Uses of Anti-CD127 antibodies in the treatment of inflammatory bowel diseases

Abstract

The application generally relates to the treatment of inflammatory bowel diseases by using an anti-CD127 antibody or antigen-binding fragment thereof. In particular, the present invention relates to uses and methods of using antagonist anti-CD127 antibody or antigen-binding fragment thereof to treat Ulcerative Colitis (UC), in a treatment regimen that may associate administration of another therapeutic compound or therapeutic method.

Description

[0001] TITLE

[0002] USES OF ANTI-CD127 ANTIBODIES IN THE TREATMENT OF INFLAMMATORY BOWEL DISEASES

[0003] FIELD OF THE INVENTION

[0004] The application generally relates to the treatment of inflammatory bowel diseases by using an antagonist anti-CD127 antibody or antigen-binding fragment thereof. In particular, the present invention relates to uses and methods of using an antagonist anti-CD127 antibody or antigen-binding fragment thereof to treat an Inflammatory Bowel Disease (IDB), in particular Crohn’s disease or Ulcerative Colitis (UC), in a treatment regimen that may associate administration of another therapeutic compound or therapeutic method.

[0005] The invention is more particularly devised to address the need of particular doses and dosing cycles which enhance the health of a patient suffering from an IBD.

[0006] BACKGROUND OF THE INVENTION

[0007] Inflammatory diseases encompass a wide range of conditions characterized by inflammation, which is a complex biological response of the body's tissues to harmful stimuli such as pathogens, damaged cells, or medical situation. These diseases can affect various parts of the body and can be either acute or chronic, leading to significant health challenges.

[0008] Chronic inflammatory diseases, and acute inflammatory diseases represent the major categories of inflammatory diseases. Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and type 1 diabetes, results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. Chronic inflammatory diseases, including inflammatory bowel disease (IBD) like Crohn's disease and ulcerative colitis, chronic obstructive pulmonary disease (COPD), and asthma, involve long-term inflammation that can lead to various complications. Acute inflammatory diseases, such as acute respiratory distress syndrome (ARDS), appendicitis, and sinusitis, involve short-term inflammation, that may require treatment for resolution.

[0009] Inflammatory diseases have a profound impact on health, manifesting in various ways. Physically, they can cause chronic pain, fatigue, and disability. For example, rheumatoid arthritis can lead to joint damage and deformities, while inflammatory bowel disease can result in severe gastrointestinal symptoms and malnutrition. Mentally, the chronic nature of these diseases often leads to depression and anxiety, as the stress of managing a long-term illness can significantly affect mental well-being. The quality of life for individuals with these diseases is frequently impaired, as daily activities and overall quality of life are often affected by limitations in mobility, work capacity, and social interactions.

[0010] Inflammatory diseases place a substantial burden on healthcare systems, with frequent doctor visits, hospitalizations, and the need for long-term medication and treatments contributing to high healthcare costs. Chronic conditions often result in early retirement or disability.

[0011] The economic impact of inflammatory diseases is profound. Direct costs include medical expenses such as hospital stays, medications, surgeries, and outpatient care. For instance, treatment of these diseases often involves expensive biologic drugs. Indirect costs, which are substantial, include lost income due to inability to work, costs associated with long-term disability. Thus, significant resources are allocated to researching and developing new treatments and cures.

[0012] Inflammatory diseases pose a significant challenge to individuals, healthcare systems, and economies worldwide. Their pervasive impact on health, societal structures, and economic stability underscores the need for improved treatments. Ulcerative colitis (UC) is a chronic IBD characterized by inflammation and ulceration of the colon and rectum's innermost lining. This condition typically presents with symptoms such as persistent diarrhea, abdominal pain and rectal bleeding. The exact cause(s) of ulcerative colitis remain(s) unknown, but it is believed to result from an abnormal immune response in genetically predisposed individuals, possibly triggered by environmental factors. The impact of ulcerative colitis on individuals' health is significant. Chronic inflammation of the colon leads to frequent and often debilitating symptoms, which can cause substantial discomfort and disrupt daily activities. In severe cases, ulcerative colitis can lead to life-threatening complications such as severe bleeding, colon perforation, and an increased risk of colon cancer. Beyond physical health, the disease also affects mental well-being, as patients often experience a reduced quality of life due to the chronic and unpredictable nature of their symptoms.

[0013] Treatment for ulcerative colitis aims to reduce inflammation, manage symptoms, and achieve and maintain remission. Current treatment options include aminosalicylates, corticosteroids, immunomodulators, and biologic therapies targeting specific components of the immune system. In some cases, surgery may be required to remove the colon and rectum when medical treatment fails to control the disease or complications arise.

[0014] Despite the availability of these treatments, several drawbacks exist. Aminosalicylates and corticosteroids, while effective in reducing inflammation, can have significant side effects when used long-term, such as increased risk of infection, bone loss, and hypertension. Immunomodulators and biologic therapies, though more targeted, are expensive and may not be accessible to all patients. They also carry risks of serious infections and malignancies due to their immunosuppressive effects. Additionally, a substantial proportion of patients do not respond adequately to these treatments or may lose response over time, necessitating a continuous search for new and more effective therapies.

[0015] Overall, while current treatments for ulcerative colitis can manage the disease and improve patient outcomes, there remains significant limitations and challenges. This underscores the need for the development of new therapeutic approaches to provide more effective and safer options for patients with ulcerative colitis.

[0016] Crohn's disease is a chronic IBD that causes inflammation of the digestive tract, potentially affecting any part from the mouth to the anus. The inflammation often spreads deep into the layers of the affected bowel tissue, leading to severe symptoms and complications. Common symptoms include persistent diarrhea, abdominal pain, weight loss, fatigue, and malnutrition. The exact cause of Crohn's disease is unknown, but it is believed to involve a combination of genetic predisposition, environmental factors, and an abnormal immune response.

[0017] This chronic inflammation can lead to the formation of scar tissue, strictures, fistulas, and abscesses, causing significant pain and potentially life-threatening complications. The disease can also affect other parts of the body, including the skin, eyes, and joints. Patients often experience periods of remission and relapse, making disease management unpredictable and challenging. The chronic nature of Crohn's disease, along with its severe symptoms, can significantly impair a person's quality of life.

[0018] Treatment for Crohn's disease aims to reduce inflammation, manage symptoms, and achieve and maintain remission. Current treatment options include antiinflammatory drugs such as aminosalicylates, corticosteroids to control acute flare-ups, immunomodulators that suppress the immune system, and biologic therapies targeting specific components of the immune response, such as tumor necrosis factor (TNF) inhibitors. In severe cases, surgery may be required to remove damaged portions of the digestive tract or to address complications such as strictures or fistulas.

[0019] Despite the availability of these treatments, several drawbacks exist. Antiinflammatory drugs and corticosteroids, while effective for short-term relief, can cause significant side effects when used long-term, including an increased risk of infections, osteoporosis, and hypertension. Immunomodulators and biologic therapies carry risks of serious infections and malignancies due to their immunosuppressive effects. There is thus a need for improved therapeutic approaches to provide more efficient options for patients with Crohn's disease.

[0020] The lnterleukin-7 receptor (IL-7R) signaling pathway is crucial in the regulation of the immune system, particularly in the development and homeostasis of T cells. IL-7R is a heterodimeric receptor composed of the IL-7Ra chain (CD127) and the common gamma chain (yc, CD132), which is shared with other cytokine receptors. The binding of interleukin-7 (IL-7) to IL-7R triggers a cascade of intracellular signaling events essential for T cell survival, proliferation, and differentiation.

[0021] IL-7 is a critical cytokine for the development of T cells in the thymus and their maintenance in the periphery. The IL-7R signaling pathway activates several downstream signaling molecules, including Janus kinases (JAK1 and JAK3) and Signal Transducers and Activators of Transcription (STAT5), which promote the expression of genes involved in cell survival and proliferation. This pathway is also involved in the homeostasis of naive and memory T cells, ensuring the immune system can respond effectively to pathogens.

[0022] In the context of inflammation, IL-7R signaling is essential for mounting an effective immune response, as IL-7 promotes the survival and expansion of T cells that are crucial for clearing infections and other inflammatory stimuli.

[0023] CD127 is expressed on thymocytes, T- and B-cell progenitors, mature T cells, monocytes, and some other lymphoid and myeloid cells. Studies have shown that IL-7R plays an important role in the proliferation and differentiation of mature T cells. Further, signaling induced by the dimerization of CD127 with the common y chain plays a pivotal role in T-cell development and maintenance of T-cell memory. Expression of CD 127 is commonly associated with central and effector memory functions in both CD4 and CD8 peripheral T cells.

[0024] Blocking IL-7R signaling has been explored as a therapeutic strategy to reduce inflammation and autoimmunity. For instance, therapies targeting IL-7R or its downstream signaling molecules aim to mitigate the aberrant immune responses seen in autoimmune diseases while preserving the pathway's essential role in normal immune function.

[0025] Antibody-based therapies require a target antigen bound to the surface of a target cell in order to exert its function. By binding to its target, the antibody can directly deliver its signal to diseased cells or immune cells or indirectly by, for example, recruiting a cytotoxic T cell. Though antibodies are an effective means in treating many disorders, including inflammatory diseases, their administration is not necessarily devoid of side effects. Adverse effects may cause a reversible or irreversible change in the health status of a patient. As adverse effects could be harmful and undesired, it is highly desirable to avoid them. However, though it is known that a medicament can cause adverse effects, its prescription and administration could not be avoided or is accepted, when the medicament has an outstanding beneficial therapeutic effect or may even be life-saving. In clinical trials, a general distinction can be made between adverse effects and serious adverse effects. Specifically, adverse effects can be classified in 5 grades in accordance with the Common Terminology Criteria for Adverse Events (AE). Grade 1 relates to mild AE, Grade 2 to moderate AE, Grade 3 to severe AE, Grade 4 to life-threatening or disabling AE, while Grade 5 means death related to AE.

[0026] In order to try to better manage these undesired side effects, there is a need for providing dose level and / or mode of administration of anti-CD127 antibodies allowing health benefit for the patient without adverse effects, or with minimal and manageable adverse effects.

[0027] SUMMARY OF THE INVENTION

[0028] To address, at least partially, the drawbacks of the state of the art, the inventors provide new uses and methods of treating inflammatory bowel diseases in a patient comprising administering a therapeutically significantly effective amount of an anti-CD127 antibody or antigen-binding fragment thereof while allowing a favorable safety and tolerability profile in the treated patient. Stated otherwise, the invention provides uses of anti-CD127 antibody and antigen-binding fragment thereof and methods wherein such compounds are administered to a patient having an IBD at determined doses for a determined period of time (i.e. according to particular dosing cycles), allowing significant efficacy and a favorable safety and tolerability profile in the treated patient. The inventors herein provide uses and administering methods of anti-CD127 antibody and antigen-binding fragment thereof as a monotherapy, a primo-therapy or as a combination therapy (either simultaneously, subsequently) with other therapeutic and / or therapeutic methods (like but not limited to surgery).

[0029] According to a first aspect, a dose of administration of an antagonist anti-CD127 antibody comprised between 380 mg and 980 mg has been shown to be significantly effective in the treatment of IBD, in particular of ulcerative colitis (UC) and well tolerated (favorable safety and tolerability profile in the treated patient).

[0030] According to a second aspect, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory disease, an auto-immune disease or a cancer, wherein a dose of 450 mg ± 15% (e.g. a dose comprised between 382,50 mg and 517,50 mg) of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0031] According to a third aspect, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory disease, an auto-immune disease or a cancer, wherein a dose of 850 mg ± 10% (e.g. a dose comprised between 765 mg and 935 mg) of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0032] Surprisingly it has been found that by administering the antagonist anti-CD127 antibody or an antigen-binding fragment thereof according to the specified dose, it is possible to reduce side effects which may be associated with the administration of such compounds. For example, administering the antagonist anti-CD127 antibody according to the specified dose may significantly, reduce or even completely eliminate, the negative side effects, in particular it may avoid over-immunosuppression, opportunistic infection, T cell depletion and / or durable lymphopenia.

[0033] Administering an antagonist anti-CD127 antibody or antigen-binding fragment thereof according to the specific dose and / or regimen of the present invention may also significantly reduce or even completely eliminate the risks that the patients taking the antagonist anti-CD127 antibody or antigen-binding fragment thereof suffers from adverse effects, such as opportunistic infection and / or durable lymphopenia. Indeed, in a previous study (Herold KC et al. JCI Insight 2019), an anti-CD127 compound was administered to patients suffering from a diabetes type I, a disease that is considered as an auto-immune and chronic inflammatory disease. Two major adverse effect were observed in the treated patients that led to stop the study. Some of treated patients suffered from opportunistic infections, in particular active viral infections like Epstein-Barr virus (EBV). Several patients suffered from T cell depletion and lymphopenia, in particular at doses equal or over 6 mg / kg. In the same study, a lack of efficiency of the administered compound was also observed. The administration at the prescribed doses of anti-CD127 antibody, in particular at the prescribed doses and according to the administration cycles disclosed herein, leads to an improvement of the health of the patients, without severe adverse effects. The provision of an anti-CD127 antibody or antigen-binding fragment thereof at a dose defined herein and in accordance with an administration cycle disclosed herein leads to a significant efficacy in the treatment of patients suffering from an IBD, in particular suffering from an ulcerative colitis, more particularly in patients suffering from moderate to severe ulcerative colitis. This significant efficacy is associated with a favorable safety and tolerability profile in the treated patient. These results are particularly significant when considering the issues in the treatment of patients suffering from a chronic disease; without severe adverse effects and with a favorable safety and tolerability profile, treatment of the patients over a long period of time can be seriously considered.

