Therapy by antagonizing il-7 or CD127, and il-12, il-23, il-12r or il-23r

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 IL12, IL-23, IL-12R or IL-23R, or comprising a bifunctional molecule targeting IL-7 or CD127 and IL12, IL-23, IL-12R or IL-23R. 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.

Description

[0001] TITLE

[0002] THERAPY BY ANTAGONIZING IL-7 OR CD127, AND IL-12, IL-23, IL-12R OR IL-23R

[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 IL12, IL-23, IL-12R or IL- 23R, or comprising a bifunctional molecule targeting IL-7 or CD127 and IL12, IL- 23, IL-12R or IL-23R. The combination therapy or the bifunctional molecule is provided for use in the treatment of a patient suffering from an inflammatory disease or an auto-immune disease.

[0005] The means of the invention are more particularly dedicated to the provision of a combination therapy, or a bifunctional, in particular bispecific, antibody comprising an anti-CD127 antibody or an antigen-binding fragment thereof and an antagonist anti-IL-23 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] 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).

[0009] Thus, there is a need for more efficient and targeted treatments for inflammatory and autoimmune diseases.

[0010] SUMMARY OF THE INVENTION

[0011] In a first aspect of the invention, it is provided a combination comprising: a. a first compound that is an antagonist of IL-7 and / or CD127; and b. a second compound that is an antagonist of IL-12 and / or IL-23, or IL-12R and / or IL-23R; for use in the treatment of an inflammatory disease or an auto-immune disease. Surprisingly, the combination therapy shows a synergistic improved therapeutic effect, as compared to the effect observed when only one of these compounds is administered. When combined in therapy, the administration of the combination as defined here above led to a synergistic improvement of the health of mice suffering from an inflammatory disease, in particular ulcerative colitis, as compared to monotherapy. In particular, the weight of the large bowel and the spleen is similar in mice treated with the defined combinations and in control mice, while the weight of the large bowel and the spleen of other mice is significatively higher in mice treated with other means and untreated mice.

[0012] After administration of the combination defined here above, the disease severity is almost the same as in control mice in all regions of the bowel, while all other mice still suffer from a sever colitis after their treatment with any other tested means. Further, the inventors found that infiltration component was minimal in treated mice, as well as inflammation, area component and hyperplasia. Thus, all criteria studied to evaluate the effects of the proposed treatment in mice suffering from IBD show a synergistic improvement in the clinical condition of these mice and an enhancement of their health compared to other proposed treatments. The superior efficacy of the combination was also confirmed using several different anti-CD127 antagonists antibodies and a bifunctional antibody.

[0013] Combining the blockade of the IL-7 / CD127 signaling pathway and of the IL-12 / IL-12R and / or IL-23 I IL-23R signaling pathway reduces inflammation and epithelia damages as compared to any other treatment and a monotherapy with either an antagonist of the IL-7 / CD127 signaling pathway or an antagonist of the IL-12 I IL-12R and / or IL-23 I IL-23R signaling pathway.

[0014] These results were not expected, particularly in view of the effect observed in mice suffering from ulcerative colitis and treated by administration in monotherapy of the compounds present in the combination according to the invention.

[0015] The mice model illustrating the invention is broadly use in preclinical stages for determining the therapeutic efficacy of new therapeutically active molecules. This model led to the identification of molecules that are currently available to treating inflammatory diseases. The model is broadly used for studying treatment of inflammatory diseases, including IBD, and the implication of IL-23 signaling pathway in inflammation is broadly recognized (Almradi A et al., doi: 10.1007 / s40259-020-00451 -w; Sewell and Kaser, 10.1093 / ecco-jcc / jjac034 wherein the effect of IL-23 blockade for decreasing T cell inflammation is discussed). Other diseases are also associated with the IL-23 signaling pathway, in particular for auto-immune diseases (psoriasis, multiple sclerosis, Arthritis in Tang et al., 10.1111 / j.1365-2567.2011 ,03522.x; autoimmune encephalomyelitis in Chen et al., 10.1172 / JCI25308; Fibrotic Autoimmune Diseases in Sisto and Lisi, doi.org / 10.3390 / jcm 12175699; systemic lupus erythematosus in Xiong et al., 10.3389 / fphar.2022.982238; Diabetes type I in Mensah-Brown et al., 10.1002 / eji.200535325; Endometriosis in Sisnett et al.,

[0016] 10.4049 / jimmunol.2400018). IL-7R implication in allergic airway inflammation is discussed in Mai et al., 10.1111 / cea.13665. IL-7R role in multiple sclerosis is discussed in Lundstrdm et al., 10.1073 / pnas.1222303110).

[0017] These results clearly indicate that the provision of a compound that is an antagonist of IL-7 or CD127 in combination with a compound that is an antagonist of IL-12 and / or IL-23 or IL-12R and / or IL-23R leads to health improvement. In a particular embodiment of the invention, it is provided a. a first compound that binds to CD127 and which is an antagonist of the IL-7 / IL-7R signaling pathway; and b. a second compound that is an antagonist of IL-12 and / or IL-23, or IL- 12R and / or IL-23R, for use in the treatment of an inflammatory disease or an auto-immune disease.

[0018] In an 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 antibody that binds to the p40 subunit of IL-23 and IL-12 and which is an antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0019] 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 anti-IL-23 antibody that binds to the p19 subunit of IL-23 and which is an antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0020] This combination allows the blockade of the IL-7 I IL-7R signaling pathway and the IL-23 / IL23R signaling pathway, without interfering with the IL-12 / IL12R signaling pathway. Blocking the IL-23 / IL23R signaling pathway may lead to an increase in the frequency of CD4+ T cells and to the promotion of a regulatory, anti-inflammatory environment. Targeting p19, one of the sub-units of IL-23, does not impact the functions associated with the IL-12 / IL12R signaling pathway.

[0021] The blockade of the IL-7 1 IL-7R signaling pathway and of the IL-12 / IL12R and / or IL-23 / IL23R signaling pathway may be achieved by providing a combination as defined here above, but also with a bifunctional molecule that recognizes and binds to at least IL-7 or CD127, and IL-12, and / or IL-23, or IL-12R and / or IL-23R.

[0022] DETAILED DESCRIPTION OF THE INVENTION

[0023] Definitions As used herein, "antibody" includes polyclonal, monoclonal, recombinant, chimeric, humanized, bispecific, multispecific, bifunctional, multifunctional and modified antibodies, as well as monovalent and divalent antigen-binding fragments thereof. Furthermore, "antibody" includes synthetic antibodies, single chain antibodies, and fragments thereof. The antibody may be a human or nonhuman antibody. A nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in human. More specifically the term “antibody” refers to a monoclonal antibody or recombinant monoclonal antibodies, or an antigen-binding fragment thereof.

[0024] 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 IL-12 and / or IL-23, or IL12-R and / or IL-23R and most particularly the extracellular domain of human CD127, or one of the subunits of IL-12 and / or IL-23 (i.e. p19 or p40 which form IL-23 or p35 or p40 which form IL-12).

[0025] 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.

[0026] 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.

[0027] As used herein, the term "specifically binds to" or "binds specifically" refers to the capability of anti-IL-7 compounds, anti-CD127 compounds, anti-IL-12 compounds, and anti-IL-23 compounds, anti-IL-12R compounds, anti-IL-23R 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 with IL-12 and to bind to IL-12 (in particular with the sub-unit p35 of IL-12 or with the subunit p40 of IL-12, and to bind to the sub-unit p35 of IL-12 or to the sub-unit p40 of IL-12), or with IL-23 and to bind to IL-23 (in particular with the sub-unit p19 of IL- 23 or with the sub-unit p40 of IL-23, and to bind to the sub-unit p19 of IL-23 or to the sub-unit p40 of IL-23), or with IL-12R and to bind to IL-12R (in particular with IL-12R|31 or with IL-12R|32), or with IL-23R and to bind to IL-23R (in particular with IL-23Rsu or with IL-12R|31 ) while they do not bind or they bind with a significantly weaker binding affinity to other molecules, in particular to other proteins. Binding and binding specificity can be assayed by SPR (Surface Plasmon Resonance e.g., Biacore), ELISA or Western Blot analysis. In a particular embodiment, the ability of the anti-CD127 compound to bind to CD127, or IL-12 or IL-23, or p19, or p35, or p40, or IL-12R, or IL-12 Rp 1 , or IL-12 Rp2, or IL-23, or IL-23su, is considered to be specific when the binding affinity is of at least about 1 x 10’6M, 1 x 10’7M,1 x 10’8M, 1 x 10’9M, 1 x 1 O’10M, 1 x 10’11M, 1 x 10’12M, or more, and / or bind to a target with an affinity that is at least two-fold greater than its affinity for a nonspecific protein.

[0028] 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.

[0029] 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 IL-12 and / or IL-23, or IL-12R and / or IL-23R, or the bifunctional antibody as disclosed herein. Particularly, combination or combination product refer to pharmaceutical products that integrate multiple therapeutic compounds to achieve an effect, in particular a synergistic effect, for improving the health of a patient, and / or for targeting multiple signaling pathways or mechanisms of action simultaneously or separately, in particular in alternation or sequentially, either administered together or separately.

[0030] 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 IL-12 and / or IL-23, or IL-12R and / or IL-23R, 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.

[0031] 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.

[0032] 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. 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.

[0033] 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, multiple sclerosis, asthma and psoriasis.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] The impact of ulcerative colitis on individuals' health is significant. Chronic inflammation of the colon leads to frequent and often debilitating symptoms, which can cause substantial discomfort and disrupt daily activities. In severe cases, ulcerative colitis can lead to life-threatening complications such as severe bleeding, colon perforation, and an increased risk of colon cancer. Beyond physical health, the disease also affects mental well-being, as patients often experience a reduced quality of life due to the chronic and unpredictable nature of their symptoms.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] Treatment for Crohn's disease aims to reduce inflammation, manage symptoms, and achieve and maintain remission. Current treatment options include antiinflammatory drugs such as aminosalicylates, corticosteroids to control acute flare-ups, immunomodulators that suppress the immune system, and biologic therapies targeting specific components of the immune response, such as tumor necrosis factor (TNF) inhibitors. In severe cases, surgery may be required to remove damaged portions of the digestive tract or to address complications such as strictures or fistulas.

[0045] 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.

[0046] 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. 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] IL-7 is a critical cytokine for the development of T cells in the thymus and their maintenance in the periphery. The IL-7 / IL-7R signaling pathway activates several downstream signaling molecules, including Janus kinases (JAK1 and JAK3) and Signal Transducers and Activators of Transcription (STAT5), which promote the expression of genes involved in cell survival and proliferation. This pathway is also involved in the homeostasis of naive and memory T cells, ensuring the immune system can respond effectively to pathogens.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] As used herein, the term “CD127” relates to a CD127 from a mammal species, preferably a human CD127, that is also known as lnterleukin-7 receptor subunit alpha (IL7R-a). CD127 is a protein that in humans is encoded by the IL7R gene. CD127 is a type I cytokine receptor and is a subunit of the functional Interleukin- 7 receptor and Thymic Stromal Lymphopoietin (TSLP) receptors. The IL-7 receptor (IL-7R) is a heterodimer consisting of two subunits: IL-7Ra (CD127) that specifically binds to IL-7 and the common y chain (yc or CD132) that is shared with receptors for several other cytokines, including IL-2, IL-4, IL-9, IL-15, and IL- 21. The binding of IL-7 to its receptor results in the dimerization of CD127 and CD132, initiating the IL-7 / IL-7R signaling pathway. This pathway includes the JAK-STAT5 pathway: Janus kinases (JAK1 and JAK3) are recruited by the dimerized receptor. Their activation leads to the phosphorylation of specific tyrosine residues on CD127. STAT5 binds to these phosphorylated tyrosine residues and is then phosphorylated by JAK1 and JAK3. Phosphorylated STAT5 dimerizes and translocates to the nucleus, wherein it promotes transcription of target genes involved in cell survival, proliferation, and differentiation.

[0055] In the context of the present invention, CD127 is preferably human CD127, and the antagonist of CD127 is preferably an antagonist of human CD127.

[0056] 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. 34. 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. 35.

[0057] 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. 36.

[0058] 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.

[0059] Interleukin-12 (IL-12) is a pro-inflammatory cytokine that plays a pivotal role in the regulation of immune responses. It is primarily produced by antigen- presenting cells, such as dendritic cells and macrophages, and acts to bridge innate and adaptive immunity. IL-12 exerts its effects by binding to the IL-12 receptor complex on T cells and natural killer (NK) cells, leading to the activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. This activation promotes the differentiation of naive T cells into T helper 1 (Th1 ) cells, which are crucial for the production of interferongamma (IFN-y), a key cytokine in cellular immunity.

