CD74 protein inhibitor compound and uses thereof

Abstract

The present invention relates to an inhibitor of CD74 protein activity or expression, for the therapeutic use thereof in the prevention and / or treatment of chronic inflammatory diseases including: chronic inflammatory rheumatisms, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases. In another embodiment, the invention relates to an isolated anti-CD74 antibody or fragment thereof, comprising six CDRs having the sequences SEQ ID NO. 3, 4, 5, 11, 12, and 13.

Description

[0001]DESCRIPTION OF THE CD74 PROTEIN INHIBITOR COMPOUND AND ITS USES. FIELD OF THE INVENTION: The present invention relates to the pharmaceutical field, and more particularly to the field of inflammatory diseases, especially chronic inflammatory diseases. STATE OF THE ART: Interleukin 17 (IL-17) is a pro-inflammatory cytokine primarily secreted by Th17 lymphocytes. IL-17 is implicated in a significant number of chronic inflammatory and / or autoimmune diseases: an excess of IL-17 has been observed in such pathologies. IL-17 represents an early initiator of inflammation and induces the secretion of numerous pro-inflammatory mediators by various cell types such as synoviocytes, skin fibroblasts, osteoblasts, macrophages, endothelial cells, and epithelial cells. By inducing the production of cytokines such as TNF, IFN-gamma and IL-1beta, IL-17 perpetuates and amplifies inflammation.Furthermore, IL-17 can act synergistically with these cytokines. For example, IL-17, in synergy with TNF, increases the survival of synoviocytes and contributes to their aggressive and invasive phenotype. IL-17 thus contributes to inflammation through various mechanisms and participates in the chronicity of many inflammatory diseases (Benedetti & Miossec, 2017; Hot et al., 2012). This involvement of IL-17 in various chronic inflammatory pathologies makes it an interesting therapeutic target. Currently, several monoclonal antibodies have been developed to target the IL-17 pathway and are used in different diseases, primarily in psoriasis. For example, Secukinumab and Ixekizumab are two monoclonal antibodies directed against IL-17A, approved by regulatory authorities for the treatment of psoriasis and ankylosing spondylitis (AS). and also for the treatment of psoriatic arthritis (PsA) in the case of Secukinumab.Bimekizumab is a monoclonal antibody directed against IL-17A and IL-17F, used in the treatment of psoriasis. Brodalumab is a monoclonal antibody directed against the IL-17RA subunit of the IL-17 receptor, which has been approved by regulatory authorities for use in the treatment of psoriasis. The importance of cell-to-cell interactions in the local production and function of IL-17 has recently been highlighted (Noack & Miossec, 2021). During chronic inflammation, immune cells migrate to the site of inflammation and interact with local stromal cells, which are "support" cells for lymphocytes and macrophages. These interactions, combined with cell activation, induce a high production of IL-17. Since cell-to-cell contact is fundamental, the molecules involved in these cell-to-cell interactions have been studied in greater detail.Surprisingly and unexpectedly, the inventors highlighted the role of the CD74 protein in the signaling pathway that induces IL-17 secretion at the site of inflammation. The CD74 protein is the gamma invariant chain of MHC II (major histocompatibility complex class II), encoded by the CD74 gene in humans. This protein enables the formation, maturation, and transport of MHC II during its formation in antigen-presenting cells. CD74 is a membrane protein expressed by B cells, monocytes, macrophages, and certain lymphocytes. Different variant forms exist, derived from the same gene through alternative splicing. The CD74 protein is also part of the MIF (macrophage migration inhibitory factor) receptor complex. The CD74 protein has a wide range of biological functions.In particular, the CD74 protein is a therapeutic target currently being studied in the context of various diseases. Patent application EP 2198 879 discloses the role of CD74 in dendritic cell migration: CD74 inhibition would increase the mobility of these cells. Overexpression of CD74 has been observed in cancer and certain autoimmune diseases, as presented in the review by Borghese & Clanchy (2011). In the treatment of these pathologies, the beneficial effect of administering antibodies directed against CD74 has been demonstrated. Numerous types of anti-CD74 antibodies exist, as presented in international application WO 2016 / 014434. For example, Milatuzumab (hLL1), a humanized monoclonal anti-CD74 antibody, has been clinically tested for the treatment of multiple myeloma, but has not yet been ultimately approved.International patent application WO 2013 / 012894 suggests the use of this antibody to treat autoimmune diseases such as ulcerative colitis and psoriasis. CD74 is currently being studied as a therapeutic target for the treatment of autoimmune diseases. US patent 10,322,176 describes the use of humanized anti-CD74 antibodies for the treatment of systemic lupus erythematosus (SLE), a rare autoimmune disease with a genetic predisposition. Applications WO 2012 / 104344 and WO 2022 / 087719 suggest that anti-CD74 antibodies could be used in the treatment of ankylosing spondylitis, an autoimmune disease, without however linking it to a state of chronic inflammation or the IL-17 signaling pathway. The CD74 protein would also play a role in the control of inflammation of the nervous system following an injury (Su et al., 2017a) as well as in diseases such as liver fibrosis, diabetes, and Alzheimer's disease (Su et al., 2017b). DESCRIPTION OF THE INVENTION This application describes, for the first time, the role played by the CD74 protein in chronic inflammatory diseases. This application relates to an inhibitor of the activity or expression of the CD74 protein, for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease. This chronic inflammatory disease is specifically chosen from: chronic inflammatory rheumatic diseases, chronic inflammatory dermatoses, chronic inflammatory bowel diseases, and chronic inflammatory neurological diseases.This application also relates to a method for quantifying immune cells and / or stromal cells expressing the CD74 protein on their surface, said cells being obtained from a biological sample of a patient, comprising a step of determining the level of cells expressing the CD74 protein, particularly using an anti-CD74 antibody. In another aspect, this application relates to a method for diagnosing a chronic inflammatory disease affecting a patient, and / or for determining the severity of said disease, comprising the quantification of immune cells and / or stromal cells expressing the CD74 protein on their surface according to the method described above, in which the level obtained is compared to a reference level.According to another aspect, the present application relates to a biomarker of the presence and / or severity of a chronic inflammatory disease, consisting of the expression level on the surface of immune and / or stromal cells of the CD74 protein, said cells being obtained from a biological sample of a patient. According to a final aspect, the present application relates to an anti-CD74 antibody isolated or fragment thereof, comprising: - a variable heavy chain comprising, in the N-terminal to C-terminal direction: o CDR1 of sequence SEQ ID NO.11; o CDR2 of sequence SEQ ID NO.1 or 12, preferably SEQ ID NO.12; eto the CDR3 of sequence SEQ ID NO.2 or 13, preferably SEQ ID NO.13 ;- and a variable light chain comprising, in the N-terminal to C-terminal direction:o the CDR1 of sequence SEQ ID NO.3 ;o the CDR2 of sequence SEQ ID NO.4 ; eto the CDR3 of sequence SEQ ID NO.5.DESCRIPTION OF FIGURES Figure 1 shows the selection, from among 15 antibodies (8314, 8288, 8321, 8305, 8332, 8349, 8328, 8358, 8350, 8340, 8353, 8301, 8296, 8335 and 8290), of those of particular interest (boxed) in the context of identifying potential molecular targets for the therapy of chronic inflammatory diseases. 1A- Percentage of inhibition of IL-17 secretion in a cell co-culture system, in the presence of a concentration of 0.1, 1 or 10 µg / ml of the tested antibody (the color code of the concentrations used is indicated on the right) 1B- Percentage of inhibition of IL-6 secretion in a cell co-culture system in the presence of a concentration of 0.1, 1 or 10 µg / ml of the antibody tested (the color code of the concentrations used is indicated on the right)1C- Labeling of synoviocytes, stimulated (in grey) or not (in black, "control") with a mixture of IL-17 (50ng / ml) and TNF (1ng / ml).After culture, the synoviocytes are incubated with the 15 pre-selected antibodies and then with a secondary antibody coupled to FITC (fluorescein isothiocyanate) for analysis by flow cytometry. Figure 2 shows the percentage of inhibition of cytokine production in a co-culture of immune and stromal cells, in the presence of a commercial anti-CD74 antibody or the previously selected antibody 8350. 