Therapy by antagonizing il-7 or CD127, and TNF-alpha

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 TNFα or TNFR1, or an agonist of TNFR2, or both or comprising a bifunctional molecule targeting IL-7 or CD127 and TNFα or TNFR1 or TNFR2. 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-TNFα antibody or an antigen binding fragment thereof.

Description

[0001] TITLE

[0002] THERAPY BY ANTAGONIZING IL-7 OR CD127, AND TNF-ALPHA

[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 TNFa or TNFR1, or an agonist of TNFR2, or both, or comprising a bifunctional molecule targeting IL-7 or CD127 and TNFa or TNFR1 or TNFR2. 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 antagonist anti-CD127 antibody or an antigen-binding fragment thereof and an antagonist anti-TNFa 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] Even though TNFa has been identified as a major regulator of inflammatory responses and is crucial for normal homeostatic mechanisms including host defense, dysregulated activation of TNFa signaling has been found to lead to the development of a diverse range of inflammatory diseases and autoimmunediseases particularly in rheumatology (including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis), gastroenterology (including Inflammatory Bowel disease such as ulcerative colitis, Crohn’s disease), dermatology (psoriasis), ophthalmology (noninfectious uveitis), central nervous system (Jang et al. 2021, Int. J. Mol. Sci).

[0009] Understanding of the TNF-a 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 TNF-a, antagonists of TNFR1 (antagonists of the TNFa I TNFR1 signaling pathway) and agonists of TNFR2 (agonists of the TNFa I TNFR2 signaling pathway).

[0010] 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). Thus, there is a need for more efficient and targeted treatments for inflammatory and autoimmune diseases.

[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 TNFa or TNFR1 , or an agonist of TNFR2, or both;

[0014] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0015] In other words, in a first aspect of the invention, it is provided a combination comprising:

[0016] a. a first compound that is an antagonist of IL-7 and / or CD127; andb. a second compound that is an antagonist of TNFa or TNFR1, and / or an agonist of TNFR2;

[0017] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0018] Surprisingly, this 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 better effect to inhibit the secretion of pro-inflammatory cytokines including IFN-y, IL-17, IL-1 (3 and IL-6 compared to monotherapy. Elevated level of secretion of these cytokines is known to be associated with auto-immune diseases and inflammatory diseases (see for example Irano et al., Int Immunol.

[0019] 2020 Dec 18;33(3): 127-148; (Jang et al. 2021, Int. J. Mol. Sci). Even more surprisingly, the inventors show that this combination therapy exhibits an enhanced, ability to inhibit inflammatory response, by synergistically reducing T-cell-mediated inflammation. This synergistic effect was entirely unexpected, as the IL-7 / CD127 signaling pathway and the TNFa / TNFRI signaling pathway are distinct, their receptors are expressed on different cell populations, and antagonists of said signaling pathways used as monotherapies can have divergent effects - particularly on regulatory T cells. The inventors show that the combinatorial strategy of an antagonist anti-human IL-7Ra with an antagonist anti-human TNFa synergistically decrease the major pro-inflammatory IFN-y cytokine secretion as compared to monotherapy. This combination exhibits an enhanced ability to inhibit inflammatory responses, acting not only by synergistically reducing effector functions of Th1 and Th17 cells (IFN-y, IL-17) but also, through myeloid cells. This highlights its potential as a promising therapeutic strategy for patients with inflammatory or autoimmune diseases.

[0020] 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. Combining the blockade of the IL-7 I CD127 signaling pathway and of the TNFa / TNFR1 signaling pathway and / or the activation of the TNFa I TNFR2 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 toamplify 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.

[0021] The results illustrating the invention 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 TNFa or TNFR1 , or an agonist of TNFR2, or both leads to a reduction of the inflammatory response by reducing the secretion of pro-inflammatory cytokines.

[0022] In a particular embodiment of the invention, it is provided

[0023] a. a first compound that binds to CD127 and which is an antagonist of the IL-7 / IL-7R signaling pathway; and

[0024] b. a second compound that is an antagonist of TNFa, and which is an antagonist of the TNFa / TNFR1 signaling pathway and / or an agonist of the TNFa / TNFR2 signaling pathway, in particular an antagonist of the TNFa / TNFR1 signaling pathway, for use in the treatment of an inflammatory disease or an auto-immune disease.

[0025] 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, wherein the combination comprises an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and an antagonist TNFa antibody or an antigen-binding fragment thereof, preferably a monoclonal antibody.

[0026] This combination allows the inhibition, reduction or blockade of the IL-7 I IL-7R signaling pathway and of the TNFa / TNFR1 signaling pathway and / or the activation or enhancement of the TNFa / TNFR2 signaling pathway.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, wherein the combination comprises an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and an antagonist TNFR1 antibody or an antigen-binding fragment thereof, preferably a monoclonal antibody.

[0027] This combination allows the inhibition, reduction or blockade of the IL-7 I IL-7R signaling pathway and the TNFa / TNFR1 signaling pathway and / or the activation or enhancement of the TNFa / TNFR2 signaling pathway., in particular allows the inhibition, reduction or blockade of the IL-7 I IL-7R signaling pathway and the TNFa / TNFRI signaling pathway.

[0028] 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, wherein the combination comprises an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and an agonist TNFR2 antibody or an antigen-binding fragment thereof, preferably a monoclonal antibody.

[0029] This combination allows the inhibition, reduction or blockade of the IL-7 I IL-7R signaling pathway and the TNFa / TNFR1 signaling pathway and / or the activation of the activation or enhancement of the TNFa / TNFR2 signaling pathway, in particular it allows the activation or enhancement of the TNFa / TNFR2 signaling pathway.

[0030] The blockade of the IL-7 I IL-7R signaling pathway and of the TNFa signaling pathway may be achieved by providing a combination as defined here above, but it may also be achieved by providing a bifunctional molecule that recognizes and binds to at least IL-7 or CD127, and TNFa or TNFR1 and / or TNFR2.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] • Definitions

[0033] As used herein, "antibody" includes polyclonal, monoclonal, recombinant, chimeric, humanized, bispecific, multispecific, bifunctional, multifunctional andmodified 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.

[0034] 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 the antibody 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.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 TNFa or TNFR1 or TNFR2 and most particularly the extracellular domain of human CD127 or TNFa. 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.

[0035] 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 IgGI, 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 mimetics as 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.

[0036] As used herein, the term "specifically binds to" or "binds specifically" refers tothe capability of anti-IL-7 compounds, anti-CD127 compounds, anti-TNFa 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 TNFa and to bind to TNFa, or to interact with TNFR1 and bind to TNFR1 , or to interact with TNFR2 and bind to TNFR2, while they do not bind or they bindwith 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 10-6 M, 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.

[0037] 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.

[0038] 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 TNFa or TNFR1 , or an agonist of TNFR2, or both, 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 orseparately, in particular in alternation or sequentially, either administered together or separately.

[0039] 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 TNFa or TNFR1 and / or an agonist TNFR2, 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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 and psoriasis.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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 oftenexperience a reduced quality of life due to the chronic and unpredictable nature of their symptoms.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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. 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.

[0057] 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.

[0058] 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.

[0059] 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 and azathioprine, 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.

[0060] 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.

[0061] 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) andSignal 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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 thedimerized 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.

[0066] In the context of the present invention, CD127 is preferably human CD127, and the antagonist of CD127 is preferably an antagonist of human CD127.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] As used herein, the term “TNF” refers to Tumor necrosis factor and “TNFa” refers to Tumor necrosis factor alpha. TNFa is the prototypic member of a large superfamily known as the TNF / TNFR superfamily, which comprises more than 40 members. The TNFa signaling pathway regulates a number of critical cell functions including cell proliferation, survival, differentiation, and apoptosis. Aberrant TNFa production and TNF receptor signaling have been associated with the pathogenesis of several diseases, including rheumatoid arthritis, Crohn’sdisease, atherosclerosis, psoriasis, sepsis, diabetes, and obesity. TNFa signaling pathway has been shown to play a pivotal role in orchestrating the cytokine cascade in many inflammatory diseases and because of this role as a “masterregulator” of inflammatory cytokine production, it has been proposed as a therapeutic target for a number of diseases. TNFa signals through two transmembrane receptors, TNFR1 and TNFR2.

[0071] TNFa is a cytokine produced primarily by activated macrophages but is also produced in other cell types such as T cells, B cells, dendritic cells or mast cells. Human TNFa is expressed as a 27-kDa (233 amino acid) protein that is then proteolytically cleaved to a 17-kDa (157 amino acid) molecule. The 76-amino-acid presequence in the 27-kDa protein is highly conserved, and seems to serve to anchor the precursor protein to the membrane. This membrane integrated 27-kDa TNFa (mTNFa) undergoes proteolytic cleavage by a metalloprotease TNFa-converting enzyme (TACE), resulting in the 17-kDa soluble TNFa (also referenced sTNFa). The 17-KDa TNFa protomers are composed of two antiparallel [3-pleated sheets with antiparallel [3-strands, which form a jelly-roll [3-structure. It is believed that mTNFa and sTNFa regulate biological responses at autocrine / paracrine and endocrine levels, respectively.