[0034] The patent application provides a specific dosage regimen for treating IBD, which includes conditions like Crohn's disease and ulcerative colitis. Previous patents and scientific literature have disclosed a related dosage regimen but for treating a different condition. The gastrointestinal tract's condition in IBD patients can affect drug absorption, necessitating adjustments in dosage to achieve therapeutic concentrations at the site of inflammation. Higher doses are usually required to ensure sufficient drug reaches the affected gut tissue, overcoming barriers like inflamed mucosa and altered permeability, to ensure localized, high- intensity therapeutic responses in IBD. The selected dose for treating IBD is effective and tailored to the specific needs of managing inflammation and promoting healing in the gastrointestinal tract. The selected dosage is specifically adapted to the proposed treatment regimen disclosed in the present patent application.

[0035] Scientists faced several issues when trying to establish the appropriate dosage that maximizes efficacy while minimizing adverse effects. In the present case, involving the treatment of IBDs, which are recurrent diseases, it is desirable to achieve a steady-state concentration of the drug that maintains therapeutic levels over a prolonged period without causing toxicity, which may contrast with acute conditions that may require different approach.

[0036] Accordingly, it is provided antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 380 mg and 980 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0037] In a particular aspect of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 380 mg and 980 mg, in particular between 450 mg - 15% and 850 mg + 15%, more particularly a dose of 380 mg, 400 mg, or 450 mg, or 500 mg, or 550 mg, or 600 mg, or 650 mg, or 700 mg or 750 mg, or 800 mg, or 850 mg, or 900 mg or 980 mg , of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least one to the patient, in particular at least twice to the patient, wherein consecutive administered doses are separated by at least 7 days, preferably at least 14 days, more preferably 14 days.

[0038] The administration of the antagonist anti-CD127 antibody or antigen-binding fragment thereof at the prescribed doses allowed to inhibit T cell infiltration at the site of inflammation. The use of the antagonist anti-CD127 antibody or antigenbinding fragment thereof at the prescribed doses allowed the diminution of the presence of immune cells at the site of inflammation after the first administration. The administration of the antagonist anti-CD127 antibody or antigen-binding fragment thereof at the prescribed doses also allowed locally the decrease in activation and survival of inflammatory IL7-receptor positive immune cells (e.g. Memory T lymphocytes, Innate Lymphoid Cells) but not of immunosuppressive cells lacking CD127 expression (e.g. Regulatory T cells), thereby potentiating the use of other therapies in combination with the administration of the antagonist anti-CD127 antibody or antigen-binding fragment thereof. The inventors have shown that a single administration, in particular through intravenous infusion of the antibody, at the prescribed doses is efficient to decrease the disease activity index (Modified Mayo Score, MMS) in ulcerative colitis based on Patients Reported Outcomes (stool frequency and the rectal bleeding subscores) and mucosal endoscopy activity (endoscopic subscore).

[0039] Further, the inventors were able to show that the patients who have received the anti-CD127 antibody or antigen-binding fragment thereof at the prescribed doses exhibit tolerance to the treatment, without severe side effects. Indeed, antibodies targeting cells of the immune system (like immune checkpoint blockers or activators) can be associated with severe side effects, like transient anemia, hemagglutination on peripheral blood smear, fatigue, headaches, fever, chills, hyperbilirubinemia, lymphopenia, infusion-related reactions, and / or arthralgias. These issues are not met or are considered to be manageable when an antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at the prescribed doses; full peripheral receptor occupancy is reached, while no severe side effect was observed in the patients.

[0040] The use of the antagonist anti-CD127 antibody at the prescribed doses allows, after the first administration, to enhance the health of the patient.

[0041] According to particular embodiments, the present invention provides an antagonist anti- CD127 antibody or antigen-binding fragment thereof for use in the treatment of Crohn’s disease or Ulcerative Colitis, preferably Ulcerative colitis.

[0042] According to particular embodiments, the present invention provides an antagonist anti- CD127 antibody or antigen-binding fragment thereof for use in combination with a second therapeutic agent, preferably an anti-inflammatory agent.

[0043] According to particular embodiments, the present invention provides an antagonist anti- CD127 antibody or antigen-binding fragment thereof for use in combination with as an add-on therapeutic regimen for treating a patient suffering from IBD and who has been or who is treated by another therapeutic agent, in particular an anti-inflammatory agent, more particularly a therapeutic agent conventionally administered for treating an inflammatory bowel disease.

[0044] According to particular embodiments, the present invention provides an antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the treatment of patients who, prior to the use, were known or shown not to respond to a IBD conventional treatment or therapy and / or exhibited disease progression of their illness despite being under treatment. According to this embodiment, the invention provides an antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the treatment of IBD in a patient who has failed treatment with at least one alternative therapeutic agent or therapeutic method.

[0045] According to particular embodiments, the present invention provides an anti- CD127 antibody or antigen-binding fragment thereof for use in the treatment of patients who have been treated with an anti-inflammatory agent, and did not positively respond or did not maintain response to the administration of the antiinflammatory agent (i.e. the patients show disease progression and / or do not show disease regression).

[0046] LEGEND FIGURES

[0047] Figure 1 : Histological response and histological improvement rates at week 10. A. Percentage of patients with histological response (Nancy histological index (NHI) < 1 ) among patients treated with placebo 450 mg, 850 mg of anti-CD127 antibody or global treated patients (450 mg+ 850 mg ). B. Histological Geboes index change from baseline in patients treated with placebo, 450 mg, 850 mg of anti-CD127 antibody or global treated groups (450 mg + 850 mg groups together).

[0048] Figure 2: Clinical remission in the Open Label Extension (OLE) for week 10 non-responder patients. Percentage of patients with symptomatic remission (defined as patients with PRO2 < 1 and RBS =0) at week 10, 14 and 34 among non-responder patients (defined as patients with PRO2 > 1 or RBS > 0 at week 10) treated with placebo, 450 mg, 850 mg of anti-CD127 antibody or global treated groups ( 450 mg+ 850 groups together) during the induction phase.

[0049] Figure 3: Clinical remission in the Open Label Extension (OLE) for week 10 responder patients. Percentage of patients with symptomatic remission (defined as patients with PRO2 < 1 and RBS =0) at week 10, 14 and 34 among responder patients (defined as patients with PRO2 < 1 at week 10) treated with placebo, 450 mg, 850 mg of anti-CD127 antibody or global treated groups (450 mg + 850 mg groups together) during the induction phase.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] • Definitions

[0052] As used herein, the term “antibody” refers to any kind of antibodies, such as monoclonal antibodies, polyclonal antibodies, recombinant antibodies, chimeric antibodies and humanized antibodies. The term “antibody” may also refer to deimmunized antibodies, i.e. antibodies wherein T-cell epitopes have been removed from the structure of the antibodies without significantly reducing the binding affinity of the antibody of its target CD127. Typically, "deimmunized" antibodies are created with human constant regions. The antibodies of the present invention include monoclonal and polyclonal antibodies. As used herein, a "monoclonal antibody" is intended to refer to a preparation of antibody molecules, antibodies which share a common heavy chain and common light chain amino acid sequence, in contrast with "polyclonal" antibody preparations which contain a mixture of antibodies of different amino acid sequence. Monoclonal antibodies can be generated by several known technologies like phage, bacteria, yeast or ribosomal display, as well as by classical methods exemplified by hybridoma-derived antibodies. Thus, the term "monoclonal" is used to refer to all antibodies derived from one nucleic acid clone. The antibodies of the present invention include recombinant antibodies. As used herein, the term "recombinant antibody" refers to antibodies which are produced, expressed, generated or isolated by recombinant means, such as antibodies which are expressed using a recombinant expression vector transfected into a host cell; antibodies isolated from a recombinant combinatorial antibody library; antibodies isolated from an animal (e.g. a mouse) which is transgenic due to human immunoglobulin genes; or antibodies which are produced, expressed, generated or isolated in any other way in which particular immunoglobulin gene sequences (such as human immunoglobulin gene sequences) are assembled with other DNA sequences. Recombinant antibodies include, for example, chimeric and humanized antibodies. The antibodies of the present invention include chimeric antibodies. As used herein, a “chimeric antibody” refers to an antibody in which the sequence of the variable domain derived from the germline of a mammalian species, such as a mouse, have been grafted onto the sequence of the constant domain derived from the germline of another mammalian species, such as a human. The antibodies of the present invention include humanized antibodies. As used herein, a “humanized antibody” refers to an antibody in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0053] Antibodies and antigen-binding fragments of antibodies comprise at least a light chain variable domain and a heavy chain variable domain, each one comprising three hypervariable domains designated CDRs (Complementary Determining Regions). These domains encompass the recognition site for the antigen, i.e., CD127, in particular human CD127, and most particularly the extracellular domain of human CD127, thereby defining antigen recognition specificity.

[0054] Each Light and Heavy chain variable domain (respectively VL and VH) has three CDRs, designated VL-CDR1 (or LCDR1 ), VL-CDR2 (or LCDR2), VL-CDR3 (or LCDR3) and VH-CDR1 (or HCDR1), VH-CDR2 (or HCDR2), VH-CDR3 (or HCDR3), respectively.

[0055] As used herein, an “antigen-binding fragment of an antibody” means a part of an antibody, i.e. a molecule corresponding to a portion of the structure of the antibody of the invention, that exhibits antigen-binding capability for CD127, possibly in its native form; such fragment especially exhibits the same or substantially the same antigen-binding specificity for said antigen compared to the antigen-binding specificity of the corresponding four-chain antibody. Advantageously, the antigen-binding fragments have a similar binding affinity as the corresponding 4-chain antibodies. However, antigen-binding fragment that have a reduced antigen-binding affinity with respect to corresponding 4-chain antibodies are also encompassed within the invention. The antigen-binding capability can be determined by measuring the affinity between the antibody and the target fragment. These antigen-binding fragments may also be designated as “functional fragments” of antibodies. Antigen-binding fragments of antibodies are fragments which comprise their hypervariable domains designated CDRs (Complementary Determining Regions) or part(s) thereof encompassing the recognition site for the antigen, i.e. the extracellular domain of CD127, thereby defining antigen recognition specificity. Antigen binding fragments of an antibody that contain the variable domains comprising the CDRs of said antibody encompass Fv, dsFv, scFv, Fab, Fab', F(ab')2. Fv fragments consist of the VL and VH domains of an antibody associated together by hydrophobic interactions; in dsFv fragments, the VH:VL heterodimer is stabilized by a disulphide bond; in scFv fragments, the VL and VH domains are connected to one another via a flexible peptide linker thus forming a single-chain protein. Fab fragments are monomeric fragments obtainable by papain digestion of an antibody; they comprise the entire L chain, and a VH-CH1 fragment of the H chain, bound together through a disulfide bond. The F(ab')2 fragment can be produced by pepsin digestion of an antibody below the hinge disulfide; it comprises two Fab’ fragments, and additionally a portion of the hinge region of the immunoglobulin molecule. The Fab' fragments are obtainable from F(ab')2 fragments by cutting a disulfide bond in the hinge region. F(ab')2 fragments are divalent, i.e. they comprise two antigen binding sites, like the native immunoglobulin molecule; on the other hand, Fv (a VHVL dimmer constituting the variable part of Fab), dsFv, scFv, Fab, and Fab' fragments are monovalent, i.e. they comprise a single antigen-binding site. These basic antigen-binding fragments of the invention can be combined together to obtain multivalent antigen-binding fragments, such as diabodies, tribodies or tetrabodies. These multivalent antigen-binding fragments are also part of the present invention.

[0056] A composition may refer in particular to a pharmaceutical composition. Such a composition may comprise pharmaceutical acceptable components, like but not limited to pharmaceutically suitable excipient or carrier or vehicle, when used for systemic or local administration. A pharmaceutically suitable carrier or vehicle refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material and formulation like phosphate buffered saline solutions, distilled water, emulsions such as oil / water emulsions, wetting agents and the like, dextrose, saline, ethanol and combinations thereof.

[0057] As used herein, the term “CD127” relates to a CD127 from a mammal species, preferably a human CD127, and most preferably human CD127 of SEQ ID No. 19. CD127, also known as lnterleukin-7 receptor subunit alpha (IL7R-a), is a protein that in humans is encoded by the IL7R gene. CD127 is a type I cytokine receptor and is a subunit of the functional lnterleukin-7 receptor and Thymic Stromal Lymphopoietin (TSLP) receptors. CD127 may correspond to the protein referenced under NCBI Sequence No. NP_002176.2. Alternatively, CD127 may correspond to a protein having the amino acid sequence of SEQ ID No. 19. The extracellular domain of CD127, which is likely to be recognized and bound to by anti-CD127 antibody or antigen-binding fragment thereof used in the invention may correspond to the amino acid sequence of SEQ ID No. 20.

[0058] The terms "cancer" and “tumor” have their general meaning in the art and refer to a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. The term "cancer" further encompasses both primary and metastatic cancers.

[0059] The term “inflammatory disease” has its their general meaning in the art and refers to a group of disease wherein an inflammatory response pursues to continuous propagation of the inflammation, thereby leading to abnormal immune response in which the inflammatory process does not end when it should or may begin when there is no infection or injury. Inflammatory diseases include Non- Alcoholic Fatty Liver Disease, endometriosis, encephalomyelitis, inflammatory bowel diseases (in particular Crohn’s disease and Ulcerative Colitis), chronic obstructive pulmonary disease, atherosclerosis, multiple sclerosis, asthma and psoriasis. The terms “auto-immune disease” refers to an immune pathological state in which the body's own immune tolerance mechanism is maladjusted or nonfunctional, leading to the damage of its own tissues and organs or abnormal function. Autoimmune diseases include rheumatoid arthritis, systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and systemic lupus erythematosus.