[0060] IL-12 is implicated in the pathogenesis of several autoimmune and inflammatory diseases due to its role in promoting Th1 responses and chronic inflammation. Elevated levels of IL-12 have been observed in conditions such as psoriasis, multiple sclerosis, Crohn's disease, and rheumatoid arthritis. These findings have spurred the development of therapeutic strategies targeting IL-12 to modulate its activity and ameliorate disease symptoms.

[0061] Notably, ustekinumab, a monoclonal antibody targeting the p40 subunit of both IL-12 and IL-23, has been approved for the treatment of psoriasis and Crohn's disease. Clinical studies have demonstrated that targeting IL-23 with such antibodies can lead to significant improvements in disease activity and patient outcomes.

[0062] IL-12 is a critical cytokine involved in the regulation of immune responses and is implicated in various autoimmune and inflammatory diseases. The development of new uses of antibodies targeting IL-12 offers promising improved clinical outcomes for patients for further enhancing the efficacy and safety of treatments.

[0063] As used herein, the term “IL-12” refers to interleukin 12. It is a heterodimeric cytokine composed of two subunits: p35 and p40. P35 (also referenced as IL-12 subunit alpha), a 35 kDa protein, is encoded by the IL12A gene. The p40 subunit (also referenced IL-12 subunit beta) is a protein of 40 kDa encoded by the IL12B gene. “IL-12R” refers to the IL-12 receptor (IL-12R), a heterodimer consisting of two subunits: IL-12R|31 that binds the p40 subunit of IL-12, and IL-12R|32 that binds the p35 subunit and is responsible for signal transduction. IL-12 binds to the IL-12R complex (IL-12R|31 and IL-12R|32), leading to receptor dimerization, which is essential for downstream signaling. IL-12 signaling includes the JAK- STAT4 pathway: intracellular effectors JAK2 and TYR2 are recruited by the dimerized receptor and activate STAT4 through its phosphorylation. STAT4 translocates to the nucleus once phosphorylated leading to gene transcription including the production of IFN-y, a cytokine critical for the immune response, in particular for the differentiation of T helper cells into Th1 cells. P40 may correspond to the protein referenced under UNIPROT Sequence No. P29460. Alternatively, p40 may correspond to a protein having the amino acid sequence of SEQ ID No. 37. P35 may correspond to the protein referenced under UNIPROT Sequence No. P29459. Alternatively, p35 may correspond to a protein having the amino acid sequence of SEQ ID No. 38. IL-12R|31 may correspond to the protein referenced under UNIPROT Sequence No. P42701. Alternatively, IL-12R|31 may correspond to a protein having the amino acid sequence of SEQ ID No. 39. IL- 12R|32 may correspond to the protein referenced under UNIPROT Sequence No. Q99665. Alternatively, IL-12R|32 may correspond to a protein having the amino acid sequence of SEQ ID No. 40.

[0064] In the context of the present invention, IL-12 is preferably human IL-12, subunit p35 is preferably the human subunit p35, subunit p40 is preferably the human subunit p40, and the compound that is an antagonist of IL-12 is preferably an antagonist of human IL-12, an antagonist of human p35 or an antagonist of human p40.

[0065] In the context of the present invention, IL-12R is preferably human IL-12R, IL- 12R|31 is preferably human IL-12R|31 , IL-12R|32 is preferably human IL-12R|32 and the compound that is an antagonist of IL-12R is preferably an antagonist of human IL-12R, an antagonist of human IL-12R|31 , or an antagonist of human IL- 12R 2.

[0066] Interleukin-23 (IL-23) is a pro-inflammatory cytokine that is crucial in the regulation of the immune response. IL-23 is primarily produced by activated dendritic cells and macrophages and plays a key role in the maintenance and proliferation of Th17 cells, a subset of T helper cells that produce interleukin-17 (IL-17) and are involved in inflammatory responses.

[0067] IL-23 is implicated in the pathogenesis of several autoimmune and inflammatory diseases, primarily through its role in sustaining chronic inflammation. Elevated levels of IL-23 and the resultant increase in Th17 cell activity have been observed in diseases such as psoriasis and inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, or rheumatoid arthritis. The involvement of IL-23 in these diseases makes it a critical target for therapeutic intervention. Administration of monoclonal antibodies that specifically bind to the p19 subunit of IL-23 and prevent IL-23 from interacting with its receptor on the surface of immune cells thereby inhibiting the downstream signaling pathways that lead to Th17 cell maintenance and proliferation, is a strategy that can lead to reduce inflammation and ameliorate disease symptoms. Several monoclonal antibodies targeting IL-23 have been developed and approved for clinical use; therapeutic antibodies such as guselkumab, tildrakizumab, and risankizumab specifically target the p19 subunit of IL-23. These agents have shown significant efficacy in the treatment of psoriasis, leading to improvements in skin lesions and overall quality of life for patients. Additionally, they are being investigated for use in other IL-23-mediated diseases, including Crohn’s disease and ulcerative colitis, with promising results.

[0068] Enhancing the effects provided by the anti-IL-23 and / or anti-l L12 antibodies could lead to new treatments that outreache the present results and expand therapeutic applications as well as improving the health of patients.

[0069] As used herein, the term “IL-23” refers to interleukin 23. It is a heterodimeric cytokine composed of two subunits p19 (a 19 kDa subunit encoded by the IL23A gene) and p40 (a 40 kDa subunit encoded by the IL12B gene, which is shared with IL-12). P19 is also referenced IL-23 subunit alpha. “IL-23R” refers to the IL- 23 receptor (IL-23R), a heterodimer consisting of two subunits: IL-23R subunit (IL-23Rsu in the present application) that binds to the p19 subunit of IL-23, and IL-12R|31 that binds to the p40 subunit of IL-23, and which is also a component of the IL-12 receptor complex. The binding of IL-23 to its receptor leads to receptor dimerization, initiating downstream signaling. IL-23 signaling includes the JAK-STAT3 pathway (i.e. activation of intracellular effectors JAK2 and TYR2 that phosphorylate STAT3). STAT3 is an intracellular effector that leads to the production of cytokines such as IL-17 and IL-22, which are involved in the inflammatory response and the maintenance of the Th17 cell lineage. P19 may correspond to the protein referenced under UNIPROT Sequence No. Q9NPF7. Alternatively, p19 may correspond to a protein having the amino acid sequence of SEQ ID No. 41. IL-23Rsu may correspond to the protein referenced under UNIPROT Sequence No. Q5VWK5. Alternatively, IL-23Rsu may correspond to a protein having the amino acid sequence of SEQ ID No. 42.

[0070] In the context of the present invention, IL-23 is preferably human IL-23, subunit p19 is preferably the human subunit p19, subunit p40 is preferably the human subunit p40, and the compound that is an antagonist of IL-23 is preferably an antagonist of human IL-23, an antagonist of human p19 or an antagonist of human p40.

[0071] In the context of the present invention, IL-23R is preferably human IL-23R, IL- 12R|31 is preferably human IL-12R|31 , IL-23Rsu is preferably human IL-23Rsu and the compound that is an antagonist of IL-23R is preferably an antagonist of human IL-23R, an antagonist of human IL-12R|31 , or an antagonist of human IL- 23Rsu.

[0072] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, preventing or delaying the recurrence or relapse of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, enabling to decrease the administered dose of one or more other medications required or used to treat the disease, increasing the quality of life, and / or prolonging survival, preventing or alleviating side-effects of current treatment, or treatments that will be developed. As used herein, an “effective amount” or “therapeutically effective amount” or a “sufficient amount” of a composition, or a compound is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends upon the context in which it is being applied, but means that a beneficial or desired result is achieved, in particular in a human suffering from a pathology, including an auto-immune disease or an inflammatory disease. • The first compound that is an antagonist of IL-7 or CD127

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] In an embodiment, the first compound inhibits or reduces the binding between IL- 7 and CD127.

[0078] 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”.

[0079] In an embodiment, the first compound is an antagonist of IL-7 that binds to, in particular specifically binds to, IL-7, and inhibits or reduces the IL-7 I IL-7R signaling pathway. Such a first compound can be defined as an “anti-IL-7 compound”.

[0080] 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”. 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”.

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

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

[0083] An antagonist of the IL-7 I IL-7R signaling pathway has the capability to inhibit or reduce the biological activity induced by the binding of IL-7 to its receptor CD127. In other words, the first compound that is an antagonist of IL-7 or CD127 used in the method of the invention or for use according to the invention has the capability to disrupt or block the binding between IL-7 and CD127, as compared to the binding between IL-7 and CD127 in absence of first compound. As used herein, an IL-7 antagonist compound or a CD127 antagonist compound, in particular an anti-IL-7 or anti-CD127 antagonist antibody or a related compound, has its general meaning in the art and refers to any compound, natural 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.

[0084] In an embodiment, it can be considered that the first compound (in particular when it is an antibody or antigen-binding fragment thereof) reduces, inhibits or blocks the binding of IL-7 to CD127 if said antibody (or antigen-binding fragment thereof) induces an increase superior to 1 log, preferably superior to 2 log, more preferably superior to 3 log, most preferably superior to 4 log, of the KD value of IL-7 to CD127 in a binding competitive assay by Blitz, as compared to the KD value of IL-7 to CD127 in presence of a control antibody (i.e. an antibody which does not specifically bind to IL-7 nor CD127).

[0085] In a particular embodiment, the anti-IL-7 or anti-CD127 compound does not induce the activation of the phosphatidylinositol 3-kinase (PI3K) and / or the ERK signaling pathway and / or does not induce the phosphorylation of STAT5, particularly does not induce the activation of the phosphatidylinositol 3-kinase and the ERK signaling pathway and does not induce the phosphorylation of STAT5.

[0086] In a particular embodiment, the anti-IL-7 or anti-CD127 compound does not induce lymphodepletion in the patient, particularly does not lead to lymphodepletion in the patient. Lymphodepletion corresponds to a reduction in the overall number of lymphocytes in the patient. An anti-IL-7 or anti-CD127 compound may be considered not to induce lymphodepletion, when it is presence, the overall number of lymphocytes in a biological sample issued from the patient, is not lower than at least 50%, preferably at least 40%, more preferably at least 30 %, even more preferably at least 20 %, and most preferably at least 10 %, as compared to a control sample obtained from the patient (e.g. a sample obtained from the same patient before administration of the anti-CD127 compound) or as compared to usual numbers of lymphocytes in a healthy human, which are known by skilled artisans.

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

[0088] In a preferred embodiment, the anti-IL-7 antibody or an antigen-binding fragment thereof to be used in the method of the invention, or for use according to the invention, is a humanized antibody, and comprises constant domains derived from human constant domains of antibodies.

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

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

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

[0092] In a preferred embodiment, the antagonist anti-CD127 antibody or an antigenbinding fragment thereof to be used in the method of the invention, or for use according to the invention, is a humanized antibody, and comprises constant domains derived from human constant domains of antibodies.

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

[0094] 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. More particularly, the heavy chain constant domain of the antagonist anti-IL-7 or anti-CD127 antibody or an antigen-binding fragment thereof may be derived from a human IgG 1 , lgG2, lgG3, or lgG4 heavy chain constant region, particularly from lgG4 heavy chain constant region. “Derived from” means encompassing some punctual mutations by amino acid substitutions such as lgG4 (S228P) or lgG1 (E333A) (see Yang and Ambrogelly, Current Opinion in Biotechnology 2014 and Okasaki et al., J Mol Biol 2004). These mutations well known from the skilled person in the art, generally modify some parent chain properties. For example, they lead to less immunogenicity compared to the parental antibody or abrogate FcyReceptor binding or avoid dimerization of the monomer antibody or stabilize the dimerization rendering antibodies better for human therapeutic uses.

[0095] In a particular embodiment of the invention, the antagonist anti-IL-7 or anti-CD127 antibody or an antigen-binding fragment thereof is a functional fragment of an anti-CD127 antibody. Functional fragments of such an antibody include but are not limited to Fv, dsFv, scFv, Fab, Fab', F(ab')2.

[0096] In a particular embodiment of the invention, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises: i) a heavy chain variable fragment comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 (FTLSDYYMA), and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2 (TISASGLRTYYPDSVKG), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3 (PLSAHYGFNYFDY), and ii) a light chain variable fragment comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA). Said above CDR domains have been identified according to the KABAT numbering.

