Therapy by antagonizing il-7 or CD127, and TL1a or tnfrsf25

Abstract

The application generally relates to a therapy comprising at least two therapeutic agents, a first therapeutic compound being an antagonist of IL-7 or CD127 and a second therapeutic compound being an antagonist of TL1A or TNFRSF25, or comprising a bifunctional molecule targeting IL-7 or CD127 and TL1A or TNFRSF25. The combination therapy or the bifunctional molecule is provided for use in the treatment of a patient suffering from an inflammatory disease or an auto-immune disease. The means of the invention are more particularly dedicated to the provision of a combination therapy, or a bifunctional, in particular bispecific, antibody comprising an anti-CD127 antibody or an antigen-binding fragment thereof and an antagonist anti-TL1A antibody or an antigen binding fragment thereof.

Description

[0001] TITLE

[0002] THERAPY BY ANTAGONIZING IL-7 OR CD127, AND TL1 A OR TNFRSF25

[0003] FIELD OF THE INVENTION

[0004] The application generally relates to a therapy comprising at least two therapeutic agents, a first therapeutic compound being an antagonist of IL-7 or CD127 and a second therapeutic compound being an antagonist of TL1A or TNFRSF25, or comprising a bifunctional molecule targeting IL-7 or CD127 and TL1A or TNFRSF25. The combination therapy or the bifunctional molecule is provided for use in the treatment of a patient suffering from an inflammatory disease or an auto-immune disease.

[0005] The means of the invention are more particularly dedicated to the provision of a combination therapy, or a bifunctional, in particular bispecific, antibody comprising an anti-CD127 antibody or an antigen-binding fragment thereof and an antagonist anti-TL1A antibody or an antigen binding fragment thereof.

[0006] BACKGROUND OF THE INVENTION

[0007] Inflammatory diseases encompass a wide range of disorders characterized by inflammation, which is the body's response to harmful stimuli such as pathogens, damaged cells, or irritants. Chronic inflammation can lead to tissue damage and contribute to the pathogenesis of various diseases, including cardiovascular diseases, diabetes, and cancer. Autoimmune diseases, a subset of inflammatory diseases, occur when the immune system mistakenly attacks the body's own tissues. Examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease.

[0008] TL1A, also called TNFSF15, is a member of tumor necrosis factor family. It is expressed in different immune cell, such as monocyte, macrophage, dendritic cell, T cell and non-immune cell, for example, synovial fibroblast, endothelial cell. TL1A competitively binds to TNFRSF25 (death receptor 3 or decoy receptor 3), providing stimulatory signal for downstream signaling pathways, and thenregulates proliferation, activation, apoptosis of and cytokine, chemokine production in effector cells. Recent findings showed that TL1A was abnormally expressed and involved in the development and pathogenesis of autoimmune diseases and inflammatory diseases including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, primary biliary cirrhosis, Kidney inflammatory diseases, Grave’s disease, systemic lupus erythematosus and ankylosing spondylitis. Therapeutic strategies for these diseases by targeting TL1A have been recently developed (Xu et al, 2022, Frontiers in Immunology). Understanding of the TL1A signalling mechanism has been expanded and applied for the treatment of inflammatory and autoimmune diseases, which has resulted in the development of therapeutic tools, including antagonists of TL1 A, and antagonists of TNFRSF25 (antagonists of the TL1A I TNFRSF25 signaling pathway).

[0009] Despite significant advances in the understanding and treatment of inflammatory and autoimmune diseases, several drawbacks persist, among which one can cite limited efficacy (current treatments do not work for all patients and often fail to induce long-term remission, or induce a partial relief and disease progression continues), side effects (conventional therapies can cause severe side effects, including gastrointestinal issues, increased infection risk, and organ damage with long-term use), tolerance and resistance (patients may develop tolerance to certain medications, reducing their effectiveness), or target specificity (many treatments lack specificity, leading to broad immunosuppression rather than targeted action).

[0010] Anti TL-1A therapeutics show good clinical efficacy in clinical trials but some patients do not respond to the treatment. New therapeutic approaches are required to improve therapeutic efficacy for the treatment of inflammatory diseases and auto-immune disease.

[0011] SUMMARY OF THE INVENTION

[0012] In a first aspect of the invention, it is provided a combination comprising:

[0013] a. a first compound that is an antagonist of IL-7 and / or CD127; and b. a second compound that is an antagonist of TL1 A or TNFRSF25;for use in the treatment of an inflammatory disease or an auto-immune disease.

[0014] The IL-71 CD127 signaling pathway and the TL1A / TNFRSF25 signaling pathway play crucial roles in immune regulation, inflammation, and disease pathogenesis. Disturbing these pathways can provide significant therapeutic benefits in autoimmune or inflammatory conditions, as illustrated in the examples illustrating the present invention. Excessive IL-7 signaling contributes to the survival and expansion of autoreactive T cells, worsening autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Blocking IL-7 signaling helps reduce autoreactive T cell populations. IL-7 enhances the secretion of pro-inflammatory cytokines (e.g., IFNy, IL-17) by T cells. TL1A amplifies Th17-mediated inflammation, which is a key driver of diseases like inflammatory bowel disease (IBD), asthma, and fibrosis. TL1A signaling promotes the production of inflammatory cytokines (e.g., IL-17, IL-13) and fibrosis-related factors, contributing to conditions such as Crohn's disease, ulcerative colitis, and systemic sclerosis. Inhibiting this pathway can mitigate inflammation and prevent fibrotic tissue damage. Thus, IL-7 and TL1A pathways both drive inflammation and immune dysregulation through distinct but complementary mechanisms. IL-7 primarily promotes T cell survival and pro-inflammatory cytokine secretion, while TL1A amplifies T cell differentiation (notably through Th17) and innate immune activation. TL1A and its receptor DR3 promote lymphocyte costimulation, mucosal hyperplasia and autoimmune inflammation.

[0015] As illustrated in the present invention, combined disruption of these pathways provides a reduction in the secretion of pro-inflammatory cytokines and thus be benefic in the treatment of diseases characterized by immune overactivation.

[0016] Surprisingly, the above combination therapy shows a significantly improved therapeutic effect, as compared to the effect observed when only one of these compounds is administered. Unexpectedly, the inventors show that the combination as defined here above has a higher effect to inhibit the secretion of IL-9, IL-6, TNFa and IFNy (all being cytokines involved in pro-inflammatoryprocesses, see for example Irano et al., Int Immunol. 2020 Dec 18;33(3):127-148; (Jang et al. 2021, Int. J. Mol. Sci), compared to monotherapy.

[0017] Using heatmap analysis and enrichment pathway analysis, the inventors demonstrated a synergistic effect but also a clear differentiation of combination treatment of anti-hlL-7Ra with anti-hTL1A Abs versus each monotherapy with a significant decrease of specific proteins affected only by the combination but not by the individual treatments. These results demonstrate that the combination therapy as defined here above has improved efficacy for the treatment of patients with inflammatory and autoimmune diseases compared to monotherapy.

[0018] Combining the blockade of the IL-7 I CD127 signaling pathway and of the TL1 A / TNFRSF25 signaling pathway allow addressing multiple pathways involved in the inflammatory response. Auto-immune and inflammatory diseases often involve a network of cytokines that work together to amplify inflammation. A single medication targeting one cytokine may leave other pro-inflammatory cytokines active, perpetuating the inflammatory cascade. Combining medications block multiple cytokines simultaneously, leading to a more comprehensive suppression of inflammation. Further, certain cytokines, like TNFa and IL-6, act in a feedback loop to sustain inflammation. Blocking one cytokine alone may reduce inflammation partially, but dual inhibition can disrupt these loops, amplifying the therapeutic effect.

[0019] These results clearly indicate that the provision of a compound that is an antagonist of IL-7 or CD127 in combination with a compound that is an antagonist of TL1 A or TNFRSF25 leads to health improvement.

[0020] In a particular embodiment of the invention, it is provided

[0021] a. a first compound that binds to CD127 and which is an antagonist of the IL-7 / IL-7R signaling pathway; and

[0022] b. a second compound that is an antagonist of TL1A, in particular an antagonist of the TL1 A / TNFRSF25 signaling pathway

[0023] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0024] In another embodiment of the invention, it is provided a combination for use in the treatment of an inflammatory disease or an auto-immune disease, whereinthe combination comprises an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and an antagonist TL1A antibody or an antigen-binding fragment thereof, preferably a monoclonal antibody.

[0025] The blockade, inhibition or reduction of the IL-7 I IL-7R signaling pathway and of the TL1A / TNFRSF25 signaling pathway may be achieved by providing a combination as defined here above, but also with a bifunctional molecule that recognizes and binds to at least IL-7 or CD127, and TL1 A or TNFRSF25.

[0026] DETAILED DESCRIPTION OF THE INVENTION

[0027] • Definitions

[0028] As used herein, "antibody" includes polyclonal, monoclonal, recombinant, chimeric, humanized, bispecific, multispecific, bifunctional, multifunctional and modified antibodies, as well as monovalent and divalent antigen-binding fragments thereof. Furthermore, "antibody" includes synthetic antibodies, single chain antibodies, and fragments thereof. The antibody may be a human or nonhuman antibody. A nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in human. More specifically the term “antibody” refers to a monoclonal antibody or recombinant monoclonal antibodies, or an antigen-binding fragment thereof.

[0029] As used herein, a "monoclonal antibody" is intended to refer to a preparation of antibody molecules, wherein antibodies 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 sequences. 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. 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 theantibody of the invention, that exhibits antigen-binding capacity for its target. 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 fragments that have a reduced antigen-binding affinity with respect to corresponding 4-chain antibodies are also encompassed within the invention. The antigen-binding capacity 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. For illustration purpose of specific embodiments of the invention, 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.

[0030] Antibodies and antigen-binding fragments of antibodies comprise at least a light chain variable fragment and a heavy chain variable fragment, 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 or IL-7 or TLIA or TNFRSF25 or TNFRSF6B and most particularly the extracellular domain of human CD127 or TL1A.

[0031] 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.

[0032] Antibodies and antigen-binding fragments thereof may comprise or derive from any of the commonly known immunoglobulin classes, including but not limited to IgA, secretory IgA, IgE, IgG and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human lgG1, lgG2, lgG3 and lgG4. Antigen-binding antibody mimetics are organic compounds that specifically bind antigens, but that are not structurally related to antibodies. They are usually artificial peptides or small proteins with a molar mass of about 3 to 20 kDa. Nucleic acids and small molecules are sometimes considered antibody mimeticsas well, but not artificial antibodies, antibody fragments and fusion proteins composed from these. Common advantages over antibodies are better solubility, tissue penetration, stability towards heat and enzymes, and comparatively low production costs. Antibody mimetics are being developed as therapeutic and diagnostic agents. Antigen-binding antibody mimetics may also be selected among the group comprising affibodies, affilins, affimers, affitins, DARPins, and Monobodies.

[0033] As used herein, the term "specifically binds to" or "binds specifically" refers to the capability of anti-IL-7 compounds, anti-CD127 compounds, anti-TL1A compounds, or the bifunctional compound as defined herein, to be used in the method of the invention or for use according to the invention to interact with IL-7 and to bind to IL-7, or to interact with CD127 and to bind to CD127, or to interact with TL1A and to bind to TL1A, or to interact with TNFRSF25 and bind to TNFRSF25, while they do not bind or they bind with a significantly weaker binding affinity to other molecules, in particular to other proteins. Binding and binding specificity can be assayed by SPR (Surface Plasmon Resonance e.g., Biacore), ELISA or Western Blot analysis. In a particular embodiment, the ability of a compound to bind to a molecule is considered to be specific when the binding affinity is of at least about 1 x 10’6M, 1 x 10’7M,1 x 10’8M, 1 x 10’9M, 1 x 1O’10M, 1 x 10’11M, 1 x 10’12M, or more, and / or a compound binds to a target with an affinity that is at least two-fold greater than its affinity for a nonspecific protein.

[0034] 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.A “combination” may refer in particular to a product comprising two or more compounds that are combined as a single entity. A combination may also refer to a compound labelled or indicated or provided for use with another specified compound, where both are required to achieve the intended use, indication, or effect. A "combination product" or a “combination” may refer to a therapeutic product that integrates two or more distinct types of components to achieve a combined therapeutic effect, components among which are the first compound that is an antagonist of IL-7 or CD127 and the second compound that is an antagonist of TL1A or TNFRSF25, or the bifunctional molecule, in particular bifunctional antibody as disclosed herein. Particularly, combination or combination product refer to pharmaceutical products that integrate multiple therapeutic compounds to achieve an effect, in particular a synergistic effect, for improving the health of a patient, and / or for targeting multiple signaling pathways or mechanisms of action simultaneously or separately, in particular in alternation or sequentially, either administered together or separately.

[0035] The term "in combination," in the context of the present invention, refers to the use of two or more therapeutic agents administered together to treat a disease or medical condition. Within the two or more therapeutic agents are included the first compound that is an antagonist of IL-7 or CD127 and the second compound that is an antagonist of TL1A or TNFRSF25, or the bifunctional antibody as disclosed herein. The term “in combination” may refer to a simultaneous administration: multiple agents are administered at the same time, either in a single formulation (e.g., a combination solution) or separately but concurrently, to achieve a combined therapeutic effect.

[0036] The term “in combination” may refer to a sequential administration: multiple agents are administered in a specific sequence, where the timing and order of administration are designed to maximize the therapeutic benefits and minimize potential adverse interactions.

[0037] The term “in combination” may refer to a co-administration: agents are given within a specific timeframe such that their effects overlap, creating a combined effect that is greater than the sum of the effects of each agent used individually,or that is more beneficial for the patient, in particular for clinical outcome, than the effect of administering only one of the agents.

[0038] The term “in combination” may refer to a sequential administration or a coadministration as an add-on therapy to a conventional therapy administered to a patient in need thereof.

[0039] 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 fatty liver disease, 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, osteoarthritis, psoriatic arthritis, multiple sclerosis, asthma, psoriasis, Kidney inflammatory diseases, systemic sclerosis-associated interstitial lung disease, Idiopathic pulmonary fibrosis and allergy.

[0040] As used herein, “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.