2A- Percentage of inhibition of IL-17 secretion 2B- Percentage of inhibition of interferon gamma secretion 2C- Percentage of inhibition of IL-10 secretion Figure 3 shows sequence alignments. 3A- Heavy chain of the isolated anti-CD74 antibody (in black, SEQ ID NO. 6) aligned with a reference sequence ID: 2J88_H designated “Ref” (in gray, SEQ ID NO. 8). CDRs are indicated in bold. 3B- Light chain of isolated anti-CD74 antibody (in black, SEQ ID NO. 7) aligned with a reference sequence ID: AAO60121.1 designated “Ref” (in gray, SEQ ID NO. 9). CDRs are indicated in bold. 3C- Heavy chain of the isolated anti-CD74 antibody (in black, SEQ ID NO. 10) aligned with a reference sequence ID: 2J88_H designated “Ref” (in gray, SEQ ID NO. 14); and aligned with a reference sequence “IGHV8-4-7*01” designated “Ref” (in gray, SEQ ID NO. 15); The identified CDRs are indicated in bold. DETAILED DESCRIPTION The present invention relates to the identification of compounds having a role in the prevention and / or treatment of a chronic inflammatory disease. These compounds have the particularity of inhibiting the activity or expression of the CD74 protein. This membrane protein is expressed by B cells, monocytes, macrophages, as well as by certain lymphocytes.The CD74 protein has been identified as a therapeutic target for the treatment of various diseases, but its involvement in chronic inflammatory diseases and IL-17 secretion had never been suggested. The invention also relates to a method for diagnosing a chronic inflammatory disease affecting a patient, and / or determining its severity, comprising the quantification of immune and / or stromal cells expressing the CD74 protein on their surface, said cells being obtained from a biological sample of said patient, in which the measured CD74 level is compared to a reference level.Finally, the present invention relates to a newly identified anti-CD74 antibody, having the property of inhibiting the activity of the CD74 protein, and allowing the quantification of the CD74 protein expression level in an individual's tissues. This antibody can therefore be used in the two prevention / treatment and diagnostic methods mentioned above. Inhibitor of the activity or expression of the CD74 protein, for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease. The present invention relates to an inhibitor of the activity or expression of the CD74 protein, for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease.This chronic inflammatory disease is specifically chosen from among: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases, and chronic inflammatory neurological diseases. The following definitions are given to facilitate understanding of the invention. The present invention relates to the pharmaceutical field and more particularly to compounds adapted to prevent and / or treat a disease affecting an individual, a subject, or a patient, these three terms being used interchangeably in this application, and designating a human being (i) susceptible to developing said disease or (ii) suffering from said disease, as can be established based on a particular clinical picture by a person skilled in the art. Inflammation, or the inflammatory response, is a natural process that occurs when the body is subjected to an attack: chemical, toxic, microbial, or traumatic.Inflammation is an essential bodily response for survival, enabling the elimination of pathogens and the repair of damage. Inflammation is a generic response, not specific to any particular external stimulus. For the purposes of this invention, an inflammatory reaction refers to the body's response to tissue injury. The inflammatory process is characterized by redness, swelling, increased temperature, and pain. At the tissue level, immune system cells secrete cytokines that cause, among other things, vasodilation, thus allowing the influx of other immune cells to the site of inflammation. Under certain conditions, an inflammatory reaction can occur in the absence of an external factor, or persist after the elimination of an external source of inflammation.The inflammation then enters an abnormal phase lasting several weeks, several years, and can last a lifetime: it is referred to as "chronic inflammation" when it persists over time, escaping the control of the immune system. Conversely, acute inflammation resolves as soon as the lesion is controlled / repaired. For the purposes of this invention, a "chronic inflammatory disease" refers to a disease characterized by the inflammatory reaction of a tissue in the absence of external factors that generate this inflammation. Millions of people suffer from chronic inflammatory diseases. These diseases can develop at any age and regardless of the patient's ethnic or geographic origin. Chronic inflammatory diseases can affect most organs and tissues of the human body, particularly the joints, the epidermis, the digestive system, and the nervous system.More specifically, the present invention relates to chronic inflammatory diseases characterized by a high secretion of IL-17 at the site of inflammation. In particular, the present invention relates to the following diseases: a) chronic inflammatory rheumatic diseases, characterized by chronic inflammation of the joints. Chronic inflammatory rheumatic diseases most often affect the joints of the hands, wrists, and knees. The main chronic inflammatory rheumatic diseases are rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis. Rheumatoid arthritis manifests as painful flare-ups and swelling of the joints, which are progressively destroyed. Spondyloarthritis, also known as spondylarthritis, is a group of diseases responsible for debilitating pain in the lumbar region and pelvis. The disease often develops in young adults, between the ages of 16 and 30.The disease eventually leads to degeneration of the affected joints and ossification of the spine. Psoriatic arthritis is a type of spondyloarthritis. The joints most frequently involved are the hips, knees, fingers, and toes. Tendons and ligaments can also become inflamed. Psoriatic arthritis is observed in approximately 30% of individuals with psoriasis. According to a preferred embodiment of the invention, the present invention relates to the following chronic inflammatory diseases: rheumatoid arthritis and psoriatic arthritis, particularly rheumatoid arthritis. b) Chronic inflammatory dermatoses, characterized by chronic inflammation of the skin and / or mucous membranes. Also known as chronic inflammatory skin diseases, these diseases present in many forms. Among the most common are psoriasis, atopic dermatitis, and hidradenitis suppurativa (HS).Psoriasis is a disease characterized by well-defined, raised, red plaques covered with whitish scales or a thin, silvery film that flakes off easily. It is estimated that 2% of the French population suffers from psoriasis. Atopic dermatitis, also called atopic eczema, primarily develops in infants and children, but can persist or appear in adolescents and adults. It is characterized by dry skin associated with eczema-like lesions (redness and itching, blisters, oozing, and crusting) that occur in flare-ups. Approximately one in ten children suffers from atopic dermatitis. Hidradenitis suppurativa (HS), also known as Verneuil's disease, is characterized by significant pain that significantly impacts the mobility of those affected. According to a preferred embodiment of the invention, the present invention relates to the following chronic inflammatory diseases: atopic dermatitis and HS.c) Inflammatory Bowel Diseases (IBD) Inflammatory bowel diseases, also known as IBD, are characterized by inflammation of the lining of a portion of the intestine due to a dysregulation of the intestinal immune system. They include Crohn's disease and ulcerative colitis (UC). Crohn's disease can affect any part of the digestive tract but is most often located at the end of the small intestine (ileum) and the beginning of the colon. The most common symptoms are persistent diarrhea, rectal bleeding, urgency, and abdominal cramps and pain. Ulcerative colitis is characterized by inflammation of the lower part of the rectum that extends, to varying degrees, into the colon. The disease causes the formation of small sores in the colon, which lead to abdominal pain.According to a preferred embodiment of the invention, the present invention relates to Crohn's disease. d) Chronic inflammatory neurological diseases, characterized by chronic inflammation of the nerves and / or the brain. The chronic form of