[0097] Alternatively, the CDR domains can be identified according to a newer version of the KABAT numbering. When identifying CDRs with this newer version of the KABAT nomenclature, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises: i) a heavy chain variable fragment comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 48 (DYYMA), and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2 (TISASGLRTYYPDSVKG), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3 (PLSAHYGFNYFDY), and ii) a light chain variable fragment comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4 (CRTSEDIYQGLA), and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5 (SANTLHI), and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6 (QQYYDYPLA).

[0098] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof comprises:

[0099] - the antibody heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0100] - 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.

[0101] In a particular embodiment of the invention, the first compound is an antagonist anti-CD127 antibody or antigen binding fragment thereof which comprises: i) a heavy chain variable fragment comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 43 (GFTLSDYY), and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 44 (ISASGLRT), and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 45 (ARPLSAHYGFNYFDY), and ii) a light chain variable fragment comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 46 (EDIYQG), and b. LCDR2 comprising or consisting in the amino acid sequence “SAN”, and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 47 (QQYYDYPLA).

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

[0103] In a particular embodiment of the invention, the antagonist anti-CD127 antibody or antigen binding fragment thereof comprises:

[0104] - the antibody heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and

[0105] - the antibody light chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 12.

[0106] In particular, said antibody or antigen-binding fragment thereof comprises a constant chain belonging to the subclass of lgG1 , lgG2, lgG3 or lgG4, in particular the subclass of lgG4.

[0107] In a particular aspect of the invention, the antagonist anti-human CD127 antibody or an antigen-binding fragment thereof 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. 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.

[0108] 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.

[0109] 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: 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.

[0110] More particularly, the isolated nucleic acid molecules or the group of isolated nucleic acid molecules encodes a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 13, and a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 14 or SEQ ID No. 15 or SEQ ID No. 16 or SEQ ID No. 17 or SEQ ID No. 18, preferably SEQ ID No. 18.

[0111] In particular, the isolated nucleic acid molecules or the group of isolated nucleic acid molecules encodes a heavy chain consisting of the amino acid sequence set forth in SEQ ID No. 13 and a light chain consisting of the amino acid sequence set forth in SEQ ID No. 18. 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: a) it inhibits or reduces the activation of the phosphatidylinositol 3-kinase and / or the ERK signaling pathway induced by IL-7, b) it does not increase the maturation of dendritic cells induced by TSLP (dendritic cells maturation may be assessed by determining an increase in the expression of cell surface marker CD40 and I or CD80 in TSLP receptor-positive cells treated with TSLP and with said compound compared to cells treated with TSLP alone), c) it does not induce the internalization of CD127 and / or inhibit the IL7-induced internalization of CD127 (CD127- internalization designates the decrease of cell surface expression of CD127 induced by the presence of IL7; the cell surface expression of CD127 in cells incubated in the presence of the anti-CD127 compound is not reduced, or is not significantly reduced, relative to cell surface expression in cells incubated in otherwise identical conditions, but in the absence of the antibody. In particular embodiments, when incubated at 37 °C for 30 to 45 minutes in the presence of 50 ng / mL of antibody, the level of CD127 cell surface expression is at least 80 %, preferably at least 90 % of its level in cells incubated in the absence of the antibody. This effect may be observed in the absence of IL- 7); d) it binds to T cells; 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 W020201 54293)

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] Not antagonizing the TSLP / TSLPR signaling pathway may mean the anti-CD127 compound does not reduce or inhibit the binding between TSLP and TSLPR and / or CD127. Alternatively, or complementarily, not antagonizing the TSLP I TSLPR signaling pathway may mean that the singling pathway induced when TSLP interact with the TSLPR I CD127 complex is not reduced or inhibited in presence of the anti-CD127 compound.

[0117] 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.

[0118] 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).

[0119] In an embodiment, the first compound is GSK-3888130 (GlaxoSmithKline, an anti-IL-7 antibody), an antagonist anti-IL-7 antibody.

[0120] 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).

[0121] • Compounds that are antagonists of IL-12 and / or IL-23 or IL12-R and / or IL- 23R

[0122] The composition to be used according to the present invention, or in a method according to the present invention, comprises a second compound that is an antagonist of IL-12, in particular human IL-12, and / or that is an antagonist of IL- 23, in particular human IL-23 or that is an antagonist of IL-12R, in particular human IL-12R, and / or that is an antagonist of IL-23R, in particular human IL-23R. Such compounds are also referenced as an antagonist of IL-12 and / or antagonist of IL-23 and / or antagonist of IL-12R and / or antagonist of IL-23R in the present disclosure.

[0123] In a particular embodiment, the second compound is an antagonist of IL-12 and / or IL-23, or IL-12R and / or IL-23R, and is selected from the list consisting of: Ebdarokimab, Ulsinumab, Ustekinumab, AVT-04, Wezlana, BAT-2206, Bmab 1200, BFI-751 , SYSA-1902, DMB-3115, FYB-202, QX-001 S, RT-111 , RBS-008, SB-17, Mirikizumab, Guselkumab, Tildrakizumab, Risankizumab, SOR-102, QX- 004N, Picankibart, FPP-005, NBL-012, ORKA-001 , IL-23R, JNJ-2113, PN-235 and PTG-200.

[0124] In another particular embodiment, the second compound is an antagonist of IL- 12 and / or IL-23, or IL-12R and / or IL-23R, and is selected from the list consisting of: Ebdarokimab, Ulsinumab, Ustekinumab, Ustekinumab-aekn (AVT-04), Ustekinumab-auub (Wezlana), Ustekinumab-hmny (BAT-2206), Ustekinumab- kfce (Bmab 1200), Ustekinumab-srlf (DMB-3115), Ustekinumab-aauz (FYB-202), ustekinumab-ttwe (SB-17), Mirikizumab, Guselkumab, Tildrakizumab, Risankizumab, Picankibart, IL-23R, and Icotokinra (JNJ-2113 or PN-235).

[0125] In the context of this patent application, an "antagonist of IL-12" or an antagonist of IL-12R refers to any substance that inhibits ore reduces the biological activity of interleukin-12 (IL-12), in particular human IL-12, or its receptor, IL-12R, in particular human IL-12R. These antagonists can prevent IL-12 from binding to its receptor, block its signal transduction pathway, or otherwise interfere with its ability to exert its biological, in particular immunological, effects. This inhibition can be achieved through various mechanisms, including a direct binding to IL-12, a direct binding to IL-12R, a blockade of IL-12R, or an interruption of downstream signaling pathways.

[0126] An antagonist of IL-12 can thus bind to IL-12 or IL-12R, and inhibits or reduces the IL-12 signaling pathway.

[0127] An antagonist of IL-12 can be a compound that inhibits or reduces downstream signaling pathway(s) induced or activated when IL-12 binds to its receptor IL-12R (i.e. the IL-12 signaling pathway).

[0128] In a particular embodiment, an antagonist of IL-12 is an antibody or an antigenbinding fragment or an antigen-binding antibody mimetic that binds to, in particular specifically binds to IL-12, in particular to a subunit of IL-12, or that binds to IL-12R, in particular a subunit of IL-12R, and inhibits or reduces the binding between IL-12 and its receptor IL-12R.

[0129] An antagonist of IL-12 can be a compound that binds to IL-12, in particular either to the subunit p35 of IL-12 or to the subunit p40 of IL-12.

[0130] An antagonist of IL-12 can be a compound that binds to IL-12 and prevents the binding between IL-12 and its receptor, IL-12 receptor (IL-12R).

[0131] An antagonist of IL-12 can be a compound that binds to IL-12 and prevents the binding between IL-12 and a subunit of IL-12R, either IL-12R|31 (that binds the p40 subunit of IL-12), or IL-12R|32 (that binds the p35 subunit of IL-12).

[0132] An antagonist of IL-12 can be a compound that binds to the subunit p35 of IL-12, and prevents the binding between IL-12R and p35, in particular between IL- 12R|32 and p35. An antagonist of IL-12 can be a compound that binds to the subunit p40 of IL-12, and prevents the binding between IL-12R and p40, in particular between IL- 12R|31 and p40.

[0133] In an embodiment, the antagonist of IL-12 is an anti-IL-12 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to IL-12.

[0134] In an embodiment, the antagonist of IL-12 is an anti-p40 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p40 of IL-12.

[0135] In an embodiment, the antagonist of IL-12 is an anti-p40 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p40 of IL-12, and blocks or inhibits the binding between IL- 12 and IL-12R, in particular between IL-12 and IL-12R|31 .

[0136] In an embodiment, the antagonist of IL-12 is an anti-p35 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p35 of IL-12.

[0137] In an embodiment, the antagonist of IL-12 is an anti-p35 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p35 of IL-12, and blocks or inhibits the binding between IL- 12 and IL-12R, in particular between IL-12 and IL-12R|32.

[0138] In an embodiment, the antagonist of IL-12R is an anti-IL-12R antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to IL-12R.

[0139] In an embodiment, the antagonist of IL-12R is an anti-IL-12R|31 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-12R|31 of IL-12R.

[0140] In an embodiment, the antagonist of IL-12R is an anti-IL-12R|31 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-12R|31 of IL-12R, and blocks or inhibits the binding between IL-12 and IL-12R, in particular between IL-12 and IL-12R|31 . In an embodiment, the antagonist of IL-12R is an anti- ll_-12R|32 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-12R|32 of IL-12R.

[0141] In an embodiment, the antagonist of IL-12R is an anti-IL-12R|32 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-12R|32 of IL-12R, and blocks or inhibits the binding between IL-12 and IL-12R, in particular between IL-12 and IL-12R|32.

[0142] It can be considered that an antagonist of IL-12 or IL-12R, in particular an antibody (or antigen-binding fragment thereof) reduces, inhibits or blocks the binding of IL-12, in particular p35 or p40, to IL-12R, in particular IL-12R|31 or IL- 12R|32, 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-12 to IL-12R in a binding competitive assay by Blitz, as compared to the KD value of IL-12 to IL-12R in presence of a control antibody (i.e. an antibody which does not specifically bind to IL-12 nor IL-12R, in particular IL-12Rp1 and IL-12R|32).

[0143] In a particular embodiment of the invention, the antagonist of IL-12 is an anti-IL- 12 or anti-IL-12R antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0144] In a particular embodiment of the invention, the antagonist of IL-12 or IL12R is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0145] In a particular embodiment of the invention, the antagonist of IL-12 is an anti-p35 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0146] In a particular embodiment of the invention, the antagonist of IL-12 is an anti-p35 antibody selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0147] In a particular embodiment of the invention, the antagonist of IL-12 is an anti-p40 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0148] In a particular embodiment of the invention, the antagonist of IL-12 is an anti-p40 antibody selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0149] In an embodiment, the antagonist of IL-12 is a soluble IL-12R. A soluble IL-12 receptor is an engineered IL-12R comprising at least one subunit of IL-12R that is not membrane-bounded but circulates in the bloodstream of the patient, thereby binding co circulating IL-12 and sequestering it away from the cell surface IL-12R.

[0150] In an embodiment, the antagonist of IL-12R is a peptide that binds to IL-12R|31 .

[0151] In an embodiment, the antagonist of IL-12R is a peptide that binds to IL-12R|31 , and blocks or inhibits the binding between IL-12 and IL-12R, in particular between IL-12 and IL-12RJ31 .

[0152] In an embodiment, the antagonist of IL-12R is a peptide that binds to IL-12R|32.

[0153] In an embodiment, the antagonist of IL-12R is a peptide that binds to IL-12R|32, and blocks or inhibits the binding between IL-12 and IL-12R, in particular between IL-12 and IL-12Rp2.

[0154] In an embodiment, the antagonist of IL-12 is selected from the list consisting of Ebdarokimab (Akeso Biopharma, an anti p40 antibody), Ulsinumab (CSPC Pharmaceutical, an anti p40 antibody), Ustekinumab (Centocor, an anti p40 antibody), AVT-04 (Alvotech, a biosimilar of Ustekinumab), Wezlana (Amgen, a biosimilar of Ustekinumab), BAT-2206 (Bio-Thera Solutions, a biosimilar of Ustekinumab), Bmab 1200 (Biocon, a biosimilar of Ustekinumab), BFI-751 (BioFactura, a biosimilar of Ustekinumab), SYSA-1902 (CSPC Pharmaceutical, a biosimilar of Ustekinumab), DMB-3115 (Dong-A, a biosimilar of Ustekinumab), FYB-202 (Formycon, a biosimilar of Ustekinumab ), QX-001 S (Jiangsu Qyuns Therapeutics, a biosimilar of Ustekinumab), RT-111 (Rani Therapeutics, a biosimilar of Ustekinumab), RBS-008 (Rophibio, a biosimilar of Ustekinumab), Uzpruvo (Alvotech and STADA, a biosimilar of Ustekinumab) and SB-17 (Samsung Biologies, a biosimilar of Ustekinumab). In a particular embodiment, the antagonist of IL-12 is selected from the list consisting of: Ebdarokimab, Ulsinumab, Ustekinumab, Ustekinumab-aekn (AVT-04), Ustekinumab-auub (Wezlana), Ustekinumab-hmny (BAT-2206), Ustekinumab-kfce (Bmab 1200), Ustekinumab-srlf (DMB-3115), Ustekinumab-aauz (FYB-202), and ustekinumab- ttwe (SB-17). These antibodies target the p40 subunit of IL-12 and IL-23, thereby preventing IL-12 from interacting with its receptor.