[0041] Chronic inflammatory diseases, and acute inflammatory diseases represent the major categories of inflammatory diseases. Chronic inflammatory diseases, including inflammatory bowel disease (IBD) like Crohn's disease and ulcerative colitis, chronic obstructive pulmonary disease (COPD), and asthma, involve longterm 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.

[0042] Inflammatory diseases have a profound impact on health, manifesting in various ways. For example, rheumatoid arthritis can lead to joint damage and deformities,while inflammatory bowel disease can result in severe gastrointestinal symptoms and malnutrition.

[0043] Inflammatory diseases encompass notably Ulcerative colitis. Ulcerative colitis (UC) is a chronic IBD characterized by inflammation and ulceration of the colon and rectum's innermost lining. This condition typically presents 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.

[0044] 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.

[0045] 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.

[0046] 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.Overall, while current treatments for ulcerative colitis can manage the disease and improve patient outcomes, there remain 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.

[0047] 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.

[0048] 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.

[0049] 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. In severe cases, surgery may be required to remove damaged portions of the digestive tract or to address complications such as strictures or fistulas.

[0050] 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.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. In particular, auto-immune disease refers to a disease selected from the group consisting of systemic sclerosis, rheumatoid arthritis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and lupus, such as systemic lupus erythematosus, primary biliary cirrhosis, ankylosing spondylitis, Grave’s disease. These diseases result 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.

[0051] Auto-immune diseases are a group of disorders characterized by the patient immune system's aberrant response against their own cells, organs or tissues. The pathogenesis of autoimmune diseases involves a complex interplay of genetic, environmental, and immunological factors. Key genetic factors include specific alleles of major histocompatibility complex (MHC) genes, which play a pivotal role in antigen presentation and immune response modulation. Environmental triggers, such as infections, toxins, and stress, may precipitate or exacerbate autoimmune conditions in genetically susceptible individuals.

[0052] The immunopathology of autoimmune diseases typically involves the loss of selftolerance, whereby autoreactive T cells and B cells recognize and attack selfantigens. This process is often mediated by a combination of autoantibodies and autoreactive lymphocytes, resulting in tissue-specific or systemic manifestations. For instance, in rheumatoid arthritis, autoantibodies against joint components lead to synovial inflammation and joint destruction, whereas in systemic lupus erythematosus, a broad array of autoantibodies target multiple organs, including the skin, kidneys, and central nervous system.

[0053] Current treatment modalities for autoimmune diseases aim to modulate the immune response and mitigate inflammation. These treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressive agents, and biologic therapies targeting specific immune pathways. NSAIDs and corticosteroids are commonly used for their antiinflammatory effects but are associated with significant side effects, particularly with long-term use. Immunosuppressive agents, such as methotrexate andazathioprine, inhibit immune cell proliferation and activity but also carry risks of infection and malignancy. Biologic therapies, including tumor necrosis factor (TNF) inhibitors and monoclonal antibodies targeting specific cytokines or immune cells, have brought improvements in the treatment of autoimmune diseases by providing more targeted and effective interventions.

[0054] The lnterleukin-7 / lnterleukin-7 receptor (IL-7 / 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.

[0055] IL-7 is a critical cytokine for the development of T cells in the thymus and their maintenance in the periphery. The IL-7 / 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.

[0056] In the context of inflammation, the IL-7 / IL-7R signaling pathway plays a dual role. It 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.

[0057] 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 CD127 is commonly associated with central and effector memory functions in both CD4 and CD8 peripheral T cells.Blocking IL-7 / IL-7R signaling pathway 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.

[0058] As used herein, the term “CD127” relates to a CD127 from a mammal species, preferably a human CD127, that is also known as lnterleukin-7 receptor subunit alpha (IL7R-a). CD127 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 Interleukin-7 receptor and Thymic Stromal Lymphopoietin (TSLP) receptors. The IL-7 receptor (IL-7R) is a heterodimer consisting of two subunits: IL-7Ra (CD127) that specifically binds to IL-7 and the common y chain (yc or CD132) that is shared with receptors for several other cytokines, including IL-2, IL-4, IL-9, IL-15, and IL-21. The binding of IL-7 to its receptor results in the dimerization of CD127 and CD132, initiating the IL-7 / IL-7R signaling pathway. This pathway includes the JAK-STAT5 pathway: Janus kinases (JAK1 and JAK3) are recruited by the dimerized receptor. Their activation leads to the phosphorylation of specific tyrosine residues on CD127. STAT5 binds to these phosphorylated tyrosine residues and is then phosphorylated by JAK1 and JAK3. Phosphorylated STAT5 dimerizes and translocates to the nucleus, wherein it promotes transcription of target genes involved in cell survival, proliferation, and differentiation.

[0059] In the context of the present invention, CD127 is preferably human CD127, and the antagonist of CD127 is preferably an antagonist of human CD127.

[0060] 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. 24. The extracellular domain of CD127, which is likely to be recognized and bound to by anti-CD127 antibody or antigenbinding fragment thereof used in the invention may correspond to the amino acid sequence of SEQ ID No. 25.As used herein, the term “IL-7” refers to interleukin 7. IL-7 is a cytokine produced primarily by stromal cells in the bone marrow and thymus. It is a glycoprotein essential for the survival, proliferation, and differentiation of lymphoid cells. IL-7 binds to the IL-7R complex (CD127 and yc), causing the receptor to dimerize and initiating the signaling cascade defined here above in relation to CD127. IL-7 may correspond to the protein referenced under UNIPROT Sequence No. P13232. Alternatively, IL-7 may correspond to a protein having the amino acid sequence of SEQ ID No. 26.

[0061] In the context of the present invention, IL-7 is preferably human IL-7, and the antagonist of IL-7 is preferably an antagonist of human IL-7.

[0062] As used herein, the term “TL1A” refers to TNF-like ligand 1A. It is also known as Vascular endothelial growth inhibitor (VEGI) and TNF superfamily member 15 (TNFSF15). TL1A is an anti-angiogenic protein. It belongs to tumor necrosis factor (ligand) superfamily. It is the sole known ligand for TNFRSF25 (death receptor 3 or DR3). TL1A is also recognized by TNFRSF6B (decoy receptor 3 or DcR3), a soluble TNFR family member that is expressed by a wide range of normal human tissues, particularly adult spleen, colon and lung.

[0063] TL1A is a transmembrane protein that self-assembles into stable trimers by interacting with TNF homology domain (THD). TL1A is mainly expressed as the membrane-bound form. The soluble TL1A (sTL1A) is produced by alternative splicing or TNF-a-converting enzyme (TACE) cleavage. TL1A is constitutively expressed in endothelial cell, and it is up-regulated in response to tumor necrosis factor-a (TNF-a) stimulation. It has been shown that sTL1A can be detected in serum and body fluids of patients with T cell-mediated inflammatory autoimmune diseases. TL1A also seems to be an important mediator of inflammation.

[0064] TL1A adopts the jelly-roll fold typical of the TNF family, with inner and outer [3 sheets. TL1A monomer is most similar to the TNF family members CD40L (PDB code, 1ALY) and TRAIL. TL1A yield an apparent molecular weight of approximately 66 kDa corresponding to 3 assembled monomers.

[0065] TL1A may correspond to the protein referenced under UNIPROT Sequence No.

[0066] 095150. Alternatively, TL1A may correspond to a protein having the amino acid sequence of SEQ ID No. 27.In the context of the present invention, TL1A is preferably human TL1A, and the antagonist of TL1 A is preferably an antagonist of human TL1 A.

[0067] TL1A signals through transmembrane receptor tumor necrosis factor receptor superfamily member 25 (TNFRSF25), also known as Death receptor 3 (DR3). TNFRSF25 is a cell surface receptor of the tumor necrosis factor receptor superfamily which mediates apoptotic signalling and differentiation, and TL1 A is only known ligand. Activated T cells express transmembrane TNFRSF25. It activates receptors, leading to apoptosis or activation of transcription factors such as NF-KB. When sTL1A binds to TNFRSF25, it activates downstream signaling cascades that modulate immune response and inflammation. Two different signaling pathways could be triggered by sTL1A / TNFRSF25 interaction, causing inflammation and apoptosis, respectively. First, death domain of TNFRSF25 combines with adapter protein TNFR-associated death domain protein (TRADD) in the cytoplasm, and then recruits TNFR-associated factor 2 (TRAF2) and receptor-interacting protein 1 (RIP1). These complexes activate MAPKs (ERK, p38, and JNK), NF-KB, and the effector kinases PI3K signaling, the activated signaling regulated expression of pro-inflammatory genes and participated in occurrence of immune related diseases. TRADD binds to Fas-associated death domain (FADD) and RIP3, and then activates cysteinyl aspartate specific proteinase-8 (caspase-8) to form complexes, which further activate downstream caspase pathways (for example, caspase-3 and -7) and induce apoptotic cell death. Combination of FADD, RIP3, RIP1 and the downstream effector molecule mixed lineage kinase domain-like protein (MLKL) forms a cytosolic “necrosome” complex after phosphorylation when caspase-8 activity is blocked. Then, MLKL oligomerizes to the cell membrane, and causes necroptotic cell death, a form of cell death with intense inflammation. In this process, NF-KB is proved to induce activation of cellular inhibitor of apoptosis proteins (c-lAP), which mediates negative feedback regulation and inhibition of cell apoptosis.

[0068] TNFRSF25 may correspond to the protein referenced under UNIPROT Sequence No. Q93038. Alternatively, TNFRSF25 may correspond to a protein having the amino acid sequence of SEQ ID No. 28.In the context of the present invention, TNFRSF25 is preferably human TNFRSF25.

[0069] TNFRSF6B, also known as soluble decoy receptor 3 (DcR3), is another receptor for TL1 A, which lacks a cytoplasmic domain. It regulates cell function by ‘decoy’ and ‘non-decoy’ action. When TNFRSF6B binds to sTL1A, it results in less lymphocyte activation, pro-inflammatory cytokine production and prevention of apoptosis. TNFRSF6B may thus abolish effects of STL1A / TNFRSF25 interaction.

[0070] TNFRSF6B may correspond to the protein referenced under UNIPROT Sequence No. 095407. Alternatively, TNFRSF6B may correspond to a protein having the amino acid sequence of SEQ ID No. 29.

[0071] 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. As used herein, an “effective amount” or “therapeutically effective amount” or a “sufficient amount” of a composition, or a compound is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends upon the context in which it is being applied, but means that a beneficial or desired result is achieved, in particular in a human suffering from a pathology, including an auto-immune disease or an inflammatory disease.• The first compound that is an antagonist of IL-7 or CD127

[0072] The composition to be used according to the present invention, or in a method according to the present invention, comprises a first compound that is an antagonist of IL-7 or CD127.

[0073] Antagonists of IL-7 or of CD127 can interfere with the binding of IL-7 to CD127, thereby inhibiting or reducing the signal transduction pathway initiated by the binding of IL-7 to its receptor CD127.

[0074] In an embodiment, the first compound is an antagonist of IL-7. An antagonist of IL-7 refers to any compound that inhibits or reduces the biological activity of IL-7.

[0075] In an embodiment, the first compound is an antagonist of CD127. An antagonist of CD127 refers to any compound that inhibits or reduces the biological activity of CD127.

[0076] In an embodiment, the first compound inhibits or reduces the binding between IL-7 and CD127.

[0077] In particular, the first compound is an antagonist anti-IL-7 compound that binds to IL-7, and inhibits or reduces the binding of IL-7 to CD127. Such a first compound can be defined as an “anti-IL-7 compound”.

[0078] In an embodiment, the first compound is an antagonist of IL-7 that binds to, in particular specifically binds to, IL-7, and inhibits or reduces the IL-7 I IL-7R signaling pathway. Such a first compound can be defined as an “anti-IL-7 compound”.

[0079] In an embodiment, the first compound is an antagonist anti-CD127 compound that binds to CD127, and inhibits or reduces the binding of IL-7 to CD127. Such a first compound can be defined as an “anti-CD127 compound”.

[0080] In an embodiment, the first compound is an antagonist of CD127 that binds to, in particular specifically binds to, CD127, and inhibits or reduces the IL-7 / IL-7Rsignaling pathway. Such a first compound can be defined as an “anti-CD127 compound”.

[0081] Anti-IL-7 compounds bind to IL-7. As used herein, an anti-IL-7 compound thus refers to a compound selected from the list consisting of antibodies; antigenbinding fragments of an antibody; antigen-binding antibody mimetics; macromolecules comprising an antibody, an antigen-binding fragments of an antibody, or an antigen-binding antibody mimetics; and which binds, in particular specifically binds, to IL-7, and that inhibits or reduces the binding of IL-7 to CD127. In particular such a compound inhibits or reduces the signaling pathway induced by the binding of IL-7 to CD127. In a preferred embodiment, the anti-IL-7 compound is a monoclonal antibody or an antigen-binding fragment thereof.

[0082] Anti-CD127 compounds bind to CD127. As used herein, an anti-CD127 compound thus refers to a compound selected from the list consisting of antibodies; antigen-binding fragments of an antibody; antigen-binding antibody mimetics; macromolecules comprising an antibody, an antigen-binding fragments of an antibody, or an antigen-binding antibody mimetics; and which binds, in particular specifically binds, to CD127, and that inhibits or reduces the binding of IL-7 to CD127. In particular such a compound inhibits or reduces the signaling pathway induced by the binding of IL-7 to CD127. In a preferred embodiment, the anti-CD127 compound is a monoclonal antibody or an antigen-binding fragment thereof.

[0083] An antagonist of the IL-7 I IL-7R signaling pathway has the capability to inhibit or reduce the biological activity induced by the binding of IL-7 to its receptor CD127. In other words, the first compound that is an antagonist of IL-7 or CD127 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 first compound. As used herein, an IL-7 antagonist compound or a CD127 antagonist compound, in particular an anti-IL-7 or anti-CD127 antagonist antibody or a related compound, has its general meaning in the art and refers to any compound, natural orsynthetic, that blocks, suppresses, inhibits or reduces the biological activity induced by the binding of IL-7 to CD127. In particular, the IL-7 antagonist compound or the CD127 antagonist compound inhibits the interactions between IL-7 and CD127. In particular, the IL-7 antagonist compound or the CD127 antagonist compound inhibits or reduces the activation of the phosphatidylinositol 3-kinase and / or the ERK signaling pathway induced by IL-7.