inflammatory nerve involvement is called chronic inflammatory polyradiculoneuropathy (CIDP). This disease causes deficits in strength and sensation that can be very severe and even fatal. Inflammatory brain diseases are diverse in terms of the tissues affected: they can affect the white matter, as in multiple sclerosis, neuromyelitis optica, or rhombencephalitis, but also both white and gray matter, or gray matter only, as is the case for autoimmune encephalitis, systemic diseases with neurological involvement, or vasculitis.All these chronic inflammatory diseases are characterized by a significant presence of IL-17 at the site of inflammation. For the purposes of this invention, the term "chronic inflammatory diseases" specifically excludes diseases such as systemic lupus erythematosus (SLE), as well as cancers. In a preferred embodiment, the chronic inflammatory disease considered is chosen from one of the following: rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, psoriasis, and atopic dermatitis. In another preferred embodiment, the chronic inflammatory disease considered is chosen from one of the following: rheumatoid arthritis and atopic dermatitis. The present invention relates more particularly to an inhibitor of the activity or expression of the CD74 protein, for its therapeutic use in the prevention and / or treatment of rheumatoid arthritis.For the purposes of this invention, the term "treatment" or "to treat" refers to an improvement in the patient's disease that can be observed clinically, histologically, and / or biochemically. The terms "treatment" or "to treat" include, but are not limited to, the improvement of a symptom or clinical, histological, and / or biochemical parameter associated with the patient's disease, or the inhibition, reduction, or delay of the progression or exacerbation of the patient's disease (including secondary damage caused by the disease) to a statistically significant degree or to a degree detectable by a person of the art. In some embodiments, the treatment is evaluated on a population basis, such that a therapy is considered to "treat" a particular disease if a statistically significant improvement in the patient's disease is observed in a population suffering from the disease in question.For the purposes of this invention, the term "prevention" or "prevent" refers to reducing the risk of an individual acquiring or developing a given disease. The terms "prevent" and "prevention" also include delaying the onset and / or reducing the frequency and / or severity of symptoms or clinical, histological, and / or biochemical parameters associated with that disease.In some embodiments, prevention is assessed on a population basis, so that a therapy is considered to "prevent" a particular disease if a statistically significant decrease in the risk of acquiring or developing the disease, and / or a statistically significant delay in the onset and / or a statistically significant decrease in the frequency and / or intensity of symptoms or clinical, histological and / or biochemical parameters associated with the disease is observed in a population likely to contract the disease in question.Inhibition of CD74 Protein Activity According to a first aspect, the invention relates to an inhibitor of CD74 protein activity, for therapeutic use in the prevention and / or treatment of a chronic inflammatory disease, in particular selected from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases. For the purposes of the invention, an "inhibitor of CD74 protein activity" means a compound that binds to the CD74 protein and prevents its biological activity, either by competing with the physiological ligand(s) of said protein; or by generating an inactive configuration of said protein; or by inhibiting its cellular transport; or by inhibiting its function according to any other molecular mechanism.The inhibition of this activity may be quantified using technologies well known to the person skilled in the art. In the case of the CD74 protein, known to act on the secretion of certain cytokines by immune and / or stromal cells, the expected effects of CD74 on the secretion of IL-17, IL-10, and / or interferon-gamma (IFN-gamma) may be quantified by ELISA in the culture medium of said cells. This inhibitor of CD74 activity may be of any molecular nature, and in particular may be chosen from a protein, peptide, nucleic acid, oligonucleotide (including an aptamer), or any chemical compound exhibiting the function of inhibiting CD74 protein activity, as may be determined by the person skilled in the art, in particular using the measurement technique mentioned above and illustrated in the examples in the application.According to one embodiment of the invention, the inhibitor of CD74 activity for its therapeutic use described above is an antibody directed against the CD74 protein or a fragment thereof. "Antibody" means a protein comprising at least one antigen-binding domain (here, the CD74 protein) and thus binding to said protein, and a constant domain comprising an Fc fragment capable of binding to Fc receptors (FcR). The term "antibody" is used herein in its broadest sense and includes monoclonal antibodies of any isotype such as IgG, IgM, IgA, IgD, and IgE, polyclonal antibodies, multispecific antibodies, chimeric, humanized, and human antibodies. The expressions "antibody directed against the CD74 protein," "anti-CD74 antibody," and "CD74-binding antibody" are used interchangeably in this application.They all refer to an antibody that binds to CD74 with a specific affinity greater than that of any other antigen, as can be determined by experimental techniques such as radioimmunoassays (RIAs) and enzyme-linked immunosorbent assays (ELISAs). Typically, such specific binding is at least twice the background level and can be more than ten times the background level. An "antibody fragment" is understood to be a portion of an anti-CD74 antibody capable of binding to the CD74 protein and thus inhibiting its activity. Such a fragment may consist of an assembly of several chains, as is the case for the whole antibody. Each chain of the fragment may be at least 5 contiguous amino acids long, preferably 7, 10, 15, 20, 25, 30, or more amino acids.According to a particular embodiment of the invention, the inhibitor of CD74 protein activity for its therapeutic use described above is a monoclonal antibody, and more particularly a humanized monoclonal antibody. For the purposes of the invention, a humanized antibody means an antibody derived from a non-human species (here, mouse) whose protein sequences have been modified to more closely resemble those of antibodies produced naturally in humans. This modification reduces their immunogenicity when administered to human patients, while preserving their ability to specifically recognize the target protein CD74. A "humanized" antibody may, in particular, mean an antibody that contains CDR regions derived from a non-human antibody (here, mouse), with the other parts of the antibody molecule being derived from one (or more) human antibodies.Furthermore, some of the residues of the skeletal segments (referred to as FRs) can be modified to maintain binding affinity (Jones et al., 1986; Verhoeyen et al., 1988; Riechmann et al., 1988). The humanized antibodies according to the invention can be prepared by techniques known to those skilled in the art, such as CDR grafting, resurfacing, superhumanization, human string content, FR libraries, guided selection, FR shuffling, and humaneering, as summarized in the review by Almagro et al., 2008. For the purposes of the invention, the term "monoclonal antibody" refers to an antibody derived from a quasi-homogeneous antibody population, in which the population comprises antibodies that are identical except for a few possible naturally occurring mutations that may be found in minimal proportions.A monoclonal antibody results from the growth of a single cell clone, such as a hybridoma, and is characterized by heavy chains of one class and subclass, and light chains of a single type. A monoclonal antibody binds specifically to a single antigenic site (i.e., a single epitope) when the antigen is presented to it. The monoclonal antibody can be produced by various methods well known to the person of art. For the purposes of the invention, a "humanized monoclonal antibody" means an antibody that contains: - variable domains, responsible for binding to the antigen, derived from an antibody of non-human origin, in particular from mice, and - constant domains, derived from one or more human antibodies. Advantageously, such a humanized antibody can be used in human therapy without generating immunological reactions due to the non-human origin of the variable domains.The humanized antibodies according to the invention can be prepared