[0155] In the context of this patent application, an "antagonist of IL-23" or an antagonist of IL-23R refers to any substance that inhibits the biological activity of interleukin- 23 (IL-23), in particular human IL-23, or its receptor, IL-23R, in particular human IL-23R. These antagonists can prevent IL-23 from binding to its receptor, block its signal transduction pathway, or otherwise interfere with its ability to exert its biological, in particular immunological, effects. This inhibition can be achieved through various mechanisms, including a direct binding to IL-23, a direct binding to IL-23R, a blockade of the IL-23 receptor, or an interruption of downstream signaling pathways.

[0156] An antagonist of IL-23 can thus bind to IL-23, in particular human IL-23, or IL- 23R, in particular human IL-23R, and inhibit or reduce the IL-23 signaling pathway.

[0157] An antagonist of IL-23 can be a compound that inhibits or reduces downstream signaling pathway(s) induced or activated when IL-23 binds to its receptor IL-23R (i.e. the IL-23 signaling pathway).

[0158] In a particular embodiment, an antagonist of IL-23 is an antibody or an antigenbinding fragment or an antigen-binding antibody mimetic that binds to IL-23, in particular to a subunit of IL-23, and inhibits or reduces the binding between IL-23 and its receptor IL-23R.

[0159] An antagonist of IL-23 can be a compound that binds to IL-23, in particular either to the subunit p19 of IL-23 or to the subunit p40 of IL-23. An antagonist of IL-23 can be a compound that binds to IL-23 and prevents the binding between IL-23 and its receptor, IL-23 receptor (IL-23R).

[0160] An antagonist of IL-23 can be a compound that binds to IL-23 and prevents the binding between IL-23 and a subunit of IL-23R, either IL-12R|31 (that binds the p40 subunit of IL-23), or IL-23Rsu (that binds the p19 subunit of IL-23).

[0161] An antagonist of IL-23 can be a compound that binds to the subunit p19 of IL-23, and prevents the binding between IL-23R and p19, in particular between IL- 23Rsu and p19.

[0162] An antagonist of IL-23 can be a compound that binds to the subunit p40 of IL-23, and prevents the binding between IL-23R and p40, in particular between IL- 12R|31 and p40.

[0163] In a particular embodiment, an antagonist of IL-23 is an antibody or an antigenbinding fragment or an antigen-binding antibody mimetic that binds to IL-23, in particular to a subunit of IL-23, and blocks or inhibits the binding between IL-23 and its receptor IL-23R.

[0164] In an embodiment, the antagonist of IL-23 is an anti-IL-23 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to IL-23.

[0165] In an embodiment, the antagonist of IL-23 is an anti-p40 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p40 of IL-23.

[0166] In an embodiment, the antagonist of IL-23 is an anti-p40 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p40 of IL-23, and blocks or inhibits the binding between IL- 23 and IL-23R, in particular between IL-23 and IL-12R|31 .

[0167] In an embodiment, the antagonist of IL-23 is an anti-p19 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p19 of IL-23.

[0168] In an embodiment, the antagonist of IL-23 is an anti-p19 antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit p19 of IL-23, and blocks or inhibits the binding between IL- 23 and IL-23R, in particular between IL-23 and IL-23Rsu.

[0169] In an embodiment, the antagonist of IL-23 is an anti-IL-23R antibody or antigenbinding fragment thereof or antigen-binding antibody mimetic that specifically binds to IL-23R.

[0170] In an embodiment, the antagonist of IL-23R is an anti-IL-12R|31 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-12R|31 of IL-23R.

[0171] In an embodiment, the antagonist of IL-23R is an anti-IL-12R|31 antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-12R|31 of IL-23R, and blocks or inhibits the binding between IL-23 and IL-23R, in particular between IL-23 and IL-12R|31 .

[0172] In an embodiment, the antagonist of IL-23R is an anti- IL-23Rsu antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-23Rsu of IL-23R.

[0173] In an embodiment, the antagonist of IL-23R is an anti-IL-23Rsu antibody or antigen-binding fragment thereof or antigen-binding antibody mimetic that specifically binds to the subunit IL-23Rsu of IL-23R, and blocks or inhibits the binding between IL-23 and IL-23R, in particular between IL-23 and IL-23Rsu.

[0174] It can be considered that an antagonist of IL-23 or IL-23R, in particular an antibody (or antigen-binding fragment thereof) reduces, inhibits or blocks the binding of IL-23, in particular p19 or p40, to IL-23R, in particular IL-23Rsu or IL- 12R|31 , 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-23 to IL-23R in a binding competitive assay by Blitz, as compared to the KD value of IL-23 to IL-23R in presence of a control antibody (i.e. an antibody which does not specifically bind to IL-23 nor IL-23R, in particular IL-23Rsu and IL-23R|31 ).

[0175] In a particular embodiment of the invention, the antagonist of IL-23 or IL-23R is an anti-IL-23 or anti-IL23R antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0176] In a particular embodiment of the invention, the antagonist of IL-23 or IL23R is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0177] In a particular embodiment of the invention, the antagonist of IL-23 is an anti-p19 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0178] In a particular embodiment of the invention, the antagonist of IL-23 is an anti-p19 antibody selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0179] In a particular embodiment of the invention, the antagonist of IL-23 is an anti-p40 antibody, or an antigen-binding fragment thereof, that is a humanized antibody, and which comprises constant domains derived from human constant domains of antibodies.

[0180] In a particular embodiment of the invention, the antagonist of IL-23 is an anti-p40 antibody selected from the group consisting of chimeric antibodies, humanized antibodies and fully human monoclonal antibodies.

[0181] In an embodiment, the antagonist of IL-23 is a soluble IL-23R. A soluble IL-23 receptor is an engineered IL-23R comprising at least one subunit of IL-23R that is not membrane-bounded but circulates in the bloodstream of the patient, thereby binding co circulating IL-23 and sequestering it away from the cell surface IL-23R.

[0182] In an embodiment, the antagonist of IL-23R is a peptide that binds to IL-23Rsu.

[0183] In an embodiment, the antagonist of IL-23R is a peptide that binds to IL-23Rsu, and blocks or inhibits the binding between IL-23 and IL-23R, in particular between IL-23 and IL-23Rsu.

[0184] In an embodiment, the antagonist of IL-23R is a peptide that binds to IL-12R|31 . In an embodiment, the antagonist of IL-23R is a peptide that binds to IL-12R|31 , and blocks or inhibits the binding between IL-23 and IL-23R, in particular between IL-23 and IL-12RJ31 .

[0185] In an embodiment, the antagonist of IL-23 is selected from the list consisting of Ebdarokimab (Akeso Biopharma, an anti p40 antibody), Ulsinumab (CSPC Pharmaceutical, an anti p40 antibody), Ustekinumab (Centocor, an anti p40 antibody), AVT-04 (Alvotech, a biosimilar of Ustekinumab), Wezlana (Amgen, a biosimilar of Ustekinumab), BAT-2206 (Bio-Thera Solutions, a biosimilar of Ustekinumab), Bmab 1200 (Biocon, a biosimilar of Ustekinumab), BFI-751 (BioFactura, a biosimilar of Ustekinumab), SYSA-1902 (CSPC Pharmaceutical, a biosimilar of Ustekinumab), DMB-3115 (Dong-A, a biosimilar of Ustekinumab), FYB-202 (Formycon, a biosimilar of Ustekinumab ), QX-001 S (Jiangsu Qyuns Therapeutics, a biosimilar of Ustekinumab), RT-111 (Rani Therapeutics, a biosimilar of Ustekinumab), RBS-008 (Rophibio, a biosimilar of Ustekinumab), Uzpruvo (Alvotech and STADA, a biosimilar of Ustekinumab) and SB-17 (Samsung Biologies, a biosimilar of Ustekinumab). In a particular embodiment, the antagonist of IL-23 is selected from the list consisting of: Ebdarokimab, Ulsinumab, Ustekinumab, Ustekinumab-aekn (AVT-04), Ustekinumab-auub (Wezlana), Ustekinumab-hmny (BAT-2206), Ustekinumab-kfce (Bmab 1200), Ustekinumab-srlf (DMB-3115), Ustekinumab-aauz (FYB-202), and ustekinumab- ttwe (SB-17). These antibodies target the p40 subunit of IL-12 and IL-23, thereby preventing IL-23 from interacting with its receptor.

[0186] In a particular embodiment of the invention, it is provided a combination comprising:

[0187] - 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

[0188] - Ustekinumab, for use in the treatment of an inflammatory disease or an auto-immune disease. In an embodiment, the antagonist of IL-23 is selected from the list consisting of Mirikizumab (Eli Lilly, an anti-p19 antibody), Guselkumab (Novartis, an anti-p19 antibody), Tildrakizumab (Merck & Co, an anti-p19 antibody), Risankizumab (Abbvie, an anti-p19 antibody), SOR-102 (Sorriso Pharmaceuticals, an anti-p19 antibody), QX-004N (Jiangsu Qyuns Therapeutics, an anti-p19 antibody), Picankibart (Innovent biologies, an anti-p19 antibody), FPP-005 (FunPeP, an antibody-inducing peptide targeting IL-23), NBL-012 (NovaRock, an anti-p19 antibody) and ORKA-001 (Oruka Therapeutics, an anti-p19 antibody). In a particular embodiment, the antagonist of IL-23 is selected from the list consisting of: Mirikizumab, Guselkumab, Tildrakizumab, Risankizumab, and Picankibart. These compounds target the p19 subunit of IL-23, preventing IL-23 from binding to its receptor and activating downstream pathways.

[0189] In a particular embodiment of the invention, it is provided a combination comprising:

[0190] - 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

[0191] - Mirikizumab, for use in the treatment of an inflammatory disease or an auto-immune disease.

[0192] In a particular embodiment of the invention, it is provided a combination comprising:

[0193] - A first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and

[0194] - Guselkumab, for use in the treatment of an inflammatory disease or an auto-immune disease.

[0195] In a particular embodiment of the invention, it is provided a combination comprising: - A first compound that is an antagonist of CD127, in particular a first compound that is an anti-CD127 antibody or antigen-binding fragment as disclosed in any embodiment herein, and

[0196] - Tildrakizumab, for use in the treatment of an inflammatory disease or an auto-immune disease.

[0197] In a particular embodiment of the invention, it is provided a combination comprising:

[0198] - 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

[0199] - Risankizumab, for use in the treatment of an inflammatory disease or an auto-immune disease.

[0200] In an embodiment, the antagonist anti-IL23R compound is selected from the list consisting of JNJ-2113 (Johnson & Johnson), PN-235 (Johnson & Johnson), PTG-200 (Johnson & Johnson) and the IL-23R inhibitor from Nimble Therapeutics. In a particular embodiment, the antagonist anti-IL23R compound is Icotokinra (JNJ-2113 or PN-235). JNJ-2113, PN-235 and PTG-200 are peptides that bind to IL-23R and inhibit IL-23 signaling.

[0201] In an embodiment of the invention, it is provided a combination comprising: a. an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and b. an antagonist anti-p19 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0202] In an embodiment of the invention, it is provided a combination comprising: a. an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and b. an antagonist anti-p40 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0203] In an embodiment of the invention, it is provided a combination comprising: a. an antagonist anti-CD127 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody, and b. an antagonist anti-p35 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.

[0204] In an embodiment, it is provided a first compound that is an antagonist of IL-7 and / or CD127, for use in a combination regimen with a second compound that is an antagonist of IL-12, and / or IL12R, and / or IL23 and / or IL-23R, for the treatment of an inflammatory disease or an auto-immune disease.

[0205] In an embodiment, it is provided a first compound that is an antagonist anti- CD127 antibody or antigen-binding fragment thereof, for use in a combination regimen with a second compound that is an antagonist of IL-12, and / or IL23 or IL12R, and / or IL-23R, for the treatment of an inflammatory disease or an autoimmune disease.