[0060] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, preventing or delaying the recurrence or relapse of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, enabling to decrease the administered dose of one or more other medications required or used to treat the disease, increasing the quality of life, and / or prolonging survival, preventing or alleviating side-effects of current treatment, or treatments that will be developed.

[0061] • Anti-CD127 antibody or antigen-binding fragment thereof

[0062] The compound to be used according to the present invention, or in the method according to the present invention, is an antagonist anti-CD127 antibody or an antigen-binding fragment thereof. As used herein, an anti-CD127 antibody refers to a compound selected from the list consisting of antibodies; antigen-binding fragments of an antibody, and may encompass macromolecules comprising an antibody, or an antigen-binding fragments of an antibody. The antagonist anti- CD127 antibody or the antigen-binding fragment thereof binds, in particular specifically binds, to CD127, in particular human CD127, in particular human CD127 of SEQ ID No. 19, in particular to the extracellular domain of (human) CD127, most particularly to the extracellular domain of human CD127 of SEQ ID No. 20. The antagonist anti-CD127 antibody or an antigen-binding fragment thereof to be used in the method of the invention, or for use according to the invention, is a humanized antibody, and comprises constant domains derived from human constant domains of antibodies.

[0063] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or an antigen-binding fragment thereof is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0064] More particularly, the heavy chain constant domain of the antagonist anti-CD127 antibody or an antigen-binding fragment thereof may be derived from a human lgG1 , lgG2, lgG3, or lgG4 heavy chain constant region, particularly from lgG4 heavy chain constant region. “Derived from” means encompassing some punctual mutations by amino acid substitutions such as lgG4 (S228P) or lgG1 (E333A) (see Yang and Ambrogelly, Current Opinion in Biotechnology 2014 and Okasaki et al., J Mol Biol 2004). These mutations well known from the skilled person in the art, generally modify some parent chain properties. For example, they lead to less immunogenicity compared to the parental antibody or abrogate FcyReceptor binding or avoid dimerization of the monomer antibody or stabilize the dimerization rendering antibodies better for human therapeutic uses.

[0065] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or an antigen-binding fragment thereof is a functional fragment of an anti-CD127 antibody. Functional fragments of such an antibody include but are not limited to Fv, dsFv, scFv, Fab, Fab', F(ab')2.

[0066] The anti-CD127 antibody or antigen binding fragment thereof to be used according to the invention or used in a method according to the invention is an antagonist. By antagonist, it should be understood that the antibody or antigen binding fragment thereof is an antagonist of the IL-7R signaling pathway induced by the binding of IL-7 to CD127. In other words, the anti-CD127 antibody or antigen binding fragment thereof used in the method of the invention or for use according to the invention has the capability to disrupt or block the binding between IL-7 and CD127, as compared to the binding between IL-7 and CD127 in absence of the anti-CD127 antibody or antigen binding fragment thereof. As used herein, an anti-CD127 antibody or antigen binding fragment thereof, has its general meaning in the art and refers to any compound, natural or synthetic, that blocks, suppresses, or reduces the biological activity of IL-7. In particular, the anti-CD127 antibody or antigen binding fragment thereof inhibits the interactions between IL-7 and CD127. In particular, the anti-CD127 antibody or antigen binding fragment thereof inhibits or reduces the activation of the phosphatidylinositol 3-kinase and / or the ERK signaling pathway induced by IL-7. In the invention, it can be considered that an antibody (or antigen-binding fragment thereof) reduces, inhibits or blocks the binding of IL-7 to CD127 if said antibody (or antigen-binding fragment thereof) induces an increase superior to 1 log, preferably superior to 2 log, more preferably superior to 3 log, most preferably superior to 4 log, of the KD value of IL-7 to CD127 in a binding competitive assay by Blitz, as compared to the KD value of IL-7 to CD127 in presence of a control antibody (i.e. an antibody which does not specifically bind to IL-7 nor CD127).

[0067] The decrease or the inhibition of the binding of (human) CD127 to (human) IL-7 means that the antibody or antigen-binding fragment thereof decreases the interaction between CD127 and IL-7, i.e. the antibody or antigen-binding fragment thereof partially or fully inhibits the binding of human CD127 to human IL-7 or in other words, specifically binds to human CD127, and antagonizes the interaction between human CD127 and human IL-7. In particular, the anti-human CD127 antibody or antigen-binding fragment thereof has the capability to decrease or inhibit the binding of (human) CD127 to (human) IL-7 by at least 50%, preferably 60%, more preferably 70%, more preferably 80% and most preferably 90%, and in a particular embodiment 100%, as compared to a negative control molecule, in a binding assay. In particular, the anti-CD127 antibody or antigen-binding fragment thereof has the capability to reduce or inhibit the binding of human CD127 to human IL-7 from 50% to 100%, more preferably from 50% to 90%, as compared to a negative control molecule, in a binding assay.

[0068] In a particular embodiment, the antagonist anti-CD127 antibody or antigen binding fragment thereof does not induce the activation of the phosphatidylinositol 3-kinase (PI3K) and / or the ERK signaling pathway and / or does not induce the phosphorylation of STAT5, particularly does not induce the activation of the phosphatidylinositol 3-kinase (PI3K) and the ERK signaling pathway and does not induce the phosphorylation of STAT5. In a particular embodiment, the antagonist anti-CD127 antibody or antigen binding fragment thereof does not induce lymphodepletion in the patient, particularly does not lead to lymphodepletion in the patient. Lymphodepletion corresponds to a reduction in the overall number of lymphocytes in the patient. An antagonist anti-CD127 antibody or antigen binding fragment thereof may be considered not to induce lymphodepletion, when it is presence, the overall number of lymphocytes in a biological sample issued from the patient, is not lower than at least 50%, preferably at least 40%, more preferably at least 30 %, even more preferably at least 20 %, and most preferably at least 10 %, as compared to a control sample obtained from the patient (e.g. a sample obtained from the same patient before administration of the antagonist anti-CD127 antibody or antigen binding fragment thereof) or as compared to usual numbers of lymphocytes in a healthy human, which are known by skilled artisans.

[0069] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof is an antagonist anti-human CD127 antibody or an antigen-binding fragment thereof which comprises: i) a heavy chain variable domain comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA) , and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2 (TISASGLRTYYPDSVKG), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3 (PLSAHYGFNYFDY), and ii) a light chain variable domain comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA).

[0070] Said above CDR domains have been identified according to the KABAT numbering. Alternatively, the CDR domains can be identified according to a newer version of the KABAT numbering. When identifying CDRs with this newer version of the KABAT nomenclature, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises: i) a heavy chain variable fragment comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 26 (DYYMA), and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2 (TISASGLRTYYPDSVKG), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3 (PLSAHYGFNYFDY), and ii) a light chain variable fragment comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA).

[0071] In a particular embodiment of the invention, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises: i) a heavy chain variable fragment comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 21 (GFTLSDYY), and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 22 (ISASGLRT), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 23 (ARPLSAHYGFNYFDY), and ii) a light chain variable fragment comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 24 (EDIYQG), and b. LCDR2 comprising or consisting in the amino acid sequence “SAN”, and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 25 (QQYYDYPLA).

[0072] Said above CDR domains have been identified according to the IMGT numbering.

[0073] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof is an antagonist anti-human CD127 antibody or an antigen-binding fragment thereof which comprises:

[0074] - the antibody heavy chain variable domain comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0075] - the antibody light chain variable domain comprises or consists in the amino acid sequence set forth in SEQ ID No. 8 or SEQ ID No. 9 or SEQ ID No. 10 or SEQ ID No. 11 or SEQ ID No. 12, preferably SEQ ID No. 12.

[0076] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof is an antagonist anti-human CD127 antibody or an antigen-binding fragment thereof which comprises:

[0077] - the antibody heavy chain variable domain comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0078] - the antibody light chain variable domain comprises or consists in the amino acid sequence set forth in SEQ ID No. 12.

[0079] In particular, said antibody or antigen-binding fragment thereof comprises a constant chain belonging to the subclass of lgG1 , lgG2, lgG3 or lgG-4, in particular the subclass of lgG4.

[0080] In a particular aspect of the invention, the antagonist anti-human CD127 antibody or an antigen-binding fragment thereof comprises: a heavy chain domain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13, and a light chain domain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 14 or SEQ ID No. 15 or SEQ ID No. 16 or SEQ ID No. 17, SEQ ID No. 18, or SEQ ID NO: 27, preferably SEQ ID No. 18.

[0081] In a particular aspect of the invention, the administered compound or the compound to be administered is an antagonist anti-human CD127 antibody which comprises a heavy chain domain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13 and a light chain domain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 18.

[0082] In a particular embodiment of the invention, the antagonist anti-human CD127 antibody or an antigen-binding fragment thereof to be used according to the invention or for use in a method according to the invention is provided as an isolated nucleic acid molecule or group of isolated nucleic acid molecules encoding the antagonist anti-human CD127 antibody or antigen-binding fragment thereof as defined herein according to the invention. Particularly, said nucleic acid molecule or group of nucleic acid molecule encodes the light chain variable domain or the light chain of an antibody provided herein, and the heavy chain variable domain or heavy chain of an antibody provided herein, according to any of the definitions provided herein. In particular, the isolated nucleic acid molecules or the group of isolated nucleic acid molecules encodes: a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID No.7, and a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 8 or SEQ ID No. 9 or SEQ ID No. 10 or SEQ ID No. 11 or SEQ ID No. 12, preferably SEQ ID No. 12.

[0083] More particularly, the isolated nucleic acid molecules or the group of isolated nucleic acid molecules encodes a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13, and a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 14 or SEQ ID No. 15 or SEQ ID No. 16 or SEQ ID No. 17, SEQ ID No. 18, or SEQ ID NO: 27 preferably SEQ ID No. 18.

[0084] In particular, the isolated nucleic acid molecules or the group of isolated nucleic acid molecules encodes a heavy chain consisting of the amino acid sequence set forth in SEQ ID No. 13 and a light chain consisting of the amino acid sequence set forth in SEQ ID No. 18.

[0085] In a particular embodiment of the invention, the antagonist anti-human CD127 antibody or antigen-binding fragment thereof as defined herein and to be used according to the invention or for use in a method according to the invention is an antagonist of the IL-7R signaling pathway induced by IL-7 (the antagonist capability of the anti-CD127 antibody or fragment may be assessed by measuring the phosphorylation of STAT5 in presence or absence of the antibody or fragment, the antibody or fragment being considered as an antagonist of the IL- 7R signaling pathway induced by IL-7 when it is able to antagonize the STAT5 phosphorylation induced by IL-7), and has at least one of the following properties, in particular at least two, preferably at least three, and more preferably all the following properties; a) it inhibits or reduces the activation of the phosphatidylinositol 3-kinase and / or the ERK signaling pathway induced by IL-7, b) it does not increase the maturation of dendritic cells induced by TSLP (dendritic cells maturation may be assessed by determining an increase in the expression of cell surface marker CD40 and I or CD80 in TSLP receptor-positive cells treated with TSLP and with said agent compared to cells treated with TSLP alone), c) it does not antagonize the TSLP / TSLPR signaling d) it does not induce the internalization of CD127 and / or inhibit the IL7-induced internalization of CD127 (CD127- internalization designates the decrease of cell surface expression of CD127 induced by the presence of IL7; the cell surface expression of CD127 in cells incubated in the presence of the anti-CD127 agent is not reduced, or is not significantly reduced, relative to cell surface expression in cells incubated in otherwise identical conditions, but in the absence of the antibody. In particular embodiments, when incubated at 37 °C for 30 to 45 minutes in the presence of 50 ng / mL of antibody, the level of CD127 cell surface expression is at least 80 %, preferably at least 90 % of its level in cells incubated in the absence of the antibody. This effect may be observed in the absence of IL-7); e) it binds to T cells. Details about how to assess if an anti-CD127 agent has or has not one of these properties may be found in WO2015 / 189302 and WO2018 / 104483 and W020201 54293).

[0086] • Dosages

[0087] In an embodiment of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 380 mg and 980 mg of the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered at least once to the patient. It should be understood that the doses of 380 mg and 980 mg are included within the specified range.

[0088] In another embodiment, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory disease, an auto-immune disease or a cancer, wherein a dose of 450 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0089] In another embodiment, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory disease, an auto-immune disease or a cancer, wherein a dose of 850 mg ± 10% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0090] In a particular aspect, it is provided antagonist anti-CD127 antibody or an antigenbinding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 450 mg - 15% and 850 mg + 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0091] In a particular aspect, it is provided antagonist anti-CD127 antibody or an antigenbinding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein:

[0092] - a dose of 450 mg ± 15% (e.g., a dose comprised between 382,50 mg and

[0093] 517.50 mg); or

[0094] - a dose of 500 mg ± 15% (e.g., a dose comprised between 425 mg and 575 mg); or

[0095] - a dose of 550 mg ± 15% (e.g., a dose comprised between 467,50 mg and

[0096] 632.50 mg);

[0097] - a dose of 600 mg ± 15% (e.g., a dose comprised between 510 mg and 690 mg); or

[0098] - a dose of 650 mg ± 15% (e.g., a dose comprised between 552,50 mg and

[0099] 747.50 mg); or - a dose of 700 mg ± 15% (e.g., a dose comprised between 595 mg and 805 mg); or

[0100] - a dose of 750 mg ± 15% (e.g., a dose comprised between 637,50 mg and

[0101] 862.50 mg); or

[0102] - a dose of 800 mg ± 15% (e.g., a dose comprised between 680 mg and 920 mg); or

[0103] - a dose of 850 mg ± 15% (e.g., a dose comprised between 722,50 mg and

[0104] 977.50 mg); of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0105] In a particular aspect of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose of 380 mg or 400 mg, or 450 mg, or 500 mg, or 550 mg, or 600 mg, or 650 mg, or 700 mg or 750 mg, or 800 mg, or 850 mg, or 900 mg or 980 mg, of the antagonist anti- CD127 antibody or antigen-binding fragment thereof is administered at least once to the patient.