[0072] TNFa may correspond to the protein referenced under UNIPROT Sequence No. P01375. Alternatively, TNFa may correspond to a protein having the amino acid sequence of SEQ ID No. 27.

[0073] In the context of the present invention, TNFa is preferably human TNFa, and the antagonist of TNFa is preferably an antagonist of human TNFa.

[0074] TNFa acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. The two TNFa receptors differ highly in their intracellular structure, which is responsible for their divergent activity. TNFR1 belongs to the family of death domain-containing receptors and is responsible for cell death, whereas TNFR2 is a TNFR-associated factor (TRAF)-interacting receptor, without a death domain, that favors cell activation. Activation from TNFR1 is responsible for a large number of inflammatory responses classically attributed to TNFa. AlthoughTNFR1 is responsible for most cellular responses to TNFa (including cytotoxicity, cell growth, NFKB activation, and upregulation of adhesion and cytokine genes), TNFR2 signaling has been reported to be important for proliferation of lymphoid cells.

[0075] TNFR1 is constitutively expressed in most mammalian tissues. Binding of TNFa onto TNFR1 is considered to be an irreversible mechanism. TNFa trimer binds to the extracellular domain of TNFR1, releasing the inhibitory protein, silencer of death domains (SODD), from the intracellular domain of TNFR1. The intracellular domain of the oligomerized TNFR1 is then bound by an adaptor protein TNF receptor-associated death domain (TRADD) which recruits additional adaptor proteins: receptor interacting protein-1 (RIP-1), a serine / threonine kinase and TNFR-associated factor 2 (TRAF2), an E3 ubiquitin ligase. This complex is then internalized and the TRADD-RIP-1-TRAF2 complex is released from TNFR1. These adapter proteins are then involved in activating key signaling pathways. RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGF[3)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of KB kinase) complex. The IKK complex then phosphorylates (primarily by I KK|3) IKBO, as well as other IKB proteins, which then leads to the ubiquitination and degradation of IKBO. This then results in the release of NFKB subunits that are bound to IKBO under unstimulated conditions. The free NFKB subunits translocate into the nucleus and evoke gene transcription. TRAF2 has also been shown to activate NFKB by binding to the IKK complex and by recruiting inhibitor of cellular apoptosis proteins (clAP)-1 and clAP-2. Stimulation of TNFR1 also activates a MAP3K called apoptosis-signaling kinase-1 (ASK-1) that associates with TRAF2 in the TRADD-RIP-1-TRAF2 complex, activating MAP2Ks, MEK-4, and MEK-6, which in turn activate c-Jun N-terminal kinases (JNKs) and p38 MAPK.

[0076] TNFR1 may correspond to the protein referenced under UNIPROT Sequence No. P19438. Alternatively, TNFR1 may correspond to a protein having the amino acid sequence of SEQ ID No. 28. In the context of the present invention, TNFR1 is preferably human TNFR1.TNFR2 is highly regulated and is typically expressed in the cells of the immune system. Binding of TNFa onto TNFR2 has both rapid on and off kinetics. The main signaling pathways activated by TNFR2 stimulation are the classical (or canonical) and the alternative (or non-canonical) NFKB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) pathway. Because of the lack of a death domain, TNFR2 is unable to recruit TRADD protein, but can instead weakly bind to TRAF2 directly (Rothe et al., 1995). Under these conditions, TRAF2 induces the non-canonical NF-KB pathway, through the activation of NF-KB-inducing kinase (NIK), which further leads to the phosphorylation of IKKa and the processing of p100, a crucial step in the nuclear translocation of p52 / RelB (Borghi et al., 2018). The alternative NF-KB pathway acts quite distinctly from the classical one, for example by being dispensable for the initial activation of naive T cells through TCR signaling but crucial for the in vivo generation and maintenance of effector and memory T cells (Sun, 2017). However, upon binding to TRAF2, TNFR2 can also recruit clAPI / 2 proteins, which are involved in TNFR1 -mediated NF-KB activation, creating crosstalk between the TNFR pathways. TNFR2 pathway activation consumes the cytosolic pool of the TRAF2-clAP1 / 2 complex, limiting its availability for other receptors, including TNFR1. Due to the role of TRAF2 and clAPs in preventing apoptosis and necroptosis in the context of TNFR1 signaling, TNFR2-mediated deprivation of these molecules is able to enhance TNFR1 -induced cell death in macrophages

[0077] TNFR2 may correspond to the protein referenced under UNIPROT Sequence No. P20333. Alternatively, TNFR2 may correspond to a protein having the amino acid sequence of SEQ ID No. 29. In the context of the present invention, TNFR2 is preferably human TNFR2.

[0078] 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, delayingor 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.

[0079] • The first compound that is an antagonist of IL-7 or CD127

[0080] 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.

[0081] 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.

[0082] 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. 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.

[0083] In an embodiment, the first compound inhibits or reduces the binding between IL-7 and CD127.

[0084] 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”.

[0085] 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 / IL-7Rsignaling pathway. Such a first compound can be defined as an “anti-IL-7 compound”.

[0086] 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”.

[0087] 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 I IL-7R signaling pathway. Such a first compound can be defined as an “anti-CD127 compound”.

[0088] 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. 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.

[0089] 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 comparedto 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 or synthetic, 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.

[0090] 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).

[0091] 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.

[0092] In a particular embodiment, the anti-IL-7 or anti-CD127 compound does not induce lymphodepletion (destruction of lymphocytes, in particular T 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 preferablyat 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] ore 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.

[0101] 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.

[0102] In a particular embodiment of the invention, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises:

[0103] i) a heavy chain variable fragment comprising:

[0104] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA), and

[0105] 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:

[0106] 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), andc. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA).

[0107] Said above CDR domains have been identified according to the KABAT numbering.

[0108] 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:

[0109] i) a heavy chain variable fragment comprising:

[0110] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 30 (DYYMA), and

[0111] 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

[0112] ii) a light chain variable fragment comprising:

[0113] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), and

[0114] b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and

[0115] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA).

[0116] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof comprises:

[0117] - the antibody heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0118] - 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.

[0119] In a particular embodiment of the invention, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises:i) a heavy chain variable fragment comprising:

[0120] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 19 (GFTLSDYY), and

[0121] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 20 (ISASGLRT), and

[0122] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 21 (ARPLSAHYGFNYFDY), and

[0123] ii) a light chain variable fragment comprising:

[0124] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 22 (EDIYQG), and

[0125] b. LCDR2 comprising or consisting in the amino acid sequence “SAN”, and

[0126] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 23 (QQYYDYPLA).

[0127] Said above CDR domains have been identified according to the IMGT numbering.

[0128] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof comprises:

[0129] - the antibody heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0130] - the antibody light chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 12.

[0131] 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.

[0132] In a particular aspect of the invention, the antagonist anti-human CD127 antibody or an antigen-binding fragment thereof comprises:

[0133] 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. 14 or SEQ ID No. 15 or SEQ ID No. 16 or SEQ ID No. 17 or SEQ ID No. 18, preferably SEQ ID No. 18.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.

[0134] 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.

[0135] 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:

[0136] 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.

[0137] 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.

[0138] 15 or SEQ ID No. 16 or SEQ ID No. 17 or SEQ ID No. 18, preferably SEQ ID No.

[0139] 18.

[0140] 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 setforth in SEQ ID No. 13 and a light chain consisting of the amino acid sequence set forth in SEQ ID No. 18.

[0141] 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:

[0142] a) it inhibits or reduces the activation of the phosphatidylinositol 3-kinase and / or the ERK signaling pathway induced by IL-7,

[0143] 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);

[0144] d) it binds to T cells;

[0145] e) it does not antagonize the TSLP / TSLPR signaling pathway.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)

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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 the invention is an antagonist of the IL-7 I IL-7R signaling pathway but does not antagonize the TSLP / TSLPR signaling pathway.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.

[0150] 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 signaling pathway induced when TSLP interact with the TSLPR I CD127 complex is not reduced or inhibited in presence of the anti-CD127 compound.

[0151] 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.

[0152] 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).

[0153] In an embodiment, the first compound is GSK-3888130 (GlaxoSmithKline, an anti-IL-7 antibody), an antagonist anti-IL-7 antibody.

[0154] 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).

[0155] • Compounds that are antagonists of TNFa or TNFR1

[0156] The composition to be used according to the present invention, or in a method according to the present invention, comprises a second compound that may be an antagonist of TNFa, in particular of human TNFa, or TNFR1, in particular human TNFR1.

