). It can be particularly expressed in units such as milligrams (mg) and is not related to the frequency of administration.

[0079] As used herein, the term “flat dose” or “fixed dose” refers to an unchanging dose of a medication that is given to a patient, regardless of his individual characteristics such as weight body, surface area (BSA) or age. The fixed or flat dose is therefore not provided as a mg / kg dose, but rather as an absolute amount of the therapeutic agent (e.g., the anti-PD-1 antibody), typically in mg. Flat doses typically refer to single medications (i.e., monotherapy), while fixed doses typically refer to the combinations of multiple medications (i.e., combined therapy).

[0080] Preferably, the administration regimen comprises a therapeutic effective dose of an anti-PDl antibody such as described herein.

[0081] An “effective amount”, a “therapeutic effective amount” , a “therapeutic effective dose” as used herein refers to the amount of active agent required (e.g., the anti-PD-1 antibody) to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents, e.g. the amount of active agent that is needed to treat the targeted disease or disorder, or to produce the desired effect. It typically protects a subject from the onset of a disease or promotes the regression of a disease as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free phase, or the prevention of injury or disability resulting from the affliction of the disease. In the context of the invention, a “therapeutic effective dose” is preferably a dose that is efficient to treat cancer.

[0082] Within the context of the invention, the term “treatment” or “treating” of cancer denotes curative, symptomatic, and preventive treatment in humans with existing cancer or tumour. The treatment will not necessarily cure the patient who has the cancer but will delay or slow the progression or prevent further progression of the disease, ameliorating thereby the patient’s condition. It designates both a curative treatment and / or a prophylactic treatment of a disease. A curative treatment is defined as a treatment resulting in cure or a treatment alleviating, improving and / or eliminating, reducing and / or stabilizing a disease or the symptoms of a disease or the suffering that it causes directly or indirectly. A prophylactic treatment comprises both a treatment resulting in the prevention of a disease and a treatment reducing and / or delaying the progression and / or the incidence of a disease or the risk of its occurrence.

[0083] In certain embodiments, such a term refers to the improvement or eradication of cancer or symptoms associated with it. In other embodiments, this term refers to minimizing the growth, spread or the worsening of cancers. Treatments according to the present invention do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.

[0084] In particular, the therapeutically effective dose or administration regimen of the invention allows to treat cancer, reduce the development of tumours and / or prevent or delay cancer relapse.

[0085] In some aspects, the therapeutically effective dose of the anti-PD-1 antibody is comprised between about between about 550 mg and about 1000 mg, between about 550 mg and about 1000 mg, between about 550 mg and about 800 mg, between about 550 mg and about 700 mg or between about 550 mg and about 650 mg, preferably between about 550 mg and about 650 mg.

[0086] In some aspects, the therapeutically effective dose of the anti-PD-1 antibody is comprised between about 550 mg and about 1000 mg, between about 600 mg and about 800 mg, between about 600 mg and about 700 mg or between about 600 mg and about 650 mg.

[0087] In a preferred embodiment, the therapeutically effective dose is of about 600 mg. The administration regimen of the invention typically comprises a dose of the anti-PD-1 antibody disclosed herein, preferably OSE-279, that is administered periodically to the patient.

[0088] As used herein the term “periodically” or “intermittently” refers to regular intervals of time, in particular in which an administration of an active ingredient (e.g., the anti-PD-1 antibody) occurs.

[0089] In some embodiments, the dose of the anti-PD-1 antibody of the invention is or is to be administered to the patient, once every two to twelve weeks, once every four to twelve weeks, once every four to nine weeks, once every four to eight weeks or once every five to seven weeks.

[0090] In some embodiments, the dose of the anti-PD-1 antibody of the invention is or is to be administered to the patient once every 2 weeks (Q2W), once every 3 weeks, (Q3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W), once every 6 weeks (Q6W), once every 7 weeks (Q7W), once every 8 weeks (Q8W), once every 9 weeks (Q9W), once every 10 weeks (Q10W), once every 11 weeks (Q11W) or once every 12 weeks (Q12W).

[0091] Preferably, the dose of the anti-PD-1 antibody of the invention is or is to be administered to the patient once every 6 weeks (Q6W).

[0092] Any one of the above-mentioned doses of the anti-PD-1 antibody can be administered at any frequency described herein.

[0093] In some embodiments, the anti-PD-1 antibody or composition of the invention is administered at a dose of 600 mg. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 600 mg once every four weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 600 mg once every five weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 600 mg once every six weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 600 mg once every seven weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 600 mg once every eight weeks.

[0094] In some embodiments, the anti-PD-1 antibody or composition of the invention is administered at a dose of 700 mg. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 700 mg once every four weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 700 mg once every five weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 700 mg once every six weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 700 mg once every seven weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 700 mg once every eight weeks.

[0095] In some embodiments, the anti-PD-1 antibody or composition of the invention is administered at a dose of 800 mg. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 800 mg once every four weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 800 mg once every five weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 800 mg once every six weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 800 mg once every seven weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of once 800 mg every eight weeks.

[0096] In some embodiments, the anti-PD-1 antibody or composition of the invention is administered at a dose of 900 mg. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 900 mg once every four weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 900 mg once every five weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 900 mg once every six weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 900 mg once every seven weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 900 mg once every eight weeks.

[0097] In some embodiments, the anti-PD-1 antibody or composition of the invention is administered at a dose of 1000 mg. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 1000 mg once every four weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 1000 mg once every five weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 1000 mg once every six weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 1000 mg once every seven weeks. In some embodiments, the anti-PD-1 antibody or composition of the invention is administered according to a regimen that delivers a dose of 1000 mg once every eight weeks.

[0098] In some embodiments, the administration regimen comprises a dose of a PD-1 antibody administered periodically, in a particular route of administration.

[0099] Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the humanized anti-PDl antibody or the pharmaceutical composition disclosed herein to the subject, depending upon the type of diseases to be treated or the site of the disease. The humanized anti-PDl antibody or the pharmaceutical composition comprising if can typically be administered orally, parenterally, enterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.

[0100] Preferably, the anti-PD-1 antibody or the composition comprising it is or is to be administered intravenously (i.e., IV administration), in particular according to the administration regimen disclosed herein.

[0101] Typically, the administration of anti-PD-1 antibody or the composition comprising it consists of an IV infusion intravenously during at least 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes or 45 minutes.

[0102] Preferably, the administration regimen of the anti-PD-1 antibody of the invention is a dose of about 600 mg of said antibody administered once every 6 weeks, preferably by an intravenous route.

[0103] The duration of treatment with the humanized anti-PD-1 antibody or with the pharmaceutical composition according to the invention can be adapted to the patient or the type of cancer.

[0104] In some embodiments, the antibody is or is to be administered for 2, 3, 4, 5, 6, or more cycles, preferably 5 cycles. A "cycle" of anticancer treatment refers to the period during which anticancer drugs are administered to a patient in a determined pattern (e.g., Q6W).

[0105] In some embodiments, the anti-PDl antibody or composition comprising it is or is to be administered, preferably Q6W, during at least 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks or 42 weeks. Optionally, the treatment may last 3, 4, 5, 6, 7, 8, 9, 10 or 11 months, or 1 or 2 years.

[0106] In some embodiments, the anti-PDl antibody or composition comprising it is or is to be administered, preferably Q4W or Q8W, during at least 16 weeks, 24 weeks, 32 weeks, 40 weeks or 48 weeks. Optionally, the treatment may last 3, 4, 5, 6, 7, 8, 9, 10 or 11 months, or 1 or 2 years.

[0107] In some embodiments, the anti-PDl antibody or composition comprising it is or is to be administered, preferably Q5W or Q10W, during at least 10 weeks, 20 weeks, 30 weeks, 40 weeks or 50 weeks. Optionally, the treatment may last 3, 4, 5, 6, 7, 8, 9, 10 or 11 months, or 1 or 2 years.

[0108] Optionally, the patient receives a flat dose of 600 mg Q6W of the PD-1 antibody of the invention, by IV infusion once on Day 1 every 6 weeks of a 12-week, a 18-week, a 24-week, a 30-week, a 36-week or a 42-week treatment period (i.e., 2, 3, 4, 5, 6 or 7 cycles, respectively). These patients typically receives a total of 2, 3, 4, 5, 6 or 7 flat doses of 600 mg of OSE-279.

[0109] In a specific aspect, patient receives a flat dose of 600 mg Q6W of the antibody PD-1 antibody of the invention, by IV infusion on Day 1 of a 30-week treatment period (i.e., 5 cycles). The patient typically receives a total of 5 flat doses of 600 mg of OSE-279.

[0110] In a specific aspect, patient receives a flat dose of 600 mg Q6W of the antibody PD-1 antibody of the invention, by IV infusion on Day 1 of a 42-week treatment period (i.e., 7 cycles). The patient typically receives a total of 7 flat doses of 600 mg of OSE-279.

[0111] Particularly, the antibody is or is to be administered, preferably Q6W, up to 1 or 2 years.

[0112] Preferably, the patient will receive up to one year of treatment. Typically, patients who experience benefits may be eligible to continue receiving the treatment.

[0113] In some embodiments, the treatment may last so as to reach a clinical benefit or as long as the disease persists. Preferably, the antibody is or is to be administered up to partial or complete response. In some embodiments, a clinical benefit is a complete response ("CR"), a partial response ("PR") or a stable disease ("SD"). In some embodiments, a clinical benefit corresponds to at least SD. In some embodiments, a clinical benefit corresponds to at least a PR. In some embodiments, a clinical benefit corresponds to a CR.

[0114] Particularly, the clinical benefit (e.g., SD, PR and / or CR) can be determined in accordance with Response Evaluation Criteria in Solid Tumours (RECIST 1.1) or in accordance with immune - related RECIST (irRECIST) guidelines.