[0106] In an embodiment of the invention, a dose comprised between 450 mg ± 15% and 850 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof (i.e. suffering from an IBD).

[0107] In an embodiment of the invention, a dose comprised between 500 mg ± 15% and 800 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof (i.e. suffering from an IBD).

[0108] In an embodiment of the invention, a dose comprised between 550 mg ± 15% and 750 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof (i.e. suffering from an IBD).

[0109] In an embodiment of the invention, a dose comprised between 600 mg ± 15% and 700 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof (i.e. suffering from an IBD).

[0110] In an embodiment of the invention, a dose of 450 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof (i.e. suffering from an IBD or suffering from an inflammatory disease, an auto-immune disease or a cancer).

[0111] In an embodiment of the invention, a dose of 850 mg ±15% of the antagonist antiCDF? antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof (i.e. suffering from an IBD or suffering from an inflammatory disease, an auto-immune disease or a cancer).

[0112] In an embodiment of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 380 mg and 980 mg of the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered at least twice to the patient. It should be understood that the doses of 380 mg and 980 mg are included within the specified range. It should be further understood that the at least two doses that are to be administered to the patient may have different weight of the antagonist anti- CD127 antibody or antigen-binding fragment thereof. In a particular embodiment, each administered dose of the antagonist anti-CD127 antibody or antigen-binding fragment is comprised between 380 mg and 980 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof. At least two doses may have the same weight. When more than 2 doses are to be administered, two or several doses may have the same weight, or each dose can have a weight different form other doses’ weight.

[0113] In an embodiment of the invention, the first dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof administered to the patient is comprised between 380 mg and 980 mg. In a more particular embodiment, the first dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof administered to the patient is comprised between 450 mg ± 15% and 850 mg ± 15%, more particularly is 450 mg ± 15% or 850 mg ± 15%. In a particular aspect, it is provided antagonist anti-CD127 antibody or an antigenbinding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 450 mg - 15% and 850 mg + 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to the patient.

[0114] In a particular aspect, it is provided antagonist anti-CD127 antibody or an antigenbinding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein:

[0115] - a dose of 450 mg ± 15% (e.g., a dose comprised between 382,50 mg and

[0116] 517.50 mg); or

[0117] - a dose of 500 mg ± 15% (e.g., a dose comprised between 425 mg and 575 mg); or

[0118] - a dose of 550 mg ± 15% (e.g., a dose comprised between 467,50 mg and

[0119] 632.50 mg);

[0120] - a dose of 600 mg ± 15% (e.g., a dose comprised between 510 mg and 690 mg); or

[0121] - a dose of 650 mg ± 15% (e.g., a dose comprised between 552,50 mg and

[0122] 747.50 mg); or

[0123] - a dose of 700 mg ± 15% (e.g., a dose comprised between 595 mg and 805 mg); or

[0124] - a dose of 750 mg ± 15% (e.g., a dose comprised between 637,50 mg and

[0125] 862.50 mg); or

[0126] - a dose of 800 mg ± 15% (e.g., a dose comprised between 680 mg and 920 mg); or

[0127] - a dose of 850 mg ± 15% (e.g., a dose comprised between 722,50 mg and

[0128] 977.50 mg); of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to the patient.

[0129] In a particular aspect of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose of 380 mg, or 400 mg, or 450 mg, or 500 mg, or 550 mg, or 600 mg, or 650 mg, or 700 mg or 750 mg, or 800 mg, or 850 mg, or 900 mg or 980 mg, of the antagonist anti- CD127 antibody or antigen-binding fragment thereof is administered at least twice to the patient.

[0130] In an embodiment of the invention, a dose comprised between 450 mg ±- 15% and 850 mg ± of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to a patient in need thereof (i.e. suffering from an IBD).

[0131] In an embodiment of the invention, a dose comprised between 500 mg ± 15% and 800 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to a patient in need thereof (i.e. suffering from an IBD).

[0132] In an embodiment of the invention, a dose comprised between 550 mg ± 15% and 750 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to a patient in need thereof (i.e. suffering from an IBD).

[0133] In an embodiment of the invention, a dose comprised between 600 mg ± 15% and 700 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to a patient in need thereof (i.e. suffering from an IBD).

[0134] In an embodiment of the invention, a dose of 450 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to a patient in need thereof (i.e. suffering from an IBD).

[0135] In an embodiment of the invention, a dose of 850 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof administered at least twice to a patient in need thereof (i.e. suffering from an IBD).

[0136] In a particular aspect of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose of 380 mg ± 15%, or 850 mg ± 15% of the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered at least twice to the patient. In an embodiment of the invention, a dose comprised between 380 mg and 980 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least three times or at least four times to a patient in need thereof (i.e. suffering from an IBD). Each dose can have a particular weight, or several or all doses can have the same weight.

[0137] In an embodiment of the invention, a dose comprised between 450 mg ± 15% (e.g., a dose comprised between 382,50 mg and 517,50 mg) and 850 mg ± 15% (e.g. a dose comprised between 722,50 mg and 977,50 mg) of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least three times or at least four times to a patient in need thereof (i.e. suffering from an IBD). Each dose can have a particular weight, or several or all doses can have the same weight.

[0138] In an embodiment of the invention;

[0139] - a dose of 450 mg ± 15% (e.g., a dose comprised between 382,50 mg and

[0140] 517.50 mg); or

[0141] - a dose of 500 mg ± 15% (e.g., a dose comprised between 425 mg and 575 mg); or

[0142] - a dose of 550 mg ± 15% (e.g., a dose comprised between 467,50 mg and

[0143] 632.50 mg);

[0144] - a dose of 600 mg ± 15% (e.g., a dose comprised between 510 mg and 690 mg); or

[0145] - a dose of 650 mg ± 15% (e.g., a dose comprised between 552,50 mg and

[0146] 747.50 mg); or

[0147] - a dose of 700 mg ± 15% (e.g., a dose comprised between 595 mg and 805 mg); or

[0148] - a dose of 750 mg ± 15% (e.g., a dose comprised between 637,50 mg and

[0149] 862.50 mg); or

[0150] - a dose of 800 mg ± 15% (e.g., a dose comprised between 680 mg and 920 mg); or

[0151] - a dose of 850 mg ± 15% (e.g., a dose comprised between 722,50 mg and

[0152] 977.50 mg); is administered at least three times or at least four times to a patient in need thereof (i.e. suffering from an IBD). Each dose can have a particular weight, or several or all doses can have the same weight.

[0153] In a particular aspect of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose of 380 mg, or 400 mg, or 450 mg, or 500 mg, or 550 mg, or 600 mg, or 650 mg, or 700 mg or 750 mg, or 800 mg, or 850 mg, or 900 mg or 980 mg, of the antagonist anti- CD127 antibody or antigen-binding fragment thereof is administered at least three times or at least four times to a patient in need thereof (i.e. suffering from an IBD or suffering from an inflammatory disease, an auto-immune disease or a cancer). Each dose can have a particular weight, or several or all doses can have the same weight.

[0154] In a particular aspect of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose of 380 mg ± 15%, or 850 mg ± 15% of the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered at least three time or at least four times to the patient.

[0155] In a particular aspect of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 450 mg 15% and 850 mg ± 15%, or between 500 mg ± 15% and 800 mg ± 15%, or between 550 mg ± 15% and 750 mg ± 15%, or between 600 mg ± 15% and 700 mg ± 15%, of the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered at least three times or at least four times to a patient in need thereof (i.e. suffering from an IBD or suffering from an inflammatory disease, an auto-immune disease or a cancer). Each dose can have a particular weight, or several or all doses can have the same weight. In an embodiment of the invention, all administered doses of the antagonist antiCDF? antibody or an antigen-binding fragment thereof are comprised between 380 mg and 980 mg.

[0156] In an embodiment of the invention, all administered doses of the antagonist antiCDF? antibody or an antigen-binding fragment thereof are comprised between 450 mg ±15% and 850 mg ± 15%, or between 500 mg ± 15% and 800 mg ± 15%, or between 550 mg ± 15% and 750 mg ± 15%, or between 600 mg ± 15% and 700 mg ± 15%.

[0157] In an embodiment of the invention, all administered doses of the antagonist anti- CD127 antibody or an antigen-binding fragment thereof correspond to:

[0158] - a dose of 450 mg ± 15% (e.g., a dose comprised between 382,50 mg and

[0159] 517.50 mg); or

[0160] - a dose of 500 mg ± 15% (e.g., a dose comprised between 425 mg and 575 mg); or

[0161] - a dose of 550 mg ± 15% (e.g., a dose comprised between 467,50 mg and

[0162] 632.50 mg);

[0163] - a dose of 600 mg ± 15% (e.g., a dose comprised between 510 mg and 690 mg); or

[0164] - a dose of 650 mg ± 15% (e.g., a dose comprised between 552,50 mg and

[0165] 747.50 mg); or

[0166] - a dose of 700 mg ± 15% (e.g., a dose comprised between 595 mg and 805 mg); or

[0167] - a dose of 750 mg ± 15% (e.g., a dose comprised between 637,50 mg and

[0168] 862.50 mg); or

[0169] - a dose of 800 mg ± 15% (e.g., a dose comprised between 680 mg and 920 mg); or

[0170] - a dose of 850 mg ± 15% (e.g., a dose comprised between 722,50 mg and

[0171] 977.50 mg).

[0172] In an embodiment of the invention, all administered doses of the antagonist anti- CD127 antibody or an antigen-binding fragment thereof are a dose of 380mg, or 400 mg, or 450 mg, or 500 mg, or 550 mg, or 600 mg, or 650 mg, or 700 mg or 750 mg, or 800 mg, or 850 mg, or 900 mg or 980 mg, in particular a dose of 450 mg or 850 mg. In an embodiment of the invention, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient in need thereof (i.e. suffering from an IBD) multiple times, and always at the same dose. In other words, a plurality of doses are administered to the patient and all administered doses are equal (i.e. they comprise the same weight of antagonist anti-CD127 antibody or antigen-binding fragment).

[0173] In an embodiment of the invention, a dose of 850 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof.

[0174] In an embodiment of the invention, a dose of 850 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to a patient in need thereof.

[0175] In an embodiment of the invention, a dose of 850 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least three times to a patient in need thereof.

[0176] In an embodiment of the invention, a dose of 850 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least four times to a patient in need thereof.

[0177] In an embodiment of the invention, a dose of 450 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least once to a patient in need thereof.

[0178] In an embodiment of the invention, a dose of 450 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least twice to a patient in need thereof.

[0179] In an embodiment of the invention, a dose of 450 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least three times to a patient in need thereof.

[0180] In an embodiment of the invention, a dose of 450 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at least four times to a patient in need thereof. In an embodiment of the invention, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at any dose specified herein, with the exception of 750 mg.

[0181] In an embodiment of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from ulcerative colitis, wherein at least one dose of the anti- CD127 antibody or an antigen-binding fragment thereof is administered to the patient, the dose of the antagonist anti-CD127 antibody or an antigen-binding fragment thereof corresponding to any dose disclosed herein.

[0182] In an embodiment of the invention, it is provided an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from Ulcerative colitis, where at least one or more than two dose(s) comprised between 380 mg and 980 mg, in particular comprises between 450 mg ±15% and 850 mg ± 15%, or between 500 mg ± 15% and 800 mg ± 15%, or between 550 mg ± 15% and 750 mg ± 15%, or between 600 mg ± 15% and 700 mg ± 15%, more particularly:

[0183] - a dose of 450 mg ± 15% (e.g., a dose comprised between 382,50 mg and

[0184] 517.50 mg); or

[0185] - a dose of 500 mg ± 15% (e.g., a dose comprised between 425 mg and 575 mg); or

[0186] - a dose of 550 mg ± 15% (e.g., a dose comprised between 467,50 mg and

[0187] 632.50 mg);

[0188] - a dose of 600 mg ± 15% (e.g., a dose comprised between 510 mg and 690 mg); or

[0189] - a dose of 650 mg ± 15% (e.g., a dose comprised between 552,50 mg and

[0190] 747.50 mg); or

[0191] - a dose of 700 mg ± 15% (e.g., a dose comprised between 595 mg and 805 mg); or

[0192] - a dose of 750 mg ± 15% (e.g., a dose comprised between 637,50 mg and

[0193] 862.50 mg); or - a dose of 800 mg ± 15% (e.g., a dose comprised between 680 mg and 920 mg); or

[0194] - a dose of 850 mg ± 15% (e.g., a dose comprised between 722,50 mg and

[0195] 977.50 mg), of the antagonist anti-CD127 antibody or antigen-binding fragment thereof, is administered to the patient at least once, in particular at least twice, in particular at least three times, in particular at least four times. In a particular embodiment, all administered doses are equal.

[0196] In an embodiment of the invention, it is provided a composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from Crohn’s disease, wherein at least one dose of the anti-CD127 antibody or an antigen-binding fragment thereof is administered to the patient, the dose of the antagonist anti-CD127 antibody or an antigen-binding fragment thereof corresponding to any dose disclosed herein.