[0157] In the context of this patent application, an "antagonist of TNFa or TNFR1" refers to any substance that inhibits or reduces the biological activity of TNFa, in particular human TNFa, or of its receptor TNFR1 , in particular of human TNFR1. These antagonists can prevent the binding between TNFa and TNFR1 , block the signal transduction pathway induced when TNFa and TNFR1 are bound, or otherwise interfere with the ability of either TNFa or TNFR1 to exert their biological effects, in particular their immunological, effects. This inhibition can be achieved through various mechanisms, including a direct binding to TNFa, a direct binding to TNFR1, or an interruption of downstream signaling pathways. The TNFa / TNFR1 signaling pathway corresponds to the signaling cascade initiated when TNFa binds to TNFR1 on the cell surface. This interaction triggers receptor trimerization and recruitment of intracellular adaptor proteins such as TRADD, RIPK1, and TRAF2, leading to the activation of downstream signaling pathways. An inhibition or reduction of the TNFa / TNFR1 signaling pathway may thus correspond to an inactivation of NF-KB and / or an inactivation of MAPK pathways (such as JNK, ERK, and p38), or a modification of cytokine production. TNFa / TNFRI signaling pathway can be monitored by measuring downstream pro-inflammatory cytokines (e.g., IL-6, IL-8) secreted in presence or in absence of the antagonist of TNFa or TNFR1 , as compared to a positive control (e.g. in presence of TNFa) and / or a negative control (e.g. an unrelated cytokine or antibody that do not interact with TNFa and TNFR1). A decrease in cytokinesecretion in the presence of the test compound indicates pathway inhibition, and thus that the compound is an antagonist of TNFa or TNFR1.

[0158] An antagonist of TNFa or TNFR1 can thus bind to TNFa or TNFR1 , and inhibits or reduces the TNFa / TNFR1 signaling pathway.

[0159] In an embodiment, the second compound binds to TNFa orTNFRI, and thereby inhibits or reduces the binding between TNFa and its receptor TNFR1 , leading to an inhibition or a reduction of the TNFa / TNFR1 signaling pathway.

[0160] An antagonist of TNFa or TNFR1 can be a compound that inhibits or reduces downstream signaling pathway(s) induced or activated when TNFa binds to TNFR1.

[0161] In a particular embodiment, an antagonist of TNFa or TNFR1 is an antibody or an antigen-binding fragment or an antigen-binding antibody mimetic that binds to, in particular specifically binds to TNFa, or that binds to TNFR1, and inhibits or reduces the binding between TNFa and at its receptors TNFR1.

[0162] An antagonist of TNFa or TNFR1 can be a compound that binds to TNFa, in particular human TNFa.

[0163] An antagonist of TNFa or TNFR1 can be a compound that binds to TNFa and prevents the binding between TNFa and its receptor TNFR1.

[0164] An antagonist of TNFa or TNFR1 can be a compound that binds to TNFR1, in particular human TNFR1.

[0165] An antagonist of TNFa or TNFR1 can be a compound that binds to TNFR1 , and prevents the binding between TNFa and TNFR1.

[0166] In an embodiment, the antagonist of TNFa orTNFRI is an anti-TNFa antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to TNFa.

[0167] In an embodiment, the antagonist of TNFa is an anti-TNFa antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specificallybinds to TNFa and blocks or inhibits the binding between TNFa and TNFR1 , and in particular is an antagonist of the TNFa / TNFR1 signaling pathway (it inhibits or reduces the TNFa / TNFR1 signaling pathway).

[0168] In an embodiment, the antagonist of TNFa orTNFRI is an anti-TNFR1 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to TNFR1.

[0169] In an embodiment, the antagonist of TNFa is an anti-TNFR1 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to TNFR1 and blocks or inhibits the binding between TNFa and TNFR1, and in particular is an antagonist of the TNFa / TNFR1 signaling pathway (it inhibits or reduces the TNFa I TNFR1 signaling pathway).

[0170] It can be considered that an antagonist of TNFa or TNFR1, in particular an antibody (or antigen-binding fragment thereof), reduces, inhibits or blocks the binding of TNFa to TNFR1, if said antagonist (in particular antibody or antigenbinding 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 TNFa to TNFR1 in a binding competitive assay by Blitz, as compared to the KD value of TNFa to TNFR1 in presence of a control antibody (i.e. an antibody which does not specifically bind to TNFa, TNFR1 ).

[0171] In a particular embodiment of the invention, the antagonist of TNFa or TNFR1 is an anti-TNFa or anti-TNFR1 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0172] In a particular embodiment of the invention, the antagonist of TNFa is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0173] In a particular embodiment of the invention, the antagonist of TNFa is an anti-TNFa 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 preferred embodiment of the invention, the second compound that is an antagonist of human TNFa is an anti-human TNFa antibody or antigen-binding fragment thereof which comprises:

[0174] i) a heavy chain variable fragment comprising:

[0175] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DYAMH), and

[0176] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (AITWNSGHIDYADSVEG), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (VSYLSTASSLDY), and ii) a light chain variable fragment comprising:

[0177] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASQGIRNYLA), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (AASTLQS), and

[0178] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QRYNRAPYT).

[0179] Said above CDR domains have been identified according to the KABAT numbering.

[0180] In another particular embodiment of the invention, the second compound that is an antagonist of human TNFa is an anti-TNFa antibody or antigen binding fragment thereof which comprises:

[0181] i) a heavy chain variable fragment comprising:

[0182] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 37 (GFTFDDYA), and

[0183] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 38 (ITWNSGHI), and

[0184] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 39 (AKVSYLSTASSLDY), and

[0185] ii) a light chain variable fragment comprising:

[0186] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 40 (QGIRNY), andb. LCDR2 comprising or consisting in the amino acid sequence “AA”, and

[0187] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 41 (QRYNRAPYT).

[0188] Said above CDR domains have been identified according to the IMGT numbering. In a particular embodiment of the invention, the anti-TNFa 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.

[0189] In a more particular embodiment of the invention, the antagonist anti-TNFa 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.

[0190] In an embodiment, the antagonist of TNFa or TNFR1 is a mutated TNFa or a soluble TNFR1 or TNFR2. A mutated TNFa that is an antagonist of TNFa or TNFR1 can be a modified form of the natural TNFa molecule that retains its ability to bind to TNFR1 with high affinity but does not induce activation of the TNFa / TNFR1 signaling pathway. This TNFa mutant functions as an antagonist by competitively inhibiting the binding of endogenous TNFa, thereby preventing receptor activation and downstream signaling. A soluble TNFR1 or TNFR2 receptor is an engineered TNFR1 or TNFR2 comprising at least a fragment of the extracellular domain of TNFR1 or TNFR2 that is not membrane-bounded but circulates in the bloodstream of the patient, thereby binding co circulating TNFa and sequestering it away from the cell surface TNFRs.

[0191] In particular, the antagonist of TNFa or TNFR1 is a soluble protein or a soluble fusion protein that comprise at least 50% in amino acid length of the extracellular domain of either TNFR1 or TNFR2, 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%. Alternatively, the antagonist of TNFa or TNFR1 is a mutated TNFa that comprise at least 50% in amino acid length of TNFa, in particular at least 60%, inparticular at least 70%, in particular at least 80%, in particular at least 90%, in particular at least 95%, but does not have the same amino acid sequence as the corresponding portion of natural TNFa and does not induce activation of TNFR1.

[0192] In an embodiment, the antagonist of TNFa or TNFR1 is a peptide that binds to TNFR1. In an embodiment, the antagonist of TNFa or TNFR1 is a peptide that binds to TNFR1 and blocks or inhibits the binding between TNFa and TNFR1.

[0193] • Compounds that are agonists of TNFR2

[0194] In an embodiment of the invention, the composition to be used according to the present invention, or in a method according to the present invention, comprises a second compound that may be an agonist of TNFR2, in particular human TNFR2.

[0195] In the context of this patent application, an "agonist of TNFR2" refers to any substance that enhances or activates the biological activity of TNFR2. These agonists can enhance the binding between TNFa and TNFR2, activate the signal transduction pathway induced when TNFa and TNFR2 are bound, or otherwise mimic the biological effects, in particular the immunological effects, provided by an activated TNFR2 (i.e. a TNFR2 that is bound to a functional TNFa). This activation can be achieved through various mechanisms, including a direct binding to TNFR2, or an activation or enhancement of downstream signaling pathways. The TNFa / TNFR2 signaling pathway corresponds to the signaling cascade initiated when TNFa or another ligand binds to TNFR2 on the cell surface. Upon activation, TNFR2 recruits intracellular adaptor proteins such as TRAF2, TRAF1, and clAPI / 2, leading to the activation of the NF-KB pathway (canonical and non-canonical), the Induction of MARK signaling pathways, enhancing tissue repair and immune modulation, and the expansion of regulatory T cells (Tregs) and other immunosuppressive effects.

[0196] An activation or enhancement of the TNFa / TNFR2 signaling pathway may be considered when cytokines such as IL-10 or TGF-[3 production or secretion. TNFa / TNFR2 signaling pathway can be monitored by measuring downstream pro-inflammatory cytokines (e.g., IL-10 or TGF-[3) secreted in presence or in absence of the agonist of TNFR2, as compared to a positive control (e.g. inpresence of TNFa) and / or a negative control (e.g. an unrelated cytokine or antibody that do not interact with TNFR2). An increase in cytokine secretion in the presence of the test compound indicates pathway activation, and thus that the compound is an agonist of TNFR2.

[0197] An agonist of TNFR2 can thus bind to TNFR2, and activates or enhances the TNFa / TNFR2 signaling pathway.