[0084] In an embodiment, it can be considered that the first compound (in particular when it is 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).

[0085] In a particular embodiment, the anti-IL-7 or anti-CD127 compound 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 and the ERK signaling pathway and does not induce the phosphorylation of STAT5.

[0086] In a particular embodiment, the anti-IL-7 or anti-CD127 compound does not induce lymphodepletion (destruction of lymphocytes, in particular? cells), in the patient, particularly does not lead to lymphodepletion in the patient. Lymphodepletion corresponds to a reduction, in particular a strong reduction, in the overall number of lymphocytes in the patient. An anti-IL-7 or anti-CD127 compound 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 anti-CD127 compound) or as compared to usual numbers of lymphocytes in a healthy human,which are known by skilled artisans. In particular, the antagonist anti-CD127 antibody or antigen binding fragment thereof does not to induce lymphodepletion, lymphodepletion being considered present when the overall number of lymphocyte in a biological sample is not inferior to 500 / pl.

[0087] In a preferred embodiment, the first compound is an antagonist anti-IL-7 antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic thereof.

[0088] In a preferred embodiment, the anti-IL-7 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.

[0089] In a particular embodiment of the invention, the anti-IL-7 compound is an anti-IL-7 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0090] In a particular embodiment of the invention, the anti-IL-7 compound is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0091] In a preferred embodiment, the first compound is an antagonist anti-CD127 antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic thereof.

[0092] In a preferred embodiment, the antagonist anti-CD127 antibody or an antigenbinding 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.

[0093] In a particular embodiment of the invention, the antagonist anti-CD127 compound is an anti-CD127 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.In a particular embodiment of the invention, the antagonist anti-CD127 compound is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0094] More particularly, the heavy chain constant domain of the antagonist anti-IL-7 or anti-CD127 antibody or an antigen-binding fragment thereof may be derived from a human IgG 1 , 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.

[0095] In a particular embodiment of the invention, the antagonist anti-IL-7 or 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.

[0096] In a particular embodiment of the invention, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises:

[0097] i) a heavy chain variable fragment comprising:

[0098] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA), and

[0099] 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:

[0100] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), andb. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and

[0101] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA).

[0102] Said above CDR domains have been identified according to the KABAT numbering.

[0103] 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:

[0104] i) a heavy chain variable fragment comprising:

[0105] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 30 (DYYMA), and

[0106] 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

[0107] ii) a light chain variable fragment comprising:

[0108] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), and

[0109] b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and

[0110] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA).

[0111] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof comprises:

[0112] - the antibody heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0113] - the antibody light chain variable fragment 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.In a particular embodiment of the invention, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises:

[0114] i) a heavy chain variable fragment comprising:

[0115] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 19 (GFTLSDYY), and

[0116] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 20 (ISASGLRT), and

[0117] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 21 (ARPLSAHYGFNYFDY), and

[0118] ii) a light chain variable fragment comprising:

[0119] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 22 (EDIYQG), and

[0120] b. LCDR2 comprising or consisting in the amino acid sequence “SAN”, and

[0121] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 23 (QQYYDYPLA).

[0122] Said above CDR domains have been identified according to the IMGT numbering.

[0123] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof comprises:

[0124] - the antibody heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0125] - the antibody light chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 12.

[0126] 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.

[0127] In a particular aspect of the invention, the antagonist anti-human CD127 antibody or an antigen-binding fragment thereof comprises:

[0128] a heavy chain variable fragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13, and a light chain variable fragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 14or SEQ ID No. 15 or SEQ ID No. 16 or SEQ ID No. 17 or SEQ ID No. 18, preferably SEQ ID No. 18.

[0129] 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 variable fragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13 and a light chain variable fragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 18.

[0130] In a particular embodiment of the invention, the antagonist anti-IL-7 or anti-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 in the form of an isolated nucleic acid molecule or group of isolated nucleic acid molecules encoding the antagonist anti-IL-7 or anti-CD127 antibody or antigen-binding fragment thereof as defined herein according to the invention.

[0131] Particularly, said nucleic acid molecule or group of nucleic acid molecule encodes the light chain variable fragment or the light chain of an antibody provided herein, and the heavy chain variable fragment 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 an anti-CD127 antibody with:

[0132] a heavy chain variable fragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 7, and a light chain variable fragment 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.

[0133] 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.

[0134] 15 or SEQ ID No. 16 or SEQ ID No. 17 or SEQ ID No. 18, preferably SEQ ID No.

[0135] 18.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.

[0136] In a particular embodiment of the invention, the antagonist anti-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:

[0137] a) it inhibits or reduces the activation of the phosphatidylinositol 3-kinase and / or the ERK signaling pathway induced by IL-7,

[0138] 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 compound compared to cells treated with TSLP alone), c) 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 compound 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);d) it binds to T cells;

[0139] e) it does not antagonize the TSLP / TSLPR signaling pathway.

[0140] Details about how to assess if an anti-compound has or has not one of these properties may be found in WO2015 / 189302 and WO2018 / 104483 and W02020154293)

[0141] In a particular embodiment of the invention the anti-CD127 compound is an antagonist anti-CD127 antibody, an antigen-binding fragment thereof, or an antigen-binding antibody mimetic thereof which does not antagonize the TSLP / TSLPR signaling pathway.

[0142] By selectively antagonizing the IL-7 / IL-7R pathway, the anti-CD127 compound specifically modulates immune responses mediated by IL-7 without interfering with TSLP signaling. TSLP-induced signaling pathways have been shown to be different, at the molecular level, from IL-7-induced pathways. In particular, while TSLP binding to its receptor also activates Jak-1 , it does not activate Jak-3 but does activate Jak-2. One major effect of TSLP is to lead to the activation of dendritic cells, inducing the overexpression of costimulatory molecules such as CD80, thereby promoting TH-2 mediated inflammatory responses.

[0143] In the presence of TSLP, dendritic cells get activated and promote T cell-mediated immune responses. Some monoclonal antibodies against CD127, presumably by modifying the way TSLP interacts with TSLP receptor, have the property to increase the maturation of dendritic cells induced by TSLP. As a consequence, a therapy with a monoclonal antibody against CD127 that would not increase the maturation of dendritic cells induced by TSLP might present a further therapeutic advantage in certain cases. It presents the benefit of IL7R blockade without the drawback of activating dendritic cells in an inflamed environment containing TSLP.

[0144] In a particular embodiment of the invention, the first compound is an antagonist of the IL-7 I IL-7R signaling pathway but does not antagonize the TSLP I TSLPR signaling pathway. In a particular embodiment of the invention, the antagonist anti-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 theinvention is an antagonist of the IL-7 I IL-7R signaling pathway but does not antagonize the TSLP I TSLPR signaling pathway.

[0145] Thymic Stromal Lymphopoietin (TSLP) is a cytokine that has a significant role in the maturation of T cells and the modulation of immune responses. The TSLP receptor is a heterodimer consisting of two subunits: TSLP Receptor (TSLPR) which is a specific receptor subunit for TSLP, and CD127. The TSLP / IL-7R signaling pathway involves the JAK-STAT Pathway: JAK 1 and JAK2 are recruited after TSLP receptor dimerization. JAK 1 and JAK2 phosphorylate specific tyrosine residues on the TSLPR and CD127 subunits. STAT5 binds to these phosphorylated residues, and is then phosphorylated, allowing its translocation into the nucleus.

[0146] Not antagonizing the TSLP / TSLPR signaling pathway may mean the anti-CD127 compound does not reduce or inhibit the binding between TSLP and TSLPR and / or CD127. Alternatively, or complementarily, not antagonizing the TSLP I TSLPR signaling pathway may mean that the singling pathway induced when TSLP interact with the TSLPR I CD127 complex is not reduced or inhibited in presence of the anti-CD127 compound.

[0147] The lack of antagonist capability of the anti-CD127 compound towards binding between TSLP and TSLPR and / or CD127 or toward the TSLP I TSLPR signaling pathway may be assessed by measuring the binding of TSLP to TSLPR and / or CD127 in presence and in absence of the anti-CD127 compound.

[0148] In an embodiment, it can be considered that an antibody (or antigen-binding fragment thereof) reduces, inhibits or blocks the binding of TSLP to TSLPR and / or CD127 if said compound 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 TSLP to TSLPR and / or CD127 in a binding competitive assay by Blitz, as compared to the KD value of TSLP to TSLP-R and / or CD127 in presence of a control antibody (i.e. an antibody which does not specifically bind to TSLP nor CD127).

[0149] In an embodiment, the first compound is GSK-3888130 (GlaxoSmithKline, an anti-IL-7 antibody), an antagonist anti-IL-7 antibody.In an embodiment, the first compound is an anti-CD127 compound selected from the list consisting of bempikibart (an anti-IL7R antibody, Bristol-Myers Squibb; (formerly ADX-914); information including sequences disclosed on WHO Drug Information, Vol. 36, No. 2, 2022, pages 330, 331), lusvertikimab (OSE Immunotherapeutics, an anti-CD127 antibody; information including sequences disclosed on WHO Drug Information, Vol. 34, No. 4, 2020, pages 999, 1000), PF-06342674 (Zura Bio, an anti-CD127 antibody).

[0150] • Compounds that are antagonists of TL1 A or TNFRSF25

[0151] The composition to be used according to the present invention, or in a method according to the present invention, comprises a second compound that is an antagonist of TL1 A, in particular of human TL1 A, or an antagonist of TNFRSF25, in particular human TNFRSF25.

[0152] In the context of this patent application, an "antagonist of TL1 A or TNFRSF25" refers to any substance that inhibits or reduces the biological activity of TL1 A, in particular human TL1A, or of receptor TNFRSF25, more particularly of human TNFRSF25. These antagonists can prevent TL1A from binding to its receptor, block the signal transduction pathway induced by the binding between TL1 A and TNFRSF25, or otherwise interfere with their ability to exert their biological effects, in particular immunological effects. This inhibition can be achieved through various mechanisms, including a direct binding to TL1A, a direct binding to TNFRSF25, or an interruption of downstream signaling pathways induced by the binding of TL1 A to TNFRSF25.

[0153] In an embodiment, an antagonist of TL1 A binds to TL1 A or TNFRSF25.

[0154] In an embodiment, an antagonist of TL1A binds to TL1A or TNFRSF25, and inhibits or reduces the TL1A / TNFRSF25 signaling pathway.

[0155] The TL1A / TNFRSF25 signaling pathway corresponds to the cascade activated when TL1A binds to its receptor TNFRSF25. When this pathway is activated, it includes the recruitment of TRADD (TNFR-associated death domain) and TRAF(TNFR-associated factors), the activation of NF-KB, the activation of MARK, and cytokine production such as IL-6, IL-9, IL-17, IL-13, IFNy, and TNFa. Thus, in an embodiment, an inhibition or a reduction of the TL1A / TNFRSF25 signaling pathway means that the recruitment of TRADD I TRAF, and / or the activation of NF-KB, and / or the activation of MARK, and / or the production and / or secretion of IL-6, IL-9, IL-17, IL-13, IFNy, and / or TNFa (in particular of IL-6, IL-9, IFNy and TNFa) is reduced in cells in presence of the antagonist of TL1A or TNFRSF25 as compared to the same cells in presence of a negative control (i.e. a compound that do not interfere with TL1A and TNFRSF25). Inhibition of the TL1A / TNFRSF25 signaling pathway can be assessed in the presence of a compound by measuring the secretion of cytokines IL-6, IL-9, IFNy and TNFa in cells treated with the antagonist. When in presence of a compound the secretion of at least one of these cytokines is reduced, the compound can be considered to be an antagonist of the TL1 A / TNFRSF25 signaling pathway.

[0156] An antagonist of TL1 A or TNFRSF25 can be a compound that inhibits or reduces downstream signaling pathway(s) induced or activated when TL1A binds to its receptor TNFRSF25.

[0157] In a particular embodiment, an antagonist of TL1 A is an antibody or an antigenbinding fragment or an antigen-binding antibody mimetic that binds to, in particular specifically binds to TL1 A, or that binds to TNFRSF25, and inhibits or reduces the binding between TL1A and TNFRSF25.

[0158] An antagonist of TL1 A can be a compound that binds to TL1 A and prevents the binding between TL1A and its receptor TNFRSF25.

[0159] An antagonist of TL1A can be a compound that binds to TNFRSF25, and prevents the binding between TL1A and TNFRSF25.

[0160] In an embodiment, the antagonist of TL1A is an anti-TL1A antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to TL1A.In an embodiment, the antagonist of TL1A is an anti-TL1A antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to TL1A and blocks or inhibits the binding between TL1A and TNFRSF25. In an embodiment, the antagonist of TL1A is an anti-TL1A antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to TL1A, and blocks or inhibits the binding between TL1A and TNFRSF25, and is in particular an antagonist of the TL1A / TNFRSF25 signaling pathway (it inhibits or reduces the TL1A / TNFRSF25 signaling pathway).

[0161] In an embodiment, the antagonist of TL1A is an anti-TNFRSF25 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to TNFRSF25.

[0162] In an embodiment, the antagonist of TL1A is an anti-TNFRSF25 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to TNFRSF25 and blocks or inhibits the binding between TL1A and TNFRSF25.

[0163] In an embodiment, the antagonist of TL1A is an anti-TNFRSF25 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to TNFRSF25 and blocks or inhibits the binding between TL1A and TNFRSF25, and in particular is an antagonist of the TL1A / TNFRSF25 signaling pathway.

[0164] It can be considered that an antagonist of TL1A, in particular an antibody (or antigen-binding fragment thereof) reduces, inhibits or blocks the binding of TL1 A to TNFRSF25, 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 TL1A to TNFRSF25 in a binding competitive assay by Blitz, as compared to the KD value of TL1 A to TNFRSF25 in presence of a control antibody (i.e. an antibody which does not specifically bind to TL1 A or TNFRSF25.