[0206] In an embodiment, it is provided a first compound that is an antagonist anti- CD127 antibody or antigen-binding fragment thereof, for use in a combination regimen with a second compound that is an antagonist of IL23, in particular a compound that is an antagonist of IL-23 and that binds to the subunit p19 or p40 of IL-23, for the treatment of an inflammatory disease or an auto-immune disease.

[0207] In an embodiment, it is provided a first compound that is an antagonist anti- CD127 antibody or antigen-binding fragment thereof, for use in a combination regimen with a second compound that is an antagonist of IL-23 and that binds to the sub-unit p19 or p40 of IL-23, for the treatment of an inflammatory disease or an auto-immune disease.

[0208] • Bifunctional molecules including bifunctional antibodies and derived molecules

[0209] In an aspect of the invention, it is provided a bifunctional molecule that comprises: - A first binding moiety, said first binding moiety binding to IL-7 or CD127, and A second binding moiety, said second binding moiety binding to IL-12 and / or IL-23 or IL-12R and / or IL-23R.

[0210] 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 IL-12, IL-23, IL-12R or IL23-R.

[0211] In particular, the bifunctional molecule inhibits (i) the binding between IL-7 and CD127, in particular human IL-7 and human CD127, and (ii) the binding between IL-12 and IL-12R and / or between IL-23 and IL-23R, in particular human IL-12 and human IL-12R and / or between human IL-23 and human IL-23R.

[0212] In a particular embodiment, the binding moiety of the bifunctional molecule that binds to CD127 comprises: 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 b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0213] - a light chain variable fragment (VL) comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the 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.

[0214] In a particular aspect of the invention, it is provided a bifunctional molecule that comprises:

[0215] - A first binding moiety, said first binding moiety binding to CD127, in particular human CD127, and

[0216] - A second binding moiety, said second binding moiety binding to IL-23, in particular to the subunit p40 or p19 of IL-23 (preferably human IL23).

[0217] 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 to IL-12, IL-23, IL-12R or IL-23R on the other hand). The first and second binding moieties are directed to two different targets, so that the molecule according to the invention is particularly “bifunctional”, i.e., is able to bind to two different targets (e.g., IL-7 or CD127 on one hand, and to IL-12, IL-23, IL-12R or IL-23R on the other hand).

[0218] In an aspect of the invention, it is provided a bifunctional molecule that comprises:

[0219] - A first binding moiety, said first binding moiety binding to IL-7 or CD127,

[0220] - A second binding moiety, said second binding moiety binding to IL-12 and / or IL-23 or IL-12R and / or IL-23R, the bifunctional molecule inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between IL-12 and IL-12R and / or between IL-23 and IL-23R.

[0221] The inhibition of the binding between IL-7 and CD127 and between IL-12 and IL- 12R and / or between IL-23 and IL-23R has the same meaning as detailed above in relation to the combinations of compounds.

[0222] In an aspect of the invention, it is provided a bifunctional molecule that comprises:

[0223] - A first binding moiety, said first binding moiety binding to IL-7 or CD127, A second binding moiety, said second binding moiety binding to IL-12 and / or IL-23 or IL-12R and / or IL-23R, the bifunctional molecule being an antagonist of IL-7 and / or CD127, and the bifunctional molecule being an antagonist of IL-12 and / or IL-23 or IL-12R and / or IL-23R.

[0224] The antagonist property of the bifunctional molecule towards IL-7, CD127, IL-12, IL-23, IL-12R and / or IL-23R has the same meaning as detailed above in relation to the combinations of compounds

[0225] The structure of several bifunctional molecules according to the invention are detailed on figure 1. These examples serve primarily to illustrate certain aspects of the invention, and the bifunctional molecules according to the invention are not limited to these specific examples. For example, in these figures, the first moiety recognizes IL-7 and / or CD127 and is shown in green, while the second moiety recognizes the subunit p19 of IL-23 or p40 of IL-23 and IL-12 and is shown in blue. These two binding moieties can be interchanged, for example (e.g., the first moiety binding to CD127 in blue and the second binding moiety binding to p19 or p40 in green).

[0226] The bifunctional molecule may particularly comprise two, three or four binding moieties. For example, the bifunctional molecule may comprise: one binding moiety that binds to IL-7 or CD127 and one binding moiety that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R; or 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 IL-12 and / or IL-23 or IL-12R and / or IL-23R; or two binding moieties that bind to IL-12 and / or IL-23 or IL-12R and / or IL- 23R, said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to IL-23, in particular to the subunit p19 of IL-23 (or p40 of IL-23 and IL-12); and one binding moiety that binds to IL- 7 or CD127, preferably CD127; or two binding moieties that bind to IL-12 and / or IL-23 or IL-12R and / or IL- 23R, said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to IL-23, in particular to the subunit p19 of IL-23 (or p40 of IL-23 and IL-12); and two binding moiety that binds to IL- 7 or CD127; said two binding moieties binding to the same or to different target(s), preferably the same target, most preferably to CD127; or 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 IL-12 and / or IL- 23 or IL-12R and / or IL-23R; three binding moieties that bind to IL-12, IL-23, IL-12R or IL-23R, said three binding moieties binding to the same or to different target(s), preferably the same target, most preferably to IL-23, in particular to the subunit p19 of IL-23 (or p40 of IL-23 and IL-12); and one binding moiety that binds to IL-7 or CD127, preferably CD127.

[0227] 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.

[0228] 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 IL-12 and / or IL-23 or IL-12R and / or IL-23R, the two immunoglobulins forming a bifunctional antibody.

[0229] In a particular embodiment, the binding moiety of the bifunctional molecule that binds to CD127 (in particular first, second, third binding moiety) comprises: a heavy chain variable fragment (VH) comprising: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 , and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0230] - a light chain variable fragment (VL) comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the 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.

[0231] According to an embodiment, the bifunctional molecule of the invention is a bifunctional antibody. As used herein, a “bifunctional” in relation to an antibody or antigen-binding fragments refers to an antibody or an antigen-binding fragments which (i) has two arms for antigen binding wherein each of the two arm binds to a different antigen or which (ii) has more than two arms wherein at least one of the arms binds to a second antigen or respectively a first antigen when at least one other arm, or the other arms, bind to the first antigen or the second antigen respectively. Otherwise stated, the bifunctional antibodies or the antigen-binding fragments may recognize at least two different antigens, preferably two different antigens, by virtue of possessing at least one region (e.g. derived from a variable region of a first antibody) that is specific for a first antigen, and at least a second region (e.g. derived from a variable region of a second antibody) that is specific for a second antigen. A bifunctional antibody specifically binds to two target antigens and is thus one type of multispecific antibody. Bifunctional 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 recognized two different targets.

[0232] 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 IL-12, IL-23, IL-12R or IL-23R. 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.

[0233] 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 EU index as in Kabat. "Hinge" refers to positions 216-230 according to the EU index as in Kabat. "CH2" refers to the second constant domain and in particular to positions 231 -340 according to the EU 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 EU 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.

[0234] The term "hinge region" refers to the flexible polypeptide comprising the amino acids between the CH1 and CH2 domains of an antibody. The hinge is defined structurally for the purposes of the present invention. The IgG 1 "hinge region" as used herein comprises residues 216-230 according to the according to the EU index as in Kabat.

[0235] The first and / or second binding moiety may comprise a CL domain. In the context of IgG antibodies, the IgG isotypes each have a light chain constant domain (CL). “CL domain” refers to the light chain immunoglobulin constant domain that is located C-terminally to the VL domain. It spans about EU index Kabat positions 107-216. A CL domain may be a naturally occurring CL domain, or a naturally occurring CL domain in which one or more amino acids have been substituted.

[0236] 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.

[0237] 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.

[0238] In addition, the bifunctional molecule may also comprise one or several peptide linkers, that allow linkage between different part of the bifunctional molecule (e.g., between a Fc chain and a binding moiety).

[0239] In an embodiment, the first and second binding moieties are Fab, so that the bifunctional molecule preferably comprises or consists of:

[0240] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0241] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1 ), and said first light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0242] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL),

[0243] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1 ), said second light and heavy chains forming the second binding moiety that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23).

[0244] 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:

[0245] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0246] (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

[0247] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL),

[0248] (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, wherein said second light and heavy chains form the second binding moiety that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23), and wherein the first and second Fc chains are complementary and form a Fc domain.

[0249] 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:

[0250] (i) a first chain that is a light chain comprising a variable domain (VL) and a constant domain (CL),

[0251] (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

[0252] (iii) a third chain comprising a variable domain (VH) and a constant domain (CL),

[0253] (iv) a fourth chain comprising a variable domain (VL) and a constant domain (CH1 ), said third and fourth chains forming the second binding moiety that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23).

[0254] Such a molecule is illustrated on Fig.lA.

[0255] In a particular embodiment, said binding moiety of the bifunctional molecule that binds to CD127 comprises: 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 b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0256] - a light chain variable fragment (VL) comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the 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.

[0257] In particular embodiment, the first chain comprises or consists of the amino acid sequence set forth in SEQ ID No. 19, the second chain comprises or consists of the amino acid sequence set forth in SEQ ID No. 20, the third chain comprises or consists of the amino acid sequence set forth in SEQ ID No. 21 and the fourth chain comprises or consists of the amino acid sequence set forth in SEQ ID No. 22.

[0258] 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:

[0259] (i) a first chain that is a light chain comprising a variable domain (VL) and a constant domain (CL),

[0260] (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-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23); and

[0261] (iii) a third chain comprising a variable domain (VH) and a constant domain (CL),

[0262] (iv) a fourth chain comprising a variable domain (VL) and a constant domain (CH1 ), said third and fourth chains forming the second binding moiety that binds to IL-7 or CD127, preferably CD127.

[0263] In a particular embodiment, said second binding moiety of the bifunctional molecule that binds to CD127 comprises: 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 b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0264] - a light chain variable fragment (VL) comprising: LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the 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.

[0265] In a more particular embodiment, the bifunctional molecule comprises a first chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 53, a second chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 54, a third chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 55 and a fourth chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 56.

[0266] 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:

[0267] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL), (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1 ), 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,

[0268] (iii) a second light chain comprising a variable domain (VL), and

[0269] (iv) a second heavy chain comprising a variable domain (VH), wherein said second light and heavy chains are linked by a peptide linker and form a scFv that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23).

[0270] 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.

[0271] 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.

[0272] 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:

[0273] (i) a first light chain comprising a variable domain (VL),

[0274] (ii) a first heavy chain comprising a variable domain (VH), 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,

[0275] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and

[0276] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1 ), wherein said second light and heavy chains form the second binding moiety that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23), and form a Fab.

[0277] 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. 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.

[0278] 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.

[0279] In particular, the scFv may be linked by its VH to the second constant domain.

[0280] Alternatively, the scFv may be linked by its VL to the second constant domain.

[0281] Such molecules are illustrated on Fig.l B and Fig. 1C.

[0282] In a particular embodiment, the binding moiety of the bifunctional molecule that binds to CD127 (in particular being a Fab or a scFv) comprises: 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 b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0283] - a light chain variable fragment (VL) comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the 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. In particular embodiment, the bifunctional molecule comprises or consists in: a first chain that comprises or consists of the first light chain and the first heavy chain, the first chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 23; and a second chain that comprises or consists of the second light chain and the second heavy chain, the second chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 24.

[0284] In particular embodiment, the bifunctional molecule comprises or consists in: a first chain that comprises or consists of the first light chain and the first heavy chain, the first chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 25; and a second chain that comprises or consists of the second light chain and the second heavy chain, the second chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 24.

[0285] In particular embodiment, the bifunctional molecule comprises or consists in: a first chain that comprises or consists in the amino acid sequence set forth in SEQ ID No. 49; and a second chain that comprises or consists in the amino acid sequence set forth in SEQ ID No. 50.

[0286] In particular, the scFv may be linked at the N-terminal end of the second light chain, in particular to the N-terminal end of the constant domain of the second light chain.

[0287] In particular embodiment, the bifunctional molecule comprises or consists in: a first chain that comprises or consists in the amino acid sequence set forth in SEQ ID No. 32; and a second chain that comprises or consists in the amino acid sequence set forth in SEQ ID No. 31.