[0115] A “partial response” refers to a significant but not complete reduction in the size or extent of a tumour or disease such as cancer. In the context of cancer treatment, a partial response is typically defined as a reduction in the dimensions of the tumour. It particularly indicates that the treatment is having a positive effect, although it has not completely eliminated the tumour or disease. A “complete response” refers to the disappearance of signs of cancer in response to treatment, in particular wherein the size of the tumour is no more measurable.

[0116] In some aspects, the partial response corresponds to a reduction in the size of the tumour of at least 30%, 35%, 40%, 45%; 50%, 55%; 60%, 65%, 70%; 75%, 80%, 85%, 90% or 95%.

[0117] In embodiments, the anti-PD-1 antibody or composition described herein is administered according to dosing regimens demonstrated to achieve a clinical benefit in some patients (for example, according to a regimen as determined by a physician, including dosing modifications). In embodiments, the anti-PD-1 antibody or composition described herein is administered until treatment is discontinued due to, e.g., disease progression or an adverse reaction or as determined by a physician. In embodiments, a clinical benefit is stable disease ("SD"), a partial response ("PR") and / or a complete response ("CR"). In embodiments, a clinical benefit is stable disease ("SD"). In embodiments, a clinical benefit is a partial response ("PR"). In embodiments, a clinical benefit is a complete response ("CR"). In embodiments, PR or CR is determined in accordance with Response Evaluation Criteria in Solid Tumours (RECIST). In embodiments, the anti-PD-1 antibody or composition is administered for a longer period to maintain clinical benefit.

[0118] In some embodiments, the anti-PD-1 antibody of the invention is used as a monotherapy.

[0119] “Monotherapy” refers to a medical treatment in which a single medication is used to manage a disease or condition. In the context of the invention, it means that in the time of treatment with the anti-PDl antibody, the patient does not receive any other anti-cancer drug or treatment. This does not rule out the patient having been previously treated for cancer (i.e., that the patient received a previous line of treatment).

[0120] The invention particularly concerns a monotherapy comprising an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death- 1 (PD-1) antibody for use in the treatment of cancer in a subject in need thereof, wherein said antibody is an antagonist of human PD-1 and comprises (a) a heavy chain comprising or consisting of an amino acid sequence of SEQ ID NO: 9, and (b) a light chain comprising or consisting of an amino acid sequence of SEQ ID NO: 10, wherein the antibody is to be administered at an administration regimen of the invention.

[0121] The invention particularly concerns a monotherapy comprising an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death- 1 (PD-1) antibody for use in the treatment of cancer in a subject in need thereof, wherein said antibody is an antagonist of human PD-1 and comprises (a) a heavy chain comprising or consisting of an amino acid sequence of SEQ ID NO: 9, and (b) a light chain comprising or consisting of an amino acid sequence of SEQ ID NO: 10, wherein the antibody is to be administered at a flat dose of between about 550 or 600 mg and about 800 mg, preferably of about 600 mg, once every four to twelve weeks, preferably every six weeks, and wherein the cancer is preferably a rare tumour, optionally with a high microsatellite instability (MSI-H) or expressing PD-L1.

[0122] Alternatively, the anti -PD-1 of the invention is used as a combination therapy.

[0123] “Combined therapy” or “Combination therapy” refers to the use of two or more therapeutic agents or treatment modalities, preferably to target different pathways involved in cancer.

[0124] In particular, the humanized anti -PD-1 antibody according to the present invention can be combined with some other potential strategies for overcoming immune evasion mechanisms with agents in clinical development or already on the market.

[0125] In an aspect, the humanized anti -PD-1 antibody and an additional therapeutic can be present in a pharmaceutical composition as described above. Alternatively, the term “combination therapy” or “combined therapy” as used herein, embraces administration of these agents (e.g., an anti -PD-1 antibody as described herein and a second or additional suitable therapeutic agent) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the agents, in a substantially simultaneous manner. Sequential or substantially simultaneous administration of each agent can be affected by any appropriate route. The agents can be administered by the same route or by different routes.

[0126] In another aspect, the invention relates to a therapeutic mean, in particular a combination product mean, which comprises as active ingredients: anti-PD-1 antibody as described herein and an additional and therapeutic agent, wherein said active ingredients are formulated for separate, sequential or combined therapy, in particular for combined or sequential use.

[0127] As used herein, the term "sequential" means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of anti-PD-1 antibody as described herein and the additional or second agent, a sequential dosage regimen could include administration of the anti-PD-1 antibody as described herein before, simultaneously, substantially simultaneously, or after administration of the second agent, but both agents will be administered in a regular sequence or order. The term "separate" means, unless otherwise specified, to keep apart one from the other. The term "simultaneously" means, unless otherwise specified, happening or done at the same time, i.e., the agents of the invention are administered at the same time. The term "substantially simultaneously" means that the agents are administered within minutes of each other (e.g., within 15 minutes of each other) and intends to embrace joint administration as well as consecutive administration, but if the administration is consecutive it is separated in time for only a short period (e.g., the time it would take a medical practitioner to administer two compounds separately).

[0128] For instance, the additional therapeutic agent can be selected in the group consisting of chemotherapy, radiotherapy, anti angiogenic agents, hypomethylating agents, cancer vaccines, peptide vaccine, angiogenesis inhibitors such as VEGFR inhibitor (preferably of VEGFR-1, VEGFR-2 and / or VEGFR-3), tyrosine kinase inhibitors, epitopes or neoepitopes from tumour antigens, myeloid checkpoints inhibitors, other immunotherapies, in particular immune checkpoint inhibitors other than PD-1, cell therapy agents (such as CAR-T cells), and HD AC inhibitors.

[0129] Particularly, the additional therapeutic agent is axitinib.

[0130] Alternatively, the additional therapeutic agent is an inhibitor of an immune checkpoint selected from the group consisting of CTLA-4, TIM-3, TIGIT, LAG-3, CEACAM (e.g., CEACAM-1, - 3 and / or -5), VISTA, BTLA, LAIR1, CD 160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, TGFR (e g., TGFR beta), B7-H1, OX- 40, CD137, CD40, IDO, and CSF-1R. Alternatively, the additional therapeutic agent is a chemotherapeutic agent, in particular a platinum-based chemotherapy such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.

[0131] Anti-PD-1 antibody and pharmaceutical composition comprising it

[0132] The invention refers to an antibody against human PD-1 (also referred herein as an anti-PDl antibody), in particular OSE-279, such as described in WO2020 / 127366, the content of which is incorporated herein by reference.

[0133] Particularly, the antibody against human PD-1 is a humanized monoclonal antibody.

[0134] In some aspects, the anti-PDl antibody is an isolated antibody, particularly a non-natural isolated antibody. Such isolated humanized anti-PDl antibody can be prepared by at least one purification step. In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95% or 99% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight of an antibody, the remainder of the weight comprising the weight of other solutes dissolved in the solvent.

[0135] Preferably, such antibody has the ability to block or inhibit the interaction between PD-1 and at least one of its ligands (e.g. PD-L1 and / or PD-L2). The ability to “block binding” or “block interaction” or “inhibit interaction” as used herein refers to the ability of an antibody to prevent the binding interaction between two molecules (e.g. PD-1 and its ligand PD-L1 and / or PD-L2) to any detectable degree.

[0136] Preferably, the antibody is an antagonist of the binding of human PD-L1 and / or PD-L2 to human PD-1, more preferably of human PD-L1 and PD-L2 to human PD-1.

[0137] The term “antagonist” as used herein, refers to a substance that block or reduces the activity or functionality of another substance. Particularly, this term refers to an antibody that binds to a cellular receptor (e.g. PD-1) as a reference substance (e.g. PD-L1 and / or PD-L2), preventing it from producing all or part of its usual biological effects (e.g. the creation of an immune suppressive microenvironment). Methods for determining the antagonist activity of an antibody are known in the art, and are for example ELISA, biosensor analysis such as Biacore and Blitz.

[0138] In particular, the humanized anti-hPD-1 antibody is capable of reducing or inhibiting the binding of PD-L1 and / or PD-L2 to PD-1 by at least 50%, 60%, 70%, preferably 80%, more preferably 90% or most preferably 100%, as compared to a negative control molecule, in a binding assay, such as a competition ELISA assay. Such an assay is disclosed in Sebaugh JL.

[0139] Guidelines for accurate EC50 / IC50 estimation. Pharm. Stat. 2011; 10: 128-134.

[0140] In certain embodiments, the anti-hPDl antibody inhibits the binding interaction between PD-1 and at least one of its ligands (e.g. PD-L1 and / or PD-L2, preferably PD-L1 and PD-L2) by at least 50%. In certain embodiments, this inhibition may be greater than 60%, greater than 70%, greater than 80%, or greater than 90%.

[0141] In one embodiment, the anti-PD-1 antibody of the invention comprises:

[0142] (i) a heavy chain variable domain comprising HCDR1 comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0143] (ii) a light chain variable domain comprising LCDR1 comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6.

[0144] Particularly, the anti-PDl antibody according to the invention comprises framework regions, in particular heavy chain variable region framework regions (HFR) HFR1, HFR2, HFR3 and HFR4 and light chain variable region framework regions (LFR) LFR1, LFR2, LFR3 and LFR4.