[0165] In a particular embodiment of the invention, the antagonist of TL1A is an anti-TL1A or anti-TL1A antibody, or an antigen-binding fragment thereof, that is ahumanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0166] In a particular embodiment of the invention, the antagonist of TL1A is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0167] In a particular embodiment of the invention, the antagonist of TL1A is an anti-TL1A antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0168] In a particular embodiment of the invention, the antagonist of TL1A is an anti-TL1A antibody selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0169] In an embodiment, the antagonist of TL1A is a soluble TNFRSF25 orTNFRSF6B. A soluble TNFRSF25 or TNFRSF6B receptor is an engineered TNFRSF25 or TNFRSF6B comprising at least a fragment of the extracellular domain of TNFRSF25 that is not membrane-bounded but circulates in the bloodstream of the patient or at least a fragment of soluble TNFRSF6B, thereby binding co circulating TL1 A and sequestering it away from the cell surface TNFRs.

[0170] In particular, the antagonist of TL1 A is a soluble protein or a soluble fusion protein that comprise at least 50% in amino acid length of the extracellular domain of either TNFRSF25 or of TNFRSF6B, in particular at least 60%, in particular at least 70%, in particular at least 80%, in particular at least 90%, in particular at least 95%.

[0171] In an embodiment, the antagonist of TL1A is a peptide that binds to TNFRSF25. In an embodiment, the antagonist of TL1 A is a peptide that binds to TNFRSF25, and blocks or inhibits the binding between TL1A and TNFRSF25.

[0172] In an embodiment, the antagonist of TL1 A or TNFRSF25 is selected from the list consisting of Tulisokibart (also named PRA023 and MK7240, a humanized anti-TL1A antibody developed by Merck), PF-06480605 (also named RVT-3101, a fully human immunoglobulin G1 monoclonal anti-TL1A antibody from Pfizer Inc),TEV- 574 (also named SAR-447189 and TEV-4857, a human antibody that targets tumor TL1A, under development by Teva in collaboration with Sanofi), SL-325 (antagonist anti-TNFRSF25 antibody under development by Shattuck Lab), XmAb-942 (a monospecific anti-TL1A antibody under development by Xencor), and biosimilars thereof.

[0173] In an embodiment, the antagonist of TL1 A is selected from the list consisting of Tulisokibart, PF-06480605, TEV- 574, XmAb-942, and biosimilars thereof.

[0174] In a preferred embodiment of the invention, the antagonist of TL1-A is an antagonist anti-TL1A antibody or antigen-binding fragment thereof which comprises:

[0175] i) a heavy chain variable fragment comprising:

[0176] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DTYMH), and

[0177] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (RIDPASGHTKYDPKFQV), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (SGGLPDV), and

[0178] ii) a light chain variable fragment comprising:

[0179] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASSSVSYMY), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (ATSNLAS), and

[0180] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QQWEGNPRT).

[0181] Said above CDR domains have been identified according to the KABAT numbering.

[0182] In another particular embodiment of the invention, the second compound is an antagonist anti-TL1A antibody or antigen binding fragment thereof which comprises:

[0183] i) a heavy chain variable fragment comprising:a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 37 (GFDIQDTY), and

[0184] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 38 (IDPASGHT), and

[0185] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 39 (ARSGGLPDV), and

[0186] ii) a light chain variable fragment comprising:

[0187] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 40 (SSVSY), and

[0188] b. LCDR2 comprising or consisting in the amino acid sequence “AT”, and

[0189] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 41 (QQWEGNPRT).

[0190] Said above CDR domains have been identified according to the IMGT numbering. In a particular embodiment of the invention, the anti-TL1A antibody or antigenbinding fragment thereof comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43. In a more particular embodiment of the invention, the antagonist anti-TL1A antibody or antigen binding fragment thereof comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 44, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 45.

[0191] In a preferred embodiment, the antagonist of TL1-A is Tulisokibart.

[0192] In an embodiment, the antagonist of TSFRSF25 is SL-325 or a biosimilar thereof.

[0193] In a particular embodiment of the invention, it is provided a combination comprising:- A first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and

[0194] - Tulisokibart,

[0195] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0196] In a preferred embodiment, it is provided a combination comprising:

[0197] - a first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and

[0198] - a second compound that is an antagonist of TL1 -A,

[0199] preferably for use in the treatment of an inflammatory disease or an auto-immune disease, wherein the second compound is an antagonist anti-TL1A antibody or antigen-binding fragment thereof which comprises:

[0200] iii) a heavy chain variable fragment comprising:

[0201] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DTYMH), and

[0202] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (RIDPASGHTKYDPKFQV), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (SGGLPDV), and

[0203] iv) a light chain variable fragment comprising:

[0204] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASSSVSYMY), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (ATSNLAS), and

[0205] - LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QQWEGNPRT),

[0206] preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43, more preferably comprises the antibodyheavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 44, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 45.

[0207] In a more preferred embodiment, it is provided a combination comprising:

[0208] - a first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and

[0209] - a second compound that is an antagonist of TL1 -A,

[0210] preferably for use in the treatment of an inflammatory disease or an auto-immune disease,

[0211] wherein the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises:

[0212] i) a heavy chain variable fragment comprising:

[0213] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA), and

[0214] 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:

[0215] 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

[0216] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA),

[0217] preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 12, more preferably comprises a heavy chain variablefragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13, and a light chain variable fragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 14 or SEQ ID No. 15 or SEQ ID No.

[0218] 16 or SEQ ID No. 17 or SEQ ID No. 18, preferably SEQ ID No. 18.

[0219] In a more preferred embodiment, it is provided a combination comprising:

[0220] - a first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and

[0221] - a second compound that is an antagonist of TL1 -A,

[0222] preferably for use in the treatment of an inflammatory disease or an auto-immune disease,

[0223] wherein the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises:

[0224] i) a heavy chain variable fragment comprising:

[0225] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA), and

[0226] 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:

[0227] 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

[0228] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA),

[0229] preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 12, more preferably comprises a heavy chain variablefragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13, and a light chain variable fragment comprising or consisting of the amino acid sequence set forth in SEQ ID No. 14 or SEQ ID No. 15 or SEQ ID No.

[0230] 16 or SEQ ID No. 17 or SEQ ID No. 18, preferably SEQ ID No. 18 and wherein the second compound is an antagonist anti-TL1A antibody or antigenbinding fragment thereof which comprises:

[0231] i) a heavy chain variable fragment comprising:

[0232] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DTYMH), and

[0233] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (RIDPASGHTKYDPKFQV), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (SGGLPDV), and

[0234] ii) a light chain variable fragment comprising:

[0235] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASSSVSYMY), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (ATSNLAS), and

[0236] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QQWEGNPRT),

[0237] preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43, more preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 44, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 45.

[0238] In a particular embodiment of the invention, it is provided a combination comprising:i) A first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and ii) PF-06480605,

[0239] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0240] In an embodiment, the antagonist of TNFRSF25 is selected from the list consisting of SL-325 (antagonist anti-TNFRSF25 antibody under development by Shattuck Lab) and biosimilars thereof.

[0241] In a particular embodiment of the invention, it is provided a combination comprising:

[0242] i) A first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and ii) SL-325,

[0243] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0244] In an embodiment of the invention, it is provided a combination comprising:

[0245] a. an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and

[0246] b. an antagonist anti-TL1A antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0247] In an embodiment of the invention, it is provided a combination comprising:

[0248] a. an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and

[0249] b. an antagonist anti-TNFRSF25 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0250] In an embodiment, it is provided a first compound that is an antagonist of IL-7 and / or CD127 (e.g., an antagonist anti-human CD127 antibody or antigenbinding fragment thereof as described herein), for use in a combination regimenwith a second compound that is an antagonist of TL1A or TNFRSF25, preferably antagonist of TL1A ((e.g., an antagonist anti-TL1A antibody or antigen-binding fragment thereof as described herein) for the treatment of an inflammatory disease or an auto-immune disease.

[0251] In an embodiment, it is provided a first compound that is an antagonist antiCDF? antibody or antigen-binding fragment thereof, for use in a combination regimen with a second compound that is an antagonist of TL1A or TNFRSF25, preferably antagonist of TL1 A (e.g., an antagonist anti-TL1 A antibody or antigenbinding fragment thereof as described herein) for the treatment of an inflammatory disease or an auto-immune disease.

[0252] In an embodiment, the second compound is selected from the group consisting of:

[0253] i) a protein comprising at least a portion of TNFRSF25 or TNFRSF6B;

[0254] and

[0255] ii) an antibody, an antigen-binding fragment thereof or an antigenbinding antibody mimetic thereof, that binds to TL1 A or TNFRSF25, and inhibits or reduces the binding between TL1A and TNFRSF25; in particular wherein said second compound is an antagonist of the TL1A / TNFRSF25 signaling pathway.

[0256] • Bifunctional molecules including bifunctional antibodies and derived molecules

[0257] In an aspect of the invention, it is provided a bifunctional molecule that comprises:

[0258] A first binding moiety, said first binding moiety binding to IL-7 or CD127, and

[0259] A second binding moiety, said second binding moiety binding to TL1A or TNFRSF25.

[0260] In a particular aspect of the invention, it is provided a bifunctional molecule, in particular a bifunctional antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic thereof, that binds to, in particular specificallybinds to, two distinct first and second antigens, the first antigen being IL-7 or CD127 and the second antigen being TL1 A or TNFRSF25.

[0261] In particular, the bifunctional molecule inhibits (i) the binding between IL-7 and CD127, in particular human IL-7 and human CD127, and (ii) the binding between TL1A and TNFRSF25, in particular human TL1A and human TNFRSF25.

[0262] In a particular aspect of the invention, it is provided a bifunctional molecule that comprises:

[0263] A first binding moiety, said first binding moiety binding to CD127, in particular human CD127, and

[0264] A second binding moiety, said second binding moiety binding to TL1A.

[0265] In a particular embodiment, the binding moiety of the bifunctional molecule that binds to CD127 comprises:

[0266] a heavy chain variable fragment (VH) comprising:

[0267] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1, and

[0268] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and

[0269] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0270] - a light chain variable fragment (VL) comprising:

[0271] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and

[0272] b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and

[0273] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6;

[0274] in particular wherein the heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and the light chain variable fragment 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; in a more particular embodiment, the heavy chaincomprises or consists in the amino acid sequence set forth in SEQ ID No: 13, and a light chain comprises or consists in the amino acid sequence set forth in SEQ ID No. 18.

[0275] In another particular embodiment, that can be combined with the previous one, the binding moiety of the bifunctional molecule that binds to TL1-A comprises :

[0276] i) a heavy chain variable fragment comprising:

[0277] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DTYMH), and

[0278] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (RIDPASGHTKYDPKFQV), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (SGGLPDV), and

[0279] ii) a light chain variable fragment comprising:

[0280] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASSSVSYMY), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (ATSNLAS), and

[0281] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QQWEGNPRT),

[0282] preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43, more preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 44, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 45.

[0283] The first and second binding moieties are directed to two different targets, so that the molecule according to the invention is “bifunctional”, i.e. , is able to bind to at least two different targets (e.g., IL-7 or CD127 on one hand, and TL1A and TNFRSF25 on the other hand).In an aspect of the invention, it is provided a bifunctional molecule that comprises: A first binding moiety, said first binding moiety binding to IL-7 or CD127,

[0284] A second binding moiety, said second binding moiety binding to TLIA and TNFRSF25,

[0285] the bifunctional molecule inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between TL1A and TNFRSF25.

[0286] The inhibition of the binding between IL-7 and CD127 and TL1 A and TNFRSF25 has the same meaning as detailed above in relation to the combinations of compounds.

[0287] In an aspect of the invention, it is provided a bifunctional molecule that comprises:

[0288] A first binding moiety, said first binding moiety binding to IL-7 or CD127,

[0289] A second binding moiety, said second binding moiety binding to TL1A or TNFRSF25,

[0290] the bifunctional molecule being an antagonist of IL-7 and / or CD127, and the bifunctional molecule being an antagonist of TL1 A and / or TNFRSF25.

[0291] The antagonist property of the bifunctional molecule towards IL-7, CD127,TL1A and TNFRSF25 has the same meaning as detailed above in relation to the combinations of compounds

[0292] The structure of several bifunctional molecules according to the invention are detailed on figure 7. These examples serve primarily to illustrate certain aspects of the invention, and the bifunctional molecules according to the invention are not limited to these specific examples. For example, in these figures, the first moiety recognizes IL-7 and / or CD127 and is shown in green, while the second moiety recognizes TL1 A or TNFRSF25 and is shown in blue. These two binding moieties can be interchanged, for example (e.g., the first moiety binding to CD127 in blue and the second binding moiety binding to TL1 A or TNFRSF25 in green).The bifunctional molecule may particularly comprise two, three or four binding moieties. For example, the bifunctional molecule may comprise:

[0293] one binding moiety that binds to IL-7 or CD127 and one binding moiety that binds TL1 A or TNFRSF25; or

[0294] two binding moieties that bind to IL-7 or CD127, said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to CD127; and one binding moiety that binds to TL1A or TNFRSF25; or

[0295] two binding moieties that bind toTLIA and / or TNFRSF25, said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to TL1A; and one binding moiety that binds to IL-7 or CD127, preferably CD127; or

[0296] two binding moieties that bind toTLIA and / or TNFRSF25, said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to TL1 A; and two binding moiety that binds to IL-7 or CD127; said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to CD127; or

[0297] three binding moieties that bind to IL-7 or CD127, said three binding moieties binding to the same or to different target(s), preferably the same target, most preferably to CD127; and one binding moiety that binds to TL1A or TNFRSF25;

[0298] three binding moieties that bind to TL1A and / or TNFRSF25, said three binding moieties binding to the same or to different target(s), preferably the same target, most preferably to TL1A; and one binding moiety that binds to IL-7 or CD127, preferably CD127.

[0299] The first and second binding moiety are preferably antigen binding domains, in particular derived from Fab, Fab', F(ab')2, Fv, single chain (scFv), CrossMAb, a dual variable domain immunoglobulin (DVD-lg), or nanobody (VHH), preferably a CrossMab, a DVD-lg, a scFV. In the bifunctional molecule, the first and second binding moiety may have the same or different formats.

[0300] For example, the first binding moiety can be on a monovalent immunoglobulin comprising a Fab fragment with an antigen-binding region recognizing IL-7 or CD127, and the second binding moiety can be another monovalentimmunoglobulin comprising a Fab fragment with an antigen-binding region recognizing to TL1A or TNFRSF25, the two immunoglobulins forming a bifunctional antibody.