by techniques well known to those skilled in the art, as described above. In most mammals, such as humans and mice, an antibody consists of four polypeptide chains: two heavy chains and two light chains linked together by a variable number of disulfide bonds. Each light chain consists of a constant domain (CL) and a variable domain (VL); the heavy chains consist of a variable domain (VH) and three or four constant domains (CH1 to CH3 or CH1 to CH4) depending on the antibody isotype. The variable domains are involved in antigen recognition, while the constant domains are involved in the biological, pharmacokinetic, and effector properties of the antibody.Constant domains are characterized by a very similar amino acid sequence from one antibody to another, typical of the species and isotype, with possibly some somatic mutations. The Fc fragment naturally consists of the constant region of the heavy chain, excluding the CH1 domain; that is, the lower hinge region and the constant domains CH2 and CH3, or CH2 to CH4 (depending on the isotype). The variable region differs from one antibody to another. Indeed, the genes encoding the heavy and light chains of antibodies are generated, respectively, by the recombination of three and two distinct gene segments called VH, DH, and JH-CH for the heavy chain, and VL and JL-CL for the light chain. The CH and CL segments do not participate in recombination and form the constant regions of the heavy and light chains, respectively.The recombination of the VH-DH-JH and VL-JL segments forms the variable regions of the heavy and light chains, respectively. The VH and VL regions each possess three hypervariable areas, or complementarity-determining regions (CDRs), called CDR1, CDR2, and CDR3, with CDR3 being the most variable as it is located in the recombination zone. These three CDRs, and particularly CDR3, are found in the portion of the antibody that will interact with the antigen and are therefore important for antigen recognition. CDR1, CDR2, and CDR3 are each preceded by FR1, FR2, and FR3, respectively, corresponding to the frame regions (FRs) that vary the least from one VH or VL segment to another. CDR3 is also followed by a frame region, FR4. Various methods for determining CDRs have been proposed, and the portion of the amino acid sequence in the variable region of a heavy or light chain of an antibody defined as the CDR varies depending on the method chosen.The first method of determination is that proposed by Kabat et al. (Kabat et al., 1991). In this method, CDRs are defined by identifying the amino acids responsible for antibody-antigen binding. A second method was proposed by IMGT, based on the determination of hypervariable regions. In this method, a unique numbering system was defined to compare variable regions independently of the antigen receptor, chain type, or species (Lefranc et al., 2003). This numbering provides a standardized definition of the frame regions ((FR1-IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the regions determining complementarity (CDR1-IMGT: positions 27 to 38, CDR2-IMGT: positions 56 to 65 and CDR3-IMGT: positions 105 to 117).Finally, there is also a so-called "common" numbering system in which the sequence of a particular CDR corresponds to the common sequence between the Kabat numbering and the IMGT numbering. In this description, the CDRs were determined according to the IMGT method implemented by the IGBLAST software provided on the NIH website, based on a comparison of: - the sequence SEQ ID NO. 6 with the reference sequence SEQ ID NO. 8, - the sequence SEQ ID NO. 7 with the reference sequence SEQ ID NO. 9, and - the sequence SEQ ID NO. 10 with the reference sequences SEQ ID NO. 14 and 15. The alignments of these sequences are shown in Figure 3. The identified CDRs have the following sequences, presented in Table 1 below. Table 1. CDR Sequences CDR2 chain SEQ ID NO. 17 aa GMGLSWIlourde CDR3 chain SEQ ID NO. 2. 3 aa NQVHeavy CDR1 chain SEQ ID NO. 35 aa QSISD Light CDR2 chain SEQ ID NO. 412 aa PRLLIKYASQSI Light CDR3 chain SEQ ID NO. 56 aa GHSFPY Light SEQ ID NO. CDR1 chain 10 GFLSTSGMG11 Heavy SEQ ID NO. CDR2 chain 7 IYWDDDK12 heavy SEQ ID NO. CDR3 chain 11 ARRDFYGGLDY13 heavy According to a particular embodiment of the invention, the inhibitor of CD74 protein activity for its therapeutic use as described above is an antibody or antibody fragment characterized in that it comprises at least one CDR having a sequence selected from SEQ ID NO. 1 to 5, or at least one CDR having a sequence selected from SEQ ID NO. 1 to 5 and 11 to 13. More particularly, said antibody or antibody fragment comprises: - a variable heavy chain (VH) comprising at least one CDR having a sequence selected from SEQ ID NO. 1 to 2, or from the sequences SEQ ID NO. 1, 2, 11, 12 and 13, and - a variable light chain (VL) comprising at least one CDR having a sequence selected from SEQ ID NO. 3 to 5. Preferably, said antibody or antibody fragment consists of at least two peptide sequences comprising, together, all the CDRs of SEQ ID NO. 1 to 5 sequences.More preferably, said antibody or antibody fragment consists of at least two peptide sequences comprising, together, the six CDRs of sequences SEQ ID NO. 3, 4, 5, 11, 12 and 13. According to a particular embodiment, said CDRs are ordered as follows: - the variable heavy chain comprises, in the N-terminal to C-terminal direction: o CDR1 of sequence SEQ ID NO. 11; o CDR2 of sequence SEQ ID NO. 1 or 12, preferably SEQ ID NO. 12; and o CDR3 of sequence SEQ ID NO. 2 or 13, preferably SEQ ID NO. 13; - the variable light chain comprises, in the N-terminal to C-terminal direction: o CDR1 of sequence SEQ ID NO. 3; o CDR2 of sequence SEQ ID NO. 4; eto the CDR3 of sequence SEQ ID NO.5. According to one embodiment of the invention, said antibody comprises:- a variable heavy chain (VH) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of the sequence SEQ ID NO.6 or 10 and 100% identity with the CDR regions of SEQ ID sequences NO. 1 to 2 or 11 to 13, and - a variable light chain (VL) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of SEQ ID sequence NO. 7 and 100% identity with the CDR regions of SEQ ID sequences NO. 3 to 5. According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with SEQ ID sequence NO. 6 or 10, and - a variable light chain (VL) comprising a peptide sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity with the SEQ ID NO sequence. 7. According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence having 100% identity with the SEQ ID NO sequence.6 or 10, and - a variable light chain (VL) comprising a peptide sequence having 100% identity with the SEQ ID NO. 7 sequence. As is apparent from Figure 3C, the SEQ ID NO. 10 sequence comprises the SEQ ID NO. 6, and further comprises 19 amino acids in the N-terminus. Thus, according to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of the SEQ ID NO. 7 sequence. 10 and 100% identity with the CDR regions of SEQ ID NO.11 to 13 sequences, and - a variable light chain (VL) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of SEQ ID NO. 7 sequence and 100% identity with the CDR regions of SEQ ID NO. 3 to 5 sequences.According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity with the SEQ ID NO. 10 sequence, and - a variable light chain (VL) comprising a peptide sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity with the SEQ ID NO. 7 sequence. According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence having 100% identity with the SEQ ID NO. 10 sequence, and - a variable light chain (VL) comprising a peptide sequence having 100% identity with the SEQ ID NO. 10 sequence. 