[0198] In an embodiment, the second compound binds to TNFR2, and thereby mimics the binding of TNFa to TNFR2, leading to an activation or enhancement of the TNFa / TNFR2 signaling pathway.

[0199] An agonist of TNFR2 can be a compound that activates or enhances downstream signaling pathway(s) induced or activated when TNFa binds to TNFR2.

[0200] In a particular embodiment, an agonist of TNFR2 is an antibody or an antigenbinding fragment or an antigen-binding antibody mimetic that binds to, in particular specifically binds to, TNFR2.

[0201] In a particular embodiment, an agonist of TNFR2 is an antibody or an antigenbinding fragment or an antigen-binding antibody mimetic that binds to, in particular specifically binds to, TNFR2, and activates TNFR2 downstream signaling.

[0202] In a particular embodiment, an agonist of TNFR2 is an antibody or an antigenbinding fragment or an antigen-binding antibody mimetic that binds to, in particular specifically binds to, TNFR2, and enhances the binding between TNFa and TNFR2.

[0203] In an embodiment, the agonist of TNFR2 is an anti-TNFR2 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to TNFR2.

[0204] In an embodiment, the agonist of TNFR2 is an anti- TNFR2 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specificallybinds to TNFR2 and constitutively activates TNFR2, and in particular is an agonist of the TNFa I TNFR2 signaling pathway (it activates or enhances the TNFa I TNFR2 signaling pathway).

[0205] In a particular embodiment of the invention, the agonist of TNFR2 is an anti-TNFR2 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0206] In a particular embodiment of the invention, the agonist of TNFR2 is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0207] In a particular embodiment of the invention, the agonist of TNFR2 is an anti-TNFR2 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0208] In an embodiment, the agonist of TNFR2 is a mutated TNFa, in particular that specifically binds to TNFR2. Such a mutated TNFa that is agonist of TNFR2 is a modified form of the natural TNFa molecule that retains its ability to bind to TNFR2 with high affinity and induces, in particular constitutively induces, the activation of the TNFa / TNFR2 signaling pathway. This TNFa mutant functions as an agonist by activating TNFR2 activation and downstream signaling. Unlike natural TNFa, which can activate both TNFR1 and TNFR2, this mutant exhibits altered receptor binding properties, allowing it to preferentially bind to and activate TNFR2, in particular with enhanced affinity or stability. This activation results in sustained stimulation of TNFR2-mediated signaling pathway, while minimizing or eliminating activation of the TNFR1 -mediated pathway.

[0209] In an embodiment, the second compound inhibits or reduces the binding between TNFa and its receptor TNFR1, and in particular is an antagonist of the TNFa I TNFR1 signaling pathway (it inhibits or reduces the of the TNFa I TNFR1 signaling pathway), and / or enhances the binding between TNFa and its receptor TNFR2 and in particular is an agonist of the TNFa I TNFR2 signaling pathway (it induces or enhances the TNFa / TNFR2 signaling pathway).In an embodiment, the second compound is selected from the group consisting of:

[0210] - a protein comprising at least a portion of TNFa or TNFR1 or TNFR2; - an antibody, an antigen-binding fragment thereof or an antigenbinding antibody mimetic thereof, that binds to TNFa or TNFR1 and inhibits or reduces the binding between TNFa and TNFR1 ; and - an antibody, an antigen-binding fragment thereof or an antigenbinding antibody mimetic thereof, that binds to TNFR2 and enhances the binding between TNFa and TNFR2 or induces or enhances the TNFa I TNFR2 signaling pathway;

[0211] in particular wherein said second compound is an antagonist of the TNFa I TNFR1 signaling pathway (it inhibits or reduces the of the TNFa I TNFR1 signaling pathway) and / or an agonist of the TNFa I TNFR2 signaling pathway (it induces or enhances the TNFa I TNFR2 signaling pathway).

[0212] • Examples of compounds that can be considered antagonists of TNFa or TNFR1 and / or agonists of TNFR2

[0213] In an embodiment, the second compound that is an antagonist of TNFa or TNFR1, or an agonist of TNFR2, or both is selected from the list consisting of etanercept (a recombinant human soluble fusion protein of TNFR2 coupled to the Fc portion of IgG), infliximab (an anti-TNF human-murine chimeric lgG1 monoclonal antibody), adalimumab (a human anti-human TNFa antibody), certolizumab pegol (a PEGylated TNFa antibody - also referenced as certolizumab), golimumab (a human anti-TNFa IgGlK monoclonal antibody), ozoralizumab (humanized monoclonal antibody, also referenced as TS-152), AM-201 (a bispecific antibody targeting TNFalpha and IL-6, under development by AbClon), ND-009 (also named NM-009, antibody against TNF-alpha under development by Ti Hotts Pharma), and biosimilars thereof (including but not limited to Infliximab-axxq (Avsola®), Infliximab-qbtx (Ixifi™), Infliximab-abda (Renflexis®), Infliximab-dyyb (Inflectra®), Etanercept-ykro (Eticovo™), Etanercept-szzs (Erelzi®), Adalimumab-fkjp (Hulio™), Adalimumab-afzb (Abrilada™), Adalimumab-bwwd (Hadlima™), Adalimumab-adaz (Hyrimoz®), Adalimumab-adbm (Cyltezo®), Adalimumab-atto (Amjevita™), atrosab (a humanized Mab against TNF receptor 1 under development by Baliopharm), atrosimab (also named ATM 001; ATM-001; ATM001; Ab against TNF receptor 1 under development by Baliopharm), solnatide (also named AP-301; AP-302; AP-303; AP301 ; AP301 -IH; AP301 -IRI; AP301 -PN, a synthetic peptide which corresponds to the structural motif of human tumour necrosis alpha, under development by Apeptico), sTNF-RI inhibitor Nanotts (nanoparticle targeting the soluble form of TNF-R1, under development by NaNotics) and biosimilars thereof, DT-001 (also named DT 001; DT-001; DT001, a multi-specific antibody agonist targeting TNFR2, developed by Dualyx), NKTR-0165 (a bivalent agonistic antibody targeting TNFR2, under development by Biolojic Design), TRB-061 (also named TRB 061; TRB-061; TRB061, a TNF receptor 2 (TNFR2) targeting agonist, under development by Trex Bio) and biosimilars thereof.

[0214] In an embodiment, the antagonist of TNFa or TNFR1 is selected from the list consisting of etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, ozoralizumab, AM-201, ND-009, and biosimilars thereof (including but not limited to Infliximab-axxq (Avsola®), Infliximab-qbtx (Ixifi™), Infliximab-abda (Renflexis®), Infliximab-dyyb (Inflectra®), Etanercept-ykro (Eticovo™), Etanercept-szzs (Erelzi®), Adalimumab-fkjp (Hulio™), Adalimumab-afzb (Abrilada™), Adalimumab-bwwd (Hadlima™), Adalimumab-adaz (Hyrimoz®), Adalimumab-adbm (Cyltezo®), Adalimumab-atto (Amjevita™). These antibodies and fusion proteins that target TNFa or TNFR1, thereby preventing interaction between TNFa and TNFR1.

[0215] In another embodiment, the antagonist of TNFa or TNFR1 is selected from the list consisting of etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, and ozoralizumab.

[0216] In a particular embodiment of the invention, it is provided

[0217] a. a first compound that binds to CD127 and which is an antagonist of the IL-7 / IL-7R signaling pathway; and

[0218] b. a second compound that is an antagonist of TNFa,for use in the treatment of an inflammatory disease or an auto-immune disease. In another embodiment, the antagonist of TNFa is adalimumab.

[0219] In a particular embodiment of the invention, 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] - etanercept,

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

[0223] In a particular embodiment of the invention, it is provided a combination comprising:

[0224] - 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

[0225] - infliximab,

[0226] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0227] In a particular embodiment of the invention, it is provided a combination comprising:

[0228] - 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

[0229] - adalimumab,

[0230] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0231] In a particular embodiment of the invention, it is provided a combination comprising:

[0232] - 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

[0233] - certolizumab,for use in the treatment of an inflammatory disease or an auto-immune disease.

[0234] In a particular embodiment of the invention, it is provided a combination comprising:

[0235] - 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

[0236] - golimumab,

[0237] for use in the treatment of an inflammatory disease or an auto-immune disease. In a particular embodiment of the invention, it is provided a combination comprising:

[0238] - 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

[0239] - ozoralizumab,

[0240] for use in the treatment of an inflammatory disease or an auto-immune disease.

[0241] In an embodiment, the antagonist of TNFR1 is selected from the list consisting of atrosab (a humanized Mab against TNF receptor 1 under development by Baliopharm), atrosimab (also named ATM 001; ATM-001; ATM001; Ab against TNF receptor 1 under development by Baliopharm), solnatide (also named AP-301; AP-302; AP-303; AP301; AP301-IH; AP301-IRI; AP301-PN, a synthetic peptide which corresponds to the structural motif of human tumour necrosis alpha, under development by Apeptico), sTNF-RI inhibitor Nanotts (nanoparticle targeting the soluble form of TNF-R1, under development by NaNotics) and biosimilars thereof. These antibodies, fusion proteins and nanoparticles target TNFR1 , thereby preventing it from interacting with its ligand.