[0301] In a particular embodiment, the binding moiety of the bifunctional molecule that binds to CD127 (in particular first, second, third binding moiety) comprises: a heavy chain variable fragment (VH) comprising:

[0302] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1, and

[0303] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and

[0304] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0305] - a light chain variable fragment (VL) comprising:

[0306] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and

[0307] b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and

[0308] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6;

[0309] in particular wherein the heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and the light chain variable fragment 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; in a more particular embodiment, the heavy chain comprises or consists in the amino acid sequence set forth in SEQ ID No: 13, and a light chain comprises or consists in the amino acid sequence set forth in SEQ ID No. 18, and / or the binding moiety of the bifunctional molecule that binds to TL1-A comprises :

[0310] i) a heavy chain variable fragment comprising:

[0311] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DTYMH), and

[0312] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (RIDPASGHTKYDPKFQV), andc. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (SGGLPDV), and

[0313] ii) a light chain variable fragment comprising:

[0314] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASSSVSYMY), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (ATSNLAS), and

[0315] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QQWEGNPRT),

[0316] preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43, more preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 44, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 45.

[0317] According to an embodiment, the bifunctional molecule of the invention is a bifunctional antibody. As used herein, a “bifunctional” in relation to an antibody or antigen-binding fragments refers to an antibody or an antigen-binding fragments which (i) has two arms for antigen binding wherein each of the two arm binds to a different antigen or which (ii) has more than two arms wherein at least one of the arms binds to a second antigen or respectively a first antigen when at least one other arm, or the other arms, bind to the first antigen or the second antigen respectively. Otherwise stated, the bifunctional antibodies or the antigen-binding fragments may recognize at least two different antigens, preferably two different antigens, by virtue of possessing at least one region (e.g. derived from a variable region of a first antibody) that is specific for a first antigen, and at least a second region (e.g. derived from a variable region of a second antibody) that is specific for a second antigen. A bifunctional antibody specifically binds to two target antigens and is thus one type of multispecific antibody. Bifunctional antibodiesinclude all antibodies or conjugates of antibodies, or polymeric forms of antibodies which are capable of recognizing two different antigens. Bifunctional antibodies include antibodies that have been reduced and reformed so as to retain their bivalent characteristics and to antibodies that have been chemically coupled so that they can have several antigen recognition sites for each antigen. In a particular embodiment, a bifunctional antibody according to the invention is a bispecific antibody, i.e. an antibody that specifically recognized two different targets.

[0318] In an embodiment, the bifunctional molecule is a bifunctional antibody that combines the light and heavy chains of two different antibodies, in particular two monoclonal antibodies, the two different antibodies binding to different target; one binding to IL-7 or CD127, the other one binding to TL1A or TNFRSF25.

[0319] The bifunctional molecule preferably comprises: i) a first and a second binding moiety, i) optionally a CH1 , ii) optionally a hinge, iii) optionally a CH2 domain and a CH3 domain.

[0320] In the context of IgG antibodies, the IgG isotypes each have three heavy chain constant regions (CH). Accordingly, "CH" domains in the context of IgG are as follows: "CH1" refers to the first constant domain (most N-terminal) of three constant domains of the heavy chain. It particularly refers to positions 118-215 according to the Ell index as in Kabat. "Hinge" refers to positions 216-230 according to the Ell index as in Kabat. "CH2" refers to the second constant domain and in particular to positions 231-340 according to the Ell index as in Kabat, and "CH3" refers to the third constant domain (most C-terminal) and in particular to positions 341-447 according to the Ell index as in Kabat. The CH domains may be naturally occurring CH domains, or naturally occurring CH domains in which one or more amino acids have been substituted.

[0321] The term "hinge region" refers to the flexible polypeptide comprising the amino acids between the CH1 and CH2 domains of an antibody. The hinge is defined structurally for the purposes of the present invention. The IgG 1 "hinge region" as used herein comprises residues 216-230 according to the according to the Ell index as in Kabat.

[0322] The first and / or second binding moiety may comprise a CL domain.In the context of IgG antibodies, the IgG isotypes each have a light chain constant domain (CL). “CL domain” refers to the light chain immunoglobulin constant domain that is located C-terminally to the VL domain. It spans about EU index Kabat positions 107-216. A CL domain may be a naturally occurring CL domain, or a naturally occurring CL domain in which one or more amino acids have been substituted.

[0323] Such bifunctional molecule preferably comprises a first Fc chain and a second Fc chain that are complementary and that together form a Fc domain. The first and second binding moieties can be on the same or different Fc chain, thereby forming a homodimer Fc domain or a heterodimer Fc domain, respectively.

[0324] In an embodiment, the bifunctional molecule comprises two binding moieties, preferably two antigen binding domains and a Fc domain. Preferably, the bifunctional molecule of the invention comprises a first and a second antigen binding domains and a Fc domain. In addition, the bifunctional molecule may also comprise a hinge domain.

[0325] In addition, the bifunctional molecule may also comprise one or several peptide linkers, that allow linkage between different part of the bifunctional molecule (e.g., between a Fc chain and a binding moiety).

[0326] In an embodiment, the first and second binding moieties are Fab, so that the bifunctional molecule preferably comprises or consists of:

[0327] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0328] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1), and

[0329] said first light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0330] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL),

[0331] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),said second light and heavy chains forming the second binding moiety that binds to TL1 A or TNFRSF25, preferably TL1 A.

[0332] In an embodiment, the bifunctional molecule may further comprise a Fc domain so that the bifunctional molecule preferably comprises two different Fab domains and a Fc domain. In particular, the bifunctional comprises or consists of:

[0333] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0334] (ii) a first heavy chain comprising a variable domain (VH), a first constant domain (CH1), optionally a hinge, a second constant domain (CH2) and a third constant domain (CH3), said CH2 and CH3 domains forming the first Fc chain, wherein said first light and heavy chains form the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0335] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL),

[0336] (iv) a second heavy chain comprising a variable domain (VH) a first constant domain (CH1), optionally a hinge, a second constant domain (CH2) and a third constant domain (CH3), said CH2 and CH3 domains forming the second Fc chain,

[0337] wherein said second light and heavy chains form the second binding moiety that binds to TL1 A or TNFRSF25, preferably TL1 A, and

[0338] wherein the first and second Fc chains are complementary and form a Fc domain.

[0339] In an embodiment, the first binding moiety is a Fab and the second binding moiety is a CrossMAb, so that the bifunctional molecule preferably comprises or consists of:

[0340] (i) a first chain that is a light chain comprising a variable domain (VL) and a constant domain (CL),

[0341] (ii) a second chain that is a heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0342] said light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and(iii) a third chain comprising a variable domain (VH) and a constant domain (CL),

[0343] (iv) a fourth chain comprising a variable domain (VL) and a constant domain (CH1),

[0344] said third and fourth chains forming the second binding moiety that binds to TL1 A or TNFRSF25, preferably TL1A.

[0345] In an embodiment, the first binding moiety is a Fab and the second binding moiety is a CrossMAb, so that the bifunctional molecule preferably comprises or consists of:

[0346] (i) a first chain that is a light chain comprising a variable domain (VL) and a constant domain (CL),

[0347] (ii) a second chain that is a heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0348] said light and heavy chains forming the first binding moiety that binds to TL1A or TNFRSF25, preferably TL1 A; and

[0349] (iii) a third chain comprising a variable domain (VH) and a constant domain (CL),

[0350] (iv) a fourth chain comprising a variable domain (VL) and a constant domain (CH1),

[0351] said third and fourth chains forming the second binding moiety that binds to IL-7 or CD127, preferably CD127.

[0352] In another embodiment, the first binding moiety is a Fab and the second binding moiety is a scFv so that the bifunctional molecule preferably comprises or consists of:

[0353] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0354] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0355] wherein said first light and heavy chains form the first binding moiety that binds to IL-7 or CD127, preferably CD127, and form a Fab,

[0356] (iii) a second light chain comprising a variable domain (VL), and(iv) a second heavy chain comprising a variable domain (VH),

[0357] wherein said second light and heavy chains are linked by a peptide linker and form a scFv that binds to TL1 A or TNFRSF25, preferably TL1 A.

[0358] In particular, the scFv may be linked at the N-terminal end of the first heavy chain, in particular to the N-terminal end of the first constant domain.

[0359] In particular, the scFv may be linked by its VH to the first constant domain. Alternatively, the scFv may be linked by its VL to the first constant domain. In another embodiment, the first binding moiety is a scFv and the second binding moiety is a Fab so that the bifunctional molecule preferably comprises or consists of:

[0360] (i) a first light chain comprising a variable domain (VL),

[0361] (ii) a first heavy chain comprising a variable domain (VH),

[0362] wherein said first light and heavy chains are linked by a peptide linker and form a scFv that binds to IL-7 or CD127, preferably CD127,

[0363] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and

[0364] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0365] wherein said second light and heavy chains form the second binding moiety that binds to TL1 A or TNFRSF25, preferably TL1 A, and form a Fab.

[0366] In particular, the scFv may be linked either at the N-terminal end of the second light or heavy chain, at the C-terminal end of the first or second light or heavy chain, preferably at the N-terminal end of the second heavy chain or the N-terminal end of the second light chain.

[0367] In particular, the scFv may be linked by its VH to the first constant domain. Alternatively, the scFv may be linked by its VL to the first constant domain. In particular, the scFv may be linked at the N-terminal end of the second heavy chain, in particular to the N-terminal end of the constant domain of the second heavy chain.

[0368] In particular, the scFv may be linked by its VH to the second constant domain. Alternatively, the scFv may be linked by its VL to the second constant domain.In a more preferred embodiment, the first binding moiety that binds to CD127 is a ScFv and the second binding moiety that binds to TL1A is a Fab so that the bifunctional molecule comprises or consists of:

[0369] (i) a first light chain comprising a variable domain (VL), preferably comprising LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 5, LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 6; more preferably comprises the light chain variable fragment 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;

[0370] (ii) a first heavy chain comprising a variable domain (VH), preferably comprising HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 1, HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 2, HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 3; more preferably comprises the heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7,

[0371] wherein said first light and heavy chains are linked by a peptide linker and form a scFv that binds to CD127, more preferably said CD127 scFv comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 46,

[0372] (iii) a second light chain comprising a variable domain (VL), preferably comprising LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 34, LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 35, LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 36; more preferably comprises the light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43; and a constant domain (CL), preferably a second light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 47, and

[0373] (iv) a second heavy chain comprising a variable domain (VH), preferably comprising HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 31 , HCDR2 comprising or consisting in the amino acid sequenceset forth in SEQ ID NO: 32, HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 33; more preferably comprises the heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42; and a constant domain (CH1 ), preferably a second heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48, wherein said second light and heavy chains form the second binding moiety that binds to TL1A, and form a Fab.

[0374] In particular, the scFv is linked at the N-terminal end of the second heavy chain, preferably by a peptide linker comprising or consisting of SEQ ID NO: 49.

[0375] In a more preferred embodiment, the bifunctional antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID No. 50 and the amino acid sequence set forth in SEQ ID No. 51.

[0376] In another embodiment, the bifunctional molecule is a dual variable domain immunoglobulin (DVD-lg protein: the molecule contains a Fc region and constant regions in a configuration similar to a conventional IgG that corresponds to a binding moiety. The molecule further contains variable domains attached to the Fc region of the first moiety. The variable domains are linked in tandem and form the ether binding moiety. Thus, in an embodiment, the bifunctional molecule preferably comprises or consists of:

[0377] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0378] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1), and

[0379] said first light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0380] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and

[0381] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0382] wherein said second light and heavy chains form the second binding moiety that binds to TL1A or TNFRSF25, preferably TL1A, the constant domains of thesecond light and heavy chains being linked to the variable domains of the first light and heavy chains, respectively.

[0383] Alternatively, the bifunctional molecule preferably comprises or consists of: (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0384] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0385] wherein said first light and heavy chains form the first binding moiety that binds to IL-7 or CD127, preferably CD127, and

[0386] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and

[0387] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0388] said second light and heavy chains forming the second binding moiety that binds to TL1 A or TNFRSF25, preferably TL1 A, and

[0389] wherein the constant domains of the first light and heavy chains are linked to the variable domains of the second light and heavy chains, respectively.

[0390] In an embodiment, the first binding moiety is a ScFv CrossMAb and the second binding moiety is an antigen-binding fragment, so that the bifunctional molecule comprises or consists of:

[0391] (i) at least one first chain comprising a variable domain (VH) and a variable domain (VL), preferably linked by a peptide linker, said at least one first chain forming a scFv CrossMab that binds to IL-7 or CD127, preferably CD127, and (ii) at least one second chain comprising a heavy chain variable fragment (VH) and a light chain constant domain (CL),

[0392] wherein said second light and heavy chains form the second binding moiety that binds to TL1 A or TNFRSF25, preferably TL1 A.

[0393] In an embodiment, it is provided a bifunctional antibody, or an antigen-binding fragment thereof or an antigen-binding antibody mimetic thereof, that binds to, in particular specifically binds to, two distinct first and second antigens, the firstantigen being IL-7 or CD127, and the second antigen being TL1A orTNFRSF25, preferably TL1A,

[0394] the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between TL1A and TNFRSF25.

[0395] In an embodiment, it is provided a bifunctional antibody, or an antigen-binding fragment thereof or an antigen-binding antibody mimetic thereof, that binds to, in particular specifically binds to, two distinct first and second antigens, the first antigen being CD127, and the second antigen being TL1A,

[0396] the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between TL1A and TNFRSF25.

[0397] • Pharmaceutical composition and administration route

[0398] In an embodiment of the invention, the combination or the bifunctional molecule further comprises any pharmaceutical vehicle, which are pharmaceutically acceptable for a formulation capable of being administered to a patient in need thereof. 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 constitution of injectable solutions.

[0399] Pharmaceutical formulations or pharmaceutical compositions may be prepared for various routes and types of administration with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, for example in the form of a lyophilized formulation, milled powder, or an aqueous solution.

[0400] The pharmaceutical formulations and compositions of the invention may be dosed and administered in amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors usually considered by medical practitioners.Pharmaceutical formulations and compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.