[0288] In particular embodiment, the bifunctional molecule comprises or consists in: a first chain that comprises or consists in the amino acid sequence set forth in SEQ ID No. 33; and a second chain that comprises or consists in the amino acid sequence set forth in SEQ ID No. 31. In another embodiment, the bifunctional molecule is a dual variable domain immunoglobulin (DVD-lg protein: the molecule contains a Fc region and constant regions in a configuration similar to a conventional IgG that corresponds to a binding moiety. The molecule further contains variable domains attached to the Fc region of the first moiety. The variable domains are linked in tandem and form the ether binding moiety. Thus, in an embodiment, the bifunctional molecule preferably comprises or consists of:

[0289] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0290] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1 ), and said first light and heavy chains forming the first binding moiety that binds to IL-7 or CD127, preferably CD127; and

[0291] (iii) a second light chain comprising a variable domain (VL) and a constant domain (CL), and

[0292] (iv) a second heavy chain comprising a variable domain (VH) and a constant domain (CH1 ), wherein said second light and heavy chains form the second binding moiety that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23), the constant domains of the second light and heavy chains being linked to the variable domains of the first light and heavy chains, respectively.

[0293] Alternatively, the bifunctional molecule preferably comprises or consists of:

[0294] (i) a first light chain comprising a variable domain (VL) and a constant domain (CL),

[0295] (ii) a first heavy chain comprising a variable domain (VH) and a constant domain (CH1 ), wherein said first light and heavy chains form the first binding moiety that binds to IL-7 or CD127, preferably CD127, and

[0296] (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 ), said second light and heavy chains forming the second binding moiety that binds to; IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23), and 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.

[0297] Such a molecule is illustrated on Fig.l D.

[0298] In a particular embodiment, the first binding moiety of the bifunctional molecule that binds to CD127 comprises: 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 b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and a light chain variable fragment (VL) comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the 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. In particular embodiment, the bifunctional molecule comprises or consists in: a heavy chain that comprises or consists of the first heavy chain and the second heavy chain, the heavy chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 26; and a light chain that comprises or consists of the first light chain and the second light chain, the second chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 27.

[0299] In particular embodiment, the bifunctional molecule comprises or consists in: a heavy chain that comprises or consists of the first heavy chain and the second heavy chain, the heavy chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 51 ; and a light chain that comprises or consists of the first light chain and the second light chain, the second chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 52.

[0300] 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:

[0301] (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

[0302] (ii) at least one second chain comprising a heavy chain variable fragment (VH) and a light chain constant domain (CL), wherein said second light and heavy chains form the second binding moiety that binds to IL-12 and / or IL-23 or IL-12R and / or IL-23R, preferably IL-23 (the subunit p40 or p19 of IL23).

[0303] Such molecules are illustrated on Fig.l E.

[0304] In a particular embodiment, the at least one first chain forming a scFv CrossMab that binds to CD127 of the bifunctional molecule comprises: 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 b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and

[0305] - a light chain variable fragment (VL) comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the 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.

[0306] In particular embodiment, the bifunctional molecule comprises or consists in: a first chain that comprises or consists in the amino acid sequence set forth in SEQ ID No. 28; and a heavy chain variable fragment that comprises or consists in the amino acid sequence set forth in SEQ ID No. 29; and a light chain variable fragment that comprises or consists in the amino acid sequence set forth in SEQ ID No. 30.

[0307] 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 IL-12, IL-23, IL-12R or IL23-R (particularly the sub-unit p19 of IL-23 or the subunit p40 of IL-12 and IL23), the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between IL-12 and IL-12R and / or between IL-23 and IL-23R.

[0308] 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 IL23, the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between IL-23 and IL-23R.

[0309] 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 the subunit p19 of IL-23, the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between IL-23 and IL-23R.

[0310] 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 the subunit p40 of IL-12 and IL-23, the bifunctional antibody inhibiting (i) the binding between IL-7 and CD127 and (ii) the binding between IL-23 and IL-23R and (iii) the binding between IL-12 and IL-12R.

[0311] • Pharmaceutical composition and administration route

[0312] 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.

[0313] 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.

[0314] 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.

[0315] Pharmaceutical formulations and compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.

[0316] 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.

[0317] 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 IL-12 and / or IL-23 or IL-12R and / or IL-23R are provided within different, distinct containers, in particular as pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient.

[0318] Further therapeutic compounds 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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, multiple sclerosis, asthma and psoriasis.

[0323] 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.

[0324] The other therapeutic agent may be administered concurrently or separately, in particular subsequently to or sequentially, with the combination or the bifunctional molecule of the invention. The other therapeutic agent may be administered according to the same dosing cycle as the combination or the bifunctional molecule of the invention, either at the same time, or separately in time. The other therapeutic agent may also be administered according to a different dosing cycle than the dosing cycle of the combination or the bifunctional molecule of the invention. The second therapeutic agent may also be administered according to the same therapeutic regimen as the combination or the bifunctional molecule of the invention.

[0325] 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. Diseases to be treated

[0326] The uses described herein as well as the methods described herein may be useful in the treatment inflammatory diseases, including Non-Alcoholic Fatty Liver Disease, endometriosis, encephalomyelitis, inflammatory bowel disease, in particular Crohn’s disease and Ulcerative Colitis, chronic obstructive pulmonary disease, atherosclerosis, rheumatoid arthritis, multiple sclerosis, asthma and psoriasis.

[0327] The uses described herein as well as the methods described herein may be useful in the treatment of inflammatory bowel diseases.

[0328] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from inflammatory bowel disease.

[0329] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from ulcerative colitis.

[0330] In a particular aspect, the composition as defined herein if for use in the treatment of a patient suffering from Crohn’s disease.

[0331] 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.

[0332] 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).

[0333] • Methods of treatment

[0334] 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, in combination with a second compound that is an antagonist of IL-12, IL-23, IL-12R and / or IL-23R.; wherein the first and second compounds are for separate or simultaneous administration, in particular for a sequential or alternate administration.

[0335] 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: a. HCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 1 , b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and a light chain variable fragment comprising: d. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, e. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; f. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6;

[0336] 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. In certain embodiments, the patient is suffering from an inflammatory disease, in particular an IBD, more particularly Crohn disease or Ulcerative colitis.

[0337] In certain embodiments, the antagonist of IL-12 or the antagonist of IL-23 is selected from the list consisting of Ebdarokimab, Ulsinumab, Ustekinumab, AVT- 04, Wezlana, BAT-2206, Bmab 1200, BFI-751 , SYSA-1902, DMB-3115, FYB- 202, QX-001 S, RT-111 , RBS-008 and SB-17.

[0338] In a particular embodiment, the antagonist of IL-12 or the antagonist of IL-23 is selected from the list consisting of: Ebdarokimab, Ulsinumab, Ustekinumab, Ustekinumab-aekn (AVT-04), Ustekinumab-auub (Wezlana), Ustekinumab-hmny (BAT-2206), Ustekinumab-kfce (Bmab 1200), Ustekinumab-srlf (DMB-3115), Ustekinumab-aauz (FYB-202), and ustekinumab-ttwe (SB-17).

[0339] In certain embodiments, the antagonist of IL-23 is selected from the list consisting of Mirikizumab, Guselkumab, Tildrakizumab, Risankizumab, SOR-102, QX- 004N, Picankibart, FPP-005, NBL-012, ORKA-001 , JNJ-2113, PN-235, PTG-200 and the IL-23R inhibitor from Nimble Therapeutics.

[0340] In certain embodiments, the antagonist of IL-23 is selected from the list consisting of: Mirikizumab, Guselkumab, Tildrakizumab, Risankizumab, Picankibart, and Icotokinra (JNJ-2113 or PN-235).

[0341] 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, in combination with a second compound that is an antagonist of IL-12, IL-23, IL-12R and / or IL-23R, 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.

[0342] 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, and a second compound that is an antagonist of IL-12, IL-23, IL-12R and / or IL-23R, 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.

[0343] 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, and a second compound that is an antagonist of IL-12, IL-23, IL-12R and / or IL-23R, 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.

[0344] 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, and the second compound that is the antagonist of IL-12, IL-23, IL-12R and / or IL-23R in distinct, different containers.

[0345] 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: a first binding moiety, said first binding moiety binding to IL-7 and / or CD127, a second binding moiety, said second binding moiety binding to IL-12, IL- 23, IL-12R and / or IL-23R (in particular to the sub-unit p19 of IL-23 or the subunit p40 of IL-12 and IL23).

[0346] 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 IL-12, IL-23, IL-12R or IL23-R (in particular the sub-unit p19 of IL-23 or the subunit p40 of IL-12 and IL23).

[0347] In one aspect of the invention, it is provided the bifunctional molecule that comprises a first binding moiety, said first binding moiety binding to IL-7 or CD127, a second binding moiety, said second binding moiety binding to IL-12, IL- 23, IL-12R or IL-23R (in particular to the sub-unit p19 of IL-23 or the subunit p40 of IL-12 and IL23), for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease.

[0348] 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 IL- 12 and IL-12R and / or between IL-23 and IL-23R, for use in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease.

[0349] DESCRIPTION OF THE FIGURES

[0350] 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.

[0351] Figure 1 illustrates different forms of bifunctional molecules targeting the sub-unit p19 of IL-23 or p40 of IL-23 and IL-12 (anti-p19 / p40) and CD127 according to the invention. A) Anti-p19 / p40xCrossMab127; B) Anti-p19 / p40-scFv127-HL; C) antipl 9 / p40-scFv127-LH; D) DVDIg anti-p19 / p40-anti-CD127 antibody; E) antipl 9 / p40-CrossMab127.

[0352] Figure 2 illustrates the protocol for monitoring the health of mice suffering from Ulcerative colitis and treated with different compounds. W : week. The different groups in figures 2 to 12 are annotated : (1 ) No T cell untreated control group (named non-colitis); (2) T cell / anti IL-7Ra + rat lgG2aK group (named Anti IL-7R mAb), (3) T cell / anti IL-7Ra + anti-l L 12 / 23p40 IgG group (named Anti IL-7R+ Anti- IL12 / 23 mAbs) and (4) T cell / lsotype of antilL-7Ra + anti-IL12 / 23p40 IgG group (named Anti-IL-12 / 23 mAb) and (5) T cell / isotype control IgGs of anti-IL-7Ra and of anti-IL12 / 23p40 (named control Abs).

[0353] Figure 3 illustrates the body weight of healthy mice and mice suffering from Ulcerative colitis over time. Diseased mice were treated with a control antibody, an anti-IL12 / IL-23 antibody (i.e. an anti-p40 antibody), an anti-IL-7Ra antibody (anti-CD127), or a combination of an anti-IL12 / IL-23 antibody (i.e. an anti-p40 antibody) and an anti-IL-7Ra antibody (anti-CD127). Data shown are the group mean weights, expressed as a percentage of starting body weight; Standard Error of the Mean (SEM) values are also shown (bars), n = 5 for the untreated control group (non-colitis); n = 10 for the T cell / Anti IL-7Ra + rat lgG2aK group (named anti IL-7R mAb), with n = 9 from day 18 and n = 8 from day 23; n = 10 for the T cell / Anti IL-7Ra + anti-IL12 / 23p40 IgG group (named Anti IL-7R+ Anti IL12 / 23 mAbs) and for the T cell / lsotype of anti-IL-7Ra + anti-12 / 23p40 IgG group (named anti-l L 12 / 23 mAb); n = 10 for the T cell / lsotype of anti IL-7Ra + rat lgG2aK group (named anti IL7R), with n = 9 from day 24. Where indicated, statistical comparisons were performed using mixed-effects analysis with Dunnett’s test. **** significantly different from the T cell / Anti-IL-7Ra + anti-IL12 / 23p40 IgG group at p < 0.0001.

[0354] Figure 4 illustrates the cumulative diarrhoea score calculated from large bowel weight / length ratio in healthy mice and mice suffering from Ulcerative colitis over time. Diseased mice were treated as detailed for Fig. 3. Data shown are the group mean cumulative diarrhoea scores; Standard Error of the Mean (SEM) values are also shown (bars), n = 5 for the untreated control group (non colitis); n = 10 for the T cell / anti IL-7Ra + rat lgG2aK group (Anti IL-7R mAb), with n = 9 from day 18 and n = 8 from day 23; n = 10 for the T cell / anti IL-7Ra + anti-l L 12 / 23p40 IgG group (Anti IL-7R+ Anti-IL12 / 23 mAbs) and for the T cell / lsotype of anti-IL-7Ra + anti-IL12 / 23p40 IgG group (Anti IL-12 / 23 mAb); n = 10 for the T cell / lsotype of Anti IL-7Ra + rat lgG2aK group (Anti IL-7R mAb), with n = 9 from day 24. Where indicated, statistical comparisons were performed using mixed-effects analysis with Dunnett’s test. ** significantly different from the T cell / Anti IL-7Ra + anti- IL12 / 23 p40 IgG group at p = 0.0016. Figure 5 illustrates the large bowel weight and length of healthy mice and mice suffering from Ulcerative colitis after treatment. Diseased mice were treated as detailed for Fig. 3. Plots show data for individual mice; group mean and standard deviation values are also shown (bars). A) large bowel weight (g); B) large bowel length (mm); C) large bowel weight: length ratio (mg / mm); D) spleen weight (g). Data from mice removed prior to the scheduled endpoint are shown by unfilled icons, n = 10 for all groups except for the untreated control group (non colitis), where n = 5 and the T cell / anti IL-7Ra + rat lgG2aK group (anti IL-7R mAb), where n = 9. Where shown, statistical comparisons were performed using Brown- Forsythe / Welch ANOVA with Dunnett’s T3 test.