7. The invention relates particularly to an antibody or antibody fragment targeting the CD74 protein, comprising: - a variable heavy chain comprising, in the N-terminal to C-terminal direction: o the CDR1 of sequence SEQ ID NO.11 ;o the CDR2 of sequence SEQ ID NO.1 or 12, preferably SEQ ID NO.12; and CDR3 of sequence SEQ ID NO.2 or 13, preferably SEQ ID NO.13; - a variable light chain comprising, in the N-terminal to C-terminal direction: CDR1 of sequence SEQ ID NO.3; CDR2 of sequence SEQ ID NO.4; and CDR3 of sequence SEQ ID NO.5, for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease chosen from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.CD74 Expression Inhibitor. According to a second aspect, the present invention relates to an inhibitor of CD74 protein expression for therapeutic use in the prevention and / or treatment of a chronic inflammatory disease, specifically chosen from among: chronic inflammatory rheumatic diseases, chronic inflammatory dermatoses, chronic inflammatory bowel diseases, and chronic inflammatory neurological diseases. Indeed, inhibiting CD74 protein expression has the same physiological effects as inhibiting its activity. For the purposes of the invention, a "CD74 protein expression inhibitor" means a compound that totally or partially inhibits the expression of the CD74 protein in a cell. Such an inhibitory compound can act at the DNA level by blocking the transcription of the gene encoding messenger RNA; or at the messenger RNA level, by degrading it or preventing its translation into protein.Such compounds are well known to the person of art. The term "CD74 expression" refers particularly to the membrane expression of this protein, which is integrated into the cell membrane and performs its functions by interacting with extracellular factors. According to one embodiment of the invention, the CD74 expression inhibitor compound is an RNA that specifically blocks the translation of messenger RNA into protein. This may be any microRNA having this function, in particular a siRNA (silencing RNA) or a shRNA (small hairpin RNA). Pharmaceutical compositions: Whether it is a compound that inhibits CD74 activity or a compound that inhibits CD74 expression, it is understood that said compound will be administered to a subject or patient in the form of a pharmaceutical composition comprising an effective amount of said compound.For the purposes of this invention, the term "pharmaceutical composition" means a composition comprising at least one compound as described herein, or pharmaceutically acceptable salts thereof. The pharmaceutical composition may also include at least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient. For the purposes of this invention, the term "effective amount" means a sufficient quantity of the compound that inhibits CD74 activity or expression to induce an immune response with a reasonable benefit-risk ratio, applicable to the medical treatment of a patient or to preventive treatment in a subject. Preferably, said pharmaceutical composition comprises a humanized antibody as defined in this application. Thus, this humanized antibody is suitable for administration to humans.The present invention also relates to a method for the prevention and / or treatment of a chronic inflammatory disease, in particular selected from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases, comprising the administration to a subject likely to develop the disease, or to a patient affected by said disease, of an inhibitor of the activity or expression of the CD74 protein.Quantification Method. The present invention also relates to a method for quantifying immune cells and / or stromal cells expressing the CD74 protein on their surface, said cells being obtained from a biological sample of a patient, comprising a step of determining the proportion of cells expressing the CD74 protein using an anti-CD74 antibody, and in particular using an antibody as described in this application. Several techniques are available for quantifying cells expressing a given protein on their surface (i.e., having membrane expression of said protein). These techniques use an antibody specific to said protein, and include, in particular, immunohistochemistry and flow cytometry.According to one embodiment of the invention, the biological sample is that of a patient suffering from a chronic inflammatory disease, specifically chosen from among: chronic inflammatory rheumatic diseases, chronic inflammatory dermatoses, chronic inflammatory bowel diseases, and chronic inflammatory neurological diseases. Quantification may be performed on cultured cells obtained from a biological sample, or in situ on a tissue sample. In a particular embodiment, the biological sample is chosen from blood, serum, synovial fluid, or tissue biopsies. Advantageously, the quantification method is implemented on a biological sample derived from tissue subjected to chronic inflammation.The biological sample may be obtained by any technique well known to those skilled in the art; this sample acquisition step is not included in the quantification process. Diagnostic Method The present invention also relates to a method for diagnosing a chronic inflammatory disease affecting a patient and / or for determining the severity of said disease, comprising the quantification of immune and / or stromal cells expressing the CD74 protein on their surface according to the quantification process described above, in which the level obtained is compared to a reference level. In particular, said chronic inflammatory disease is selected from among: chronic inflammatory rheumatic diseases, chronic inflammatory dermatoses, chronic inflammatory bowel diseases, and chronic inflammatory neurological diseases.Quantifying the surface expression of CD74 protein in cells yields a "CD74 membrane expression level." In the diagnostic method of the invention, this expression level is then compared to a reference expression level. This reference level can be the mean or median of several values ​​determined from multiple samples obtained from a plurality of healthy subjects and / or patients with chronic inflammatory diseases of known nature and severity. According to one embodiment of the invention, the reference level represents the absence of a chronic inflammatory disease. Such a reference value is obtained using the quantification method described above, performed on biological samples obtained from healthy subjects without clinical signs of the chronic inflammatory disease in question.According to another embodiment of the invention, the reference value is representative of the presence of a chronic inflammatory disease. In these biological samples, the CD74 protein is quantified by implementing the method for quantifying the membrane expression of the CD74 protein by cells from a biological sample as described above, the biological samples being obtained from patients whose nature and severity of the chronic inflammatory disease in question are known. According to a specific embodiment of the invention, the membrane expression level of CD74 is compared to two reference values: a reference value representative of the presence of a chronic inflammatory disease, and a reference value representative of the absence of a chronic inflammatory disease.According to another embodiment of the invention, the reference value is a value called a "threshold" or "cut-off," which is determined from reference values ​​representative of the absence and presence of said diseases. This reference value is an arbitrary value, representing the "boundary" between the "healthy" and "disease" statuses. This "threshold" reference value can be readily determined by those skilled in the art using their general knowledge. According to another embodiment of the invention, the reference value is a threshold value representative of the severity of a chronic inflammatory disease. If the measured CD74 protein expression level is below this threshold value, the disease will be considered "mild"; if the measured CD74 protein expression level is above this threshold value, the disease will be considered "severe."The present invention also relates to a biomarker for the presence and / or severity of a chronic inflammatory disease, consisting of the expression level of the CD74 protein on the surface of immune and / or stromal cells, said cells being obtained from a biological sample of a patient. According to one embodiment of the invention, the value of said biomarker (i.e., the membrane expression level of the CD74 protein) will be compared to reference values ​​as described above, in order to obtain a diagnostic conclusion regarding the presence and / or severity of a chronic inflammatory disease. Isolated anti-CD74 antibody. The present invention also relates to an isolated anti-CD74 antibody or fragment thereof comprising at least one CDR having a sequence selected from SEQ ID NO. 1 to 5, or from SEQ ID NO. 3, 4, 5, 11, 12, and 13.In particular, this antibody or fragment thereof comprises at least two peptide sequences, including a CDR region of sequence SEQ ID NO. 1; and / or a CDR region of sequence SEQ ID NO. 2; and / or a CDR region of sequence SEQ ID NO. 3; and / or a CDR region of sequence SEQ ID NO. 4; and / or a CDR region of sequence SEQ ID NO. 5; and / or a CDR region of sequence SEQ ID NO. 11; and / or a CDR region of sequence SEQ ID NO. 12; and / or a CDR region of sequence SEQ ID NO. 13. According to a preferred embodiment, said antibody or antibody fragment comprises: - a variable heavy chain (VH) comprising at least one CDR having a sequence selected from SEQ ID NO. 1 to 2 and SEQ ID NO. 11 to 13, and - a variable light chain (VL) comprising at least one CDR having a sequence selected from SEQ ID NO. 1. 