[0401] Pharmaceutical formulations and compositions described herein may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, in particular intravenous infusion, intraarterial, inhalation, intradermal, intrathecal, epidural, and infusion techniques), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal, particularly intravenous, more particularly intravenous infusion. Topical administration can also involve the use of transdermal administration such as transdermal patches.

[0402] The combination of the invention and the bifunctional molecule of the invention may be provided in the form of a kit comprising any combination as disclosed herein, in particular for the combination wherein the antagonist of anti-CD127 or IL7 and the antagonist of TL1A or TNFRSF25 are provided within different, distinct containers, in particular as pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient.

[0403] • Further therapeutic compounds

[0404] In some embodiments, the combination according to the invention for use in the method of the invention or for use according to the invention, or the bifunctional molecule of the invention, is administered to the patient in combination with another therapeutic agent or composition, for example a standard (conventional) treatment. Thus, the present invention relates also to the combination as defined herein for use in the method of the invention or for use according to the invention with as an adjuvant treatment for use in the treatment of an inflammatory disease or an autoimmune disease. As used herein the term “adjuvant treatment” is a treatment that is given after a primary treatment, such as surgery, or after administration of conventional treatment of the disease affecting the patient and which does not fully cure the patient.

[0405] The present invention relates also to the combination as defined herein for use in the method of the invention or for use according to the invention, or thebifunctional molecule of the invention, with as a conventional treatment for use in the treatment of an inflammatory disease or an autoimmune disease. As used herein, the term “standard or conventional treatment” refers to any treatment of inflammatory disease or autoimmune disease (drug, surgery, etc.) usually administrated to a patient who suffers from such a disease.

[0406] Such administration may be simultaneous, separate or sequential. For simultaneous administration, the agents may be administered as one composition or as separate compositions, as appropriate. The further therapeutic agent is typically relevant for the disorder to be treated. Exemplary therapeutic agents include other antibodies, cytotoxic agents, therapeutic agents, cell cycle control / apoptosis regulating agents, hormonal regulating agents, antiinflammatory agents, antibiotics and probiotics.

[0407] In some embodiments, the combination for use in the method of the invention or for use according to the invention, or the bifunctional molecule of 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. The further therapeutic agent is typically relevant for the disorder to be treated. Exemplary therapeutic agents include anti-inflammatory drugs.

[0408] In some embodiments, the combination for use in the method of the invention or for use according to the invention or the bifunctional molecule of 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, Kidney inflammatory diseases, atherosclerosis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple sclerosis, asthma and psoriasis.

[0409] In some embodiments, the combination for use in the method of the invention or for use according to the invention or the bifunctional molecule of the invention, is used in a combination treatment with an agent conventionally used for treatingan auto-immune disease, in particular systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis, Grave’s disease and systemic lupus erythematosus.

[0410] The other therapeutic agent may be administered concurrently or separately, in particular subsequently to or sequentially, with the combination or the bifunctional molecule of the invention. The other therapeutic agent may be administered according to the same dosing cycle as the combination or the bifunctional molecule of the invention, either at the same time, or separately in time. The other therapeutic agent may also be administered according to a different dosing cycle than the dosing cycle of the combination or the bifunctional molecule of the invention. The second therapeutic agent may also be administered according to the same therapeutic regimen as the combination or the bifunctional molecule of the invention.

[0411] The invention also concerns the use of the combination or the bifunctional molecule of the invention according to any embodiment disclosed herein, either alone or in combination with another 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 sequential administration to a patient in need thereof and under one of the listed therapies.

[0412] • Diseases to be treated

[0413] 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, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, asthma and psoriasis.

[0414] The uses described herein as well as the methods described herein may be useful in the treatment of inflammatory bowel diseases.In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from inflammatory bowel disease.

[0415] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from ulcerative colitis.

[0416] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from Crohn’s disease.

[0417] 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, Grave’s disease 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.

[0418] The uses described herein as well as the methods described herein may be useful in the treatment of autoimmune cutaneous diseases involving pathogenic T cells, like cutaneous Psoriasis, cutaneous Lupus, Alopecia Aerata, Vitiligo, or pathogenic involving T resident memory cells (TRM).

[0419] In a particular embodiment of the invention, it is provided

[0420] a. a first compound that is an antagonist of IL-7 and / or CD127 (e.g.

[0421] antagonist anti-CD127 antibody or antigen-binding fragment thereof); and

[0422] b. a second compound that is an antagonist of TL1 A (and in particular antagonist of the TL1A / TNFRSF25 signaling pathway) (e.g., antagonist anti-TL1-A antibody or antigen-binding fragment thereof such as Tulisokibart),

[0423] for inhibiting or reducing the secretion of at least one cytokine, in particular at least two, at least three, more particularly all the cytokines selected from the group consisting of IL-9, IL-6, TNFa and IFNy.

[0424] Methods of treatmentIn one aspect of the invention, it is provided a method of treating a patient suffering from an autoimmune disease or an inflammatory disease, the method comprising administering to a patient having said disease a therapeutically effective amount of a first compound that is an antagonist of IL-7 or CD127, the first compound being in particular a compound that is an antagonist of the IL-7 / IL-7R signaling pathway (e.g. antagonist anti-CD127 antibody or antigen-binding fragment thereof), in combination with a second compound that is an antagonist of TL1A or TNFRSF25, the second compound being in particular a compound that is an antagonist of the TL1A / TNFRSF25 signaling pathway, preferably an antagonist of TL1A (e.g., antagonist anti-TL1-A antibody or antigen-binding fragment thereof); wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0425] In another aspect of the invention, it is provided a method of inhibiting inflammation associated with the interleukin-7 (IL-7) signaling pathway and / or associated with the TL1A signaling pathway, the method comprising administering to a patient in need thereof an effective amount of a first compound that is an antagonist of IL-7 and / or CD127, the first compound being in particular a compound that is an antagonist of the IL-7 / IL-7R signaling pathway (e.g. antagonist anti-CD127 antibody or antigen-binding fragment thereof), in combination with a second compound that is an antagonist of TNFa or TNFRSF25, the second compound being in particular a compound that is an antagonist of the TL1A / TNFRSF25 signaling pathway; preferably an antagonist of TL1A (e.g., antagonist anti-TL1-A antibody or antigen-binding fragment thereof), wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0426] In another aspect of the invention, it is provided a method of inhibiting or reducing the secretion of at least one cytokine, in particular at least two, at least three, more particularly all the cytokines selected from the group consisting of IL-9, IL-6, TNFa and IFNy; the method comprising administering to a patient in needthereof an effective amount of a first compound that is an antagonist of IL-7 and / or CD127, the first compound being in particular a compound that is an antagonist of the IL-7 / IL-7R signaling pathway (e.g. antagonist anti-CD127 antibody or antigen-binding fragment thereof), in combination with a second compound that is an antagonist of TNFa orTNFRSF25, the second compound being in particular a compound that is an antagonist of the TL1A / TNFRSF25 signaling pathway, preferably an antagonist of TL1 A (e.g. , antagonist anti-TL1 -A antibody or antigenbinding fragment thereof); wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0427] In certain embodiments, the first compound is an anti-CD127 compound that is an antibody or antigen-binding fragment thereof that comprises a heavy chain variable fragment comprising:

[0428] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1,

[0429] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2;

[0430] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0431] a light chain variable fragment comprising:

[0432] d. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4,

[0433] e. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5;

[0434] f. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6;

[0435] In certain embodiments, the anti-CD127 compound is an antibody or antigenbinding fragment thereof that comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment 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. In certain embodiments, the anti-CD127 compound is an antibodyor antigen-binding fragment thereof that 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 amino acid sequence set forth in SEQ ID No. 18.

[0436] In a particular embodiment, the second compound is an antagonist anti-TL1-A antibody or antigen-binding thereof which comprises

[0437] a heavy chain variable fragment (VH) comprising:

[0438] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31, and

[0439] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32; and

[0440] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33; and

[0441] a light chain variable fragment (VL) comprising:

[0442] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34, and

[0443] b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35; and

[0444] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36;

[0445] in particular wherein the heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 42, and the light chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 43; in a more particular embodiment, the heavy chain comprises or consists in the amino acid sequence set forth in SEQ ID No: 44, and a light chain comprises or consists in the amino acid sequence set forth in SEQ ID No. 45.

[0446] In certain embodiments, the patient is suffering from an inflammatory disease, in particular an IBD, more particularly Crohn disease or Ulcerative colitis.

[0447] In one aspect of the invention, it is provided a first compound that is an antagonist of IL-7 and / or CD127, the first compound being in particular a compound that is an antagonist of the IL-7 / IL-7R signaling pathway (e.g. antagonist anti-CD127 antibody or antigen-binding fragment thereof), in combination with a secondcompound that is an antagonist of TL1A or of TNFRSF25, preferably an antagonist of TL1A (e.g., antagonist anti-TL1-A antibody or antigen-binding fragment thereof) for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease; in particular wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0448] In an aspect of the invention, it is provided the combination of compounds as defined herein for treating a human being suffering from an inflammatory disease or an auto-immune disease.

[0449] In an embodiment, it is provided a combination comprising a first compound that is an antagonist of IL-7 and / or CD127, the first compound being in particular a compound that is an antagonist of the IL-7 / IL-7R signaling pathway (e.g. antagonist anti-CD127 antibody or antigen-binding fragment thereof), and a second compound that is an antagonist of TL1A or of TNFRSF25, preferably an antagonist of TL1A (e.g., antagonist anti-TL1-A antibody or antigen-binding fragment thereof) for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease; in particular wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0450] In an embodiment, it is provided a first compound that is an antagonist of IL-7 and / or CD127, the first compound being in particular a compound that is an antagonist of the IL-7 / IL-7R signaling pathway (e.g. antagonist anti-CD127 antibody or antigen-binding fragment thereof), and a second compound that is an antagonist of TL1 A or of TNFRSF25, preferably an antagonist of TL1 A (e.g., antagonist anti-TL1-A antibody or antigen-binding fragment thereof), for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease; in particular wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.A manufactured medicament can be provided in the form of a kit comprising the first compound that is an antagonist of IL-7 and / or CD127, the first compound being in particular a compound that is an antagonist of the IL-7 / IL-7R signaling pathway (e.g. antagonist anti-CD127 antibody or antigen-binding fragment thereof), and the second compound that is the antagonist of TL1A or of TNFRSF25, preferably an antagonist of TL1A (e.g., antagonist anti-TL1-A antibody or antigen-binding fragment thereof)in distinct, different containers.

[0451] In one aspect of the invention, it is provided a method of treating a patient suffering from an autoimmune disease or an inflammatory disease, the method comprising administering to a patient having said disease a therapeutically effective amount of a bifunctional molecule that comprises:

[0452] a first binding moiety, said first binding moiety binding to IL-7 or CD127, a second binding moiety, said second binding moiety binding to TL1A or TNFRSF25 or TNFRSF6B.

[0453] In one aspect of the invention, it is provided a method of treating a patient suffering from an autoimmune disease or an inflammatory disease, the method comprising administering to a patient having said disease a therapeutically effective amount of a bifunctional molecule that comprises:

[0454] a first binding moiety, said first binding moiety binding to CD127, a second binding moiety, said second binding moiety binding to TL1A.

[0455] In a preferred embodiment, the first binding moiety that binds to CD127 is a ScFv and the second binding moiety that binds to TL1A is a Fab, more preferably, the bifunctional molecule comprises or consists of:

[0456] (i) a first light chain comprising a variable domain (VL), preferably comprising LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 5, LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 6; more preferably comprises the light chain variable fragment 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;(ii) a first heavy chain comprising a variable domain (VH), preferably comprising HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 1, HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 2, HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 3; more preferably comprises the heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7,

[0457] wherein said first light and heavy chains are linked by a peptide linker and form a scFv that binds to CD127, more preferably said CD127 scFv comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 46,

[0458] (iii) a second light chain comprising a variable domain (VL), preferably comprising LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 34, LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 35, LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 36; more preferably comprises the light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43; and a constant domain (CL), preferably a second light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 47, and

[0459] (iv) a second heavy chain comprising a variable domain (VH), preferably comprising HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 31 , HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 32, HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 33; more preferably comprises the heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42; and a constant domain (CH1 ), preferably a second heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48, wherein said second light and heavy chains form the second binding moiety that binds to TL1A, and form a Fab.

[0460] In particular, the scFv is linked at the N-terminal end of the second heavy chain, preferably by a peptide linker comprising or consisting of SEQ ID NO: 49.In a more preferred embodiment, the bifunctional antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID No. 50 and the amino acid sequence set forth in SEQ ID No. 51.

[0461] In another aspect of the invention, it is provided a method of treating a patient suffering from an autoimmune disease or an inflammatory disease, the method comprising administering to a patient having said disease a therapeutically effective amount of a bifunctional molecule, in particular a bifunctional antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic thereof, that binds to, in particular specifically binds to, two distinct first and second antigens, the first antigen being IL-7 or CD127 and the second antigen being TL1A or TNFRSF25.

[0462] In another aspect of the invention, it is provided a method of inhibiting inflammation associated with the interleukin-7 (IL-7) signaling pathway and / or associated with the TL1A / TNFRSF25 signaling pathway, the method comprising administering to a patient in need thereof an effective amount of a bifunctional molecule, in particular a bifunctional antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic thereof, that binds to, in particular specifically binds to, two distinct first and second antigens, the first antigen being IL-7 or CD127 and the second antigen being TL1A or TNFRSF25.

[0463] In one aspect of the invention, it is provided the bifunctional molecule that comprises

[0464] a first binding moiety, said first binding moiety binding to IL-7 or CD127, a second binding moiety, said second binding moiety binding to TL1A or TNFRSF25,

[0465] for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease.

[0466] In another aspect of the invention, it is provided the bifunctional molecule which inhibits (i) the binding between IL-7 and CD127 and (ii) the binding between TL1A and TNFRSF25, for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease.DESCRIPTION OF THE FIGURES

[0467] Some of the figures, to which the present application refers, are in color. The application as filed contains the color print-out of the figures, which can therefore be accessed by inspection of the file of the application at the patent office.

[0468] Figure 1 illustrates the percentage of inhibition of IL-9 secretion by TH9 cells treated with a control antibody, an anti-TL1A antibody, or a combination of an anti-TL1 A antibody and an anti-IL-7Ra antibody, compared to the same untreated cells.