[0197] In an embodiment of the invention, it is provided a composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from Crohn’s disease, where at least one or more than two dose(s) between 380 mg and 980 mg, in particular comprises between 450 mg ±15% and 850 mg ± 15%, or between 500 mg ± 15% and 800 mg ± 15%, or between 550 mg ± 15% and 750 mg ± 15%, or between 600 mg ± 15% and 700 mg ± 15%, more particularly:

[0198] - a dose of 450 mg ± 15% (e.g., a dose comprised between 382,50 mg and

[0199] 517.50 mg); or

[0200] - a dose of 500 mg ± 15% (e.g., a dose comprised between 425 mg and 575 mg); or

[0201] - a dose of 550 mg ± 15% (e.g., a dose comprised between 467,50 mg and

[0202] 632.50 mg);

[0203] - a dose of 600 mg ± 15% (e.g., a dose comprised between 510 mg and 690 mg); or

[0204] - a dose of 650 mg ± 15% (e.g., a dose comprised between 552,50 mg and

[0205] 747.50 mg); or - a dose of 700 mg ± 15% (e.g., a dose comprised between 595 mg and 805 mg); or

[0206] - a dose of 750 mg ± 15% (e.g., a dose comprised between 637,50 mg and

[0207] 862.50 mg); or

[0208] - a dose of 800 mg ± 15% (e.g., a dose comprised between 680 mg and 920 mg); or

[0209] - a dose of 850 mg ± 15% (e.g., a dose comprised between 722,50 mg and

[0210] 977.50 mg), of the antagonist anti-CD127 antibody or antigen-binding fragment thereof, is administered to the patient at least once, in particular at least twice, in particular at least three times, in particular at least four times. In a particular embodiment, all administered doses are equal, an in particular all administered doses comprises 850 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof.

[0211] In a particular embodiment, the dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof to be administered corresponds to the weight of active ingredient contained in the composition wherein said active ingredient consists of the antagonist anti-CD127 antibody or antigen-binding fragment thereof, in particular as defined herein according to their CDRs, their heavy and light variable domains, or their full heavy and light chains.

[0212] • Pharmaceutical composition

[0213] In an embodiment of the invention, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is provided in the form of a pharmaceutical composition. A pharmaceutical composition may further comprise any pharmaceutical vehicle, which is pharmaceutically acceptable for a formulation capable of being administered to a patient in need thereof, in particular for intravenous administration, more particularly for intravenous infusion administration. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the formulation of injectable solutions.

[0214] In an embodiment, it is provided a pharmaceutical composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof and histidine acetate.

[0215] In an embodiment, it is provided a pharmaceutical composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof and sorbitol.

[0216] In an embodiment, it is provided a pharmaceutical composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof and glycine.

[0217] In an embodiment, it is provided a pharmaceutical composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof and polysorbate 20.

[0218] In an embodiment, it is provided a pharmaceutical composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof and water.

[0219] In an embodiment, it is provided a pharmaceutical composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof and two or more ingredients selected from the list consisting in histidine acetate, sorbitol, glycine, polysorbate 20, and water.

[0220] In an embodiment, it is provided a pharmaceutical composition comprising an antagonist anti-CD127 antibody or an antigen-binding fragment thereof and histidine acetate, sorbitol, glycine, polysorbate 20, and water.

[0221] In particular, the pharmaceutical composition contains 100 mg of antagonist anti- CD127 antibody or an antigen-binding fragment thereof (50 mg / ml) in 20 mM histidine acetate (pH 5.5), 180 mM sorbitol, 50 mM glycine, and 0.02% (w / w) Tween 20.

[0222] Particularly, the pharmaceutical composition can be supplied as 2 ml extractable volume vials containing 100 mg of antagonist anti-CD127 antibody or an antigenbinding fragment thereof (50 mg / ml) in 20 mM histidine acetate (pH 5.5), 180 mM sorbitol, 50 mM glycine, and 0.02% (w / w) Tween 20. In an embodiment of the invention, the antagonist anti-CD127 antibody or an antigen-binding fragment thereof or the pharmaceutical composition is intravenously administrated, in particular by intravenous infusion.

[0223] • Administration or dosing cycles

[0224] In a particular embodiment the administration of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is performed at administration cycles wherein each cycle defines a specific dosing schedule for administering antagonist anti-CD127 antibody or antigen-binding fragment thereof, in particular a dosing schedule that discloses the administered dose(s) and the time interval(s) between administrations of two consecutive doses of the antagonist anti-CD127 antibody or antigen-binding fragment thereof.

[0225] In an embodiment of the invention, a dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered more than one time to the patient.

[0226] In an embodiment of the invention, a dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at a dosing schedule of once per week, or once every two weeks, or once every three weeks, or once every four weeks, or once every five weeks, or once every more than five weeks.

[0227] In another embodiment of the invention, a dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered at a dosing schedule of once per week, or once every two weeks, or once every three weeks, or once every four weeks, or once every five weeks, or once every six weeks, or once every seven weeks, or once every eight weeks, or one every nine weeks, or once every ten weeks.

[0228] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient at least twice, with a period comprising at least 7 days, ± 2 days, in particular ± 1 day, between the first two administrations of the composition.

[0229] In an embodiment, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient at least twice, wherein consecutive administered doses are separated by at least 7 days. The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient at least twice, with a period comprising at least 14 days, ± 2 days, in particular ± 1 day, between the first two administrations of the composition.

[0230] In an embodiment, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient at least twice, wherein the first two consecutive administered doses are separated by at least 14 days, more preferably 14 days.

[0231] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient at least twice, with a period comprising at least 21 days, ± 2 days, in particular ± 1 day, between the first two administrations of the composition.

[0232] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient at least twice, with a period comprising at least 28 days, ± 2 days, in particular ± 1 day, between the first two administrations of the composition.

[0233] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient two or more times, with a period comprising at least 7 days, ± 2 days, in particular ± 1 day, between two administrations of the composition.

[0234] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient two or more times, with a period comprising at least 14 days, ± 2 days, in particular ± 1 day, between two administrations of the composition.

[0235] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient two or more times, with a period comprising at least 21 days, ± 2 days, in particular ± 1 day, between two administrations of the composition.

[0236] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient two or more times, with a period comprising at least 28 days, ± 2 days, in particular ± 1 day, between two administrations of the composition.

[0237] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered to the patient at least three times, the first two administrations being separated by a period of at least 14 days, ± 2 days, in particular ± 1 day, in particular a period of 14 days, ± 2 days, in particular ± 1 day, the second and third administrations being separated by a period of at least 21 days, ± 2 days, in particular ± 1 day, preferably at least 28 days, ± 2 days, in particular ± 1 day, more preferably a period of 28 days.

[0238] In an embodiment, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient at least three times, the first two administered doses being separated by a period of at least 14 days, in particular a period of 14 days, the second and third administered doses being separated by a period of at least 21 days, preferably at least 28 days, more preferably a period of 28 days.

[0239] In an embodiment, in particular for the treatment of a patient suffering from Ulcerative colitis or Crohn’s disease, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient at least three times, the first two administered doses being separated by a period of 14 days, the second and third administered doses being separated by a period of 28 days.

[0240] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered in a dosing cycle, a dosing cycle being the time period between an administration, especially the first administration, of the antagonist anti-CD127 antibody or antigen-binding fragment thereof and the next, especially second, administration of the antagonist anti-CD127 antibody or antigen-binding fragment thereof. The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered several times according to a regular dosing cycle (i.e. the time period between two consecutive administrations is the same, like every 7 days, or every 14 days or every 21 days for example). Alternatively, the antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administrated several times according to an evolving dosing cycle (i.e. the time period between two consecutive administrations may be lower or higher as compared to the time period of a previous or a later dosing cycle).

[0241] Different cycles may exhibit differences in the duration of the cycle, in the period between two administration and / or the content of the administered doses either compared individually and / or per cycle and / or in the timing or frequency of administration. Cycles may be repeated identically over the whole treatment duration or different cycles may successively apply, in particular depending on the response to the treatment and / or depending on the use of one or multiple therapeutic agents. Cycles may be interrupted by treatment-free period of time or by contrast may not be interrupted by such period of time.

[0242] In some embodiments, of the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is administered at any one of the disclosed doses every 7 days, ± 2 days, in particular ± 1 day, or every 14 days, ± 2 days, in particular ± 1 day, or every 21 days, ± 2 days, in particular ± 1 day.

[0243] In a particular embodiment, the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered to the patient at any one of the disclosed doses during one or more dosing cycles, at least one dosing cycle being of at least 14 days± 2 days, in particular ± 1 day, more particularly exactly 14 days.

[0244] In a particular embodiment, the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered to the patient at any one of the disclosed doses during one or more dosing cycles, at least one dosing cycle being of at least 28 days± 2 days, in particular ± 1 day, more particularly exactly 28 days.

[0245] In a particular embodiment, the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered to the patient at any one of the disclosed doses during one or more dosing cycles, at least one dosing cycle being of at least 14 days± 2 days, in particular ± 1 day, more particularly exactly 14 days, and at least one other dosing cycle being of at least 28 days± 2 days, in particular ± 1 day, more particularly exactly 28 days.

[0246] In an embodiment of the invention, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient every 28 days, ± 2 days, in particular ± 1 day, starting after the second or third administration of the antagonist anti-CD127 antibody or antigen-binding fragment thereof.

[0247] In an embodiment of the invention, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient every 28 days starting from the third administered dose.

[0248] In an embodiment, in particular for the treatment of a patient suffering from Ulcerative colitis or Crohn’s disease, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient at least four times, the first two administered doses being separated by a period of 14 days, the second and third administered doses being separated by a period of 28 days, and then every 28 days.

[0249] In a particular embodiment, the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered to the patient at any dose disclosed herein, in particular a dose comprised between 380 mg and 980 mg, or between 450 mg ± 15% and 850 mg ± 15%, during one or more dosing cycles, at least one dosing cycle being of 14 days, ± 2 days, in particular ± 1 day, more particularly exactly 14 days, or at least one dosing cycle being of 28 days, ± 2 days, in particular ± 1 day, more particularly exactly 28 days.

[0250] In a particular embodiment, the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered to the patient at any dose disclosed herein, in particular a dose comprised between 380 mg and 980 mg, or between 450 mg ± 15% and 850 mg ± 15%, during two or more dosing cycles, at least one dosing cycle being of 14 days, ± 2 days, in particular ± 1 day, more particularly exactly 14 days, and at least one subsequent dosing cycle being of 28 days, ± 2 days, in particular ± 1 day, more particularly exactly 28 days.

[0251] In a particular embodiment, the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered to the patient at any dose disclosed herein, in particular a dose comprised between 380 mg and 980 mg, or between 450 mg ± 15% and 850 mg ± 15%, during three or more dosing cycles, at least one dosing cycle being of 14 days, ± 2 days, in particular ± 1 day, more particularly exactly 14 days, at least one subsequent dosing cycle being of 28 days, ± 2 days, in particular ± 1 day, more particularly exactly 28 day, and at least one subsequent dosing cycle being of 28 days, ± 2 days, in particular ± 1 day, more particularly exactly 28 days. In particular, each dosing cycle starting from the third is of 28 days, ± 2 days, in particular ± 1 day, more particularly exactly 28 days.

[0252] In an embodiment of the invention, it is provided the antagonist anti-CD127 antibody or antigen-binding fragment thereof for administration according to a regimen comprising administering doses during a loading stage (induction phase) and a maintenance stage (extension phase).

[0253] To this end, it is provided the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use according to the invention or in a method according to the invention, wherein the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to a patient in need thereof, in particular suffering from an inflammatory bowel disease, more particularly from ulcerative colitis (UC) or Crohn’s disease, and even more preferably ulcerative colitis, according to the following regimen: a) during a loading dose regimen (induction phase), administering a loading dose (induction dose) comprising between 380 mg and 980 mg, in particular between 450 mg ± 15% and 850 mg ± 15%, more particularly any dose disclosed herein, even more particularly 450 mg ± 15% or 850 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof at day 0, day 0 + 14 days, day 0 + 42 days, and optionally b) during a maintenance dose regimen (extension phase) that follows the loading dose regimen (induction phase), in particular that starts at day 0+ 70 days (at week 10 of the dose regimen), administering a maintenance dose (extension dose) comprising between 380 mg and 980 mg, in particular between 450 mg ± 15% and 850 mg ± 15%, more particularly any dose disclosed herein, even more particularly 450 mg ± 15% or 850 mg ± 15% of the antagonist anti-CD127 antibody or antigen-binding fragment thereof every 28 days (every four weeks) for the duration of the treatment protocol (in particular week 14, week 18, week 22, week 26, week 30, week 34, week 38, week 42, week 46, or week 50 of the dosage regimen). Since a loading dose (induction dose) is administered at day 0 + 42 days, the first maintenance dose (extension dose) is administered 28 days after administration of the last loading dose (induction dose) (at day 0 + 70 days; week 10 of the dosage regimen).

[0254] In a preferred embodiment, the maintenance dose regimen (extension phase) lasts for a period of at least 8 weeks, at least 12 weeks, at least 16 weeks at least 20 weeks, at least 24 weeks or at least 28 weeks. .In a preferred embodiment, the patient is treated during a period of at least 6 months that begins with the loading dose regimen (induction phase) as defined above, and continues with the maintenance dose regimen (extension phase) as defined above.

[0255] In one embodiment, it is provided the antagonist anti-CD127 antibody or antigenbinding fragment thereof for use according to the invention or in a method according to the invention, wherein the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to a patient in need thereof, in particular suffering from an inflammatory bowel disease, more particularly from ulcerative colitis (UC) or Crohn’s disease, and even more preferably ulcerative colitis, according to the following regimen: a) during a loading dose regimen (induction phase), administering a loading dose (induction dose) of 450 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof at day 0, day 0 + 14 days, day 0 + 42 days, and optionally b) during a maintenance dose regimen (extension phase) that follows the loading dose regimen (induction phase),, in particular that starts at day 0+ 70 days (at week 10 of the dose regimen),, administering a maintenance dose (extension dose) of 450 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof every 28 days (every four weeks) for the duration of the treatment protocol (in particular week 14, week 18, week 22, week 26, week 30, week 34, week 38, week 42, week 46, or week 50 of the dosage regimen).. Since a loading dose (induction dose) is administered at day 0 + 42 days, the first maintenance dose (extension dose) is administered 28 days after administration of the last loading dose (induction dose) (at day 0 + 70 days; week 10 of the dosage regimen).