[0242] In an embodiment, the agonist of TNFR2 is selected from the list consisting of DT-001 (also named DT 001; DT-001; DT001, a multi-specific antibody agonist targeting TNFR2, developed by Dualyx), NKTR-0165 (a bivalent agonistic antibody targeting TNFR2, under development by Biolojic Design), TRB-061(also named TRB 061; TRB-061; TRB061, a TNF receptor 2 (TNFR2) targeting agonist, under development by Trex Bio) and biosimilars thereof. These antibodies, fusion proteins and nanoparticles target TNFR2, acting by modulating TNFR2 which is highly expressed in Tregs, where increasing and activating Treg cells can restore the regulatory or effector T cells which suppress the unwanted inflammatory and / or autoimmune reaction.

[0243] In an embodiment of the invention, it is provided a combination comprising: an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and

[0244] an antagonist anti-TNFa antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0245] In a more preferred embodiment, it is provided a combination comprising:

[0246] - a first compound that is an antagonist anti-human CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody as disclosed in any embodiment herein, and

[0247] - a second compound that is an antagonist of human TNFa, preferably for use in the treatment of an inflammatory disease or an autoimmune disease,

[0248] wherein the second compound is an antagonist anti-human TNFa antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, preferably comprising:

[0249] i) a heavy chain variable fragment comprising:

[0250] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DYAMH), and

[0251] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (AITWNSGHIDYADSVEG), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (VSYLSTASSLDY), and ii) a light chain variable fragment comprising:

[0252] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASQGIRNYLA), andb. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (AASTLQS), and

[0253] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QRYNRAPYT),

[0254] preferably comprising the antibody heavy chain variable fragment which comprises or consists in the amino acid sequence set forth in SEQ ID No. 42, and the antibody light chain variable fragment which comprises or consists in the amino acid sequence set forth in SEQ ID No. 43, more preferably comprising the antibody heavy chain variable fragment which comprises or consists in the amino acid sequence set forth in SEQ ID No. 44, and the antibody light chain variable fragment which comprises or consists in the amino acid sequence set forth in SEQ ID No. 45.

[0255] In a more preferred embodiment of the invention, it is provided a combination comprising:

[0256] - a first compound that is an antagonist anti-human CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody and

[0257] - a second compound that is an antagonist of human TNFa, preferably an antagonist anti-human TNFa antibody or antigen-binding fragment thereof, preferably a monoclonal antibody,

[0258] preferably for use in the treatment of an inflammatory disease or an autoimmune disease,

[0259] wherein the first compound is an antagonist anti-human CD127 antibody or antigen binding fragment thereof which comprises:

[0260] - a heavy chain variable fragment comprising:

[0261] o HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA), and o HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2 (TISASGLRTYYPDSVKG), and o HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3 (PLSAHYGFNYFDY), and- a light chain variable fragment comprising:

[0262] o LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), and

[0263] o LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and

[0264] o LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA),

[0265] 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. 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, more preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 13, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in in SEQ ID No. 14 or SEQ ID No. 15 or SEQ ID No. 16 or SEQ ID No. 17 or SEQ ID No.

[0266] 18, preferably SEQ ID No. 18.

[0267] In a more preferred embodiment of the invention, it is provided a combination comprising:

[0268] - a first compound that is an antagonist anti-human CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody as disclosed in any embodiment herein, and, and

[0269] - a second compound that is an antagonist of human TNFa, preferably for use in the treatment of an inflammatory disease or an auto-immune disease,

[0270] wherein the first compound is an antagonist anti-human CD127 antibody or antigen binding fragment thereof which comprises:

[0271] - a heavy chain variable fragment comprising:

[0272] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA), andb. 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 - a light chain variable fragment comprising:

[0273] 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

[0274] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA),

[0275] 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. 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, more preferably comprises the antibody heavy chain variable fragment comprising or consisting in the amino acid sequence set forth in SEQ ID No. 13, and the antibody light chain variable fragment comprising or consisting in the amino acid sequence set forth in in SEQ ID No. 14 or SEQ ID No. 15 or SEQ ID No. 16 or SEQ ID No. 17 or SEQ ID No.

[0276] 18, preferably SEQ ID No. 18, and

[0277] wherein the second compound is an antagonist anti-human TNFa antibody or antigen-binding fragment thereof which comprises:

[0278] - an heavy chain variable fragment comprising:

[0279] i) HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DYAMH), and ii) HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (AITWNSGHIDYADSVEG), and iii) HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (VSYLSTASSLDY), and

[0280] - a light chain variable fragment comprising:i) LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASQGIRNYLA), and

[0281] ii) LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (AASTLQS), and iii) LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QRYNRAPYT), 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 comprises or consists in the amino acid sequence set forth in SEQ ID No. 45.

[0282] In an embodiment of the invention, it is provided a combination comprising:

[0283] a. an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and

[0284] b. an antagonist anti-TNFR1 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0285] In an embodiment of the invention, it is provided a combination comprising:

[0286] a. an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and

[0287] b. an agonist anti-TNFRR2 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0288] 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 regimen with a second compound that is an antagonist of TNFa or TNFR1 , or an agonistof TNFR2, or both, preferably an antagonist of human TNFa (e.g., an antagonist anti-human TNFa antibody or antigen-binding fragment thereof as described herein) for the treatment of an inflammatory disease or an auto-immune disease.

[0289] In an embodiment, it is provided a first compound that is an antagonist antiCDF? antibody or antigen-binding fragment thereof as described above, for use in a combination regimen with a second compound that is an antagonist of TNFa or TNFR1 , or an agonist of TNFR2, or both, for the treatment of an inflammatory disease or an auto-immune disease.

[0290] In an embodiment, it is provided a first compound that is an antagonist antiCDF? antibody or antigen-binding fragment thereof as described above, preferably wherein said antagonist anti-CD127 antibody or antigen-binding fragment thereof binds to, in particular specifically binds to, human CD127, and inhibits or reduces the binding between human IL-7 and human CD127, and in particular is an antagonist of the IL-7 I IL-7R signaling pathway, for use in a combination regimen with a second compound that is an antagonist of human TNFa, preferably an anti-TNFa antibody or antigen-binding fragment thereof as described above or a soluble fusion protein of TNFR2, for the treatment of an inflammatory disease or an auto-immune disease.

[0291] In a preferred embodiment, the antagonist anti-CD127 antibody or antigenbinding fragment thereof comprises: a heavy chain variable fragment (VH) comprising: HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1, and HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0292] a light chain variable fragment (VL) comprising: LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in 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 sequenceset 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.

[0293] • Bifunctional molecules including bifunctional antibodies and derived molecules

[0294] In an aspect of the invention, it is provided a bifunctional molecule that comprises:

[0295] - A first binding moiety, said first binding moiety binding to IL-7 or CD127, and

[0296] - A second binding moiety, said second binding moiety binding to TNFa, TNFR1 or TNFR2.

[0297] 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 specifically binds to, two distinct first and second antigens, the first antigen being IL-7 or CD127 and the second antigen being TNFa, TNFR1 or TNFR2.

[0298] In particular, the bifunctional molecule (i) inhibits the binding between IL-7 and CD127, in particular human IL-7 and human CD127, and (ii) inhibits the binding between TNFa and TNFR1 (in particular between human TNFa and human TNFR1 ), in particular inhibits the binding between TNFa and TNFR1 and reduces or inhibits the TNFa / TNFR1 signaling pathway and / or (ii’) enhances the binding between TNFa and TNFR2 (in particular between human TNFa and human TNFR2), or binds to TNFR2 and induces or enhances the TNFa I TNFR2 signaling pathway .

[0299] In a particular aspect of the invention, it is provided a bifunctional molecule that comprises:

[0300] - A first binding moiety, said first binding moiety binding to CD127, in particular human CD127, and

[0301] - A second binding moiety, said second binding moiety binding to TNFa, in particular human TNFa.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 TNFa, TNFR1 or TNFR2 on the other hand).

[0302] In an aspect of the invention, it is provided a bifunctional molecule that comprises:

[0303] - A first binding moiety, said first binding moiety binding to IL-7 or CD127,

[0304] - A second binding moiety, said second binding moiety binding to TNFa and TNFR1 and / or between TNFa and TNFR2,

[0305] the bifunctional molecule inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between TNFa and TNFR1 and / or enhances the binding between TNFa and TNFR2 and / or induces or enhances the TNFa I TNFR2 signaling pathway.

[0306] The inhibition of the binding between IL-7 and CD127 and TNFa and TNFR1 and / or the enhancement of the binding between TNFa and TNFR2 and / or the enhancement of the TNFa I TNFR2 signaling pathway has the same meaning as detailed above in relation to the combinations of compounds.

[0307] In an aspect of the invention, it is provided a bifunctional molecule that comprises:

[0308] - A first binding moiety, said first binding moiety binding to IL-7 or CD127,

[0309] - A second binding moiety, said second binding moiety binding to TNFa, TNFR1 or TNFR2,

[0310] the bifunctional molecule being an antagonist of IL-7 and / or CD127, and the bifunctional molecule being an antagonist of TNFa.