[0469] Figure 2 illustrates the percentage of inhibition of TNFa secretion by PBMC cells treated with a control antibody, an anti-TL1A antibody, or a combination of an anti-TL1 A antibody and an anti-IL-7Ra antibody, compared to the same untreated cells.

[0470] Figure 3 illustrates the percentage of inhibition of IL-6 secretion by PBMC cells treated with a control antibody, an anti-TL1A antibody, or a combination of an anti-TL1 A antibody and an anti-IL-7Ra antibody, compared to the same untreated cells.

[0471] Figure 4 illustrates the percentage of inhibition of (A) IFNy by TH1 cells and (B) IFNy by TH17 cells treated with a control antibody, an anti-TL1A antibody, or a combination of an anti-TL1 A antibody and an anti-IL-7Ra antibody, compared to the same untreated cells.

[0472] Figure 5 : Isolated cells from Ulcerative colitis and Crohn’s disease patients were treated with isotypes control, anti-hlL-7Ra Ab, anti-hTL1A Ab or combination of anti-hlL-7Ra with anti-hTL1A Abs during 48h and secreted molecules were quantified and compared between each condition. (A) Venn representation shows significant number of proteins modified by monotherapies or combination treatment. 10 proteins were found to be downregulated specifically under combination treatment of anti-hlL-7Ra with anti-hTL1A Abs compared with monotherapies. (B) Enrichment pathway analysis of the 10 proteins significantly decreased only in the combination treatment of anti-hlL-7Ra with anti-hTL1 A Abs related to the mechanism of action (MoA) (string database).

[0473] Figure 6: : Isolated cells from Ulcerative colitis and Crohn’s disease patients were treated with isotypes control, anti-hlL-7Ra Ab, anti-hTL1A Ab orcombination of anti-hlL-7Ra with anti-hTL1A Abs during 48h. Protein in the supernatant were quantified and compared between each group. (A) Heatmap representation shows proteins differentially expressed with pvaiue adjusted<0.05 and an absolute estimate >=1 across all groups of treatment (string database). The comparison of all samples demonstrates a clear differentiation and synergistic effect of combination treatment of anti-hlL-7Ra with anti-hTL1A Abs versus each monotherapy with a significant decrease of multiple proteins. (B) Enrichment pathway analysis of protein significantly differentially expressed (string database) across all group comparisons (string database).

[0474] Figure 7: (A) Illustration of different constructions of bispecific anti-human IL-7Ra and anti-human TL1-A antagonist antibodies. Construction 1 was used for the following data, herein designated on the Figure 7 as “Bi-specific anti-hlL-7Ra / Anti-hTL1 A Ab”. (B) Binding of antagonist bispecific anti-human IL-7Ra and anti-human TL1-A on human IL-7Ra and human TL1-A proteins as measured by ELISA binding, (C) Inhibition of IFNy by TH1 cells after treatment with isotype, a combination of antagonists of anti-human TL1-A antibody and an anti-human IL-7Ra antibody, or an antagonist bispecific antibody anti-human IL-7Ra and antihuman TL1-A. Data are represented as percentage of inhibition of IFNg secretion after normalization with no treatment

[0475] EXAMPLES

[0476] • IL-9 secretion by TH9 cells assay

[0477] Material and methods:

[0478] Human peripheral mononuclear cells (PBMCs) were added at 100000 cells / wel in precoated P96-well plates with OKT3 at 0.1 ug / ml and incubated with 10pg / ml of antagonist anti-human TL1a antibody (anti-TL1A, Tebubio, reference T80560, Tulisokibart, the anti-hTL1 A antibody has the 6 CDRs referenced SEQ ID No. 31 to No. 36 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. 42, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 43, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 44, and a light chain consisting in the amino acid sequence set forth in SEQ ID No.45)) alone or in combination with antagonist anti-human IL7Ra antibody (Ose Immunotherapeutics - the anti-hlL7Ra antibody has 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). in the presence of human IL7 at 5ng / ml (Miltenyi reference 130-095-367), human TGFb at 3ng / ml (Miltenyi, reference 130-095-066), human IL-4 at 20ng / ml (Miltenyi, reference 130-094-117) and human TL1A at 100ng / ml (Cliniscience, reference HY-P71913) in IMDM complete media during 5 days at 37°C. After 5 days, the supernatant was collected and concentration of IL-9 secretion was quantified by ELISA assay (Biotechne, reference DY209).

[0479] Results

[0480] As illustrated in Figure 1, the combination of anti-human IL-7Ra and anti-human TL1A significantly decreases the secretion of IL-9, a pro-inflammatory cytokine, by human T cells compared to anti TL-1A monotherapy.

[0481] Anti-human TL1A blocking antibody has a limited effect to inhibit IL-9 secretion by T cells when compared to the combination therapy. The combination of an antagonist anti-TL1A antibody with an antagonist anti-human IL-7Ra antibody (that blocks human IL-7Ra-induced signaling) enhances the inhibition of IL-9 secretion compared to anti TL-1A monotherapy antibodies (~25 % inhibition vs ~75% inhibition, n=3). The combination of anti-human IL-7R and anti-human TL1A is far superior to monotherapy. This data demonstrates the advantage of combining an anti-human TL1 A with anti-human IL-7Ra to suppress inflammation through the decrease of IL-9 cytokine secreted by pathogenic Th9 T cells.

[0482] • TNFa secretion by PBMC cells assay

[0483] Material and methods:

[0484] Human PBMCs were added at 100000 cells / well and incubated with 10pg / ml of an antagonist anti-human TL1a antibody (anti-TL1A, Tebubio, reference T80560, Tulisokibart) alone or in combination with antagonist anti-human IL7Ra antibody(Ose Immunotherapeutics, the same as in the first example) in the presence of human IL7 at 5ng / ml (Miltenyi reference 130-095-367), human TGFb at 3 ng / ml (Miltenyi, reference 130-095-066), human IL-4 at 20ng / ml (Miltenyi, reference 130-094-117) and human TL1A at 100 ng / ml (Cliniscience, reference HY-P71913) in IMDM complete media during 5 days at 37°C. After 5 days, the supernatant was collected and hTNFa secretion was quantified using ELISA assay (Biotechne, reference DY209).

[0485] Results

[0486] As illustrated on Figure 2, combining an antagonist anti-human IL-7Ra antibody and an antagonist anti-human TL1 A greatly inhibits secretion of TNFa by human PBMCs compared to monotherapy with the antagonist anti TL1-A antibody. The inventors have tested the effect of combining a blocking anti-human IL-7Ra with a blocking anti-human TL1A on secretion of TNF by human PBMCs. PBMCs were stimulated with human IL-7, human TGFb, human IL-4 and human TL1A cytokine to trigger TNFa cytokine secretion. Using this assay, the inventors show that monotherapy with an antagonist anti-human TL1 A antibody has increase the inhibition of TNFa secretion compared to control antibodies. Interestingly, the inventors show that the combination of anti-human IL-7R and anti-human TL1 A has significantly higher effect to inhibit TNFa secretion compared to monotherapy anti TL-1A. This data demonstrates the advantage of combining an antagonist anti-human TL1A antibody with an antagonist anti-human IL-7Ra antibody to suppress inflammation through the decrease of pro inflammatory TNFa and IL-9 cytokines to enhance therapeutic effect of Anti TL-1 A therapy.

[0487] • IL-6 secretion by PBMC cells assay

[0488] Material and methods:

[0489] Human PBMC cells were added at 100000cells / w and incubated with 10pg / ml of an antagonist anti-human IL7Ra antibody (Ose Immunotherapeutics - the same antibody as in previous experiments) and 10pg / ml of an antagonist anti-human TL1a antibody (anti-TL1A, Tebubio, reference T80560), or an antagonist antihuman TL1a antibody (anti-TL1A, Tebubio, reference T80560) alone. Cells were stimulated with human IL7 at 5ng / ml (Miltenyi, reference 130-095-367), human IL-12 at 2ng / ml (Miltenyi, reference 130-129-722), human IL-18 at 20 ng / ml(Biolegend, reference 592104) and human TL1A at 100ng / ml (Cliniscience, reference HY-P71913) in IMDM complete medium during 5 days at 37°C. After 5 days, the supernatant was collected. Measure of hlL-6 secretion was performed after 5 days at 37°C (Duoset, R&D, reference DY206).

[0490] Results

[0491] As illustrated on Figure 3, combining an antagonist anti-human IL-7Ra antibody with an antagonist anti-human TL1A antibody greatly inhibits the secretion of IL-6 by human PBMC.

[0492] It has been described that human anti-TNFa antibody are not able to decrease concentration of hlL-6 in human anti-TNFa resistant Inflammatory Bowel Disease patients. Anti-human TL1A antibody can inhibit IL-6 cytokine secretion. This is confirmed by the experiment, where the inhibition of IL-6 secretion is increased by 20% in presence of the antagonist anti-TL1 A antibody. Figure 3 further shows that the combination of an antagonist anti-human IL-7R antibody and an antagonist anti-human TL1A antibody has better effect to inhibit IL-6 secretion compared to control antibodies and monotherapy with the anti-TL1A antibody. This data demonstrates the advantage of combining an anti-human TL1A with anti-human IL-7Ra to suppress inflammation through the decrease of pro inflammatory cytokines still present after human anti-TNFa and human TL1A therapies or in human having a resistance to treatment with an anti-TNFa.

[0493] • IFNy secretion by TH1 cells and TH17 cells assays

[0494] Material and methods:

[0495] IFNy secretion by TH1 cells assay: Human PBMCs were added at 100000cells / w and incubated with 10pg / ml of an antagonist anti-human IL7Ra antibody (Ose Immunotherapeutics - the same as in the previous examples) and 10pg / ml of an antagonist anti-human TL1 a antibody (anti-TL1A, Tebubio, reference T80560), or an antagonist anti-human TL1a antibody (anti-TL1A, Tebubio, reference T80560) alone. Cells were stimulated with human IL7 at 5ng / ml (Miltenyi, reference 130-095-367), human IL-12 at 2ng / ml (Miltenyi, reference 130-129-722), human IL-18 at 20 ng / ml (Biolegend, reference 592104) and human TL1A at 100ng / ml (Cliniscience, reference HY-P71913) in IMDM complete medium during 2 days at37°C. After 2 days, the supernatant was collected. Measure of hlFNg secretion was performed after 2 days at 37°C (Biolegend, reference 430116).

[0496] IFNy secretion by TH 17 cells assay: Human PBMCs were added at 100000cells / w and incubated with 10pg / ml of an antagonist anti-human IL7Ra antibody (Ose Immunotherapeutics - the same as in the previous examples) and 10pg / ml of an antagonist anti-human TL1a antibody (anti-TL1A, Tebubio, reference T80560), or an antagonist anti-human TL1a antibody (anti-TL1A, Tebubio, reference T80560) alone. Cells were stimulated with human TGFb at 3ng / ml (Miltenyi, reference 130-095-066), human IL6 at 20ng / ml (Miltenyi, reference 130-093-929), human IL7 at 5ng / ml (Miltenyi, reference 130-095-367) and human TL1A at 100ng / ml (Cliniscience, reference HY-P71913) in precoated plate with OKT3 at 100 ng / m in IMDM complete medium during 2 days at 37°C. After 2 days, the supernatant was collected. Measure of IFNy secretion was performed after 2 days at 37°C (Biolegend, reference 430116).

[0497] Results

[0498] As illustrated on Figure 4A and 4B, combining an antagonist anti-human IL-7Ra antibody and an antagonist anti-human TL1A antibody greatly inhibit the secretion of IFNy and TNFa by human PBMC, as compared to a stimulation with an antagonist anti-human TL1A antibody.

[0499] Anti-human TL1A antibody can slightly inhibit IFNy cytokine secretion. The inventors have tested the combination with an antagonist anti-human IL-7Ra antibody (blocking human IL-7Ra) in combination with an antagonist anti-human TL1A antibody (blocking human TL1A activity) in vitro using human PBMC cells incubated with human IL-7, human IL-12, human IL-18 and human TL1 A cytokine to trigger IFNy cytokine secretion secreted by TH1 cells. Also, the inventors have tested the combination in vitro using human PBMC cells incubated with human IL-7, human TGFB, human IL-6 and human TL1A cytokine to trigger IFNy cytokine secreted by TH17 cells. The data illustrated on figure 4 show that the combination of the antagonist anti-human IL-7R antibody and the antagonist antihuman TL1A antibody has a better effect to inhibit IFNy secretion compared to control antibodies and antagonist anti-TL1A antibody alone. The combination of the antagonist anti-human IL-7R antibody and the antagonist anti-human TL1A antibody is far superior to the monotherapy with the antagonist anti TL-1Aantibody that only shows minimal effect. This data demonstrates the potential clinical advantage of combining an antagonist anti-human TL1 A antibody with an antagonist anti-human IL-7Ra antibody to suppress inflammation through the decrease of pro inflammatory cytokines by different T cell subpopulation that are pathogenic for inflammatory and autoimmune disease.

[0500] Conclusion:

[0501] The combination of an antagonist anti-IL7Ra antibody with an antagonist anti-TL1a antibody demonstrates significant potential for therapeutic intervention by effectively reducing the secretion of key pro-inflammatory cytokines, including IL-6, IL-7, TNFa, and IFNy. This dual-targeted approach disrupts critical signaling pathways involved in inflammatory responses, offering a promising strategy for mitigating inflammation disorders and associated immune dysfunctions. By modulating the production and secretion of these cytokines, which play pivotal roles in the pathogenesis of various autoimmune and inflammatory diseases, this combination therapy holds great promise for improving clinical outcomes and enhancing immune regulation.

[0502] • Protein expression analysis.

[0503] Material and methods:

[0504] Intestinal biopsies were obtained from patients diagnosed with ulcerative colitis (UC) and Crohn’s disease (CD) patients. Tissue samples were enzymatically digested to isolate cells. More than 1 x10A5 cells were seeded per well in 96-well plates under the following conditions: isotype controls, monotherapy: Anti-hTL1A Ab (anti-human TL1A antibody : Tulisokibart, Tebubio, reference T80560, the anti-hTL1 A antibody has the 6 CDRs referenced SEQ ID No. 31 to No. 36 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. 42, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 43, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 44, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 45)) or anti-hlL7Ra Ab (anti-human CD127 - Ose Immunotherapeutics, the anti-hlL7Ra Ab has the 6 CDRs referenced SEQ ID No. 1 to No. 6 herein (particularly, it is anantibody 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.