[0145] Particularly, the anti-PDl antibody or antigen binding fragment comprises heavy chain variable region framework regions (HFR) HFR1, HFR2, HFR3 and HFR4 comprising an amino acid sequence of SEQ ID NOs: 11, 12, 13 and 14, respectively, optionally with one, two or three modification(s) selected from substitution(s), addition(s), deletion(s) and any combination thereof, in particular at any position but positions 27, 29 and 32 of HFR3, i.e., of SEQ ID NO: 13. Preferably, the anti-PDl antibody or antigen binding fragment comprises HFR1 of SEQ ID NO: 11, HFR2 of SEQ ID NO: 12, HFR3 of SEQ ID NO: 13 and HFR4 of SEQ ID NO: 14.

[0146] Alternatively or additionally, the anti-PDl antibody or antigen binding fragment comprises light chain variable region framework regions (LFR) LFR1, LFR2, LFR3 and LFR4 comprising an amino acid sequence of SEQ ID NOs: 15, 16, 17 and 18, respectively, optionally with one, two or three modification(s) selected from substitution(s), addition(s), deletion(s) and any combination thereof. Preferably, the humanized anti-PDl antibody or antigen binding fragment comprises LFR1 of SEQ ID NO: 15, LFR2 of SEQ ID NO: 16, LFR3 of SEQ ID NO: 17 and LFR4 of SEQ ID NO: 18. The VL and VH domain of the antibody according to the invention typically comprises four framework regions interrupted by three complementary determining regions preferably operably linked in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (from amino terminus to carboxy terminus).

[0147] Preferably, the anti-human-PD-1 humanized antibody comprises: (a) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence of SEQ ID NO: 7; and (b) a light chain variable region (VL) comprising or consisting of an amino acid sequence of SEQ ID NO: 8.

[0148] In one embodiment, the anti-PDl antibody typically comprises a hinge and / or a Fc region. Preferably, the humanized anti-PDl antibody comprises an IgG4 hinge and / or a Fc region. Preferably, the antibody comprises CH2 and CH3 domains or includes hinge-CH2-CH3. In a preferred embodiment, the constant region contains a hinge region, a CH2 and / or a CH3 domain derived from a human IgG4 heavy chain.

[0149] In one embodiment, the heavy chain (CH) and the light chain (CL) comprises the VL and VH sequences as described hereabove.

[0150] In preferred embodiments, the constant region is derived from a human immunoglobulin heavy chain, for example, IgGl, IgG2, IgG3, IgG4, or other classes. In a further aspect, the human constant region is selected from the group consisting of IgGl, IgG2, IgG2, IgG3 and IgG4. Preferably, the humanized anti-PDl antibody comprises an IgG4 Fc-region. Preferably, the humanized anti-PDl antibody is of the IgG4 isotype.

[0151] In another specific aspect, the antibody comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P; L234A / L235A, S228P + M252Y / S254T / T256E, and K444A. Even more preferably, the humanized anti-hPDl antibody comprises an IgG4 Fc-region with a S228P mutation that stabilizes the IgG4.

[0152] Preferably, the four polypeptide chains of the anti-PD-1 antibody are linked together by disulfide bonds. Each heavy chain contains one consensus sequence for N-linked glycosylation (in position 294).

[0153] Preferably, the anti-human-PD-1 antibody comprises: (a) a heavy chain comprising or consisting of an amino acid sequence of SEQ ID NO: 9, and (b) a light chain comprising or consisting of an amino acid sequence of SEQ ID NO: 10. In certain aspects, the humanized anti-PD-1 antibody binds human PD-1 with affinities equal or lower than 10-8 M, preferably equal or lower than 10-9 M. In one aspect, the affinity is equal or lower than 1,5 x 10-9 M. The affinity can be measured by any method available to the person skilled in the art, for example by biosensor analysis such as surface plasmon resonance (SPR) Biacore Analysis, Blitz analysis and Scatchard plot.

[0154] Binding affinity can be expressed KD or dissociation constant, and an increased binding affinity corresponds to a decreased KD. One way of determining binding affinity of antibodies to PD-1 is by measuring binding affinity of Fab fragments of the antibody. To obtain Fab fragments, an antibody can be cleaved with papain or expressed recombinantly. The affinity of an anti-PD-1 antibody can be determined by surface plasmon resonance (BIAcore3000™ surface plasmon resonance (SPR) system, BIAcore, INC, Piscaway N.J.). Kinetic association rates (kon) and dissociation rates (kog) (generally measured at 25 °C.) are obtained; and equilibrium dissociation constant (KD) values are calculated as koff / kon.

[0155] Particularly, the antibodies provided herein bind to human PD-1 with an affinity constant (KD) equal to or lower than 0.75 to 1.34 nM, preferably equal to or lower than 0.75 to 1 nM, more preferably equal to or lower than 0.75 to 0.8 nM, as may be determined by Blitz analysis. This system allows the measurement of rate and affinity constants for binding interactions (ka, kd, KD).

[0156] In some aspect, the anti-PD-1 antibody of the invention is comprised in a pharmaceutical composition.

[0157] As used herein, a “pharmaceutical composition” refers to a preparation of one or more of the active agents, such as comprising a humanized anti-PDl antibody according to the invention, with optional other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active agent to an organism.

[0158] Compositions of the present invention can be in a form suitable for any conventional route of administration or use. In one embodiment, a “composition” typically intends a combination of the active agent, e.g., the anti-PD-1 antibody, and a naturally-occurring or non-naturally- occurring carrier, inert or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers. An "acceptable vehicle" or “acceptable carrier” as referred to herein, is any known compound or combination of compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions.

[0159] In some instances, the anti-PDl antibody is comprised in a composition comprising sodium acetic acid, Glycine, Mannitol and Polysorbate.

[0160] In some instances, the anti-PDl antibody is comprised in a formulation buffer consisting of 30 mM sodium acetic acid, 200 mM Glycine, 50 mM Mannitol, 200 ppm Polysorbate 80 at pH 4.8.

[0161] Typically, the composition is in the form of dose unit containing 100 mg of OSE-279 antibody and is filled aseptically in 2 mL extractable volume clear glass ISO 2R Type I vials closed by rubber stopper and aluminium seals with a flip-off cap.

[0162] Preferably, the reconstitution of the Investigational Medicinal Product (IMP) to adjust the concentration before administration (e.g., intravenous infusion) of the anti-PD-1 antibody will be performed on the site pharmacy by appropriate dilutions in NaCl 0.9% solution.

[0163] As used herein, the term “medicament” refers to any substance or composition with curative or preventive properties against disorders or diseases.

[0164] The present invention also relates to a pharmaceutical composition comprising the humanized anti -human PD1 antibody described herein, preferably as the active ingredient or compound.

[0165] Optionally, the pharmaceutical composition may further comprise an additional therapeutic agent as detailed below.

[0166] The pharmaceutical composition according to the invention can be formulated for any conventional route of administration. The means of making such a composition have been described in the art (see, for instance, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005)). Preferably, the pharmaceutical composition according to the invention is formulated for intravenous route of administration.

[0167] Methods and uses

[0168] In a second aspect, the invention concerns the administration regimen disclosed herein for use in the treatment of cancer. Particularly, the invention relates to a method for treating a cancer based on the administration regimen disclosed herein. It also relates to the use of an administration regimen according to the invention for the treatment of cancer. In a particular aspect, the invention concerns an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death- 1 (PD-1) antibody or a pharmaceutical composition comprising it, for use in the treatment of cancer in a subject in need thereof, wherein said antibody is an antagonist of human PD-1 and comprises:

[0169] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0170] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein said antibody is to be administered periodically at a dose of at least 550 or 600 mg.

[0171] The invention also concerns a method of treating a cancer in a subject in need thereof, wherein the method comprises administering periodically a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal anti-Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0172] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0173] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 550 or 600 mg.

[0174] The invention particularly concerns a method of treating a cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of at least 550 or 600 mg of an immunoglobulin G4 (IgG4) humanized monoclonal anti-Programmed Death-1 (PD-1) antibody as disclosed herein, such that the subject achieves clinical or objective response, such as stable disease, partial response, or complete response for at least 1 month. The invention also concerns a method of reducing tumour size or burden in a subject suffering from cancer, wherein the method comprises administering periodically a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0175] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0176] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 550 or 600 mg.

[0177] As used herein, the term “tumour burden” refers to the total amount of tumour mass distributed throughout the body. Tumour burden particularly refers to the total number of cancer cells or the total size of the tumour throughout the body. Tumour burden can be determined by a variety of methods known in the art, such as measuring the size of a tumour using callipers after the tumour is removed from a subj ect, or using imaging techniques (e.g., ultrasound, bone scanning, computed tomography (CT), or magnetic resonance imaging (MRI) scanning) when the tumour is in vivo.

[0178] As used herein, the term “tumour size” refers to the total size of a tumour, which can be measured as the length and width of the tumour. Tumour size can be determined by a variety of methods known in the art, such as measuring the size of a tumour using callipers after the tumour is removed from a subj ect, or using imaging techniques (e.g., bone scanning, ultrasound, CT, or MRI scanning) when the tumour is in vivo.

[0179] In a particular aspect, the invention concerns a method for inducing or increasing PD-1 receptor occupancy on T cells, preferably CD8+ T cells, in a subject suffering from cancer, wherein the method comprises administering periodically a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal anti-Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0180] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0181] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 600 mg, thereby achieving a PD-1 receptor occupancy of at least 75% on T cells, preferably CD8+ T cells.

[0182] Also provided herein is a method of treating a subject having cancer, wherein the method comprises administering periodically a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0183] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0184] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 550 or 600 mg, and wherein the method results in a PD-1 receptor occupancy of at least 75%, 85% or 95% on T cells, preferably CD8+ T cells, of said subject.

[0185] “T cell” or “T lymphocytes” as used herein includes CD4 + T cells, CD8 + T cells, T helper cells, effector T cells, effector memory stem like T cells, Tumor Infiltrating Lymphocyte (TIL), anergic T cells and exhausted T cells. Preferably, the T cell is a CD8 + T cells (also known as a cytotoxic T cell, CTL).