[0311] The antagonist property of the bifunctional molecule towards IL-7, CD127 and TNFa has the same meaning as detailed above in relation to the combinations of compounds.

[0312] In a particular embodiment, the binding moiety of the bifunctional molecule that binds to CD127 comprises:

[0313] a heavy chain variable fragment (VH) comprising:a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1, and

[0314] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and

[0315] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0316] - a light chain variable fragment (VL) comprising:

[0317] a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and

[0318] b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and

[0319] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6;

[0320] 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.

[0321] In another particular embodiment, the binding moiety of the bifunctional molecule that binds to TNFa comprises:

[0322] - a heavy chain variable fragment (VH) comprising:

[0323] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31, and

[0324] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32; and

[0325] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33; and

[0326] a light chain variable fragment (VL) comprising:a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34, and

[0327] b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35; and

[0328] c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36;

[0329] 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.

[0330] 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.

[0331] The bifunctional molecule may particularly comprise two, three or four binding moieties. For example, the bifunctional molecule may comprise:

[0332] one binding moiety that binds to IL-7 or CD127 and one binding moiety that binds TNFa, TNFR1 or TNFR2; or

[0333] 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 TNFa, TNFR1 or TNFR2; or

[0334] two binding moieties that bind to TNFa, TNFR1 and / or TNFR2, said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to TNFa; and one binding moiety that binds to IL-7 or CD127, preferably CD127; or

[0335] two binding moieties that bind to TNFa, TNFR1 and / or TNFR2, said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to TNFa; and two binding moiety that binds to IL-7 orCD127; said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to CD127; or

[0336] 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 TNFa, TNFR1 and / or TNFR2;

[0337] three binding moieties that bind to TNFa, TNFR1 and / or TNFR2, said three binding moieties binding to the same or to different target(s), preferably the same target, most preferably to TNFa; and one binding moiety that binds to IL-7 or CD127, preferably CD127.

[0338] 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.

[0339] 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 monovalent immunoglobulin comprising a Fab fragment with an antigen-binding region recognizing to TNFa, TNFR1 and / or TNFR2, the two immunoglobulins forming a bifunctional antibody.

[0340] 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 secondregion (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 antibodies include 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 recognizes two different targets.

[0341] 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 TNFa, TNFR1 or TNFR2. 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.

[0342] 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.

[0343] 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 lgG1 “hinge region” asused herein comprises residues 216-230 according to the according to the Ell index as in Kabat.

[0344] The first and / or second binding moiety may comprise a CL domain.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] In addition, the bifunctional molecule may also comprise one or several peptide linkers, that allow linkage between different parts of the bifunctional molecule (e.g., between a Fc chain and a binding moiety).

[0349] In an embodiment, the first and second binding moieties are Fab, so that the bifunctional molecule preferably comprises or consists of:

[0350] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0351] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1), and

[0352] said first light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0353] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL),(iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0354] said second light and heavy chains forming the second binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TN Fa.

[0355] 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:

[0356] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0357] (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

[0358] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL),

[0359] (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,

[0360] wherein said second light and heavy chains form the second binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TNFa, and

[0361] wherein the first and second Fc chains are complementary and form a Fc domain.

[0362] 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:

[0363] (i) a first chain that is a light chain comprising a variable domain (VL) and a constant domain (CL),

[0364] (ii) a second chain that is a heavy chain comprising a variable domain (VH) and a constant domain (CH1),said light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0365] (iii) a third chain comprising a variable domain (VH) and a constant domain (CL),

[0366] (iv) a fourth chain comprising a variable domain (VL) and a constant domain (CH1),

[0367] said third and fourth chains forming the second binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TNFa.

[0368] 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:

[0369] (i) a first chain that is a light chain comprising a variable domain (VL) and a constant domain (CL),

[0370] (ii) a second chain that is a heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0371] said light and heavy chains forming the first binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TNFa; and

[0372] (iii) a third chain comprising a variable domain (VH) and a constant domain (CL),

[0373] (iv) a fourth chain comprising a variable domain (VL) and a constant domain (CH1),

[0374] said third and fourth chains forming the second binding moiety that binds to IL-7 or CD127, preferably CD127.

[0375] 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:

[0376] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0377] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0378] 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,(iii) a second light chain comprising a variable domain (VL), and

[0379] (iv) a second heavy chain comprising a variable domain (VH),

[0380] wherein said second light and heavy chains are linked by a peptide linker and form a scFv that binds to TNFa, TNFR1 and / or TNFR2, preferably TNFa.

[0381] 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.

[0382] 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.

[0383] 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:

[0384] (i) a first light chain comprising a variable domain (VL),

[0385] (ii) a first heavy chain comprising a variable domain (VH),

[0386] 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,

[0387] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and

[0388] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0389] wherein said second light and heavy chains form the second binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TNFa, and form a Fab.

[0390] 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.

[0391] 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.

[0392] 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 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 correspond 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:

[0393] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0394] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1), and

[0395] said first light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0396] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and

[0397] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0398] wherein said second light and heavy chains form the second binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TNFa, the constant domains of the second light and heavy chains being linked to the variable domains of the first light and heavy chains, respectively.

[0399] Alternatively, the bifunctional molecule preferably comprises or consists of: (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0400] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0401] wherein said first light and heavy chains form the first binding moiety that binds to IL-7 or CD127, preferably CD127, and

[0402] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and(iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1),

[0403] said second light and heavy chains forming the second binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TN Fa, and

[0404] 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.

[0405] 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:

[0406] (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),

[0407] wherein said second light and heavy chains form the second binding moiety that binds to TNFa, TNFR1 and / or TNFR2, preferably TNFa.

[0408] 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 IL-7 or CD127, and the second antigen being TNFa, TNFR1 and / or TNFR2, preferably TNFa.,

[0409] the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between TNFa and TNFR1 and / or between TNFa and TNFR2.

[0410] 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 TNFa,

[0411] the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between TNFa and TNFR1 and / or between TNFa and TNFR2.Pharmaceutical composition and administration route

[0412] 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.

[0413] 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.

[0414] 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.

[0415] 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.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 TNFa are provided within different, distinct containers, in particular as pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient.

[0416] • Further therapeutic compounds

[0417] 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.

[0418] 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 the bifunctional 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.

[0419] 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.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.

[0420] 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, atherosclerosis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple sclerosis, asthma and psoriasis.

[0421] 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 treating an auto-immune disease, in particular systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and systemic lupus erythematosus.

[0422] 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 tothe same therapeutic regimen as the combination or the bifunctional molecule of the invention.

[0423] 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.

[0424] • Diseases to be treated

[0425] The uses described herein as well as the methods described herein may be useful in the treatment inflammatory diseases, including Non-Alcoholic Fatty Liver Disease, endometriosis, encephalomyelitis, inflammatory bowel disease, in particular Crohn’s disease and Ulcerative Colitis, chronic obstructive pulmonary disease, atherosclerosis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple sclerosis, asthma and psoriasis.

[0426] The uses described herein as well as the methods described herein may be useful in the treatment of inflammatory bowel diseases.

[0427] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from inflammatory bowel disease.

[0428] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from ulcerative colitis.

[0429] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from Crohn’s disease.

[0430] The uses described herein as well as the methods described herein may be useful in the treatment of autoimmune diseases, in particular rheumatoid arthritis, systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and systemic lupus erythematosus. In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from rheumatoid arthritis, systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis, and systemic lupus erythematosus.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).

[0431] In a particular embodiment of the invention, it is provided

[0432] a. a first compound that is an antagonist of IL-7 and / or CD127 (e.g.

[0433] antagonist anti-CD127 antibody or antigen-binding fragment thereof) ; and

[0434] b. a second compound that is an antagonist of TNFa or TNFR1 (and in particular antagonist of the TNFa / TNFR1 signaling pathway) (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof such Adalimumab), or an agonist of TNFR2 (and in particular agonist of the TNFa / TNFR2 signaling pathway), or both (and in particular antagonist of the TNFa / TNFR1 signaling pathway and agonist of the TNFa / TNFR2 signaling pathway);

[0435] for inhibiting or reducing the secretion of IFNy, IL-1 [3 or IL-6, in particular IFNy, and IL-1 (3 or IL-6, more particularly IFNy, and IL-1 [3 and IL-6.