[0505] 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)) and combination treatment: Anti-hTL1A + anti-hlL7Ra Abs at 10 pg / ml. A cytokine cocktail consisting of IL-7 (5 ng / mL) (Miltenyi, 130-095-368) and TL1A (250 ng / mL) (MedChem Express, HY-P71913) and OKT3-coated wells (2.5 pg / mL) have been used for stimulation. Cells were incubated for 48 hours at 37 °C in a humidified atmosphere with 5% CO2. After incubation, culture supernatants were collected and analyzed using the multiplex assay quantifying secreted cytokine. Protein quantification was performed using Next Generation Sequencing (NGS) and Venn representation was conducted with the bioinformatic tool (https: / / bioinformatics.psb.ugent.be / cgibin / liste / enn / calculate_venn.htpl).

[0506] Protein-protein interaction analysis and the enrichment pathway analysis of significantly differentially expressed protein were conducted with the STRING database (Szklarczyk D, et al. Nucleic Acids Res. 2023 Jan 6;51(D1):D638-646). Differential expression analysis was conducted with a linear mixed model nameds Imer for R and the heatmap representation shows proteins differentially expressed with pvaiue adjusted<0.05 and an absolute estimate >=1.

[0507] Results:

[0508] The inventors assessed if the combination of TL1 A / IL-7Ra blockade axis can be beneficial compared to monotherapy treatment to enhance therapeutic effect for the treatment of inflammatory and auto-immune diseases. To evaluate this, cells from Ulcerative Colitis and Crohn diseases patients were isolated, stimulated and treated with separate antibodies or in combination. After 48h, supernatant was isolated and secreted proteins were quantified and compared between monotherapies or combination treatment as shown on Figure 5A.

[0509] Venn representation shows that anti-hlL7Ra monotherapy specifically down regulates 7 proteins while anti-hTL1A monotherapy downregulates 17 different proteins. This data demonstrated that each therapy has a distinct mechanism of action and clearly a different biological activity. In combination treatment group ofanti-hlL-7Ra with anti-hTL1A Abs, 5 proteins similar to anti-hlL-7Ra monotherapy and 16 proteins similar to anti-hTL1A monotherapy are significantly downregulated suggesting that combination treatment accentuate effect of each monotherapy. Surprisingly, 10 proteins were found to be downregulated specifically under combination therapy of anti-hlL-7Ra with anti-hTL1A Abs compared with monotherapies (Figure 5A). Among the 10 specifics proteins, a reduction of TH17, JAK STAT and inflammation pathway are decreased as illustrated in Figure 5B using enrichment analysis pathway. The combination treatment shows a unique subnetwork with 10 proteins affected only by the combination but not by the individual treatments suggesting that combination treatment has synergistic effects due to modulation of specific gene networks. Using heatmap analysis and enrichment pathway analysis (Figure 6A / B) comparing all samples demonstrate a clear differentiation and synergistic effect of combination treatment of anti-hlL-7Ra with anti-hTL1A Abs versus each monotherapy with a significant decrease of multiple proteins. Figure 6B demonstrates that proteins that are significantly decrease in combination treatment versus monotherapy are associated with Th1, Th17 and Jak-STAT signaling pathway, inflammatory bowel disease pathway and fibrosis. This analysis demonstrates specific and significant efficacy of combining anti IL-7Ra and anti TL1 A with surprisingly a synergistic effect to dampens inflammation for the treatment of inflammatory disease or autoimmune disease.

[0510] • Biological effect of bispecific anti-hTL1A / anti-hlL-7Ra antibody Material and methods:

[0511] To evaluate biological effect of bispecific anti-hTL1 A / anti-hlL-7Ra antibody (SEQ ID NO: 50 and 51), a bioassay on Th1 cells was performed and IFNy secretion was quantified as per following protocol. Human PBMCs were added at 100000cells / w and incubated with 10pg / ml of an antagonist anti-human IL-7Ra antibody (anti-human CD127-Ose Immunotherapeutics, the anti-hlL7Ra Ab has 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, moreparticularly 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)) and 10pg / ml of an antagonist antihuman TL1Aa antibody (anti-hTL1A, Tulisokibart, Tebubio, reference T80560, the anti-hTL1A antibody has the 6 CDRs referenced SEQ ID No. 31 to No. 36 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.

[0512] 42, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 43, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 44, and a light chain consisting in the amino acid sequence set forth in SEQ ID No.

[0513] 45)) (combination therapy), or 10ug / ml of an antagonist bispecific anti-human IL-7Ra and anti-human TL1A antibody (bispecific therapy, SEQ ID NO: 50 and 51) or 10pg / ml of isotypes (control). Cells were stimulated with human IL-7 at 5 ng / ml (Miltenyi, reference 130-095-368), human IL-12 at 2 ng / ml (Miltenyi, reference 130-129-722), human IL-18 at 20 ng / ml (Biolegend, reference 592104) and human TL1A at 1000ng / ml (MedChem Express, reference HY-P71913) in IMDM complete medium during 5 days at 37°C. After 5 days, the supernatant was collected. Measure of hlFNy secretion was performed after 5 days at 37°C (Biolegend, reference 430116).

[0514] For activity ELISA assay, recombinant hCD127 (Sino Biologicals, Beijing, China; reference 10975-H08H) or recombinant hTL1A (Sino Biologicals, Beijing, China; reference 17049-H07H4) were immobilized on plastic at 1 pg / ml overnight at 4°C. After washing and saturation, dilutions of tested antibodies were added to measure binding. After incubation 2h at 37°C and washing, polyclonal donkey anti-human IgG labelled peroxidase (Jackson Immunresearch; reference 709-035-149) were added 1h at 37°C and revealed by conventional methods.

[0515] Results

[0516] The inventors evaluate the potential of Bispecific anti-TL1A / Anti-hlL-7Ra antibody (Constructions Figure 7A). Bispecific anti-TL1A / Anti-IL-7Ra antibody have been validated on TL1A and CD127 binding on Figure 7B. Efficacy of Bispecific versus 2 antibodies combination was evaluated in IFNy Th1 assay using human PBMCs. As shown in Figure 7C, both treatments significantly inhibitIFNy secretion compared to isotype control. A slight higher inhibitory effect is observed with Bispecific antibody versus combination of mono specific treatments, highlighting advantage of bispecific construction by blocking simultaneously 2 targets.

[0517] Importantly, the bispecific antibody demonstrates a slightly greater inhibitory activity, these data support the current invention of employing either anti TL1A / Anti IL-7Ra combination treatment through monospecific antibodies combination treatment or bispecific format to prevent overall inflammation and autoimmune disease, not only T cells but can also downregulate indirectly other proinflammatory factors, fibrosis mediators produced by microenvironmental cells.

Claims

CLAIMS1. A combination comprising:a. a first compound that is an antagonist of IL-7 or CD127; and b. a second compound that is an antagonist of TL1 A or TNFRSF25; for use in the treatment of an inflammatory disease or an auto-immune disease.

2. The combination for use according to claim 1 , wherein the first compound binds to, in particular specifically binds to, CD127, and inhibits or reduces the binding between IL-7 and CD127, and in particular is an antagonist of the IL-7 I IL-7R signaling pathway.

3. The combination for use according to claim 1 or 2, wherein the first compound is an anti-CD127 antibody or an antigen-binding fragment thereof.

4. A first compound that is an antagonist anti-CD127 antibody or antigenbinding fragment thereof, for use in a combination regimen with a second compound that is an antagonist of TL1 A or TNFRSF25, for the treatment of an inflammatory disease or an auto-immune disease.

5. The combination for use according to any one of claims 1-3, or the first compound for use according to claim 4, wherein the first compound is an anti-CD127 antibody or antigen-binding fragment thereof which comprises:ii) a heavy chain variable fragment (VH) comprising:a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1, andb. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; andc. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; andiii) a light chain variable fragment (VL) comprising:a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, andb. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; andc. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; andin particular wherein the antibody heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No.7, and the antibody light chain variable fragment 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.

6. The combination for use according to any one of claims 1-3 or 5, or the first compound for use according to claim 4 or 5, wherein the first compound is an anti-CD127 antibody or antigen-binding fragment thereof that 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 amino acid sequence set forth in SEQ ID No. 18.

7. The combination for use according to any one of claims 1 -3 or 5-6, or the first compound for use according to any one of claims 4 to 6, wherein the second compound inhibits or reduces the binding between TL1A and its receptor TNFRSF25, and in particular is an antagonist of the TL1A / TNFRSF25 signaling pathway.

8. The combination for use according to any one of claims 1 -3 or 5-7, or the first compound for use according to any one of claims 4 to 7 wherein the second compound is selected from the group consisting of:i) a protein comprising at least a portion of TNFRSF25 or TNFRSF6B;andii) an antibody or an antigen-binding fragment thereof, that binds, in particular specifically binds, to TL1A or TNFRSF25, and inhibits or reduces the binding between TL1A and TNFRSF25;in particular wherein said second compound is an antagonist of the TL1A / TNFRSF25 signaling pathway.

9. The combination for use according to any one of claims 1 -3 or 5-8, or the first compound for use according to any one of claims 4 to 8, wherein the second compound is an antibody or an antigen-binding fragment thereof that binds to, in particular specifically binds to, TL1 A or TNFRSF25, or is a human soluble fusion protein comprising or consisting of at least a fragment of the extracellular domain of either TNFRSF25 or TNFRSF6B, preferably TNFRSF6B.

10. The combination for use according to any one of claims 1-3 or 5-9, or the first compound for use according to any one of claims 4 to 9, wherein the second compound that is an antagonist of TL1A orTNFRSF25 is selected from the list consisting of Tulisokibart, PF-06480605, TEV- 574, XmAb- 942, and biosimilars thereof.

11. The combination for use according to any one of claims 1-3 or 5-10, or the first compound for use according to any one of claims 4 to 10, wherein the second compound is an antagonist anti-TL1A antibody or antigenbinding fragment thereof, preferably which comprises:a heavy chain variable fragment comprising:a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DTYMH), andb. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (RIDPASGHTKYDPKFQV), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (SGGLPDV), and- a light chain variable fragment comprising:d. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASSSVSYMY), ande. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (ATSNLAS), and- LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QQWEGNPRT),preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43, more preferably comprises the antibody heavy chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 44 and the antibody light chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 45.

12. The combination for use according to any one of claims 1-3 or 5-11, or the first compound for use according to any one of claims 4 to 11 , wherein:a. the first compound is an antagonist anti-CD127 antibody or antigenbinding fragment thereof, preferably a monoclonal antibody, and b. the second compound is an antagonist anti-TL1A antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

13. A bifunctional molecule, in particular a bifunctional antibody or an antigenbinding fragment thereof, that binds to, in particular specifically binds to, two distinct first and second antigens, the first antigen being IL-7 or CD127, in particular CD127, and the second antigen being TL1A or TNFRSF25, in particular TL1 A.

14. The bifunctional molecule according to claim 13, which inhibits (i) the binding between IL-7 and CD127 and (ii) the binding between TL1A and TNFRSF25.

15. The bifunctional antibody or an antigen-binding fragment thereof according to claim 13 or 14 comprising a first binding moiety that binds to CD127 and a second binding moiety that binds to TL1A.

16. The bifunctional antibody or an antigen-binding fragment thereof according to claim 15 wherein the first binding moiety comprises:(i) a first light chain comprising a variable domain (VL), preferably comprising LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 5, LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 6; more preferably comprises the light chain variable fragment 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; (ii) a first heavy chain comprising a variable domain (VH), preferably comprising HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 1 , HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 2, HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 3; more preferably comprises the heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7.

17. The bifunctional antibody or an antigen-binding fragment thereof according to claim 15 or 16 wherein the second binding moiety comprises: - a second light chain comprising a variable domain (VL), preferably comprising LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 34, LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 35, LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 36; more preferably comprises the light chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 43; and a constant domain (CL), preferably a second light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 47, and- a second heavy chain comprising a variable domain (VH), preferably comprising HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 31, HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 32, HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID NO: 33; more preferably comprises the heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 42; and a constant domain (CH1), preferably a second heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48.

18. The bifunctional antibody or an antigen-binding fragment thereof according to any one of claims 13 to 17, wherein said first light and heavy chains are linked by a peptide linker and form a scFv that binds to CD127, more preferably said scFv comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 46.

19. The bifunctional antibody or an antigen-binding fragment thereof according to any one of claims 13 to 18, comprising a first amino acid sequence set forth in SEQ ID No. 50 and a second amino acid sequence set forth in SEQ ID No. 51.

20. The bifunctional antibody or antigen-binding fragment thereof according to any one of claims 13 to 19, for use in the treatment of an inflammatory disease or an auto-immune disease.

21. The combination for use according to any one of claims 1-3 or 5-12, or the first compound for use according to any one of claims 4 to 12, or the bifunctional antibody or antigen-binding fragment thereof for use according to claim 20, wherein the inflammatory disease is selected from the group consisting of Non Alcoholic Fatty Liver Disease, endometriosis, encephalomyelitis, inflammatory bowel disease, in particular Crohn’s disease and Ulcerative Colitis, chronic obstructive pulmonary disease,Kidney inflammatory diseases, atherosclerosis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple sclerosis, asthma and psoriasis.

22. The combination for use according to any one claims 1-3 or 5-12, or the first compound for use according to any one of claims 4 to 12, or the bifunctional antibody or antigen-binding fragment thereof for use according to claim 20, wherein the auto-immune disease is selected from the group consisting of systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis, Grave’s disease and systemic lupus erythematosus.

23. The combination for use according to any one of claims 1-3 or 5-12, or the first compound for use according to any one of claims 4 to 12, wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

24. The combination for use according to any one of claims 1-3 or 5-12, or the first compound for use according to any one of claims 4 to 12, wherein the first compound and the second compound are separately provided in the form of pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient.

25. A kit, preferably for use according to any one of claims 1-12 comprising the combination according to any one of claims 1-3 or 5-12, or the first compound according to any one of claims 4-12, wherein the first and second compounds are provided within different, distinct containers, in particular as pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient.

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