3 to 5. Preferably, said antibody or antibody fragment consists of at least two peptide sequences comprising, together, all the CDRs of SEQ ID NO. 1 to 5 sequences.More preferably, said antibody or antibody fragment comprises six CDRs having the sequences SEQ ID NO. 3, 4, 5, 11, 12 and 13, and preferably comprises: - a heavy chain comprising the 3 CDRs of sequence SEQ ID NO. 11, 12 and 13 and - a light chain comprising the 3 CDRs of sequence SEQ ID NO. 3, 4 and 5. According to a particular embodiment, said CDRs are ordered as follows: - the variable heavy chain comprises, in the N-terminal to C-terminal direction: o CDR1 of sequence SEQ ID NO. 11; o CDR2 of sequence SEQ ID NO. 1 or 12, preferably SEQ ID NO. 12; eto the CDR3 of sequence SEQ ID NO.2 or 13, preferably SEQ ID NO.13 ;- the variable light chain includes, in the N-terminal to C-terminal direction:o the CDR1 of sequence SEQ ID NO.3 ;o the CDR2 of sequence SEQ ID NO.4 ; eto the CDR3 of sequence SEQ ID NO.5.According to one embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of the SEQ ID NO. 6 or 10 sequence and 100% identity with the CDR regions of SEQ ID NO. 1 to 2 or 11 to 13 sequences, and - a variable light chain (VL) exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of the SEQ ID NO. 6 sequence. 7 and 100% identity with the CDR regions of SEQ ID NO.3 to 5 sequences. According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the SEQ ID NO.6 or 10 sequence, and - a variable light chain (VL) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the SEQ ID NO.7 sequence.According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence having 100% identity with the SEQ ID NO. 6 or 10 sequence, and - a variable light chain (VL) comprising a peptide sequence having 100% identity with the SEQ ID NO. 7 sequence. According to a particular embodiment, this antibody comprises a heavy chain (VH) comprising a peptide sequence as presented in SEQ ID NO. 6 or 10 and a light chain (VL) comprising a peptide sequence as presented in SEQ ID NO. 7. Preferably, said antibody comprises a heavy chain (VH) comprising a peptide sequence as presented in SEQ ID NO. 10 and a light chain (VL) comprising a peptide sequence as presented in SEQ ID NO. 7.According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of the SEQ ID NO. 10 sequence and 100% identity with the CDR regions of SEQ ID NO. 11 to 13 sequences, and - a variable light chain (VL) comprising a peptide sequence exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of the SEQ ID NO. 7 sequence and 100% identity with the CDR regions of SEQ ID NO. 13 sequences. 3 to 5. According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity with the SEQ ID NO. 10 sequence, and - a variable light chain (VL) comprising a peptide sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity with the SEQ ID NO. 7 sequence.According to another embodiment of the invention, said antibody comprises: - a variable heavy chain (VH) comprising a peptide sequence having 100% identity with the SEQ ID NO. 10 sequence, and - a variable light chain (VL) comprising a peptide sequence having 100% identity with the SEQ ID NO. 7 sequence. Advantageously, the antibody according to the invention "blocks" the inflammatory biological effects of CD74, in particular strongly inhibiting the secretion of IL-17, but having little effect on the secretion of IL-10, a cytokine with anti-inflammatory properties (as illustrated in Figure 2). Another advantage of this antibody is its ability to bind to a particular isoform of the CD74 protein, obtained by alternative splicing, whose biological function is still unknown. This antibody can be used in all fields, and in particular in the pharmaceutical and cosmetic fields.Preferably, said antibody is a humanized antibody, comprising the 6 CDRs mentioned above and also including human sequences. The invention also relates to this antibody for use as a medicinal product. The invention also relates to this antibody for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease, or an autoimmune disease such as systemic lupus erythematosus. The invention also relates to this antibody for its therapeutic use in the prevention and / or treatment of cancer. The invention also relates to the cosmetic, non-therapeutic use of this antibody to treat inflammatory conditions of keratinous materials, particularly of the skin, hair, and nails.EXAMPLES The experimental data presented in Example 1 illustrate the method for selecting an antibody that inhibits the secretion of interleukin-17, an inflammatory cytokine that is highly produced and secreted in chronic inflammatory diseases. The molecular target of this antibody has been identified, opening up numerous avenues for the therapy of chronic inflammatory diseases associated with high IL-17 secretion. Example 2 illustrates the functional characterization of this identified antibody. Example 3 relates to the structural characterization of this antibody, including its peptide sequence and hypervariable regions (CDRs) by alignment with reference sequences. Example 1. Screening a library of 75 anti-synoviocyte antibodies and selecting an antibody of interest. 75 anti-synoviocyte antibodies were obtained by immunizing BALBc mice with synoviocytes.Samples Synoviocytes were obtained from the synovial tissue of rheumatoid arthritis (RA) patients who had undergone joint surgery and met the American College of Rheumatology criteria for RA. The synovial tissue was cut into small pieces and then placed in 6-well plates in Dulbecco's modified Eagle medium (DMEM; Eurobio, Courtaboeuf, France) supplemented with 10% fetal bovine serum (FBS; Life Technologies, Carlsbad, CA, USA), 2 mM L-glutamine and 100 U / ml penicillin / streptomycin (complete DMEM). The cells were maintained at 37°C in an incubator humidified with 5% carbon dioxide and used between passages 4 and 9. Peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated by Ficoll-Hypaque density gradient centrifugation (Eurobio, Courtaboeuf, France).The study protocol was approved by the Institutional Review Board of the Hospices Civils de Lyon, France (accession number AC-2016-272), and written informed consent was obtained from the patients. Acquisition of anti-synoviocyte antibodies: Germ-free BALB / c mice were immunized by three successive intraperitoneal injections of Freund's adjuvant (Sigma Chemical Co.) and PR synoviocyte lysate (1x10. 6cells / injection / mouse). Splenocytes were harvested 3 days after the last intravenous injection and fused with SP2 / 0 cells using polyethylene glycol-1000 and cultured in 96-well plates according to standard procedures. Hybridoma supernatants were analyzed by immunofluorescence to detect reactivity against synoviocytes versus COS7 cells. Synoviocyte-positive and COS7-negative hybridomas were cloned using a limiting dilution method, amplified, and cultured at high density in CL 350 flasks (Sartorius, Göttingen, Germany). After sodium sulfate precipitation of the supernatants, monoclonal antibodies (mAbs) were purified by anion-exchange chromatography on a Q Ceramic HyperD (Pall Corporation, New York, NY, USA).Screening: These 75 antibodies were tested and selected on co-culture of synoviocytes and PBMCs (peripheral blood mononuclear cells), according to the protocol presented below. Synoviocytes were cultured in 96-well plates, at a concentration of 2.10. 4Cells were incubated overnight to form a cell bed. The following day, PBMC cells were added at a PBMC / synoviocyte ratio of 5:1, with stimulation using phytohemaglutinin (PHA, 5 µg / ml) in the presence of a separate antibody (5 µg / ml) in each well. The co-culture plate was then placed in an incubator at 37°C and 5% CO2 for 48 hours. After 48 hours of incubation, the culture supernatants (SN) were collected by centrifugation, and the concentrations of IL-17 and IL-6 were measured by ELISA (Enzyme-Linked Immunoassay) according to the distributor's instructions (DIACLONE, France). Results of the first screening stage: Of the 75 antibodies tested, the majority inhibited IL-17 production, 5 antibodies increased IL-17 production, and 15 had no effect. The effects on IL-6 production were similar. Based on the effect on IL-17 production, an initial selection of 15 antibodies was made.Second screening step: dose-response effect. To confirm the role of these 15 selected antibodies, different antibody concentrations were used (from 10 µg / ml to 0.1 µg / ml) to determine the dose-response of the cultured cells. Figures 1A and 1B show the percentages of inhibition obtained on the production of IL-17 and IL-6 compared to the control. To verify that the selected antibodies are specifically directed against synoviocytes, cell labeling was performed on activated and unactivated cells with a mixture of IL-17 (50 ng / ml) and TNF (1 ng / ml). The synoviocytes were cultured for 48 hours, with or without stimulation. After 48 hours, they were incubated with the 15 pre-selected antibodies and then with a secondary antibody coupled to FITC (fluorescein isothiocyanate) for