[0355] Figure 6 illustrates the colitis severity in all regions of the bowel of healthy mice and mice suffering from Ulcerative colitis after treatment. Diseased mice were treated as detailed for Fig. 3. n = 10 for all groups except for the untreated control group, where n = 5 and the T cell / anti-IL-7Ra + rat lgG2aK group (Anti IL-7R mAb), where n = 9. Where indicated, statistical comparisons were performed using Brown-Forsythe / Welch ANOVA, in combination with Dunnett’s test, as appropriate.

[0356] Figure 7 illustrates the colitis severity in the proximal region of the bowel of healthy mice and mice suffering from Ulcerative colitis after treatment. Diseased mice were treated as detailed for Fig. 3. Where indicated, statistical comparisons were performed using Brown-Forsythe / Welch ANOVA, in combination with Dunnett’s test, as appropriate.

[0357] Figure 8 illustrates the colitis severity in the middle region of the bowel of healthy mice and mice suffering from Ulcerative colitis after treatment. Diseased mice were treated as detailed for Fig. 3. Where indicated, statistical comparisons were performed using one-way in combination with Dunnett’s test, as appropriate.

[0358] Figure 9 illustrates the colitis seventy in the distal region of the bowel of healthy mice and mice suffering from Ulcerative colitis after treatment. Diseased mice were treated as detailed for Fig. 3. Where indicated, statistical comparisons were performed using one-way in combination with Dunnett’s test, as appropriate.

[0359] Figure 10 illustrates the area component score in all regions of the bowel of healthy mice or mice suffering from Ulcerative colitis after treatment. Criteria for scoring includes epithelial hyperplasia, morphological changes within epithelium, infiltration of inflammatory cells into the mucosa, other signs of active inflammation (sub-mucosal infiltrate, crypt loss, ulceration, crypt abscess formation, erosion)). Diseased mice were treated as detailed for Fig. 3. Data points represent the mean component score for individual mice; group mean and standard deviation values are also shown (bars) n = 10 for all groups except for the untreated control group, where n = 5 and the T cell / Anti IL-7Ra + rat lgG2aK group (Anti IL-7R mAb), where n = 9. Where indicated, statistical comparisons were performed using one-way (Area) in combination with Dunnett’s test, as appropriate.

[0360] Figure 11 illustrates the hyperplasia component score in all regions of the bowel of healthy mice or mice suffering from Ulcerative colitis after treatment. Criteria for scoring are those detailed for fig. 10. Diseased mice were treated as detailed for Fig. 3. Data points represent the mean component score for individual mice; group mean and standard deviation values are also shown (bars). Data from mice removed prior to the scheduled endpoint are shown by unfilled icons, n = 10 for all groups except for the untreated control group, where n = 5 and the T cel l / Anti- IL-7Ra + rat lgG2aK group (Anti IL-7R mAb), where n = 9. Where indicated, statistical comparisons were performed using Brown-Forsythe / Welch ANOVA (Hyperplasia), in combination with Dunnett’s test, as appropriate;

[0361] Figure 12 illustrates the infiltration component score in all regions of the bowel of healthy mice or mice suffering from Ulcerative colitis after treatment. Criteria for scoring are those detailed for fig. 10. Diseased mice were treated as detailed for Fig. 3. Data points represent the mean component score for individual mice; group mean and standard deviation values are also shown (bars), n = 10 for all groups except for the untreated control group, where n = 5 and the T cell / anti IL- 7Ra + rat lgG2aK group (Anti IL-7R mAb), where n = 9. Where indicated, statistical comparisons were performed using Kruskal-Wallis analysis in combination with Dunn’s test.

[0362] Figure 13 illustrates the inhibition of IL17 secretion (normalized to the negative control) by CD4 T cells activated by human IL7 and human IL23, in the presence of anti-human CD127 and / or anti-human IL23 (anti-hp19). Anti-hlL7R: antihuman IL7R (anti-human CD127) antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18); Anti-hp19: anti-human IL23p19 antibody Guselkumab.

[0363] Figure 14 illustrates the inhibition of IFNg secretion (normalized to the negative control) by CD4 T cells activated by human IL7 and human IL23, in the presence of anti-human CD127 and / or anti-human IL23 (anti-hp19). Left panel: Anti-hlL7R: anti-human IL7Ra (anti-human CD127, 1 pg / mL) antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18); Anti-hp19: anti-human IL23p19 antibody (Guselkumab). Right panel: anti-human CD127 (bempikibart, 1 pg / mL); Anti- hp19: anti-human IL23p19 antibody (Guselkumab)n=3.

[0364] Figure 15 illustrates the inhibition of IFNg secretion (normalized to the negative control) by CD4 T cells activated by human IL7 and human IL23, in the presence of anti-human IL7Ra (10pg / mL) and / or anti-human IL23 (anti-hp19). Left panel: Anti-hlL7R: anti-human CD127 (PF06342674); Anti-hp19: anti-human IL23p19 antibody (Guselkumab). Right panel : Anti-hlL7R: anti-human IL7Ra (N13B2-h3); Anti-hp19: anti-human IL23p19 antibody (Guselkumab), n=3.

[0365] Figure 16 illustrates the inhibition of IFNg secretion (normalized to the negative control) by CD4 T cells activated by human IL7 and human IL23, in the presence of bispecific anti-hlL7Ra x anti-hp19 antibody (SEQ ID NO: 53-36), anti-human IL7Ra or anti-human IL23 (anti-hp19). Anti-hlL7R: anti-human IL7Ra (anti-human CD127) antibody having the 6 CDRS referenced SEQ ID No. 1 to No. 6 herein (particularly, it is an antibody that comprises the antibody heavy chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 7, and the antibody light chain variable fragment comprising the amino acid sequence set forth in SEQ ID No. 12, more particularly it is an antibody that has a heavy chain consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain consisting in the amino acid sequence set forth in SEQ ID No. 18); Anti- hp19: anti-human IL23p19 antibody (Guselkumab), bispecific anti-hlL7R x anti- hp19 antibody (SEQ ID NO: 53-36).

[0366] EXAMPLES

[0367] Experimental settings are detailed on the Figure 2 On study day 0, immunodeficient mice received a single intraperitoneal injection of CD4+CD62L+T cells to induce colitis. Control mice that received no T cells acted as untreated negative controls.

[0368] T cell-recipient mice were randomized into eight groups of 10 mice prior to the initiation of Test Item / Vehicle administration on day 0. Four groups of mice were used to test the treatment combination of, Anti-IL7Ra (anti-CD127) IgG antagonist (blocking) antibody, and an anti-IL-12 / 23 (i.e. anti-p40) IgG antagonist (blocking) antibody, with one group treated with both therapeutic antibodies, one group treated with both respective isotype control IgGs and two groups treated with one therapeutic antibody and the appropriate isotype control for the other. Anti-IL7Ra IgG (InVivoMAb anti-mouse IL-7Ra (anti- mouse CD127), Euromedex, BX-BE00651 Lot: 829622M1 , and its isotype control (Isotype Control - InVivoMAb rat lgG2a, anti-trinitrophenol, Euromedex, BX-BE0089 I Lot: 829622M1 ), were administered every three days, at a dose of 5 mg / kg since day 0 and the anti-IL-12 / 23 (i.e. anti-p40) IgG and its isotype control (rat lgG2aK) are in-house antibodies.

[0369] The large bowel was removed, flushed, and its weight and length recorded. The large bowel was then split into three regions (proximal, mid, and distal) and the tissue was fixed in neutral-buffered formalin for histological analysis.

[0370] Combination treatment with antagonist anti-CD127 (anti-IL-7Ra) and antagonist anti-IL-12 / 23 p40 IgG antibodies demonstrated superior efficacy compared to monotherapies associated with significant amelioration significant reduction in all measured colitis symptoms and histopathological endpoints compared to monotherapy with antagonist anti-CD127 (anti-IL-7Ra) antibody or antagonist anti p40 antibody demonstrating synergistic activity of combining both therapies. All data obtained are detailed below.

[0371] In-life data:

[0372] Over the period of the study, the untreated negative control mice showed an increase in mean body weight as expected since mice did not develop colitis while mice injected with T cells and Isotype controls (control mabs) showed a significant weight loss due to development of colitis post T cell transfer validating the model (Figure 3). Anti IL-7Ra (anti-CD127) monotherapy treatment did not show significant improvement on weight parameter compared to Isotype control group. However, the double therapeutic antibody treatment (Anti-IL-7Ra IgG + anti-p40 IgG) showed high efficacy with significant difference relative to both the T cell / Anti-CD127 IgG monotherapy group and the T cell / isotype controls (at p = 0.0004 and p = 0.0018, respectively) on the weight parameter.

[0373] The body weight profiles of the T cell / anti IL-7Ra + anti-p40 IgG group and the T cell / rat IgG + anti-p40 IgG group were very similar to each other, with the two groups having almost identical mean body weights on day 28 and similar to untreated mice (without colitis) demonstrating maximal effect of the anti-IL-7Ra + anti-p40 IgG combination treatment as well as anti p40 IgG treatment monotherapy on the weight parameter.

[0374] Regarding diarrhea incidence (Figure 4), the T cell / control antibody group demonstrated a steady increase in diarrhoea incidence validating induction of colitis in the mouse model (Figure 4). Interestingly, the effect of the double therapeutic antibody treatment (Anti-CD127 IgG + anti-p40 IgG) in reducing diarrhoea incidence was statistically significant, relative to the T cell / Anti- CD127 IgG + rat lgG2aK group (p = 0.0016, statistical comparisons were performed using mixed-effects analysis with Dunnett’s test). Between other groups no significant differences was obtained.

[0375] Post-mortem tissue measurements:

[0376] The development of colitis in T cell-recipient mice is associated with an increase in the mean large bowel weight and a decrease in large bowel length, resulting in an increase in the mean weight: length ratio of the large bowel (Figure 5 A, B &C). The T cell / Isotype control group and the T cell / Anti-CD127 IgG monotherapy demonstrated similar colitis-associated changes with mean large bowel weight:length ratios of (4.95 ± 0.75) mg / mm and (4.73 ± 1.14) mg / mm, respectively validating induction of colitis pathological changes in the model post T cell transfer.

[0377] The administration of anti-p40 IgG + anti-CD127 was associated with significant a reduction in large bowel weight: length ratio having a ratio of (2.03 ± 0.29) mg / mm. The reduction in large bowel weight:length ratio observed in response to the administration of both therapeutic antibodies in combination was statistically significant, relative to the other three treatment groups in this arm of the study (p < 0.0001 ) demonstrating the synergistic efficacy of combining treatment anti -CD127 antagonists with anti-IL23 and / or IL-12 antagonists to treat colitis while each monotherapy anti -CD127 or anti IL-23 / 12 alone did not achieve such therapeutic effect. Large bowel ratio in the combination group was similar to untreated mice without colitis showing high therapeutic efficacy of this combinatorial strategy (Figure 5 A, B, C).