[0186] As used herein, “receptor occupancy” refers to the extent to which receptors (e.g., PD-1) on the surface of cells are bound by specific molecules (e.g., the anti-PD-1 antibody of the invention). The concept of receptor occupancy is typically used to determine the efficacy and potency of drugs targeting specific receptors. Receptor occupancy can be quantitatively assessed using various experimental techniques known to the man skilled in the art, including radioligand binding assays, fluorescence microscopy, or functional assays measuring downstream signalling events.

[0187] Preferably, the percentage of PD-1 receptor occupancy is of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

[0188] Particularly, the percentage of PD-1 receptor occupancy reached by using the administration regimen of the invention, preferably 600 mg Q6W, is between 75% and 100%, preferably between 85% and 100%, even more preferably between 90% and 100%, most preferably between 95% and 100%,.

[0189] Preferably, the percentage of PD-1 receptor occupancy reached by using the administration regimen of the invention is of about 100%. Preferably, the percentage of PD-1 receptor occupancy reached by using the administration regimen of 600 mg Q6W is of about 100%.

[0190] In some instances, the percentage of receptor occupancy of the antibody on T cells is reached within 48 hours of administration of the first dose of the anti-PD-1 antibody and / or is maintained for at least 3 weeks after administering the last dose of the antibody.

[0191] In some instances, the percentage of PD-1 receptor occupancy of the antibody on T cells is reached within 1 hour, 2hours, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours or 72 hours after the administration of a dose of the anti-PD-1 antibody or composition comprising it, preferably of the first dose of the anti-PD-1 antibody or composition comprising it.

[0192] In some instances, the percentage of PD-1 receptor occupancy of the anti-PD-1 antibody on T cells, preferably on CD8+ T cells, is maintained for at least 21 days, 24 days, 30 days, 36 days or 42 days (i.e., 6 weeks) after administering the dose of the anti-PD-1 antibody or composition comprising it.

[0193] In some instances, the percentage of PD-1 receptor occupancy of the anti-PD-1 antibody on T cells, preferably on CD8+ T cells, is maintained during the full cycle after the administration of a dose of the anti-PD-1 antibody or composition comprising it or is maintained between a first and second dose of the PD-1 antibody or composition comprising it or until the administration of the next dose. This means that if a cycle is 6 weeks (i.e., administration regimen of Q6W), the PD-1 receptor occupancy is maintained during 6 weeks or until the administration of the next dose. Preferably, when the anti-PD-1 antibody is administered at a dose of 600 mg Q6W, the percentage of PD-1 receptor occupancy of the anti-PD-1 antibody on T cells, preferably on CD8+ T cells, is maintained at a percentage of between 85% and 100% or between 95% and 100%, preferably of about 100% during the cycle, i.e., during 6 weeks after administration of the dose of the anti-PD-1 antibody of the invention, preferably OSE-279.

[0194] In a particular aspect, the invention concerns a method for inducing PD-1 receptor occupancy on T-cells, preferably CD8+ T cells, in a subject suffering from cancer, wherein the method comprises administering periodically a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0195] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0196] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 600 mg and is administered Q6W, thereby achieving a PD-1 receptor occupancy of at least 85% 90%, 95%, or 100% on T cells, preferably CD8+ T cells.

[0197] Preferably, such PD-1 receptor occupancy is maintained at a percentage of at least 85%, 90%, 95%, or 100% during 6 weeks or until the administration of the next / following therapeutically effective dose.

[0198] The invention also concerns the periodical use of a composition comprising about 550 or 600 mg to about 1000 mg of an immunoglobulin G4 (IgG4) humanized monoclonal antiProgrammed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, for treating a cancer in a subject in need thereof.

[0199] The invention also concerns the periodical use of a flat dose of about 550 or 600 mg to about 1000 mg of an anti PD-1 antibody in the preparation of a medicament for the treatment of cancer; wherein said antibody is an immunoglobulin G4 (IgG4) humanized monoclonal antiProgrammed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6. Particularly, this use is according to an administration regimen such as described herein.

[0200] Subject and Cancer

[0201] The subject to treat by the regimen of the invention may be a human, particularly a human at the prenatal stage, a new-born, a child, an infant, an adolescent or an adult, in particular an adult of at least 30 years old, at least 40 years old, at least 50 years old, at least 60 years old, or at least 70 years old. Preferably, the subject is a human of between 30 and 80 years old.

[0202] As used herein, the term “subject”, “host”, “individual,” or “patient” are used interchangeably.

[0203] Particularly, a subject in need of a treatment is a patient having, suspected of having, or at risk for cancer, preferably a PD-1 or PD-L1 positive cancer, even more preferably a cancer where PD-1 or PD-L1 is expressed or overexpressed. For example, a patient suitable for the treatment can be identified by examining whether such a patient carries PD-L1 positive tumour cells. Additionally, or alternatively, the subject suitable for the treatment is a subject having tumour infiltrating T cells that express or overexpress PD-1.

[0204] Accordingly, the uses and methods of the invention may comprise a step of identification and / or selection of a patient suffering or at risk for cancer. In some embodiments, when receiving the treatment of the invention (in particular as a monotherapy), the subject has already been treated with one or more different cancer treatment modalities, such as surgery, chemotherapy, radiotherapy or immunotherapy. Preferably, the subject has already received at least one line of systemic therapy (e.g., chemotherapy or immunotherapy) at the exclusion of an anti-PD-1 therapy.

[0205] Alternatively, the patient has not previously been treated with a cancer treatment modality.

[0206] Particularly, the subject is affected with a cancer that involves the PD-l / PDL-1 pathway, particularly wherein, at least one of the ligands of PD-1 (e.g. PDL-1 and / or PDL-2) or PD-1 is / are expressed, especially overexpressed. Preferably, the subject is suffering from cancer, even more preferably from a PD1, PD-L1 and / or PD-L2 positive cancer.

[0207] The term "cancer" as used herein is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body.

[0208] A “tumour”, when applied to a subject diagnosed with or suspected of having cancer, refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumours and secondary neoplasms.

[0209] Preferred cancers for treatment include cancers typically responsive to immunotherapy, such as PD-1 immunotherapy.

[0210] In some aspects, the cancer is a solid cancer, preferably an advanced solid cancer. Solid tumours typically occur in various parts of the body, such as bones, muscles, organs, and connective tissues. Examples of solid tumours are sarcomas and carcinomas.

[0211] In some aspects, the cancer is an advanced cancer, particularly a stage III or IV cancer (preferably as determined by the TNM system (Tumour, Node, Metastasis) of cancer staging), preferably a stage IV cancer. A cancer is considered stage III or IV when it has grown and spread to nearby tissues or lymph nodes (stage III) or has metastasized (stage IV).

[0212] In some aspects, the cancer is a stage IV cancer with lung metastasis.

[0213] In some embodiments, the solid cancer is an advanced hepatocellular carcinoma, particularly a stage III or IV hepatocellular carcinoma. In some aspects, the cancer is a hepatocellular carcinoma that has metastasised, in particular a hepatocellular carcinoma with lung metastasis.

[0214] In some embodiments, the cancer is a solid rare tumour, preferably an advanced solid rare tumour, even more preferably a stage IV solid rare tumour, particularly with lung metastasis. Typically, “rare cancers” are identified as those with an incidence of less than 6 per 100,000 persons per year. In particular, the rare cancer is classified as “rare” according to the classification of the “Rarecare” project (European initiative aimed at improving the surveillance of rare cancers across the European Union (EU), launched in 2006), such as available in https: / / www.rarecarenet.eu / rarecarenet / cancerlist, said list being incorporated herein by reference.

[0215] Particularly, the solid rare cancer is selected from the group consisting of central nervous system rare cancers (CNS), digestive rare cancers, endocrine organ rare cancers, female genital rare cancers, male genital and urogenital rare cancers, haematological rare cancers, head & neck rare cancers, thoracic rare cancers, neuroendocrine tumours (NET) rare cancers, skin rare cancers and sarcomas.

[0216] Preferably, the rare tumour is selected from the group consisting of sarcoma (preferably soft tissue sarcoma, bone sarcoma or gastrointestinal sarcoma), squamous cell carcinoma, neuroendocrinal tumour and carcinoma of the thyroid or parathyroid gland.

[0217] In some embodiments, the cancer is a squamous cell carcinoma. Preferably, the squamous cell carcinoma is selected from the list consisting of Squamous cell carcinoma of nasal cavity and sinuses, nasopharynx, hypopharynx, larynx, oropharynx, oral cavity, lips, oesophagus, stomach, small intestine, colon, rectum, anal canal, pancreas, liver, gallbladder, trachea, lung, thymus, thyroid, lungs, corpus uteri, cervix uteri, vulva, vagina, prostate, penis, kidney, pelvis, ureter, bladder, eye, ear and skin. Such squamous cell carcinoma can typically be squamous carcinoma, verrucous carcinoma, squamous cell carcinoma spindle cell, papillary squamous cell carcinoma, Adenosquamous carcinoma, Lymphoepithelial carcinoma, Undifferentiated carcinoma or Basaloid squamous cell carcinoma.