[0436] • Methods of treatment

[0437] 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 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 antigenbinding fragment thereof), in combination with a second compound that is an antagonist of TNFa or TNFR1, or an agonist of TNFR2, or both, the second compound being in particular a compound that is an antagonist of the TNFa / TNFR1 signaling pathway or an agonist of the TNFa / TNFR2 signaling pathway, more particularly the second compound being in particular a compound that is an antagonist of theTNFa / TNFR1 signaling pathway (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof such Adalimumab); whereinthe first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0438] 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 TNFa 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 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 TNFR1, or an agonist of TNFR2, or both, the second compound being in particular a compound that is an antagonist of the TNFa / TNFRI signaling pathway or an agonist of the TNFa / TNFR2 signaling pathway or both; more particularly the second compound being a compound that is an antagonist of the TNFa / TNFR1 signaling pathway (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof such Adalimumab); wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0439] In another aspect of the invention, it is provided a method of inhibiting or reducing the secretion of IFNy or IL-6 or both (of IFNy and / or IL-6), the method comprising administering to a patient in need thereof an 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 TNFa or TNFR1, or an agonist of TNFR2, or both, the second compound being in particular a compound that is an antagonist of the TNFa / TNFR1 signaling pathway or an agonist of the TNFa / TNFR2 signaling pathway or both; more particularly the second compound being a compound that is an antagonist of the TNFa / TNFR1 signaling pathway (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof such Adalimumab); wherein the first and second compoundsare for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0440] 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:

[0441] a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1,

[0442] b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2;

[0443] c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0444] a light chain variable fragment comprising:

[0445] d. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4,

[0446] e. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5;

[0447] f. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6;

[0448] 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 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.

[0449] In a particular embodiment, the second compound is an antagonist anti-TNFa antibody or antigen-binding thereof which comprises

[0450] a heavy chain variable fragment (VH) comprising:d. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31, and

[0451] e. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32; and

[0452] f. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33; and

[0453] - a light chain variable fragment (VL) comprising:

[0454] d. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34, and

[0455] e. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35; and

[0456] f. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36;

[0457] 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.

[0458] In certain embodiments, the patient is suffering from an inflammatory disease, in particular an IBD, more particularly Crohn disease or Ulcerative colitis.

[0459] 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 second compound that is an antagonist of TNFa or of TNFR1 (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof such Adalimumab) and / or an agonist of TNFR2, 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.In an aspect of the invention, it is provided the combination of compounds as defined herein s for treating a human being suffering from an inflammatory disease or an auto-immune disease.

[0460] 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 TNFa or of TNFR1 (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof such Adalimumab) and / or an agonist of TNFR2, 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.

[0461] 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 TNFa (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof such Adalimumab) or of TNFR1 and / or an agonist of TNFR2, 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.

[0462] 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 TNFa (e.g., antagonist anti-TNFa antibody or antigen-binding fragment thereof suchAdalimumab) or TNFR1 and / or an agonist of TNFR2 in distinct, different containers.

[0463] 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:

[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 TNFa or TNFR1 or TNFR2.

[0465] 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:

[0466] a first binding moiety, said first binding moiety binding to CD127, a second binding moiety, said second binding moiety binding to TNFa. 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 TNFa or TNFR1 or TNFR2.

[0467] 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 TNFa 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 TNFa or TNFR1 or TNFR2.In one aspect of the invention, it is provided the bifunctional molecule that comprises

[0468] a first binding moiety, said first binding moiety binding to IL-7 or CD127, a second binding moiety, said second binding moiety binding to TNFa or TNFR1 or TNFR2,

[0469] for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease.

[0470] 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 TNFa and TNFR1 and / or enhances the binding between TNFa and TNFR2 and / or binds to TNFR2 and induces or enhances the TNFa I TNFR2 signaling pathway, for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease.

[0471] DESCRIPTION OF THE FIGURES

[0472] 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.

[0473] Figure 1 illustrates the percentage of inhibition of IFNy (Figure 1A) and IL-17 (Figure 1 B) secretion by human PBMC cells treated with either a control antibody, or an anti-hTNFa antibody, or an anti-hlL7Ra antibody, or with a combination of an anti-hTNFa antibody with an anti-hlL7Ra antibody. Wilcoxon matched pairs signed rank test has been performed.

[0474] Figure 2 illustrates the percentage of inhibition of IL-6 secretion by human PBMC cells treated with either a control antibody, or an anti-TNFa antibody, or anti-TNFa antibody and an anti-hlL7Ra antibody in presence of a cytokine cocktail (IL-7 + TNFa) and precoated okt3 plate.

[0475] Figure 3 illustrates the percentage of inhibition of IL1 [3 secretion by human PBMC cells from ulcerative colitis and Crohn disease patients treated with either a control antibody, or an anti-hTNFa antibody, or an anti-hlL7Ra antibody, or with a combination of an anti-hTNFa antibody with an anti-hlL7Ra antibody in presence of a cytokine cocktail (IL-7 + TNFa) and precoated okt3 plate.EXAMPLES

[0476] Material and methods:

[0477] • IFNy secretion assay

[0478] Human healthy Peripheral blood mononuclear were added at 100000cells / w in P96-well plates and were stimulated and incubated with either a control antibody, or an anti-human TNFa antibody (Adalimumab, Evidentic, reference MA8208, 1ug / mL, the anti-hTNFa 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.

[0479] 45) alone or an anti-hlL7Ra alone (Ose Immunotherapeutics, 1ug / ml- 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)); or an anti-human TNFa antibody with an anti-hlL7Ra antibody (1ug / ml) in presence of human IL7 at 5ng / mL (Miltenyi reference 130-095-368), human TNFa at 500ng / mL (Miltenyi reference 130-094-024) in IMDM complete medium during 5 days at 37°C.

[0480] After 5 days, PMA at 15ng / ml and ionomycin at 1 pg / ml stimulation was performed during 12h at 37°C before supernatant was collected. IFNy (ELISA, BioLegend, 430116) secretion was measured by ELISA after 6 days at 37°C. Statistics parameters were measured with Wilcoxon matched pairs signed rank test in non-parametric study. n= 7.IL-17 secretion assay

[0481] Human healthy Peripheral blood mononuclear were added at 100000cells / w in P96-well plates and were stimulated and incubated with either a control antibody, or an anti-human TNFa antibody (Adalimumab, Evidentic, reference MA8208, 10ug / mL, the anti-hTNFa 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.

[0482] 45) alone or an anti-hlL7Ra alone (Ose Immunotherapeutics, 10ug / ml- 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)); or an anti-human TNFa antibody with an anti-hlL7Ra antibody (10ug / ml) in presence of human IL7 at 5ng / mL (Miltenyi reference 130-095-368), human TNFa at 500ng / mL (Miltenyi reference 130-094-024) in IMDM complete medium during 5 days at 37°C.

[0483] After 5 days, PMA at 15ng / ml and ionomycin at 1 pg / ml stimulation was performed during 12h at 37°C before supernatant was collected. IL-17 (ELISA, BioLegend, 430116) secretion was measured by ELISA after 6 days at 37°C. Statistics parameters were measured with Wilcoxon matched pairs signed rank test in non-parametric study. n= 7.IL-6 secretion assay

[0484] Human Peripheral mononuclear cells from healthy donors were isolated. PBMCs were added at 100000cells / w in P96-well plates and incubated with 10pg / ml of anti-human hTNFa alone (Adalimumab, Evidentic, reference MA8208, the anti-hTNFa 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 in combination with anti-human anti-hlL7Ra (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) and stimulated with human IL7 at 5ng / ml (Miltenyi, reference 130-095-368) and human TNFa at 100ng / ml (Miltenyi, reference 130-094-024) in IMDM complete medium at 37°C. After 5 days, PMA at 15ng / ml and ionomycin at 1pg / ml stimulation was performed during 12h at 37°C before supernatant was collected. Secretion of IL-6 was measured by ELISA (hlL-6 Duoset, R&D, reference DY206) after 6 days at 37°C.

[0485] • IL-1 [3 secretion assay

[0486] Human PBMC were obtained from patients diagnosed with Ulcerative colitis (UC) and Crohn’s disease (CD). More than 1 x 105cells were seeded per well in 96-well plates under the following conditions: isotype controls, monotherapy: antihuman TNFa antibody (Adalimumab, Evidentic, reference MA8208 the anti-hTNFa 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 variablefragment 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 an anti-hlL7Ra (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)); and combination treatment: an anti-human TNFa antibody (Adalimumab, Evidentic, reference MA8208 with an anti-hlL7Ra antibody (Ose Immunotherapeutics).

[0487] The inventors used a cytokine cocktail consisting of IL-7 (5 ng / mL) (Miltenyi, 130-095-368) and TNFa (100 ng / mL) (Miltenyi, 130-094-024 on OKT3-coated wells (2.5 pg / mL). Cells were incubated for 48 hours at 37 °C in a humidified atmosphere with 5% CO2. Supernatant Collection was performed. Protein Analysis using Kit U-Plex Biomarker multiplex (MSD, K15010K-1) were used to analyze human cytokines secretion.

[0488] Results:

[0489] Combination treatment of antagonist anti human TNFa and an antagonist anti-human IL-7Ra synergistically enhances the inhibition of IFNy secretion

[0490] The effect of the combination of an antagonist anti-human IL-7Ra antibody (that inhibits the human IL-71 IL-7R signaling pathway) with an antagonist anti-human TNFa antibody (that inhibits the human TNFa / TNFR signalling pathway) on human IFNy secretion by healthy human activated PBMC has been tested (see Figure 1A).This assay demonstrates that monotherapy with an antagonist anti-human TNFa significantly inhibits IFNy secretion as compared to control antibodies (*: p = 0.0312 Controls Abs vs anti-human TNFa).