[0378] During necropsy on Day 28, spleen was harvested and weighted. The double isotype IgG control group showed a significant increase in spleen weight similar to the anti-CD127 monotherapy. Administration of anti-p40 IgG was associated with a significant reduction in mean spleen weight (p < 0.05) and more importantly T cell / Anti- CD127 IgG + anti-p40 IgG group demonstrated the highest difference with a mean spleen weight of (48.5 ± 7.2) mg and significantly different than anti IL-7R monotherapy and Isotype controls (Figure 5D)

[0379] Histopathology:

[0380] T cell-recipient mice developed a colitis characterized by epithelial hyperplasia, goblet cell depletion and infiltration of inflammatory cells into the mucosa and sub-mucosa; other signs of active inflammation such as crypt abscesses, crypt loss and ulceration. The histopathology observations were used to calculate a colitis seventy score for the large bowel as a whole (total score, all regions), but also independently with regional scores for proximal, mid and distal large bowel (Figure 6 to 12). The control group (T cell / rat lgG2a + rat lgG2aK) had a mean colitis seventy score of 5.74 ± 1 .05 while non colitis negative control mice had a score around 0 (Figure 6). Administration of anti-CD127 + anti-p40 IgG showed statistically significant reduction in the colitis severity score for the large bowel in all regions compared to monotherapies anti-CD127 or anti p40 alone (p<0.001 or p=0.0007 respectively). An overall colitis seventy score as low as 0.66 ± 0.49 was obtained for Anti IL-7R + Anti IL-12 / 23 group (Figure 6). For monotherapies anti-IL-12 / 23 (anti-p40 IgG) group and the T cell / Anti-IL-7R IgG had colitis seventy scores (for the large bowel as whole) of 2.08 ± 0.79 and 5.16 ± 1 .55, respectively. Importantly the severity score (Total score) of the combinatorial strategy was similar to noncolitis mice, confirming on histopathology the strong therapeutic effect of combination therapy to higher extend than monotherapies that had partial therapeutic effect (Figure 6). Complete abrogation of colitis seventy score was observed in proximal and distal regions in the combination therapy group similar to mice without colitis (Figure 7 & 9). A significant difference in Mid region of combination versus each monotherapy was also observed (Figure 8). The reduction in overall colitis severity in the T cell / Anti- CD127 IgG + anti-p40 IgG group was significantly better than that observed in the groups that received just one therapeutic antibody (in combination with the appropriate isotype control), in addition to the double isotype control group (p < 0.0007).

[0381] Additionally, Anti -CD127 + Anti IL-23 / IL-12 combinatorial strategy demonstrated significant superior therapeutic efficacy on Area component score (Figure 10), Hyperplasia component score (Figure 11) and Infiltration component score (Figure 12) compared to monotherapies anti -CD127 or anti IL-12 / 23 (i.e. anti- p40) separately. These scores are key to define degree of inflammation in the colon. As shown on Figure 10, 11 & 12, Anti -CD127 and anti p40 had similar score as negative control mice demonstrating once again maximal efficacy of the strategies for the treatment of colitis on this mouse experiment.

[0382] Conclusion:

[0383] T cell-recipient mice developed a colitis characterized by the development of diarrhoea and body weight loss I reduced body weight gain. Post-mortem examination revealed an increase in large bowel weight: length ratio, with microscopic examination of H&E-stained large bowel cross-sections showing epithelial hyperplasia and inflammatory cell infiltration into the mucosa in isotype control groups confirming development a colitis in mice.

[0384] Administration of antagonist anti-IL-12 / 23 (i.e. anti-p40) IgG, in combination with antagonist Anti-CD127 antibody IgG, was associated with high reduction of inflammatory colitis associated significant reduction in measured colitis symptoms and all histopathological endpoints. A synergistic efficacy of the combinatorial strategy is observed when an antagonist anti IL-23 and / or IL-12 antibody with antagonist anti-CD127 antibody are administrated in a combination treatment, while each single treatment was not able to have such therapeutic effect of reducing colitis.

[0385] Functional assay with anti-human IL7Ra (anti-CD127) antibody and anti-human anti-IL23 antibody:

[0386] CD4 T cells from healthy donors were isolated with magnetic isolation kit (Miltenyi, reference 130-096-533). For stimulation, CD4 T cells were added at 100000 cells / well in P96-well plates coated with 2,5pg / ml of anti-CD3 (OKT3, Ose Immunotherapeutics) and incubated with 1 or 10pg / ml of different anti-human CD127 antibodies (“anti-hlL7R” from 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), Bempikibart anti-human CD127 antibody (Q32Bio, distributed by Proteogenix reference PX-TA2052), PF-06342674 anti-human CD127 antibody (Pfizer, distributed by Clinisciences reference orb1818090), N13B2-h3 anti-human CD127 antibody (Ose Immunotherapeutics (VH / VL-SEQ ID NO: 7 and 8)), bispecific anti-human CD127 x anti-hp19 antibody (SEQ ID: NO: 53-56) or / and anti-human IL23p19 (Guselkumab, Selleckchem reference A2438). CD4 T cells were stimulated with human IL7 at 5ng / ml (Miltenyi reference 130-095-367), human IL23 at 50ng / ml (Miltenyi reference 130-095-758) plus human IL1 b at 20ng / ml (Miltenyi, reference 130-095-374) in IMDM complete medium. Supernatant were collected after 7days at 37°C to measure IL17 or IFNg secretion (Biotechne reference DY317).

[0387] As illustrated on Figure 13, the results revealed that monotherapy with the antihuman p19 antibody effectively inhibited IL-17 secretion by CD4+ T cells. Similarly, monotherapy with the anti-human IL-7R antibody achieved comparable levels of inhibition of IL-17 secretion. Notably, the combination of anti-IL-7R and anti-p19 antibodies demonstrated a synergistic effect, producing significantly greater inhibition of IL-17 secretion compared to either antibody used alone.

[0388] These findings confirm the superior efficacy of combining an anti-human CD127 antibody with an anti-human IL-23 antibody in suppressing IL-17 secretion, thereby reducing inflammation driven by pathogenic Th17 cells. This combination therapy represents a promising strategy for the treatment of inflammatory diseases.

[0389] Then, the inhibition of IFNg secretion by CD4+ T-cells was evaluated.

[0390] As shown in Figure 14 (left panel), monotherapy with the anti-human p19 antibody was found to effectively inhibit IFNg secretion by CD4+ T cells. Similarly, monotherapy with the anti-human CD127 antibody achieved comparable levels of IFNg secretion inhibition. Notably, combining anti-CD127 and anti-p19 antibodies produced a significantly greater inhibitory effect on IFNg secretion than either antibody used alone.

[0391] These findings confirm the superior efficacy of combining an anti-human CD127 antibody with an anti-human IL-23 antibody to suppress IFNg secretion, and reduce inflammation driven by pathogenic Th1 cells.

[0392] The superiority of this combination has been demonstrated using several different anti-human CD127 antibodies, showing that this effect is not specific to a single antibody.

[0393] The combination of the Bempikibart anti-human CD127 antibody (Q32Bio) and anti-p19 antibody (Figure 14, right panel), the PF-06342674 anti-human CD127 (Pfizer) antibody and anti-p19 antibody or the N13B2-h3 anti-human CD127 antibody (OSE immunotherapeutics) and anti-p19 antibody (Figure 15) demonstrated a synergistic effect. All these combinations produced significantly greater inhibition of IFNg secretion than either antibody used alone. These results confirm that the synergistic efficacy of combining an anti-human CD127 antibody with an IL-23 antagonist is not specific to a single antibody.

[0394] The inventors have constructed a bispecific antibody that targets human p19 and human IL-7Ra (anti-human CD127) (SEQ ID No: 53, 54, 55 and 56). A CD4 activation assay was performed in the presence of human IL7, human IL23 and human IL1 b under the same experimental conditions described above.

[0395] The bispecific anti-CD127 x anti-p19 antibody demonstrated a synergistic effect, producing significantly greater inhibition of IFNg secretion than either antibody used alone (Figure 16).

Claims

1. CLAIMS1. A combination comprising: a. a first compound that is an antagonist of IL-7 or CD127 and that is an anti-IL7 or CD127 antibody or antigen-binding fragment thereof; and b. a second compound that is an antagonist of IL-12 and / or IL-23, or IL-12R and / or IL-23R; for use in the treatment of an inflammatory disease or an auto-immune disease.

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

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

4. A first compound that is an antagonist of CD127 and that is an anti-CD127 antibody or antigen-binding fragment thereof, for use in a combination regimen with a second compound that is an antagonist of IL-12 and / or IL- 23 or IL-12R and / or IL-23R, for the treatment of an inflammatory disease or an auto-immune disease.

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

6. The combination for use according to any one of claims 1 -3 or 5, or the first compound for use according to claim 4 or 5, wherein the first compound is an anti-CD127 antibody or antigen-binding fragment thereof that comprises a heavy chain comprising or consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 18.

7. The combination for use according to any one of claims 1 -3 or 5-6, or the first compound for use according to any one of claims 4 to 6, wherein the second compound inhibits or reduces the binding between IL-12 and its receptor IL-12R, and / or inhibits or reduces the binding between IL-23 and its receptor IL-23R.

8. The combination for use according to any one of claims 1 -3 or 5-7, or the first compound for use according to any one of claims 4 to 7, wherein the second compound is selected from the group consisting of:- an anti-IL-12 antibody, or an antigen-binding fragment thereof,- an anti-IL-23 antibody, or an antigen-binding fragment thereof,- an anti-IL-12R antibody or an antigen-binding fragment thereof, and- an anti-IL-23R antibody or an antigen-binding fragment thereof..

9. The combination for use according to any one of claims 1 -3 or 5-8, or the first compound for use according to any one of claims 4 to 8, wherein the second compound that is an antagonist of IL-12 and / or IL-23, or IL-12R and / or IL-23R, is selected from the list consisting of: Ebdarokimab, Ulsinumab, Ustekinumab, Ustekinumab-aekn (AVT-04), Ustekinumab- auub (Wezlana), Ustekinumab-hmny (BAT-2206), Ustekinumab-kfce (Bmab 1200), Ustekinumab-srlf (DMB-3115), Ustekinumab-aauz (FYB- 202), ustekinumab-ttwe (SB-17), Mirikizumab, Guselkumab, Tildrakizumab, Risankizumab, Picankibart, IL-23R, and Icotokinra (JNJ- 2113 or PN-235).

10. The combination for use according to any one of claims 1 -2 or 5-9, or the first compound for use according to any one of claims 4 to 9, wherein the second compound binds to, in particular specifically binds to, a sub-unit of IL-12, in particular the sub-unit p35 or the sub-unit p40, and / or to a subunit of IL-23, in particular the sub-unit p19 or the sub-unit p40.

11. The combination for use according to any one of claims 1 -3 or 5-10, or the first compound for use according to any one of claims 4 to 10, wherein the second compound binds to, in particular specifically binds to, the sub-unit p19 or the subunit p40 of IL-23, and wherein the second compound is an antibody, an antigen-binding fragment thereof, or an antigen-binding antibody mimetic thereof.

12. The combination for use according to any one of claims 1 -3 or 5-11 , or the first compound for use according to any one of claims 4 to 11 , wherein: a. the first compound is an antagonist anti-CD127 antibody or antigenbinding fragment thereof, preferably a monoclonal antibody, and b. the second compound is an antagonist anti-p19 antibody or an antagonist anti-p40 antibody or antigen-binding fragment thereof, preferably a monoclonal antibody.13.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 IL-7 or CD127 which inhibits the binding between IL-7 and CD127 and the second antigen being IL-12, IL-23, IL-12R or IL23- R, in particular the subunit p40 or the subunit p19 of IL23, which inhibits the binding between IL-12 and IL-12R and / or between IL-23 and IL-23R.

14. The bifunctional antibody or antigen binding fragment thereof according to claim 13 comprising a first binding moiety that binds to 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 , and b. HCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 2; and c. HCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 3; and- a light chain variable fragment (VL) comprising: a. LCDR1 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 4, and b. LCDR2 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 5; and c. LCDR3 comprising or consisting in the amino acid sequence set forth in SEQ ID No: 6; in particular wherein the heavy chain variable fragment comprises or consists in the amino acid sequence set forth in SEQ ID No. 7, and thelight 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.

15. The bifunctional antibody or antigen binding fragment thereof according to claim 13 or 14, wherein the first compound is an anti-CD127 antibody or antigen-binding fragment thereof that comprises a heavy chain comprising or consisting in the amino acid sequence set forth in SEQ ID No: 13, and a light chain comprising or consisting in the amino acid sequence set forth in SEQ ID No. 18.

16. The bifunctional antibody or an antigen-binding fragment thereof according to any one of claims 13 to 15 comprising a first chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 53, a second chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 54, a third chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 55 and a fourth chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 56.

17. The bifunctional antibody or antigen-binding fragment thereof according to any one of claims 13 to 16, for use in the treatment of an inflammatory disease or an auto-immune disease.

18. The combination for use according to any one of claims 1 -3 or 5-12, or the first compound for use according to any one of claims 4 to 12, or the bifunctional antibody or antigen-binding fragment thereof for use according to claim 17, 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.

19. The combination for use according to any one of claims 1 -3 or 5-12, or the first compound for use according to any one of claims 4 to 12, or the bifunctional antibody or antigen-binding fragment thereof for use according to claim 17, wherein the auto-immune disease is selected from the group consisting of systemic sclerosis, multiple sclerosis, type I diabetes, type II diabetes, autoimmune thyroiditis and systemic lupus erythematosus.

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

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

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

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