[0218] In some embodiments, the cancer is a neuroendocrine tumour. Particularly, the neuroendocrine tumour is selected from the group consisting of Well differentiated not functioning endocrine carcinoma of pancreas and digestive tract (such as Carcinoid tumour and Islet cell carcinoma), Well differentiated functioning endocrine carcinoma of pancreas and digestive tract (such as Insulinoma, malignant, Glucagonoma, malignant, Somatostatinoma, malignant, Gastrinoma, malignant, VIP-oma, Other ectopic hormone producing tumours), Poorly differentiated endocrine carcinoma of pancreas and digestive tract (such as Large cell endocrine carcinoma and Small cell endocrine carcinoma), Mixed endocrine-exocrine carcinoma of pancreas and digestive tract Endocrine carcinoma of thyroid gland (such as Medullary carcinoma, Mixed medullary-follicular carcinoma, Well differentiated endocrine tumours, Poorly differentiated endocrine carcinoma), neuroendocrine carcinoma of the parathyroid gland, Neuroendocrine carcinoma of skin (such as Merkel cell carcinoma), Typical and atypical carcinoid of the lung (such as bronchial carcinoid tumour), Neuroendocrine carcinoma of other sites (such as Well differentiated endocrine tumours, carcinoid, Well differentiated endocrine tumours, atypical carcinoid, Poorly differentiated endocrine carcinoma), Pheochromocytoma, and Paraganglioma.

[0219] In some embodiments, the cancer is an oncocytic carcinoma, particularly affecting an organ or tissue selected from the group consisting of thyroid gland, salivary glands, kidney, nasal cavity, paranasal sinuses, bronchus, parathyroid, ovary, upper mediastinum, lung and breast, preferably is an oncocytic carcinoma of the thyroid (OCA).

[0220] Preferably, the cancer is a carcinoma of the thyroid or parathyroid gland, preferably an oncocytic carcinoma of the thyroid.

[0221] In some aspects, the cancer is an oncocytic carcinoma of the thyroid that has metastasised, in particular an oncocytic carcinoma of the thyroid with lung metastasis.

[0222] In some embodiment, the tumour is a sarcoma. Preferably, the tumour is not a Kaposi sarcoma.

[0223] The term “sarcoma” typically refers to a malignancy derived from mesenchymal tissues (including connective tissues and muscles), which occurs mostly in the skin, under the skin, in the periosteum and at both ends of long bones.

[0224] In a particular aspect, the solid cancer is a sarcoma selected from the group consisting of soft tissue sarcoma, bone sarcoma (such as Osteogenic sarcoma, in particular Conventional osteosarcoma, Teleangectatic osteosarcoma, Small cell osteosarcoma, Paraosteal osteosarcoma, High grade surface osteosarcoma, Low grade central osteosarcoma, Periosteal osteosarcoma, Secondary osteosarcoma), Synovial sarcoma, Chondrogenic sarcomas (such as Chondrosarcoma, Mesenchymal chondrosarcoma, Clear cell chondrosarcoma, Dedifferentiated chondrosarcoma, Notochordal sarcomas, chordoma, Vascular sarcomas (such as Angiosarcoma), Ewing’s sarcoma (such as Peripheral neuroectodermal tumour), Epithelial tumours, adamantinoma, Other high grade sarcomas (such as fibrosarcoma, malignant fibrous histiocytoma) and Gastrointestinal stromal sarcoma (GIST).

[0225] In a particular aspect, the solid cancer is a soft tissue sarcoma. The “soft tissue sarcoma” is derived from fat, fascia, muscles, fibres, lymph and blood vessels, each with different histological and biological properties and different local infiltration and hematogenous and lymphatic metastases. Liposarcoma and fibrosarcoma may also occur in the retroperitoneum. The incidence of the disease is high in middle-aged and old people, and there is no gender difference. Soft tissue sarcoma can occur in any body part. About 75% of the lesions are located in the extremities (most commonly in the thighs). Soft tissue sarcomas are mostly malignant.

[0226] In some embodiment, the cancer is a soft tissue sarcoma selected from the group consisting of soft tissue sarcoma of head and neck (such as Sarcoma NOS, Epithelioid sarcoma, Desmoplastic small round cell tumour, Fibrosarcoma, Fibromyxosarcoma, Infantile fibrosarcoma, Myxoinflammatory fibroblastic sarcoma, Malignant fibrous histiocytoma, DFSP, Well differentiated liposarcoma, Myxoid liposarcoma, Pleomorphic liposarcoma, Mixed type liposarcoma, Dedifferentiated liposarcoma, Leiomyosarcoma, Pleomorphic rhabdomyosarcoma, Extrarenal rhabdoid tumour, Synovial sarcoma, Clear cell sarcoma of soft tissue, Epithelioid angiosarcoma, Epithelioid haemangioendothelioma, Extraskeletal osteosarcoma, Extraskeletal myxoid chondrosarcoma, Malignant peripheral nerve sheath tumours, Malignant glomus tumours (glomangiosarcoma), Intimal Sarcoma, Low grade fibromyxoid sarcoma, Low grade myofibroblastic sarcoma, PEComas, Sclerosing epithelioid fibrosarcoma and Undifferentiated pleomorphic sarcoma (UPS), preferably UPS); Soft tissue sarcoma of limbs, Soft tissue sarcoma of superficial trunk, Soft tissue sarcoma of mediastinum, Soft tissue sarcoma of heart, Soft tissue sarcoma of breast, Soft tissue sarcoma of uterus, Soft tissue sarcoma of paratestis, Soft tissue sarcomas of other genitourinary tract (such as vulva, vagina, ovary, penis, prostate, testis, kidney, renal pelvis, ureter, bladder, urethra), Clear cell sarcoma of kidney, Malignant rhabdoid tumour of kidney, Soft tissue sarcoma of viscera, Soft tissue sarcoma of retroperitoneum and peritoneum, Soft tissue sarcoma of pelvis, Soft tissue sarcoma of skin (such as dermatofibrosarcoma protuberans (DFSP)), Soft tissue sarcoma of paraorbit, Soft tissue sarcoma of brain and other parts of the nervous system, Embryonal rhabdomyosarcoma of soft tissue, Alveolar rhabdomyosarcoma of soft tissue, alveolar soft part sarcoma (ASPS), Ewing’s sarcoma of soft tissue (such as Ewing Sarcoma, Peripheral neuroectodermal tumour, Primitive neuroectodermal tumour).

[0227] In some particular aspects, the cancer is an alveolar soft part sarcoma (ASPS) or an undifferentiated polymorphic sarcoma (UPS). “Alveolar soft part sarcoma (ASPS)” is a rare and slow-growing type of soft tissue sarcoma, it displays a unique histological pattern with large, eosinophilic cells arranged in an alveolar-like architecture. The genetic hallmark of ASPS is a chromosomal translocation that fuses the TFE3 transcription factor gene to the ASPL gene, which is found at 17q25.

[0228] In some very particular aspects, the cancer is a ASPS TFE3+. "TFE3+" typically refers to the expression, overexpression or abnormal activation of the TFE3 gene (Transcription Factor Binding to IGHM Enhancer 3). TFE3 overexpression has been associated with enhancing cell cycle progression and cancer development.

[0229] “Undifferentiated polymorphic sarcoma (UPS)” previously known as malignant fibrous histiocytoma, is a rare and aggressive type of soft tissue cancer of indeterminate origin, which occurs in both soft tissues and bones. It was first described in 1961. The primary therapies include pre-operative chemotherapy, post-operative chemotherapy and surgical resection.

[0230] In some aspects, the cancer is ASPS or UPS that has metastasised, in particular a ASPS or UPS with lung metastasis.

[0231] Alternatively, the cancer is liquid cancer, such a hematologic cancer. The most common types of liquid cancers include leukaemia, lymphoma, and myeloma. In a particular embodiment, the cancer is a lymphoma.

[0232] In some aspects, the cancer is a solid tumour, preferably a rare solid tumour, with a high microsatellite instability (MSI-H) and / or expressing PD-L1.

[0233] In some embodiments, the cancer is a PD-L1 positive tumour.

[0234] Preferably, by “PD-L1 positive tumour cells” is intended to refer to a population of tumour cells in which PD-L1 is expressed in at least 10% of tumour cells, preferably in at least 15%, 20%, 30%, 40% or 50 % of tumour cells.

[0235] In some embodiments, the cancer is an anal SCC expressing PD-L1, preferably an anal SCC having 15% of PD-L1 positive cells.

[0236] In some embodiments, the cancer is an oncocytic thyroid cancer expressing PD-L1, preferably an oncocytic thyroid cancer having 80% of PD-L1 positive cells.

[0237] In some embodiments, the cancer has a high microsatellite instability (MSI-H).

[0238] As used herein “high microsatellite instability” or “MSI-H” in cancer refers to a genetic condition where cancer cells exhibit a high number of mutations within microsatellites. MSI-H is particularly classified by the instability of two or more microsatellite loci. MSI-H can be detected by comparing the length of microsatellite repeats in tumour cells with normal cells, using methods known to the skilled person in the art, such as Polymerase Chain Reaction (PCR) or Next Generation Sequencing (NGS).

[0239] In some embodiments, the cancer is a UPS with MSI-H or an ASPS with MSI-H.

[0240] Alternatively, the cancer is microsatellite stable (MSS).

[0241] In some embodiments, the cancer is a Hepatocellular carcinoma (HCC) MSS or an oncocytic thyroid cancer MSS, in particular an oncocytic thyroid cancer PDL1 MSS.

[0242] Kit and uses thereof

[0243] Finally, the invention concerns a kit for treating a subject suffering from cancer, a kit for use in the treatment of cancer in a subj ect in need thereof, or the use of a kit for the treatment of cancer, wherein the kit comprises:

[0244] (a) a dosage ranging from 550 or 600 mg to 1000 mg of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:

[0245] (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and

[0246] (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, and

[0247] (b) instructions for using the antibody in an administration regimen of the invention, in particular such as described in the section “Administration regimen of OSE279 or of a composition comprising it” here above.