[0491] Also, this assay leads to highlight that an antagonist anti-human IL7Ra significantly inhibits IFNy secretion as compared to control antibodies (**: p = 0.0078 Controls Abs vs anti-human IL7Ra).

[0492] Surprisingly, these data shows that the combinatorial strategy of an antagonist anti-human IL-7Ra with an antagonist anti-human TNFa synergistically decrease the IFN-y cytokine secretion by hPBMC cells as compared to isotype antibodies (** : p = 0.0078) and to monotherapy (*: p = 0.0156 combination vs anti-TNFa and ** : p = 0.0078 combination vs anti-IL7Ra).

[0493] These results suggest that combining an antagonist anti-human TNFa antibody with an antagonist anti-human IL-7Ra antibody significantly enhances the therapeutic efficacy in inflammatory and autoimmune diseases by synergistically reducing T-cell-mediated inflammation, notably pathogenic Th1 cells.

[0494] Combined treatment with antagonist anti-human TNFa and anti-human IL-7Ra antibodies significantly decrease secretion of IL-17 by T cells compared to each monotherapy treatment

[0495] The effect of the combination of an antagonist anti-human IL-7Ra antibody (that inhibits the human IL-71 IL-7R signaling pathway) with an antagonist anti-human TNFa antibody (that inhibits the human TNFa / TNFR signalling pathway) on human IL-17 secretion by healthy human activated PBMC has been tested (see Figure 1B). IL-17 is a cytokine produced by the Th17 subset, a key pathogenic T-cell population implicated in the development and progression of inflammatory and autoimmune diseases. This assay demonstrates that monotherapy with an anti-human TNFa inhibits IL-17 secretion as compared to control antibodies (*: p = 0.0312 Controls Abs vs anti-human TNFa). Also, this assay highlights that antihuman IL7Ra inhibits IL-17 secretion as compared to control antibodies (*: p = 0.0156 Controls Abs vs anti-human IL7Ra).

[0496] Interestingly, data shows that the combinatorial strategy of an anti-human IL-7Ra and anti-human TNFa significantly decreases secretion of IL-17 compared toisotype (** : p = 0.0078) and compared to each monotherapy (*: p = 0.0391 combination vs anti-TNFa ; ** : p = 0.0234 combination vs anti-IL7Ra).

[0497] These findings indicate that combining an antagonist anti-human TNFa antibody with an antagonist anti-human IL-7Ra antibody markedly improves therapeutic outcomes in inflammatory and autoimmune disorders by suppressing the activity of pathogenic Th17 cells.

[0498] Combination treatments with antagonists anti human TNFa and anti-human IL-7Ra enhances inhibition of IL-6 secretion

[0499] The combination of an anti-human IL-7Ra antibody (that blocks IL-7Ra-induced signaling) in combination with an anti-human TNFa antibody (that blocks human TNFa activity) has been tested on healthy human PBMCs. The data illustrated on Figure 2 show that monotherapy anti-human TNFa antibody has no effect to inhibit IL-6 secretion as compared to control antibody. Interestingly, the combination of anti-human IL-7R with an anti-human TNFa has enhances the inhibition of IL-6 secretion as compared to monotherapy with an anti-human TNFa. These results demonstrate the therapeutic advantage of combining an anti-human TNFa antibody with an anti-human IL-7Ra antibody for the treatment of inflammatory diseases, effectively suppressing inflammation by inhibiting the production of pro-inflammatory cytokines by myeloid cells.

[0500] Combination treatment with antagonists anti human TNFa and anti-human IL-7Ra enhances inhibition of IL-1 [3 secretion by human PBMC cells isolated from Ulcerative Colitis and Crohn Disease patients.

[0501] The antagonist anti-human IL-7Ra and the antagonist anti-human TNFa, when used as monotherapies, inhibit the secretion of human IL-1 [3. Combination therapy more efficiently inhibits the secretion of IL-1 (3 than monotherapies. This inhibitory effect involves myeloid cells (see Figure 3).

[0502] These results suggest that combining an antagonist anti-human TNFa antibody with an antagonist anti-human IL-7Ra antibody significantly enhances the therapeutic efficacy in inflammatory and autoimmune diseases by more effectively reducing inflammation involving myeloid cells.Conclusion:

[0503] In conclusion, the combination of an antagonist anti-hlL-7Ra antibody with an antagonist anti-TNFa antibody exhibits an enhanced, ability to inhibit inflammatory response, by synergistically reducing T-cell-mediated inflammation, but also, through myeloid cells. This synergistic effect was entirely unexpected, as the IL-7 / CD127 signaling pathway and the TNFa / TNFR1 signaling pathway are distinct, their receptors are expressed on different cell populations, and antagonists of said signaling pathways used as monotherapies can have divergent effects - particularly on regulatory T cells. This highlights its potential as a promising therapeutic strategy for patients with inflammatory or autoimmune diseases.

Claims

CLAIMS1. A combination comprising:a. a first compound that is an antagonist anti-human CD127 antibody or antigen-binding fragment thereof; andb. a second compound that is an antagonist of human TNFa, for use in the treatment of an inflammatory disease or an autoimmune disease,wherein said anti-human CD127 antibody or antigen-binding fragment thereof 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;in 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.

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

3. A first compound that is an anti-human CD127 antibody or antigen-binding fragment thereof as defined in Claim 1 or 2, for use in a combination regimen with a second compound that is an antagonist of human TNFa, for the treatment of an inflammatory disease or an auto-immune disease.

4. The combination for use according to any one of claims 1-2, or the first compound for use according to claim 3, wherein the first compound is an anti-human 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.

5. The combination for use according to any one of claims 1-2 or 4, or the first compound for use according to claim 3 or 4, wherein the second compound binds to, in particular specifically binds to human TNFa, and inhibits or reduces the binding between human TNFa and its receptor TNFR1, and in particular is an antagonist of the TNFa / TNFR1 signaling pathway.

6. The combination for use according to any one of claims 1 -2 or 4-5, or the first compound for use according to any one of claims 3-5, wherein the second compound is an antibody, or an antigen-binding fragment thereof that binds to, in particular specifically binds to, human TNFa.

7. The combination for use according to any one of claims 1 -2 or 4-6, or the first compound for use according to claim 3-6, wherein the second compound that is an antagonist of human TNFa is selected from the list consisting of etanercept, infliximab, adalimumab, certolizumab, golimumab, ozoralizumab and biosimilars thereof, preferably adalimumab.

8. The combination for use according to any one of claims 1 -2 or 4-7, or the first compound for use according to claim 3-7, wherein the second compound that is an antagonist of human TNFais an anti-human TNFa antibody or antigen-binding fragment thereof that comprises:i) a heavy chain variable fragment comprising:a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DYAMH), andb. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (AITWNSGHIDYADSVEG), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (VSYLSTASSLDY), and ii) a light chain variable fragment comprising:a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASQGIRNYLA), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (AASTLQS), andc. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QRYNRAPYT),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 comprising 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.

9. A bifunctional antibody or an antigen-binding fragment thereof, that binds to, in particular specifically binds to, two distinct first and second antigens, the first antigen being human CD127 and the second antigen being human TNFa.

10. The bifunctional molecule according to claim 9, which inhibits (i) the binding between human IL-7 and human CD127 and (ii) the binding between human TNFa and human TNFR1.

11. The bifunctional antibody or antigen binding fragment thereof according to claim 9 or 10 comprising a first binding moiety that binds to human CD127 comprising: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; and- 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;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.

12. The bifunctional antibody or antigen-binding fragment thereof according to any one of claims 9 to 11 comprising a second binding moiety that binds to human TNFa comprising:i) a heavy chain variable fragment comprising:a) HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 31 (DYAMH), andb) HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 32 (AITWNSGHIDYADSVEG), and c) HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 33 (VSYLSTASSLDY), and ii) a light chain variable fragment comprising:a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 34 (RASQGIRNYLA), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 35 (AASTLQS), andc. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 36 (QRYNRAPYT),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.

13. The bifunctional molecule according to any one of claims 9 to 12, for use in the treatment of an inflammatory disease or an auto-immune disease.

14. The combination for use according to any one of claims 1-2 or 4-8, or the first compound for use according to claim 3-8, or the bifunctional molecule, for use according to claim 13, 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, atherosclerosis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple sclerosis, asthma and psoriasis.

15. The combination for use according to any one claims 1 -2 or 4-8, or the first compound for use according to any one of claims 3-8, or the bifunctional molecule for use according to claim 13, wherein the auto-immune disease is selected from the group consisting of systemic sclerosis, multiplesclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and systemic lupus erythematosus.

16. The combination for use according to any one of claims 1-2 or 4-8, or the first compound for use according to any one of claims 3-8, wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

17. The combination for use according to any one of claims 1-2 or 4-8, or the first compound for use according to any one of claims 3-8, wherein the first compound and the second compound are separately provided in the form of pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient.

18. A kit, preferably for use according to any one of claims 1-8; wherein the kit comprises the combination according to any one of claims 1-2 ; 4-8, 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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