analysis by flow cytometry. As observed in Figure 1C, only 9 out of 15 antibodies bind to synoviocytes.However, antibodies that were not positive in this test were not necessarily excluded, due to their inhibitory activity on IL-17 secretion; the target of these antibodies could be expressed intracellularly in the absence of cell-cell interaction, or by immune cells present in co-cultures. The 7 antibodies highlighted in Figure 1 were retained for subsequent experiments aimed at identifying their targets. Expression cloning. For this purpose, an expression cloning technique adapted from the technique described in the article (Valladeau et al., 2000) was implemented. The protocol includes the following steps: 1. creation of a specific cDNA expression library included in expression plasmids; 2. transfection of HEK 293 cells with said library and selection of positive cells by magnetic sorting and extraction of plasmids from the selected cells using the NucleoBond® PC kit (Macherey Nagel); 3.Production of said plasmids by bacteria (Top10, Invitrogen) transformed by electroporation; 4. Transfection of HEK 293 cells with the bacterial plasmids; 5. Selection of HEK 293 cells positive for the tested antibodies (i.e., recognized by the antibodies and therefore expressing their targets); extraction of the plasmids; 6. Transfection of the bacteria with the extracted plasmids, returning to step 3. Several cycles are performed until the number of cells positive for the antibodies of interest approaches 100%. At this point, the final step (6) consists of sequencing the plasmids to obtain the antibody target sequence and thus identify it. After three cloning cycles, three plasmids were sequenced to identify the target expressed by the positive cells. One of the plasmids contains a sequence that was identified using BLAST software (NCBI) as the CD74 protein. Example 2.Functional Characterization of Antibody 8350: The specific antibody for this identified target was confirmed by immunolabeling on HEK 293 cells expressing said target after transfection: antibody 8350 (see Figure 1) is able to bind to cells expressing this target, both on the cell surface and intracellularly. To confirm the biological effects of the selected antibody 8350, its effects on interleukin and interferon secretion were compared to the effects obtained with a commercial anti-CD74 antibody (obtained from Thermo Fisher Scientific, part number 14-0747-82). As illustrated in Figure 2A, both antibodies inhibit IL-17 secretion in co-cultures of immune and stromal cells. An opposing effect on IFN-gamma production is also observed (Figure 2B).Interestingly, the commercial antibody strongly inhibits the secretion of IL-10, an anti-inflammatory cytokine, whereas the 8350 antibody identified by screening has a limited effect on this production. In an inflammatory context, not inhibiting the secretion of this cytokine IL-10, which has anti-inflammatory properties, while inhibiting that of IL-17, is advantageous. Finally, it is likely that the antibody identified here possesses additional functionalities compared to those of already known anti-CD74 antibodies, making it a promising candidate for therapeutic use. Example 3.Structural Characterization of the Identified Anti-CD74 Antibody: Antibody 8350 was sequenced according to the following protocol: - RNA extraction from antibody-producing cells; - RT-PCR amplification of the RNA (qPCRBIO SyGreen 1-Step Go, Eurobio); - Further PCR amplification (REDTaq ReadyMix PCR reaction, Sigma); - The resulting PCR products were purified (MinElute PCR Purification Kit, Qiagen) and sent for sequencing to MicroSynth France-Biofidal. The resulting sequences (SEQ ID NO. 6, 7, and 10) were then aligned with reference sequences (SEQ ID NO. 8, 9, 14, and 15) using the online tool BLAST (NCBI). The results are presented in Figures 3A, 3B, and 3C. For the heavy chain sequence SEQ ID NO.6, a match was established with a heavy chain immunoglobulin defined on BLAST as follows: >Chain H, FAB [Mus musculus] Sequence ID: 2J88_H Length: 191 - Range 1: 21 to 129. The complementarity-determining regions (CDRs) numbered CDR2 (SEQ ID NO.1) and CDR3 (SEQ ID NO.2) were identified by homology with the location of the CDRs in the reference sequence. For the heavy chain with sequence SEQ ID NO.10, which includes sequence SEQ ID NO.6, a match was established with two reference immunoglobulins designated "2J88_H(2-129)" (SEQ ID NO.14) and "germline IGHV8-4-7*01" (SEQ ID NO.15). Three CDRs were thus identified by homology: CDR1 (SEQ ID NO.11), CDR2 (SEQ ID NO.12) and CDR3 (SEQ ID NO.13). For the light chain (SEQ ID NO.7), a match was established with an immunoglobulin light chain defined on BLAST as follows: immunoglobulin light chain variable region, partial [Mus musculus] Sequence ID:AAO60121.1 Length: 121 - Range 1: 17 to 115 The complementarity-determining regions numbered CDR1 (SEQ ID NO. 3), CDR2 (SEQ ID NO. 4) and CDR3 (SEQ ID NO. 5) were identified by homology with the location of the CDRs in the reference sequence. Table 2. Sequences cited in the application Designation Size Sequence CDR2 chain SEQ ID NO. 17 aa GMGLSW1 heavy CDR3 chain SEQ ID NO. 2. 3 aa NQV heavy CDR1 chain SEQ ID NO. 35 aa QSISDlight CDR2 chain SEQ ID NO. 412 aa PRLLIKYASQSIlight CDR3 chain SEQ ID NO. 56 aa GHSFPYlight TCSFSGFSLSTSGMGLSWIRQPSGKGLEWLAHIYWD Heavy chain DDKRYNPSLKSRLTISRDTSSNQVFLKITSVDTADTA SEQ ID NO. 6A c 8350111 aa TYYCARRDFYGGLDYWGQGTSVTVSSAKTTPPSVY PLA DGVSFSCRASQSISDFLHWYQQKSHESPRLLIKYASQ Light chain SEQ ID NO. 7 99 aa SISGIPSRFSGSGSGSDFTLIISSVEPEDVGVYYCQNG Ac 8350 HSFPYTFGGGTKLEVKRADAAPTV Heavy chain TCSFSGFSLSTSGMGVSWIRQPSGKGLEWLAHIYWD SEQ ID NO. 8 of reference 109 aa DDKRYNPSLKSRLTISKDTSRNQVFLKITSVDTADTA (aa 21 to 129) TYYCTLYYGSVDYWGQGTSVTVSSAKTTPPSVYPLA Light chain DRVSLSCRASQIISDYLHWYQQKSHESPRLLIKYASQS SEQ ID NO. Reference 99 aa ISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNG (aa 17 to 115) HSFPFTFGSGTKLEIKRADAAPTV SEQ ID NO. VKLEESGPGILQPSQTLSLTCSFSGFSLSTSGMGLS 10 Chaine lourde WIRQPSGKGLEWLAHIYWDDDKRYNPSLKSRLTISR 130 aa A c 8350 DTSSNQVFLKITSVDTADTATYYGARRDFYGGLDY WGQGTSVTVSSAKTTPPSVYPLA SEQ ID NO. CDR1 chain 10 GFSLSTSGMG11 heavy SEQ ID NO. CDR2 channel 7 IYWDDDK12 Heavy SEQ ID NO. CDR3 chain 11 ARRDFYGGLDY13 Heavy SEQ ID NO. Heavy chain VTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGVSW 14 Reference IRQPSGKGLEWLAHIYWDDDKRYNPSLKSRLTISKDT SRNQVFLKITSVDTADTATYYCTLYYGSVDYWGQG 2J88_H (aa 2- TSVTVSSAKTTPPSVYPLA 129) SEQ ID NO. Heavy chain VTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGVSW 15 Reference IRQPSGKGLEWLAHIYWDDDKRYNPSLKSRLTISKDT IGHV8-4-7*01 SRNQVFLKITSVDTADTATYYCARR BIBLIOGRAPHICAL REFERENCES PATENTS EP 2 198 879WO 2016 / 014434 US 10,322,176 REFERENCES BIBLIOGRAPHIQUESBenedetti G, Miossec P. Interleukin 17 contributes to the chronicity of inflammatory diseasessuch as rheumatoid arthritis. Eur J Immunol 2014, 44(2):339-347.Hot A, Lenief V, Miossec P. Combination of IL-17 and TNFalpha induces a pro-inflammatory,pro-coagulant and pro-thrombotic phenotype in human endothelial cells. Ann Rheum Dis 2012, 71(5):768-776. Noack M, Miossec P. Importance of lymphocyte-stromal cell interactions in autoimmune and inflammatory rheumatic diseases. Nat Rev Rheumatol. 2021 Sep;17(9):550-564. Borghese F, Clanchy FI. CD74: an emerging opportunity as a therapeutic target in cancer and autoimmune disease. Expert Opin Ther Targets. 2011 Mar;15(3):237-51. Su Y, Wang Y, Zhou Y, Zhu Z, Zhang Q, Zhang X, Wang W, Gu X, Guo A, Wang Y. Macrophage migration inhibitory factor activates inflammatory responses of astrocytes through interaction with CD74 receptor. Oncotarget. 2017 Jan 10;8(2):2719-2730.(2017a) Su H, Na N, Zhang X, Zhao Y. The biological function and significance of CD74 in immune diseases. Inflamm Res. 2017 Mar;66(3):209-216. (2017b) Almagro JC, Fransson J. Humanization of antibodies. Front Biosci. 2008 Jan 1;13:1619-33. Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md. (1991) Lefranc MP, Pommié C, Ruiz M, Giudicelli V, Foulquier E, Truong L, Thouvenin-Contet V, Lefranc G. IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev Comp Immunol. 2003 Jan;27(1):55-77. Valladeau J, Ravel O, Dezutter-Dambuyant C, Moore K, Kleijmeer M, Liu Y, Duvert-Frances V, Vincent C, Schmitt D, Davoust J, Caux C, Lebecque S, Saeland S. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation ofBirbeck granules. Immunity. 2000 Jan;12(1):71-81. Jones PT, Dear PH, Foote J, Neuberger MS, Winter G.Replacing the complementarity- determining regions in a human antibody with those from a mouse. Nature. 1986 May 29-Jun 4;321(6069):522-5. Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature. 1988 Mar 24;332(6162):323-7. Verhoeyen M, Milstein C, Winter G. Reshaping human antibodies: grafting an antilysozyme activity. Science. 1988 Mar 25;239(4847):1534-6.