[0248] The kit may particularly comprise means to prepare a composition comprising the anti -PD-1 antibody, in particular for intravenous administration. In the context of the present invention, the humanized anti-hPD-1 antibody or composition comprising it may be packaged in a container, recipient or otherwise.

[0249] The kits may also comprise means for containing a sterile, pharmaceutically acceptable buffer and / or other diluent, preferably suitable for intravenous administration in a human subject.

[0250] The kit according to the invention may also be formulated into a syringe compatible composition, in particular for intravenous administration or infusion.

[0251] In some embodiments, the kit further includes an additional agent for treating cancer or an infectious disease, and the additional agent may be combined with the humanized anti-PDl antibody, or other components of the kit of the present invention or may be provided separately in the kit. Particularly, the kits described herein may include one or more additional therapeutic agents such as those described in the “Combined Therapy” described hereabove. The kit(s) may be tailored to a particular cancer for an individual and comprise respective second cancer therapies for the individual as described hereabove.

[0252] In some embodiments, the kit can comprise instructions for use in accordance with any of the methods and uses described herein. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit in the form of a leaflet or instruction manual).

[0253] Description of the Figures

[0254] Figure 1 summarizes the subjects treated during the study, with their cancer type, dosage and administration regimen and disease evolution.

[0255] Figure 2 is a graph representing the pharmacokinetic profile of the anti-PDl antibody, for the three different dosages, at different time points before (ClDlpredose) or after (C1D1, C1D2 and C2D1 predose) a first cycle of administration.. “C” stands for Cycle while “D” stands for Day.

[0256] Figure 3 is a graph representing the Receptor Occupancy of CD8+ T cells, for all patients treated with the same dose (i.e., 100 mg, 300 mg, or 600 mg) of the anti-PDl antibody, at different time points.

[0257] Figure 4 shows CT-scans of a patient recruited for the study, suffering from an undifferentiated pleomorphic sarcoma (UPS) and, before and after (24 weeks) being treated with the anti-PDl antibody disclosed herein at a dose of 600mg Q6W. Figure 5 illustrates CT-scans of two patients recruited for the study, suffering from an Oncocytic Thyroid cancer or a hepatocarcinoma cancer, both treated with the anti-PDl antibody disclosed herein. The CT scans of the patient suffering from the Oncocytic Thyroid cancer illustrates the tumor before the treatment and after 12 weeks of treatment with the anti-PDl antibody disclosed herein at a dose of 600mg Q6W. The CT scans of the patient suffering from hepatocarcinoma cancer show the tumor before treatment and after 36 weeks of treatment with the anti-PDl antibody disclosed herein at a dose of 600mg Q6W.

[0258] Others features and advantages of the invention will become clearer in the following examples which are given for purposes of illustration and not by way of limitation.

[0259] Examples

[0260] MATERIAL AND METHODS

[0261] Abbreviations

[0262] NOAEL=No Observed Adverse Event Level; MSS=Microsatellite Stable; MSI- H=Microsatellite Instability-High; CPS=Combined Positive Score; MTD= Maximum Tolerated Dose; RP2D=Recommended Phase 2 Dose; PR, SD=Partial Response, Stable Disease; DL=Dose Level; DLT=Dose Limiting Toxicity; STS= soft tissue sarcoma

[0263] DRUG PRODUCT

[0264] Description:

[0265] The OSE-279 Drug Product (DP) is a sterile solution for IV administration.

[0266] The anti-PDl antibody used in the experiments presented herein is OSE-279 such as described in WO2020 / 127366. OSE-279 comprises a VH sequence as set forth in SEQ ID NO: 7 and a VL sequence as set forth in SEQ ID NO: 8. OSE-279 comprises a heavy chain sequence as set forth in SEQ ID NO: 9 and a light chain sequence as set forth in SEQ ID NO: 10.

[0267] Strength and packaging / Dosage:

[0268] The OSE-279 DP sterile solution is provided at a nominal concentration of 50 mg / mL in a formulation buffer consisting of 30 mM sodium acetic acid, 200 mM Glycine, 50 mM Mannitol, 200 ppm Polysorbate 80 at pH 4.8. Each unit contains 100 mg of OSE-279 antibody and is filled aseptically in 2 mL extractable volume clear glass ISO 2R Type I vials closed by rubber stopper and aluminium seals with a coloured flip-off cap.

[0269] Storage conditions:

[0270] Each OSE-279 DP vials is stored in the outer carton, in order to protect from light at < -60°C. The use by date information is provided and the vials are for single use only, unused contents must be discarded appropriately.

[0271] Handling instructions:

[0272] The reconstitution of the Investigational Medicinal Product (IMP) to adjust the concentration before infusion is be performed on the site pharmacy by appropriate dilutions in NaCl 0.9% solution. A pharmacy manual with detailed instructions for IMP reconstitution is be provided to the site. The IMP is be reconstituted by the pharmacy in accordance with this manual.

[0273] OSE-279, the IMP is manufactured in accordance with Good Manufacturing Practice (GMP) as required by the current GCP

[0274] DOSAGE

[0275] The study evaluates the Maximal Tolerated Dose (MTD) and / or Recommended Phase 2 Doses (RP2D), the safety, pharmacokinetic (PK) and RO or pharmacodynamic (PD) profile and preliminary efficacy of single-agent OSE-279 when administered as an IV infusion every 3 or 6 weeks in up to 24 patients with advanced solid tumours or lymphomas.

[0276] OSE-279 is be given once every 3 weeks (Q3W) at escalating dose of 100 mg (DL1) and 300 mg (DL2) (flat dose) to determine the MTD and first RP2D; one cycle of treatment is 21 days, thus there is one dose of OSE-279 per cycle. At the dose level 3 (DL3) OSE-279 is given once every 6 weeks (Q6W) at the dose of 600 mg (flat dose) to determine the MTD and second RP2D; one cycle of treatment is 42 days with one OSE-279 administration.

[0277] No observed adverse effect level (NOAEL) was determined in cynomolgus monkeys at a dose of 100 mg / kg, for a dose of 600 mg Q6W, so that the predicted Cmax and AUCtau would provide a 19 fold and 5 fold safety margin, respectively, compared to the Cmax and AUC observed at 100 mg / kg in monkeys.

[0278] The dose of 600 mg with every 6 weeks administration is proposed as an efficient dose regimen that is in addition convenient for scheduling purposes and patient compliance. PRIMARY ENDPOINT

[0279] • Occurrence of dose limiting toxicity (DLT) for MTD determination.

[0280] For all dose levels DLT observation period is defined as the first 21 days after receiving the 1stinjection of OSE-279 of Cycle 1.

[0281] SECONDARY ENDPOINTS

[0282] Efficacy:

[0283] • Objective Response Rate (ORR): Complete Response (CR) and Partial Response (PR) based on RECIST 1.1 / RECIL and iRECIST;

[0284] • Disease Control Rate (DCR): Complete Response (CR), Partial Response (PR) and Stable Disease (SD) based on RECIST 1.1 / RECIL and iRECIST;

[0285] • Time to response;

[0286] • Duration of Response (DR);

[0287] • Progression Free Survival (PFS);

[0288] • DCR at 12 weeks (CR+PR+SD);

[0289] • Overall Survival (OS).

[0290] Pharmacokinetics and Pharmacodynamics:

[0291] • Pharmacokinetic parameters;

[0292] • Detection of anti-OSE-279 antibodies.

[0293] Safety:

[0294] Nature, incidence and severity of TEAE (including DLT and AE of special Interest (AESI)), of SAE, SUSARs graded according to the Common Terminology Criteria for Adverse Events (CTCAE) grading.

[0295] EXPLORATORY ENDPOINTS

[0296] PD-1 receptor occupancy (RO) or other pharmacodynamic markers: immune-related pharmacodynamic effect on patient’s T cells.

[0297] A RP2D is determined based on all available data, including safety, preliminary efficacy and PK / PD. Patients are enrolled in the clinical study after checking their eligibility during the screening period:

[0298] - Male or female adult patients (> 18 years at the time of ICF signature).

[0299] Signed and dated informed consent (ICF) prior to any trial-specific procedures. Patients should be able and willing to comply with study visits and procedures as per protocol.

[0300] - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

[0301] Tumour type: a. advanced solid tumours or lymphomas for which anti-PD-l / PD-Ll has shown efficacy (e.g., with high microsatellite instability or MSI-H) but is not available in the centre / country (no marketing authorization, no reimbursement, no early access program, etc.), or; b. rare tumours with reported significant activity of anti-PDl (e.g., TLS+ sarcomas, alveolar soft part sarcomas, etc.), or; c. PD-L1 positive tumours.

[0302] - Prior treatment with at least one line of systemic therapy and no standard of care available.

[0303] STUDY TREATMENT ADMINISTRATION

[0304] The IMP volume flow must not exceed 200 ml / h for DL1, DL2 and DL3. Thus patients at DL1 (100 mg Q3W flat dose) and at DL2 (300 mg Q3W flat dose) receive a volume of 100 ml of OSE-279 by IV infusion in 30 minutes on Day 1 (DI) of a 21-day treatment period. Patients at DL3 (600 mg Q6W flat dose) receive a volume of 120 ml of OSE-279 by IV infusion in 36 minutes on Day 1 (DI) of a 42-day treatment period. Infusions are delivered at the site, with a 4-hour post-infusion surveillance by the sites’ medical staff for the first two cycles then reduced to a 2-hour post-infusion surveillance for the following cycles.

[0305] The drug is administered every 3 weeks at DL1 and DL2 and every 6 weeks at DL3 (on DI of each cycle). The patient receive up to one year of treatment. Patients who experience benefits may be eligible to continue receiving the treatment.