[0256] In a preferred embodiment, the maintenance dose regimen (extension phase) lasts for a period of at least 8 weeks, at least 12 weeks, at least 16 weeks at least 20 weeks, at least 24 weeks or at least 28 weeks.

[0257] In a preferred embodiment, the patient is treated during a period of at least 6 months that begins with the loading dose regimen (induction phase) as defined above, and continues with the maintenance dose regimen (extension phase) as defined above.

[0258] In one embodiment, it is provided the antagonist anti-CD127 antibody or antigenbinding fragment thereof for use according to the invention or in a method according to the invention, wherein the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to a patient in need thereof, in particular suffering from an inflammatory bowel disease, more particularly from ulcerative colitis (UC) or Crohn’s disease, and even more preferably ulcerative colitis, according to the following regimen: a) during a loading dose regimen (induction phase), administering a loading dose (induction dose) of 850 mg of the antagonist anti-CD127 antibody or antigen-binding fragment thereof at day 0, days 0 + 14 days, day 0 + 42 days, and optionally b) during a maintenance dose regimen (extension phase) that follow the loading dose regimen (induction phase), in particular that starts at day at day 0+ 70 days (at week 10 of the dose regimen), administering a maintenance dose extension dose) of 850 mg of the antagonist anti- CD127 antibody or antigen-binding fragment thereof every 28 days (every four weeks) for the duration of the treatment protocol(in particular week 14, week 18, week 22, week 26, week 30, week 34, week 38, week 42, week 46, or week 50 of the dosage regimen)..

[0259] Since a loading dose (induction dose) is administered at day 0 + 42 days, the first maintenance dose (extension dose) is administered 28 days after administration of the last loading dose (induction dose) (at day 0 + 70 days; week 10 of the dosage regimen).

[0260] In a preferred embodiment, the maintenance dose regimen (extension phase) lasts for a period of at least 8 weeks, at least 12 weeks, at least 16 weeks at least 20 weeks, at least 24 weeks or at least 28 weeks.

[0261] In a preferred embodiment, the patient is treated during a period of at least 6 months that begins with the loading dose regimen (induction phase) as defined above, and continues with the maintenance dose regimen (extension phase) as defined above.

[0262] In an embodiment of the invention, it is provided the antagonist anti-CD127 antibody or antigen-binding fragment thereof for administration during a period of at least 10 weeks, or at least 14 weeks, or at least 18 weeks, or at least 22 weeks, or at least 26 weeks, or at least 30 weeks, or at least 34 weeks. In an embodiment of the invention, it is provided the antagonist anti-CD127 antibody or antigenbinding fragment thereof for administration during a period of at least 6 months. The dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof can be any dose as defined herein.

[0263] In an embodiment of the invention, it is provided the antagonist anti-CD127 antibody or antigen-binding fragment thereof for administration at any dose defined herein and during a period of at least 10 weeks, or at least 14 weeks, or at least 18 weeks, or at least 22 weeks, or at least 26 weeks, or at least 30 weeks, or at least 34 weeks, the efficacy of the treatment being observable starting on week 10. The efficacy of the treatment can be determined by monitoring factors that are commonly examined for assessing the effect of a medicine in the treatment of a disease (e.g. molecule expressions, biopsy analyses, histology, tissue appearance, disease score, etc.). Efficacy results can be determined by calculating the Modified Mayo Score as exemplified in the present application.

[0264] In an embodiment of the invention, it is provided the antagonist anti-CD127 antibody or antigen-binding fragment thereof for administration at any dose defined herein and during a period of at least 10 weeks, or at least 14 weeks, or at least 18 weeks, or at least 22 weeks, or at least 26 weeks, or at least 30 weeks, or at least 34 weeks, wherein the treated patient tolerates the treatment during a period of at least 10 weeks, or at least 14 weeks, or at least 18 weeks, or at least 22 weeks, or at least 26 weeks, or at least 30 weeks, or at least 34 weeks. In an embodiment of the invention, it is provided the antagonist anti-CD127 antibody or antigen-binding fragment thereof for administration at any dose defined herein and during a period of at 6 months, wherein the treated patient tolerates the treatment during a period of at least 10 weeks, or at least 14 weeks, or at least 18 weeks, or at least 22 weeks, or at least 26 weeks, or at least 30 weeks, or at least 34 weeks. The tolerance can be determined according by monitoring factors commonly examined for assessing the tolerance of a patient to a medicine. As examples, tolerance can be determined by monitoring adverse events (including severe AEs), clinical laboratory assessments, vital signs, ECGs, physical examination, and immunogenicity assessments. Tolerance can be determined by monitoring the factors listed in the safety / tolerance table provided in the examples of the invention.

[0265] • Second therapeutic compounds

[0266] In some embodiments, the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is administered to the patient in a combination therapy, with a standard (conventional) treatment, or in an add-on therapy. Combination therapy involves either administration in a combination product and administered together of the active agents, or as a combination treatment wherein active agents are administered separately, consecutively or simultaneously. The present invention relates thus to the combination treatment using an antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention with a conventional treatment for use in the treatment of inflammatory bowel disease. As used herein, the term “standard or conventional treatment” refers to any treatment of inflammatory bowel disease (drug, surgery, etc.) usually administrated to a patient who suffers from IBD. In some embodiments, the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is administered to the patient in a combination treatment with at least one further therapeutic agent, in particular a further therapeutic agent conventionally administered for treating an inflammatory disease, more particularly a further therapeutic agent conventionally administered for treating IBD.

[0267] Such administration may be simultaneous, separate, especially in alternation or in parallel, in particular sequential. For simultaneous administration, the agents may be administered as one composition of co-formulated agents or as separate compositions, as appropriate. The further therapeutic agent is typically relevant for the disorder to be treated. Exemplary therapeutic agents include antiinflammatory drugs.

[0268] The antagonist anti-CD127 antibody or antigen-binding fragment thereof may be administered in a combination treatment with at least one other (distinct) therapeutic compound. The antagonist anti-CD127 antibody or antigen-binding fragment thereof may also be administered in a combination treatment with a plurality (i.e. more than one, like two, three of four for example) of other therapeutic compounds.

[0269] In some embodiments, the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is used in a combination treatment with a second therapeutic agent.

[0270] In some embodiments, the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is used as an add-on therapeutic regimen.

[0271] In some embodiments, the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is used in a combination treatment with an anti-inflammatory agent, in particular an agent conventionally used for treating inflammatory disease, in particular Non Alcoholic Fatty Liver Disease, endometriosis, encephalomyelitis, inflammatory bowel disease, in particular Crohn’s disease and Ulcerative Colitis, chronic obstructive pulmonary disease, atherosclerosis, rheumatoid arthritis, multiple sclerosis, asthma and psoriasis.

[0272] In some embodiments, the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is used in a combination treatment with an agent conventionally used for treating an auto-immune disease.

[0273] The second therapeutic agent may be selected from the group consisting of immunotherapeutic agents, anti-inflammatory agents, and probiotics, in particular anti-inflammatory agents selected from the group consisting of aminosalicylates, such as mesalamine, balsalazide, olsalazine, corticosteroid.

[0274] In some embodiments, the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use in the method of the invention or for use according to the invention is administered to the patient in combination with a standard (conventional) treatment of Ulcerative colitis or Crohn’s disease.

[0275] The second therapeutic agent may be administered concurrently or separately, in particular subsequently to or in alternation, in particular sequentially, with the antagonist anti-CD127 antibody or antigen-binding fragment. The second therapeutic agent may be administered according to the same dosing cycle as the antagonist anti-CD127 antibody or antigen-binding fragment, either at the same time, or separately in time. The second therapeutic agent may also be administered according to a different dosing cycle than the dosing cycle of the antagonist anti-CD127 antibody or antigen-binding fragment. The second therapeutic agent may also be administered in the same way as the anti-CD127 antibody or antigen-binding fragment thereof (e.g., by intravenous administration for example), or in a different way.

[0276] The invention also concerns the use of the antagonist anti-CD127 antibody or antigen-binding fragment according to any embodiment disclosed herein, either alone or in combination with a second therapeutic agent, and / or with a pharmaceutical suitable vehicle as defined here in, for use in a combination therapy with another treatment including surgery, immunotherapy, targeted therapy, in particular for simultaneous, separated, or alternative, in particular sequential administration to a patient in need thereof and under one of the listed therapies.

[0277] • Administration route

[0278] In typical embodiments, the composition of the invention is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration, in particular intravenous infusion administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the pharmaceutical can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule indicating the quantity of active agent. Where the pharmaceutical is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the pharmaceutical is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0279] In some embodiments, antagonist anti-CD127 antibody or antigen-binding fragment is administered orally, subcutaneously, parenterally (e.g. in the form of a liquid), rectally (i.e. in the form of a suppository), topically (e.g. in the form of a transdermal patch, ointment, or cream), or intranasally. In other words, the uses of the antagonist anti-CD127 antibody or antigen-binding fragment thereof and the methods of using such a compound may be performed through an administration route encompassing oral administration, local administration to the gastrointestinal (Gl) tract, in particular through oral administration. In particular, provided herein are compositions suitable for systemic administration, in particular for parenteral or enteral administration, in particular for intravenous injection or infusion or oral administration. Enteric administration may be either a local administration to the digestive tract, or a systemic administration. The route of administration may encompass the use of a device allowing administration in particular injection or infusion of said composition (a “delivery device”). Examples of administration routes may include but are not limited to the use of the active compounds as a solution, in particular a sterile aqueous solution, suspension, as a solid, in particular a freeze-dried or a lyophilized solid, adsorbed on a patch, suspended or reconstituted and administrated as a solution, as a pill, tablet or other solid form suitable for oral administration, in particular with delayed or extended release. Preferably, the antagonist anti-CD127 antibody or antigenbinding fragment thereof is administered subcutaneously or intravenously, preferentially intravenously more preferentially by intravenous infusion administration.

[0280] In a preferred embodiment of the invention, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is formulated for (or is in a form suitable for) intravenous administration, in particular for intravenous infusion administration.

[0281] In an embodiment of the invention, it is provided a pharmaceutical composition comprising the antagonist anti-CD127 antibody or antigen-binding fragment thereof, the pharmaceutical composition being formulated for (or being in a form suitable for) intravenous administration , in particular for intravenous infusion administration.

[0282] In an embodiment of the invention, the antagonist anti-CD127 antibody or antigen-binding fragment thereof is intravenously administered, in particular through intravenous infusion.

[0283] In an embodiment of the invention, the pharmaceutical composition comprising the antagonist anti-CD127 antibody or antigen-binding fragment thereof is intravenously administered, in particular through intravenous infusion.

[0284] In an embodiment of the invention, it is provided a kit comprising the antagonist anti-CD127 antibody or antigen-binding fragment thereof for use according to any one of the embodiments disclosed herein, and a device suitable for a local administration, in particular a subcutaneous, intravenous or oral delivery device, in particular for intravenous administration, more particularly for intravenous infusion administration. In particular, the device suitable for local administration comprises the antagonist anti-CD127 antibody or antigen-binding fragment thereof at the prescribed dose for direct administration of the antagonist antiCDF? antibody or antigen-binding fragment thereof to the patient, without the need to dilute, to complete or to reconstitute the product before administration. Optionally associated with such kit(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0285] • Diseases to be treated

[0286] The uses described herein as well as the methods described herein may be useful in the treatment inflammatory diseases, including Non-Alcoholic Fatty Liver Disease, endometriosis, encephalomyelitis, inflammatory bowel disease, in particular Crohn’s disease and Ulcerative Colitis, chronic obstructive pulmonary disease, atherosclerosis, rheumatoid arthritis, multiple sclerosis, asthma and psoriasis

[0287] The uses described herein as well as the methods described herein may be useful in the treatment of inflammatory bowel diseases.

[0288] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from inflammatory bowel disease.

[0289] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from ulcerative colitis.

[0290] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from Crohn’s disease.

[0291] The uses described herein as well as the methods described herein may be useful in the treatment of autoimmune diseases, in particular rheumatoid arthritis, systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and systemic lupus erythematosus. In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from rheumatoid arthritis, systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and systemic lupus erythematosus.

[0292] The uses described herein as well as the methods described herein may be useful in the treatment of auto-immune cutaneous diseases involving pathogenic T cells, like cutaneous Psoriasis; cutaneous Lupus, Alopecia Aerata, Vitiligo, or pathogenic involving T resident memory cells (TRM).

[0293] • Patients

[0294] In a particular aspect of the invention, the uses and methods described herein are for the treatment of a patient who has been, prior to the use, treated for their IBD and has shown resistance to the treatment and / or disease progression despite being treated. The prior treatment may encompass any standard of conventional treatment of IBD, in particular Crohn’s disease or Ulcerative colitis. The term “standard or conventional treatment” refers to any treatment of IBD , in particular Crohn’s disease or Ulcerative colitis (drug, surgery, radiotherapy, etc.) usually administrated to or performed on a patient who suffers from IBD, in particular Crohn’s disease or Ulcerative colitis.

[0295] In a particular aspect of the invention, the uses and methods described herein are for the treatment of a patient who has been treated, is treated or will be treated with an anti-inflammatory agent.

[0296] In a particular aspect of the invention, the uses and methods described herein are for the treatment of patients with ulcerative colitis (particularly moderate to severe active), in particular who have failed or are intolerant to previous treatment, more particularly who have failed or are intolerant to previous treatment with immunosuppressors, anti-tumor necrosis factor (TNF)-a (in particular anti-tumor necrosis factor (TNF)-a antibodies), anti-integrin (in particular anti-integrin antibodies), corticosteroids, anti-IL12 and / or anti-IL23 (in particular anti-IL12 and / or anti-IL23 antibodies).