Claims

1. CLAIMS 1. An inhibitor of CD74 protein activity or expression, for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease selected from: chronic inflammatory rheumatic diseases, chronic inflammatory dermatoses, chronic inflammatory bowel diseases, and chronic inflammatory neurological diseases.

2. An inhibitor of CD74 protein activity for its therapeutic use according to claim 1, characterized in that it is an antibody directed against the CD74 protein or a fragment of said antibody.

3. An inhibitor of CD74 protein activity for its therapeutic use according to claim 2, characterized in that the anti-CD74 antibody is a humanized monoclonal antibody. 4.Inhibitor of CD74 protein activity for its therapeutic use according to claim 2 or 3, characterized in that said antibody or antibody fragment comprises: - a variable heavy chain comprising, in the N-terminal to C-terminal direction: o CDR1 of sequence SEQ ID NO.11; o CDR2 of sequence SEQ ID NO.1 or 12, preferably SEQ ID NO.12; and o CDR3 of sequence SEQ ID NO.2 or 13, preferably SEQ ID NO.13; - a variable light chain comprising, in the N-terminal to C-terminal direction: o CDR1 of sequence SEQ ID NO.3; o CDR2 of sequence SEQ ID NO.4; and o CDR3 of sequence SEQ ID NO.5.

5. Inhibitor of the activity or expression of the CD74 protein for its therapeutic use according to claim 1, characterized in that it is an inhibitor of its expression, and in particular an siRNA or an shRNA.6.Method for quantifying immune cells and / or stromal cells expressing the CD74 protein on their surface, said cells being obtained from a biological sample of a patient, comprising a step of determining the rate of cells expressing the CD74 protein by means of an anti-CD74 antibody, and in particular by means of an antibody as described in claim 4.

7. Method for quantifying cells expressing the CD74 protein on their surface according to claim 6, characterized in that the biological sample is that of a patient suffering from a chronic inflammatory disease chosen from: inflammatory rheumatic diseases. chronic inflammatory dermatoses, chronic inflammatory bowel diseases, and chronic inflammatory neurological diseases.

8. A method for quantifying cells expressing the CD74 protein on their surface according to claim 6 or 7, characterized in that the biological sample is selected from blood, serum, synovial fluid, or tissue biopsies.

9. A method for diagnosing a chronic inflammatory disease affecting a patient and / or determining the severity of said disease, comprising the quantification of immune and / or stromal cells expressing the CD74 protein on their surface according to the method as defined in any one of claims 6 to 8, wherein the level obtained is compared to a reference level. 10.Biomarker of the presence and / or severity of a chronic inflammatory disease, consisting of the expression level on the surface of immune and / or stromal cells of the CD74 protein, said cells being obtained from a biological sample of a patient.

11. Isolated anti-CD74 antibody or fragment thereof comprising six CDRs having the SEQ ID NO. 3, 4, 5, 11, 12 and 13 sequences, and preferably comprising a heavy chain comprising the 3 CDRs of SEQ ID NO. 11, 12 and 13 sequences and a light chain comprising the 3 CDRs of SEQ ID NO. 3, 4 and 5 sequences.

12. Anti-CD74 antibody isolated or fragment thereof according to claim 11 comprising:- a variable heavy chain comprising, in the N-terminal to C-terminal direction:o CDR1 of sequence SEQ ID NO.11;o CDR2 of sequence SEQ ID NO.1 or 12, preferably SEQ ID NO.12; ando CDR3 of sequence SEQ ID NO.2 or 13, preferably SEQ ID NO.13; - a variable light chain comprising, in the N-terminal to C-terminal direction: o CDR1 of sequence SEQ ID NO. 3; o CDR2 of sequence SEQ ID NO. 4; and o CDR3 of sequence SEQ ID NO.

5.

13. Anti-CD74 antibody isolated according to claim 11, comprising a heavy chain comprising a peptide sequence SEQ ID NO. 6 or 10 and a light chain comprising a peptide sequence SEQ ID NO.

7.

14. Antibody according to any one of claims 11 to 12, characterized in that it is humanized.

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