[0306] Patients preferably continue on study treatment(s) until disease progression with no clinical benefit, unacceptable toxicity or patient’s refusal to continue, whichever occurs first. In case of documented progressive disease by RECIST 1.1, patient preferably continue on study treatments until progressive disease is confirmed by iRECIST.

[0307] Dose escalation

[0308] The dose escalation rules follow a Bayesian Optimal INterval (BOIN) design, enrolling a total of 2 patients per cohort until:

[0309] • all cohorts are fully enrolled or

[0310] • a MTD or a RP2D is established.

[0311] During the dose escalation, patient cohorts are sequentially enrolled. The 1st cohort started OSE-279 treatment with a dose of 100 mg Q3W administered by IV infusion on Day 1 of the treatment cycle. Administration of the 1 st dose of investigational product for the first 2 patients of each dose level must be staggered by a minimum of 48 hours. Dosing of the 2ndpatient at each dose level may proceed only in the absence of significant safety concerns in the 1 st patient. The next planned cohorts received 300 mg Q3W, then 600 mg Q6W.

[0312] Dosing decisions are based on the rate of DLT (see below):

[0313] • Enrolment in the next cohort occur once all of the initial patients enrolled in the previous cohort have completed 21 day of safety assessments and the data have been reviewed by the DEC at a DEC meeting (although pre-screening for the next dose cohort may begin prior to confirmation that the current dose is safe);

[0314] • In the case of one DLT is observed in one of the 2 initial patients, the cohort could be expanded to a total of 6 patients per DEC’s request;

[0315] • Additional cohorts or cohort expansion to 6 patients may be added as determined by the DEC, even in the absence of DLT, based on emerging safety and PK data;

[0316] • At least 6 patients are treated at the MTD and / or RP2D;

[0317] • The dose of OSE-279 may be reduced to the lower level in case of severe adverse event during a DEC meeting;

[0318] • Intra-patient dose escalation to the next dose level found to be safe and tolerable, may be considered at the discretion of the DEC and is only permitted for patient who have not experienced significant toxicity related to OSE-279 dosing. RESULTS

[0319] In this FIH study, 20 subjects were treated with at least 5 weeks of follow-up, with 13 tumour types, the most frequent being STS (n=4) and anal SCC (n=3); median age was 61.5y (range 34-81), 10 / 20 subjects (50.0%) were female, median number of prior metastatic lines was 2 (range 1-6).

[0320] As illustrated by Figure 1, 1 confirmed partial response (PR) was observed in a Hepatocellular carcinoma (HCC) MSS with a Combined Positive Score (CPS) of 3 after one dose of OSE279 300mg; 4 confirmed PRs have been reported with 600mg q6w, in subjects with UPS MSI-H, Anal SCC PD-L1, oncocytic thyroid cancer PD-L1 MSS and STS ASPS TFE3 + ; SD>16 weeks was seen in 5 subjects at multiple DLs.

[0321] As seen on Figure 2, pharmacokinetic (PK) profile showed good exposure and doseproportionality among the three doses used, with the highest exposure with the 600 mg dose. The pharmacokinetic data show that the antibody maximum serum concentrations were reached shortly after the end of infusion. Mean OSE279 concentrations for DL3 (10 subjects) were 184 pg / mL at DI, then decreased as expected to 57 pg / mL at CID 15, showing a good 6-fold and 2- fold dose proportionality compared to DL1 and DL2, respectively. Furthermore, all three doses showed a long-lasting effect.

[0322] Receptor Occupancy (RO) was maintained and within the boundaries of simulations (i.e. 94.1±36.9% and 98.3±36.8% at 100 mg and 300 mg, respectively), as illustrated in Figure 3.

[0323] Biopsies from the tumor of several patients were obtained, and analyzed. The results are illustrated on figures 4 and 5, which show the effects of the administration regimen of OSE- 279 on metastasis in the lungs.

[0324] A patient having undifferentiated pleomorphic sarcoma (STS-UPS) was treated with OSE279 at a regimen of 600 mg Q6W during 24 weeks. The results are illustrated on figure 4.

[0325] The CT scan of the patent’s lungs before and after the treatment showed a shrinkage of more than 56 % of the volume of the first tumor (from 28.7mm to 12.6mm) and more than 75% of the volume of the second tumor (30mm to 7.5mm).

[0326] A patient having Oncocytic Thyroid cancer was treated with OSE279 at a regimen of 600 mg Q6W during 12 weeks. The results are illustrated on figure 5, left panel.

[0327] The CT scan of the patent’s left lung apex and of the left cervical nodes before and after the treatment showed a shrinkage of more than 44 % of the volume of the tumor located in the lung (from 65.8mm to 36.7mm) and more than 41% of the volume of the tumor located in the cervical nodes (48.2mm to 28.2mm).

[0328] A patient having hepatocellular carcinoma (HCC) was treated with OSE279 at a regimen of 600 mg Q6W during 36 weeks. The results are illustrated on figure 5, right panel. The CT scan of the patent’s left lung before and after the treatment showed a shrinkage of more than 70 % of the volume of the tumor (from 37mm to 10.8mm).

[0329] Conclusions

[0330] In this FIH study, OSE279 showed a manageable safety profile with signs of efficacy in the first 20 subjects treated (RR 25%). 4 PRs (RR 36%) and 3 SD were reported at 600 mg q6w in 11 subjects treated. PK and pharmacodynamic profiles were consistent with modelling.

Claims

Claims1. An immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody or a pharmaceutical composition comprising it, for use in the treatment of cancer in a subject in need thereof, wherein said antibody is an antagonist of human PD-1 and comprises:(i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and(ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein said antibody is to be administered periodically at a therapeutically effective dose of at least 550 or 600 mg.

2. A method of treating a cancer in a subject in need thereof, wherein the method comprises administering periodically to said subject a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:(i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and(ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 550 or 600 mg.

3. A method for inducing or increasing PD-1 receptor occupancy on T cells in a subject suffering from cancer, wherein the method comprises administering periodically to said subject a therapeutically effective dose of an immunoglobulin G4 (IgG4) humanized monoclonal antiProgrammed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:(i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and(ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the therapeutically effective dose is of at least 550 or 600 mg, thereby achieving a PD- 1 receptor occupancy of at least 75% on T cells.

4. The method of claim 3, wherein the at least 75% of receptor occupancy of the antibody on T cells is reached within 48 hours of administration of the dose of the antibody and / or is maintained for at least 21 days after administering the dose of the antibody.

5. The antibody or composition for use according to claim 1, or the method according to any one of claims 2-4, wherein the antibody comprises: (a) a VH comprising or consisting of an amino acid sequence of SEQ ID NO: 7; and (b) a VL comprising or consisting of an amino acid sequence of SEQ ID NO: 8.

6. The antibody or composition for use according to claim 1 or 5, or the method according to any one of claims 2-5, wherein the antibody comprises an IgG4 with a mutation consisting of S228P.

7. The antibody or composition for use according to any one of claims 1, 5 and 6, or the method according to any one of claims 2-6, wherein the antibody comprises: (a) a heavy chain comprising or consisting of an amino acid sequence of SEQ ID NO: 9, and (b) a light chain comprising or consisting of an amino acid sequence of SEQ ID NO: 10.

8. The antibody or composition for use according to any one of claims 1 and 5-7 or the method according to any one of claims 2-7, wherein the therapeutically effective dose is comprised between about 550 mg and about 1000 mg, preferably between about 600 and about 1000 mg, even more preferably between about 600 mg and about 800 mg.

9. The antibody or composition for use according to claim 8 or the method according to claim 8, wherein the therapeutically effective dose is of about 600 mg.

10. The antibody or composition for use according to any one of claims 1 and 5-9 or the method according to any one of claims 2-9, wherein the antibody is or is to be administered once every four to twelve weeks, once every four to nine weeks, once every four to eight weeks or once every five to seven weeks.

11. The antibody or composition for use according to any one of claims 1 and 5-9 or the method according to any one of claims 2-9, wherein the antibody is or is to be administered once every 4 weeks (Q4W), once every 5 weeks (Q5W), once every 6 weeks (Q6W), once every 7 weeks (Q7W), once every 8 weeks (Q8W), once every 9 weeks (Q9W), once every 10 weeks (Q10W), once every 11 weeks (Q11W) or once every 12 weeks (Q12W).

12. The antibody or composition for use according to any one of claims 1 and 5-9 or the method according to any one of claims 2-9, wherein the antibody is or is to be administered once every 6 weeks (Q6W), preferably at a dose of about 600 mg.

13. The antibody or composition for use according to any one of claims 1 and 5-12 or the method according to any one of claims 2-12, wherein the antibody is or is to be administered for 2, 3, 4, 5, 6, or more cycles, preferably 5 cycles.

14. The antibody or composition for use according to any one of claims 1 and 5-13 or the method according to any one of claims 2-13, wherein the antibody is or is to be administered during at least 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks or 42 weeks.

15. The antibody or composition for use according to any one of claims 1 and 5-14 or the method according to any one of claims 2-14, wherein the antibody is or is to be administered up to 1 or 2 years or up to complete or partial response.

16. The antibody or composition for use according to any one of claims 1 and 5-15 or the method according to any one of claims 2-15, wherein the antibody is or is to be administered intravenously.

17. The antibody or composition for use according to any one of claims 1 and 5-16 or the method according to any one of claims 2-16, wherein the subject has previously been treated with one or more different cancer treatment modalities, such as surgery, chemotherapy, radiotherapy, immunotherapy or any combination thereof.

18. The antibody or composition for use according to any one of claims 1 and 5-17 or the method according to any one of claims 2-17, wherein the antibody is or is to be administered as a monotherapy.