[0297] In a particular aspect of the invention, the uses and methods described herein are for the treatment of a patient who has been, prior to the use, treated for their auto-immune disease, in particular rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and type 1 diabetes.

[0298] • Methods of diagnostic and treatment

[0299] In an embodiment, the invention concerns a method for treating IBD, in particular Crohn’s disease or Ulcerative colitis, in a patient, the method comprising administering at least once, preferably several times, to the patient a composition comprising a dose as defined herein of an antagonist anti-CD127 antibody or antigen-binding fragment thereof.

[0300] In another embodiment, the invention concerns a method for treating inflammatory disease in a patient, the method comprising administering at least once, preferably several times, to the patient a composition comprising a dose as defined herein of an antagonist anti-CD127 antibody or antigen-binding fragment thereof.

[0301] In another embodiment, the invention concerns a method for treating an autoimmune disease in a patient, the method comprising administering at least once, preferably several times, to the patient a composition comprising a dose as defined herein of an antagonist anti-CD127 antibody or antigen-binding fragment thereof.

[0302] In another embodiment, the invention concerns a method for treating a patient suffering from IBD, in particular Crohn’s disease or Ulcerative Colitis, in a patient, wherein at least one dose as disclosed herein of the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered is administered to the patient.

[0303] In another embodiment, the invention concerns the use of a composition comprising an antagonist anti-CD127 antibody or antigen-binding fragment thereof, as defined herein, in the manufacture of a medicament comprising any dose as defined, in particular for the treatment of inflammatory disease, more particularly IBD, even more particularly Ulcerative Colitis.

[0304] In an embodiment, the invention concerns a method for treating IBD in a patient, the method comprising administering at least once to the patient a composition comprising a dose as defined herein of an antagonist anti-CD127 antibody or an antigen-binding fragment thereof

[0305] EXAMPLES

[0306] Clinical study protocol A randomized, double-blind, study to evaluate the efficacy and the safety of the administered anti-CD127 antibody versus placebo in patients with moderate to severe active ulcerative colitis who have failed or are intolerant to previous treatment(s) has been performed.

[0307] The study population (patients with moderate to severe ulcerative colitis [UC] who have failed or are intolerant to immunosuppressors, anti-tumor necrosis factor (TNF)-a, anti-integrin, ustekinumab and / or corticosteroids) was selected since this population consists of patients who are in need of alternative new therapies to avoid for as long time as possible the complications linked to the disease and in whom the safety profile of an anti-CD127 antibody can be reliably assessed. The double-blind, placebo-controlled design corresponds to a standard design in this disease and will allow the detection of differences between efficacy in active treatment versus a placebo.

[0308] Previous UC induction studies have evaluated initial endpoints at 8 to 12 weeks, and the present study proposes that Week 10 assessments for biologically naive and experienced patients be used. Ten weeks is expected to be sufficient time for some degree of mucosal healing to occur and for clinical symptoms to improve. The use of endoscopy and histology maximizes objectivity in assessment of drug effect. Use of centrally read endoscopy will further reduce bias in assessment of endoscopic healing. At Week 10, an open-label administration of an antagonist antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18) at Weeks 10, 14, 18, 22, 26, 30, and 34 will be offered to all patients regardless of their treatment allocation in the previous double-blind period followed by follow up visits until week 50 considering the continuous exposure of the product. This will allow every patient, including those treated initially with the placebo, to be given the opportunity to receive the active treatment for a sufficient time. This administration will be done at the high dose level of the anti-CD127 antibody described here above (i.e. , 850 mg).

[0309] The multicenter, randomized, double-blind, placebo-controlled, parallel-group study in patients with moderate to severe active UC is designated as follow.

[0310] The study includes 4 periods: screening, induction, optional extension, and follow-up.

[0311] Screening Phase: 8 weeks maximum

[0312] Following the screening period, eligible patients will be randomized and enter the 10-week placebo-controlled induction phase. The randomization will be stratified according to 2 variables: previous exposure to biologies (yes / no) and concomitant use of steroids (yes / no). The targeted proportion of biologies non naive patients had to be within 50%-60% of the total population (i.e., the proportion of biologies naive patients had to be within 40%- 50% of the total population). Up to the 108 first inclusions, only 17 patients with previous exposure to biologies have been enrolled. Therefore, only patients with previous exposure to biologies and primary non response or secondary loss of response will be randomized from the 109th patient to the last randomized patient.

[0313] Induction Phase: Week 0 to Week 10

[0314] In the first step of the study (i.e. before the outcome of the pre-specified Futility Analysis, Global Protocol V1.0), patients were randomly assigned on Week 0 in a 1 :1 :1 ratio to receive 1 of the following regimens:

[0315] • Placebo intravenous (IV) infusion at Week 0, Week 2, and Week 6;

[0316] • anti-CD127 antibody described here above (antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18)) at a Low Dose (450 mg) IV infusion at Week 0, Week 2, and Week 6;

[0317] • anti-CD127 antibody (the antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18)) described here above at a High Dose (850 mg) IV infusion at Week 0, Week 2, and Week 6.

[0318] Infusions are delivered in an in-patient clinic for 1 hour, with a 2-hour post-infusion surveillance. Clinical examination is performed and vital signs are checked before each infusion. Vital signs are recorded every 30 minutes during the infusion and during the 2-hour post-infusion surveillance period.

[0319] At Week 10, all the patients have a visit to record all the components of the primary and main secondary endpoints.

[0320] Open Label Extension Phase (OLE): Week 10 to Week 34

[0321] At Week 10 all the patients are asked to participate in an open-label extension period and those willing to continue the study in accordance with the clinical investigator receive additional infusions at Weeks 10, 14, 18, 22, 26, 30, and 34 at the high dose level of the anti-CD127 antibody administered during the induction phase and described here above (antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18)) (i.e., 850 mg).

[0322] Study drug is administered as described above during the Induction Phase. Safety Follow up Phase: Week 10 to Week 22 or Week 34 to Week 50

[0323] If the patient does not participate in the OLE, the safety follow-up period during which no study treatment is administered will start after Week 10 and lasts 12 weeks after the end of the induction phase (Week 10 to Week 22 corresponding to 12 weeks after the last administration). In such case, 1 mandatory follow-up visit is conducted at Week 22. If the patient participates in the OLE Phase, the safety follow-up period lasts 16 weeks after the last administration (Week 34 to Week 50, 16 weeks after the last administration) and 2 mandatory follow-up visits are conducted at Week 38 and at Week 50. An independent Data Safety Monitoring Board (DSMB) is set up to primarily take care of the safety of the participating patients by reviewing the safety and tolerability data of the investigational drug on a regular basis.

[0324] An interim futility analysis has been completed as planned in the V1.0 Global Protocol of the study after 30% of the patients had completed the Induction Phase.

[0325] Patients to be treated:

[0326] The inclusion and exclusion criteria are disclosed in the following tables.

[0327]

[0328]

[0329]

[0330] Table 1 : inclusion criteria for selecting patients to be treated.

[0331] The study is conducted at approximately 75 to 90 centers in Europe. An estimated number of 150 patients was initially expected to be randomized, with 138 expected to complete the Induction Phase and around 100 expected to enter the OLE phase.

[0332] The predicted number of patients who would be enrolled at each active investigational site is between 1 and 3. The total study is expected to last around 3 years from First Patient in to Last Patient Last Follow-up Visit. The total study duration for an individual patient will be approximately up to 30 weeks (210 days) if the patient does not enter into the OLE or up to 58 weeks (406 days) if the patient participates in the OLE to include: • Screening (up to 8 weeks / 56 days)

[0333] • Randomization at Week 0 (1 day)

[0334] • Induction Phase (10 weeks, with treatment visits at Week 0, 2, and 6)

[0335] • Optional OLE Phase (24 weeks, with treatment visits at Weeks 10, 14,18, 22, 26, 30, and 34)

[0336] • Safety follow-up with no study drug administration from Week 10 to Week 22 (12 weeks I 84 days) or from Week 34 to Week 50 (16 weeks / 112 days): i.e., last follow-up visit 16 weeks after the last infusion in both situations.

[0337] Efficacy Assessments:

[0338] Efficacy is assessed using the modified Mayo Score for Assessment of Ulcerative Colitis (including stool frequency, rectal bleeding, and mucosal appearance at endoscopy [endoscopic sub-score]), clinical response, PROs (stool frequency and rectal bleeding), endoscopy, histology (including the Nancy Histological Index Score, the Geboes score and the RHI), measurements of CRP and fecal calprotectin, UCEIS, and the UC 100 score.

[0339] PK / PD Assessments:

[0340] Pharmacokinetics and PD are assessed using PK and receptor occupancy (RO) (in a subgroup of 20 patients), histologic PD markers (e.g., transcriptom ic analysis of colon biopsies samples using Nano String); and stool analysis for fecal biomarkers (such as microbiota).

[0341] Safety Assessments:

[0342] Safety is assessed by adverse events (including SAEs), clinical laboratory assessments, vital signs, ECGs, physical examination, and immunogenicity assessments.

[0343] Statistical Methods and

[0344] Size Calculation:

[0345] Two fixed doses to be tested 450mg and 850mg groups versus placebo: Primary endpoint on efficacy assessment of the anti-CD127 antibody defined in the protocol vs placebo on the reduction of the modified Mayo Score at Week 10. Sample size of 46 per group (138 patients in total) was expected to achieve 80% power to reject the null hypothesis of equal means (i.e., when the population mean reduction from baseline of the Modified Mayo Score was 1 on placebo and 2.5 on active treatment leading to a mean difference of 1 .5.

[0346] Preplanned futility analysis:

[0347] A preplanned futility analysis was conducted early on 30% of the population recruited only on patients completing Week 10 assessment, with availability of the primary endpoint at Week 10 (58 patients: 450mg n= 18 / 850mg n=19 / Placebo n= 21 ). These data were analyzed by the independent DSMB (Drug safety monitoring committee and the DSMB recommended stopping the 450mg group for futility. 108 patients were already enrolled in the first part of the study before futility (n=36 Group 850mg / n=35 Group 450mg / n=35 Group Placebo). The futility of the 450mg group was surprisingly not confirmed in this population recruited (L450 n=35) versus placebo.

[0348] Due to the low percentage in post biologies strata observed in the first part ( Part I period), an amendment to increase the post biologic strata, with only patients biologies experienced was implemented in the second part of the study.

[0349] After futility, the new recruitment focused only on additional patients entering in the trial post biologies failure, considering a dropout rate of 15%, with the objectives of recruiting additional patients with prior exposure to biologies in order to reach the expected 43 patients with prior exposure to biologies (Part II period post futility: 28 Patients enrolled: 450mg 0 pts / 850mg 14 pts / Placebo 14 pts).

[0350] Final analysis:

[0351] The initial Statistical Analysis Plan, before the database lock was on the comparison of the 850mg group versus placebo, as the 450mg was considered as futile.

[0352] Since the futility of the 450mg group was surprisingly not confirmed in this population recruited (L450 n=35) versus placebo and was efficient versus placebo with more patients included as compared to the time of the early futility analysis, he final Statistical Analysis Plan was thus reconsidered and followed the strategy which was initially planned in the protocol: the final statistical analysis reconsidered both treated groups L850mg, L450mg versus placebo and a global treatment effect with pooled treated groups: The Full Analysis Set (FAS) of efficacy analysis was conducted on 134 patients (group of 850mg L850 n= 50 patients I group of 450mg L450: n= 35 I L850 / 450 pooled treated groups n= 85 I Placebo group n= 49). Safety Set: considering all randomized patients who received at least one dose of study treatment (including the L450 group) n=136 patients.

[0353] Per protocol population PP: ITT Intention to treat population without major deviations.

[0354] Final Analysis

[0355] Primary Endpoint:

[0356] The treatment difference was assessed with an ANCOVA model which included terms to adjust for the baseline MMS value, stratification factors, and baseline MMS as covariates. Missing MMS or Subscores at Week 10 were computed using a multiple imputation approach under MAR (Missing At Random) assumption. Imputation was performed on L850 and placebo patients and included treatment groups, MMS at baseline, real stratification factors, gender, age at screening and UC duration.

[0357] For the final analysis, the treatment difference was assessed with an ANCOVA model which included treatment groups (L450, L850, L850 / 450 or Placebo), MMS at baseline and real stratification factors as covariates. Missing MMS or subscores at Week 10 were computed using a Multiple Imputation Approach under MAR Assumption. Imputation was performed on L450, L850 and Placebo patients by treatment group and included MMS at baseline, real stratification factors, gender, age at screening and Ulcerative Colitis duration. No comparison was planned between L450 and L850.

[0358] The average of the adjusted difference in the mean change from baseline to Week 10 between the treatments was reported with the standard errors of the mean, two-sided 95% confidence interval, and P-value obtained from the multiple imputed datasets. Five sensitivity analyses were performed to support the main “missing at random” (MAR) analysis (PP, Last observation carried forward or Baseline Observation carried forward LOCF / BOCF, complete case, composite strategy and “not missing at random” (NMAR) analyses).

[0359] Secondary endpoints: They were analysed (proportion, logistic or ANCOVA models) applying the same derivations and multiple imputations (from 100 completed datasets) as for primary criteria, using estimands. Treatment effects from these 100 analyses were then combined using Rubin’s Method. The response function was the log odds (logit) of the proportion of patients responding with associated p-value. Estimates of the treatment differences in response function and associated 95% confidence Interval Cl for L850, L450 and both L850 and L450 against placebo were computed from the model and the results were back transformed to give point estimates of the difference in proportions and associated 95% Cl.

[0360] Exploratory endpoints were analyzed using the same methods as those used for the primary and secondary endpoints.