19. The antibody or composition for use according to any one of claims 1 and 5-18 or the method according to any one of claims 2-18, wherein the antibody is used or for use in combination with another anti -cancer treatment, preferably selected from the group consisting of chemotherapy, radiotherapy, anti angiogenic agents, hypomethylating agents, cancer vaccines, peptide vaccine, angiogenesis inhibitors, tyrosine kinase inhibitors, epitopes orneoepitopes from tumour antigens, myeloid checkpoints inhibitors, immunotherapies, cell therapy agents and HD AC inhibitors, a peptide vaccine, a chemotherapy, an immune checkpoint inhibitor other than an anti-PD-1, a tyrosine kinase inhibitor, a VEGF receptor inhibitor and any combination thereof.

20. A monotherapy comprising an immunoglobulin G4 (IgG4) humanized monoclonal antiProgrammed Death- 1 (PD-1) antibody for use in the treatment of cancer in a subject in need thereof, wherein said antibody is an antagonist of human PD-1 and comprises (a) a heavy chain comprising or consisting of an amino acid sequence of SEQ ID NO: 9, and (b) a light chain comprising or consisting of an amino acid sequence of SEQ ID NO: 10, wherein the antibody is to be administered at a flat dose of between about 600 mg and about 1000 mg once every four to twelve weeks, preferably every six weeks, and wherein the cancer is preferably a rare tumour, optionally with a high microsatellite instability (MSI-H) or expressing PD-L1.

21. A kit for treating a subject suffering from cancer, wherein the kit comprises:(a) a dosage ranging from 600 mg to 1000 mg of an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising:(i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and(ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, and(b) instructions for using the antibody in a periodic regimen of any one of claims 10-15.

22. Use of a composition comprising an immunoglobulin G4 (IgG4) humanized monoclonal anti -Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of human PD-1 and comprising (i) a heavy chain variable domain comprising a complementary determiningregion 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and (ii) a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, for the manufacture of a medicament for treating a cancer in a subject in need thereof, wherein said antibody is or is to be administered periodically at a therapeutically effective dose of at least 600 mg.

23. Use of a flat dose of between about 600 mg and about 1000 mg of an anti PD-1 antibody in the manufacture of a medicament for the treatment of cancer; wherein said antibody is an immunoglobulin G4 (IgG4) humanized monoclonal anti-Programmed Death-1 (PD-1) antibody, said antibody being an antagonist of t human PD-1 and comprising (i) a heavy chain variable domain comprising a complementary determining region 1 (HCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 2 and a HCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 3, and a light chain variable domain comprising a complementary determining region 1 (LCDR1) comprising or consisting of an amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 5 and a LCDR3 comprising or consisting of an amino acid sequence of SEQ ID NO: 6, wherein the treatment comprises a periodic regimen.

24. The antibody or composition for use according to any one of claims 1 and 5-19, the method according to any one of claims 2-19, the monotherapy of claim 20, the kit according to claim 21 or the use of any one of claims 22-23, wherein the cancer is an advanced solid cancer or a lymphoma.

25. The antibody or composition for use according to any one of claims 1 and 5-19, the method according to any one of claims 2-19, the monotherapy of claim 20, the kit according to claim 21 or the use of any one of claims 22-23, wherein the cancer is a solid rare tumour, optionally with a high microsatellite instability (MSI-H) or expressing PD-L1.

26. The antibody or composition for use according to claim 24 or 25, the method according to claim 24 or 25, the monotherapy according to claim 24 or 25, the kit according to claim 24 or 25 or the use according to claim 24 or 25, wherein the cancer is a stage III or IV cancer.

27. The antibody or composition for use according to claim 24, the method according to claim24, the monotherapy according to claim 24, the kit according to claim 24 or the use according to claim 24, wherein the cancer is an advanced hepatocellular carcinoma.

28. The antibody or composition for use according to claim 25, the method according to claim25, the monotherapy according to claim 25, the kit according to claim 25 or the use according to claim 25, wherein the solid rare tumour is selected from the group consisting of sarcoma, preferably soft tissue sarcoma, squamous cell carcinoma, neuroendocrinal tumour and oncocytic carcinoma.

29. The antibody or composition for use according to claim 25, the method according to claim 25, the monotherapy according to claim 25, the kit according to claim 25 or the use according to claim 25, wherein the solid rare tumour is a neuroendocrinal tumour selected from the group consisting of Well differentiated not functioning endocrine carcinoma of pancreas and digestive tract, Well differentiated functioning endocrine carcinoma of pancreas and digestive tract, Poorly differentiated endocrine carcinoma of pancreas and digestive tract, Mixed endocrine- exocrine carcinoma of pancreas and digestive tract Endocrine carcinoma of thyroid gland, neuroendocrine carcinoma of the parathyroid gland, Neuroendocrine carcinoma of skin, Typical and atypical carcinoid of the lung, Pheochromocytoma, and Paraganglioma.

30. The antibody or composition for use according to claim 25, the method according to claim 25, the monotherapy according to claim 25, the kit according to claim 25 or the use according to claim 25, wherein the solid rare tumour is a soft tissue sarcoma selected from the group consisting of soft tissue sarcoma of head and neck (such as Sarcoma NOS, Epithelioid sarcoma, Desmoplastic small round cell tumour, Fibrosarcoma, Fibromyxosarcoma, Infantile fibrosarcoma, Myxoinflammatory fibroblastic sarcoma, Malignant fibrous histiocytoma, DFSP,Well differentiated liposarcoma, Myxoid liposarcoma, Pleomorphic liposarcoma, Mixed type liposarcoma, Dedifferentiated liposarcoma, Leiomyosarcoma, Pleomorphic rhabdomyosarcoma, Extrarenal rhabdoid tumour, Synovial sarcoma, Clear cell sarcoma of soft tissue, Epithelioid angiosarcoma, Epithelioid haemangioendothelioma, Extraskeletal osteosarcoma, Extraskeletal myxoid chondrosarcoma, Malignant peripheral nerve sheath tumours, Malignant glomus tumours (glomangiosarcoma), Intimal Sarcoma, Low grade fibromyxoid sarcoma, Low grade myofibroblastic sarcoma, PEComas, Sclerosing epithelioid fibrosarcoma or Undifferentiated pleomorphic sarcoma (UPS)); Soft tissue sarcoma of limbs, Soft tissue sarcoma of superficial trunk, Soft tissue sarcoma of mediastinum, Soft tissue sarcoma of heart, Soft tissue sarcoma of breast, Soft tissue sarcoma of uterus, Soft tissue sarcoma of paratestis, Soft tissue sarcomas of other genitourinary tract (such as vulva, vagina, ovary, penis, prostate, testis, kidney, renal pelvis, ureter, bladder, urethra), Clear cell sarcoma of kidney, Malignant rhabdoid tumour of kidney, Soft tissue sarcoma of viscera, Soft tissue sarcoma of retroperitoneum and peritoneum, Soft tissue sarcoma of pelvis, Soft tissue sarcoma of skin (such as dermatofibrosarcoma protuberans (DFSP)), Soft tissue sarcoma of paraorbit, Soft tissue sarcoma of brain and other parts of the nervous system, Embryonal rhabdomyosarcoma of soft tissue, Alveolar rhabdomyosarcoma of soft tissue, alveolar soft part sarcoma (ASPS), Ewing’s sarcoma of soft tissue (such as Ewing Sarcoma, Peripheral neuroectodermal tumour, Primitive neuroectodermal tumour), preferably is UPS or ASPS .

31. The antibody or composition for use according to claim 25, the method according to claim 25, the monotherapy according to claim 25, the kit according to claim 25 or the use according to claim 25, wherein the solid rare tumour is a squamous cell carcinoma (SCC) selected from the group consisting of Squamous cell carcinoma of nasal cavity and sinuses, nasopharynx, hypopharynx, larynx, oropharynx, oral cavity, lips, oesophagus, stomach, small intestine, colon, rectum, anal canal, pancreas, liver, gallbladder, trachea, lung, thymus, thyroid, lungs, corpus uteri, cervix uteri, vulva, vagina, prostate, penis, kidney, pelvis, ureter, bladder, eye, ear and skin, preferably is anal SCC.

32. The antibody or composition for use according to claim 25, the method according to claim 25, the monotherapy according to claim 25, the kit according to claim 25 or the use according to claim 25, wherein the solid rare tumour is an oncocytic carcinoma affecting an organ or tissueselected from the group consisting of thyroid gland, salivary glands, kidney, nasal cavity, paranasal sinuses, bronchus, parathyroid, ovary, upper mediastinum, lung and breast, preferably is an oncocytic carcinoma of the thyroid (OCA).

33. The antibody or composition for use according to claim 25, the method according to claim 25, the monotherapy according to claim 25, the kit according to claim 25 or the use according to claim 25, wherein the solid rare tumour has a high microsatellite instability (MSI-H), preferably is a UPS with MSI-H or an ASPS with MSI-H.

34. The antibody or composition for use according to claim 25, the method according to claim 25, the monotherapy according to claim 25, the kit according to claim 25 or the use according to claim 25, wherein the solid rare tumour expresses PD-L1, preferably is an anal SCC expressing PD-L1.

35. The antibody or composition for use according to any one of claims 1, 5-19, and 24-34, the method of any one of claims 2-19, and 24-34, the monotherapy of any one of 20 and 24-34, the kit of any one of claims 21 and 24-34, or the use of any one of claims 22-34, wherein the subject is a human of at least 30 years old.

36. The antibody or composition for use according to any one of claims 1, 5-19, and 24-35, the method of any one of claims 2-19, and 24-35, the monotherapy of any one of 20 and 24-35, the kit of any one of claims 21 and 24-35, or the use of any one of claims 22-35, wherein the cancer is a stage IV cancer with lung metastasis.

Images