[0361] Additional analyses were conducted in other populations to further explore the efficacy of the administered anti-CD127 in order to identify patients who could or not particularly benefit from the treatment. The effects on efficacy of the stratification factors (previous exposure to biologies, concomitant treatment with corticosteroids) were evaluated.

[0362] Specific analysis in the subgroup of patients with FCP> 250pg / g;

[0363] These analyses were performed according to the same methodology as those used for primary and secondary endpoints.

[0364] Safety Analysis:

[0365] Analyses were performed in the safety set.

[0366] The number of treatment emergent adverse events (TEAEs) and the number and percentage of patients with TEAEs were summarized by system organ class (SOC) and preferred term (PT) by treatment arm for each of the different categories of TEAEs including drug-related, severe, severe drug-related, serious, serious drug-related TEAEs, TEAEs with fatal outcome, drug-related TEAEs with fatal outcome, TEAEs leading to withdrawal from the study and drug-related TEAEs leading to withdrawal from the study

[0367] A specific analysis focused on predefined Adverse Events of Special Interest (AES I): Allergy (local and systemic due to protein injection), Infections and Lymphopenia (related to the mechanism of action of the administered anti-CD127 antibody, which is a pure IL7R inhibitor). Results of the study of an anti-CD127 antibody vs Placebo in Patients with Moderate to Severe Active Ulcerative Colitis (NCT04882007-CoTikiS)

[0368] - Results of the Induction phase

[0369] The randomized, double-blind Phase 2 clinical trial CoTikiS has evaluated the efficacy and the safety of an anti-CD127 antibody (antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18 - referenced as “the Antibody” in the rest of this section “examples”) versus placebo in 136 patients with moderate to severe active UC who failed, lost response, or were intolerant to previous treatment(s)* Primary endpoint was the efficacy assessment of the Antibody versus placebo on the reduction of the Modified Mayo score** at week 10. Secondary endpoints included clinical remission, endoscopic remission, endoscopic improvement, histological response and histological improvement rates ***.

[0370] Primary endpoint**: a significant decrease of the Modified Mayo Score (MMS) is achieved versus placebo at week 10:

[0371] The 850 mg group (n=50, Placebo n=49) in the initial analysis obtained significant results at week 10 versus Placebo on the improvement of the MMS with a -0.82 (95%CI: -1.63. -0.01 ) difference^ in treatment effect between the Antibody and placebo (p=0.047).

[0372] The 450 mg group (n=35, Placebo n=49) obtained significant results versus placebo (the 450 mg group was considered as exploratory as prematurely interrupted***) with a difference^ of -1.17 (95%CI: -2.18; -0.16) between the Antibody and placebo (p=0.023). The global treatment effect is significant considering the 450+850mg groups together versus placebo showing a difference^ of -0.88 (95%CI: -1.64; -0.12) between the Antibody and placebo (p= 0.024).

[0373] These efficacy results were confirmed in the final analysis.

[0374] Key Secondary endpoints****

[0375] Clinical remission at week 10: 12.7% for the 850 mg group versus 4,8% for the Placebo group; 23,4% for the 450 mg group.

[0376] Endoscopic remission at week 10: 19.3% for the 850 mg group versus 13.3% for the Placebo group; 36.6% for the 450 mg group.

[0377] Endoscopic improvement at week 10: 23.6 % for the 850 mg group versus 14.7 % for the Placebo group; 46.2% for the 450 mg group.

[0378] These efficacy results were confirmed in the final analysis

[0379] Histological response (Nancy histological index (NHI) < 1 ) at week 10: 31 % for the 850 mg group versus 10% for the Placebo group ; 45% for the 450 mg group and 37% for the global treated group (450mg+850mg groups together) (See Figure 1A). Histological improvement rate (Histological Geboes index change from baseline) at week 10: - 4.2 for the 850 mg group versus -0.7 for the Placebo group; -2.9 for the 450 mg group, and -3.7 for the global treated group (450mg+850 mg groups together) (See Figure 1 B)

[0380] Safety results: no safety signal was reported by the Data Safety Monitoring Board during the trial. Both doses of the Antibody show favorable safety profile in comparison with placebo, with similar rates of adverse events across the 3 treatment groups.

[0381] * Previous corticosteroids, Immunosuppressive agents or previous biological treatments

[0382] ** Ulcerative Colitis is a chronic inflammatory disease of the rectum and colon characterised by mucosal inflammation, abdominal pain associated with symptoms and frequency of diarrhoea and rectal bleeding. The moderate to severe UC is measured by a Modified Mayo Score (MMS) between 4 and 9, inclusive. The primary endpoint is the mean change at Week 10 from baseline in the Modified Mayo Score, a Disease Activity Index for UC defined by the addition of the stool frequency and the rectal bleeding sub-scores (two patient’s clinical elements as Patient Reported Outcomes) and the endoscopic sub-score (mucosal endoscopy activity), assessed by an endoscopist through a central reading platform.

[0383] MLeast Square Mean Difference between the Antibody and placebo=difference between groups of the Mean change in MMS between baseline and W1O (Analysis of Covariance model)

[0384] *** An interim Futility analysis performed early (33% of patients) by the IDMC proposed interruption of the 450 mg group for risk of futility but not confirmed at final analysis. The 850 mg group was hence considered as initial primary analysis.

[0385] Final analysis integrated L850; L450, L850 / 450 pooled groups the comparison of the Treated groups versus placebo

[0386] ****Secondary endpoints: Clinical remission defined as no individual sub-score of > 1 point and a rectal bleeding at 0, therefore a stool frequency sub-score of 0 or 1 and an endoscopic sub-score of 0 or 1.

[0387] Endoscopic remission defined as a Mayo endoscopic sub-score at zero.

[0388] Endoscopic improvement defined as a Mayo endoscopic sub-score < 1 point.

[0389] The following table summarizes the treatment-emergent adverse events (TEAE) observed in the patients treated with the placebo, the Antibody at a low dose (450 mg), or the Antibody at a high dose (850 mg) (Safety population; N=136), during the Induction Double Blind Period (during the 10 week-induction phase of treatment).

[0390] Table 1 : Summary of Treatment-Emergent Adverse Events (TEAE) observed in the safety population (N=136) treated with a placebo or the Antibody at low dose (450 mg) or high dose (850 mg) during the 10 week-induction phase of treatment. N: number of individuals in the category; (%): percentage of individuals in the category who suffered from the Adverse event(s) identified in the left column; [E]: number of events identified in the left column observed in the category of individuals. *: AESI=Adverse Event of Specific Interest (defined per protocol as : lymphopenia of CTCAE grade 3 or more, allergy, or any infection).

[0391] These results clearly illustrate that the antiCD127 Antibody has a significant efficacy (measured by the improvement of the Modified Mayo Score**) during the 10 week-induction phase of treatment. Further, the safety and tolerability profile in the whole patient population across the two doses tested and until week 34 is favorable (in particular no clinical prejudicial opportunistic infections and lymphopenia were observed in the same rate in all groups including placebo), indicating that long-term use can be considered.

[0392] - Results of the Open Label Extension phase (OLE phase)

[0393] At Week 10, an open-label administration of an anti-CD127 antibody was offered to all patients regardless of their treatment allocation in the previous double-blind period (i.e. the induction phase). This allowed every patient, including those treated initially with the placebo, to be given the opportunity to receive the active treatment for a sufficient time. This administration was done at the high dose level of the Antibody described here above (i.e., 850 mg).

[0394] Efficacy is assessed using PROs (stool frequency and rectal bleeding) in nonresponder and responder patients at week 10 of the induction phase.

[0395] Clinical remission: a significant increase of the percentage of patients with symptomatic remission (defined as patients with PRO2 <1 and RBS=0) is observed at week 14 and week 34, during the open-label extension phase in nonresponder patients of the induction phase at week 10 (defined as patients with PRO 2 > 1 or RBS > 0 at week 10) (See Figure 2). The clinical efficacy is maintained in week 10 responder patients (defined as patients with PRO 2 <1 and RBS = 0 at week 10) (Figure 3).

[0396] Rectal bleeding improvement: 97% and 96% of all patients showed a rectal bleeding improvement (RBS < 1 ) at week 14 and 34, respectively versus 88% for the global treated group (pooled anti-CD127 antibody treated patients with 450 mg or 850 mg) at the end of induction phase. Rectal bleeding remission : 66% and 82% of all patients showed a rectal bleeding improvement (RBS = 0) at week 14 and 34, respectively versus 54% in pooled anti-CD127 antibody treated patients at the end of induction phase. Safety results: no increase in incidence or severity of AESI (Adverse Event of Specific Interest (defined per protocol as : lymphopenia of CTCAE grade 3 or more, allergy, or any infection) during the 24 weeks of OLE phase is observed. Grade 3 lymphopenia is reported in 2.5% of patients: all 3 patients had grade 1 (2 patients) or grade 2 (1 patient) lymphopenia at baseline. Table 2: Summary of Adverse Event of Specific Interest (defined per protocol as

[0397] Placebo 450 mg 850 mg Total

[0398] Induction phase dose (N=49) (N=36) (N=51) (N=136) group: N(%) N(%) N(%) N(%)

[0399] At least one AESI 10 (23.8%) 9 (29.0%) 16 (34.0%) 35

[0400] (29.2%) Covid-19 3 (7.1%) 3 (9.7%) 6 (12.8%) 12

[0401] (10.0%) Nasopharyngitis 1 (2.4%) 1 (3.2%) 2 (4.3%) 4 (3.3%)

[0402] Lymphopenia 2 (4.8%) 1 (3.2%) — 3 (2.5%)

[0403] Asymptomatic Covid-19 — 1 (3.2%) 1 (2.1%) 2 (1.7%)

[0404] Influenza 1 (2.4%) — 1 (2.1%) 2 (1.7%)

[0405] Sinusitis — — 2 (4.3%) 2 (1.7%)

[0406] : lymphopenia of CTCAE grade 3 or more, allergy, or any infection) during the 24 weeks of OLE phase in all patients treated with the Antibody at 850 mg. N: number of individuals in the event; (%): percentage of individuals in the category who suffered from the Adverse event(s) identified in the left column.

Claims

CLAIMS1. An antagonist anti-CD127 antibody or an antigen-binding fragment thereof, for use in the treatment of a patient suffering from an inflammatory bowel disease, wherein a dose comprised between 380 mg and 980 mg of the antagonist antiCDF? antibody or antigen-binding fragment thereof is administered to the patient at least twice, and wherein consecutive administered doses, in particular the first two consecutive administered doses, are separated by at least 7 days, preferably at least 14 days, more preferably by 14 days.

2. The antagonist anti-CD127 antibody or an antigen-binding fragment thereof according to claim 1 , for use according to claim 1 , which comprises: i) a heavy chain variable domain comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 , and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and ii) a light chain variable domain comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the antibody heavy chain variable domain comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable domain comprises or consists in the amino acid sequence set forth in SEQ ID No. 8 or SEQ ID No. 9 or SEQ ID No. 10 or SEQ ID No. 11 or SEQ ID No. 12, preferably SEQ ID No. 12.

3. The antagonist anti-CD127 antibody or an antigen-binding fragment thereof according to claim 1 or 2, for use according to any one of claims 1 or 2, which comprises a heavy chain comprising or consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain comprising or consisting in the amino5 acid sequence set forth in SEQ ID No. 18.

4. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claim 1 to 3, for use according to any one of claim 1 to 3, wherein the patient suffers from ulcerative colitis (UC) or Crohn’s disease,10 preferably ulcerative colitis.

5. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, for use according to any one of claims 1 to4, wherein the anti-CD127 antibody or antigen-binding fragment thereof is15 administered at a dosing schedule of once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every more than five weeks.

6. The antagonist anti-CD127 antibody or antigen-binding fragment thereof 20 according to any one of claims 1 to 5, for use according to any one of claims 1 to5, wherein the first dose of the antagonist anti-CD127 antibody or antigen-binding fragment thereof administered to the patient is comprised between 380 mg and 980 mg.

257. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, for use according to any one of claims 1 to6, wherein the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered to the patient at least three times, the first two administered doses being separated by a period of at least 14 days, in particular30 a period of 14 days, the second and third administered doses being separated by a period of at least 21 days, preferably at least 28 days, more preferably a period of 28 days.

8. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to claim 5 for use according to claim 7, wherein the antagonist anti- CD127 antibody or antigen-binding fragment thereof is administered to the patient every 28 days starting from the third administered dose.

59. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, for use according to any one of claim 1 to8, wherein all administered doses of the antagonist anti-CD127 antibody or an antigen-binding fragment thereof are comprised between 380 mg and 980 mg.1010. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, for use according to any one of claims 1 to9, wherein the antagonist anti-CD127 antibody or antigen-binding fragment 15 thereof is administered in combination, in particular as an add-on therapeutic regimen, more particularly sequentially or simultaneously, with a second therapeutic agent, in particular a second therapeutic agent conventionally administered for treating an inflammatory bowel disease.2011. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to claim 10, for use according to claim 10, wherein the second therapeutic agent is administered to the patient according to the same administration cycle as the antagonist anti-CD127 antibody or antigen-binding fragment.2512. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 11 , for use according to any one of claims 1 to 11 , wherein the antagonist anti-CD127 antibody or antigen-binding fragment thereof is formulated for intravenous administration, in particular for intravenous30 infusion administration.

13. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 12, for use according to any one of claims 1to 12, wherein the antagonist anti-CD127 antibody or antigen-binding fragment thereof is intravenously administrated, in particular by intravenous infusion.

14. The antagonist anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 13, for use according to any one of claims 1 to 13, wherein the antagonist anti-CD127 antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutical composition, said pharmaceutical composition further comprising histidine acetate, sorbitol, glycine, polysorbate 20, and / or water.

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