CD74 PROTEIN INHIBITOR COMPOUND AND ITS USES

Abstract

The present invention relates to an inhibitor of CD74 protein activity or expression, for 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. In another aspect, the invention relates to an isolated anti-CD74 antibody or fragment thereof, comprising at least one CD74 receptor (CDR) having a sequence selected from SEQ ID NO. 1 to 5.

Description

Title of the invention: CD74 PROTEIN INHIBITOR COMPOUND AND ITS USES FIELD OF INVENTION

[0001] 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

[0002] Interleukin 17 (IL-17) is a pro-inflammatory cytokine primarily secreted by Th7 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, IL-17-γ, and IL-1β, 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.LTL-17 therefore contributes to inflammation through various mechanisms, and participates in the chronicity of many inflammatory diseases. (Benedetti & Miossec, 2017; Hot et al., 2012).

[0003] This involvement of IL-17 in various chronic inflammatory diseases 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 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. Finally, Brodalumab is a monoclonal antibody directed against the IL-17RA subunit of the IL-17 receptor, which has been approved by regulatory authorities for its use in the treatment of psoriasis.

[0004] The importance of cellular 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 serve as 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.

[0005] Surprisingly and unexpectedly, the inventors highlighted the role of the CD74 protein in the signaling pathway inducing the secretion of IL-17 at the site of inflammation.

[0006] The CD74 protein is the invariant gamma 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. This CD74 protein is a membrane protein expressed by B cells, monocytes, macrophages, and certain lymphocytes. Several variant forms exist, derived from the same gene by alternative splicing.

[0007] The CD74 protein is also part of the MIF (Macrophage migration Inhibitory Factor) receptor complex.

[0008] The CD74 protein has a wide range of biological functions. In particular, this CD74 protein is a therapeutic target currently being studied in the context of various diseases.

[0009] Patent application EP 2 198 879 discloses the role of CD74 in the migration of dendritic cells: inhibition of CD74 would increase the mobility of these cells.

[0010] Overexpression of CD74 has been observed in cancer and certain autoimmune diseases, as presented in the review by (Borghese & Clanchy, 2011). In the context of treating these pathologies, the beneficial effect of administering antibodies directed against CD74 has been demonstrated.

[0011] Many types of anti-CD74 antibodies exist, as shown in international application WO 2016 / 014434. For example, Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has been clinically tested for the treatment of multiple myeloma, but has not been ultimately validated.

[0012] 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.

[0013] The CD74 protein also appears to play a role in controlling inflammation of the nervous system following 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

[0014] The present application describes here, for the first time, the role played by the CD74 protein in chronic inflammatory diseases.

[0015] 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.

[0016] This chronic inflammatory disease is in particular chosen from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.

[0017] The present 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 rate of cells expressing the CD74 protein, and in particular by means of an anti-CD74 antibody.

[0018] According to another aspect, the present 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 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.

[0019] According to another aspect, the present application relates to a biomarker of the presence and / or severity of a chronic inflammatory disease, consisting of an 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.

[0020] According to a final aspect, the present application 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. DESCRIPTION OF THE FIGURES

[0021] [Fig.1] Fig.1 represents 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 the identification of potential molecular targets for the therapy of chronic inflammatory diseases.

[0022] A- 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 pg / ml of the antibody tested (the color code of the concentrations used is indicated on the right)

[0023] B- 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 pg / ml of the antibody tested (the color code of the concentrations used is indicated on the right)

[0024] C- Staining of synoviocytes, stimulated (in grey) or not (in black, “control”), with a mixture of IL-17 (50 ng / ml) and TNF (ng / ml). After culture, the synoviocytes are incubated with the 15 pre-selected antibodies and then with a FITC-coupled secondary antibody (fluorescein isothiocyanate) for analysis by flow cytometry.

[0025] [Fig.2] Fig.2 represents 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.

[0026] A- Percentage of inhibition of IL-17 secretion

[0027] B- Percentage of inhibition of interferon gamma secretion

[0028] C- Percentage of inhibition of IL-10 secretion

[0029] [Fig.3] Sequence alignment.

[0030] A- 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 grey, SEQ ID NO. 8). CDRs are indicated in bold.

[0031] B- Light chain of the isolated anti-CD74 antibody (in black, SEQ ID NO. 7) aligned with a reference sequence ID: AAO60121.1 designated “Ref” (in grey, SEQ ID NO. 9). CDRs are indicated in bold. DETAILED DESCRIPTION

[0032] The present invention relates to the identification of compounds that play 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, and certain lymphocytes. CD74 has been identified as a therapeutic target for the treatment of various diseases, but its involvement in chronic inflammatory diseases and in IL-17 secretion had never been suggested.

[0033] 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 sample biological of said patient, in which the measured CD74 level is compared to a reference level.

[0034] 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 level of expression of the CD74 protein in the tissues of an individual, this antibody therefore being able to be used in the two prevention / treatment and diagnostic processes mentioned above.

[0035] Inhibitor of the activity or expression of the CD74 protein, for its therapeutic use in the prevention and / or treatment of chronic inflammatory disease

[0036] 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.

[0037] This chronic inflammatory disease is in particular chosen from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.

[0038] The following definitions are given to facilitate understanding of the invention.

[0039] 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 on the basis of a particular clinical picture by a person of art.

[0040] 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 response of the body for its survival, enabling the elimination of aggressors and the repair of damage. Inflammation is a generic response, not specific to any particular external stimulus.

[0041] For the purposes of this invention, an inflammatory reaction refers to the body's response to tissue damage. 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, thereby allowing the influx of other immune cells to the site of inflammation.

[0042] Under certain conditions, an inflammatory reaction develops in the absence of an external factor, or persists after the elimination of an external source of inflammation. The inflammation then enters an abnormal phase during It can last several weeks, several years, and even 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 damage is controlled / repaired.

[0043] For the purposes of the invention, a "chronic inflammatory disease" means a disease characterized by the inflammatory reaction of a tissue in the absence of external elements generating this inflammation.

[0044] Millions of people suffer from chronic inflammatory diseases. These diseases can develop at any age and regardless of the patients' ethnic or geographic origin.

[0045] Chronic inflammatory diseases can affect most organs and tissues of the human body, particularly the joints, epidermis, digestive system and nervous system.

[0046] More specifically, the present invention relates to chronic inflammatory diseases characterized by a high secretion of IL-17 at the site of inflammation.

[0047] In particular, the present invention relates to the following diseases:

[0048] a) chronic inflammatory rheumatism, characterized by chronic inflammation of the joints

[0049] 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.

[0050] Rheumatoid arthritis is characterized by painful flare-ups and swelling of the joints, which are progressively destroyed.

[0051] Spondyloarthritis is a group of pathologies that cause debilitating pain in the lumbar region and pelvis. The disease often develops in young adults, between 16 and 30 years of age. Eventually, the disease leads to degeneration of the affected joints and ossification of the spine.

[0052] Psoriatic arthritis is a type of spondyloarthritis. The joints most frequently affected 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.

[0053] b) chronic inflammatory dermatoses, characterized by chronic inflammation of the skin and / or mucous membranes

[0054] Also known as chronic inflammatory skin diseases, these diseases present in multiple forms. Among the most frequent are psoriasis, atopic dermatitis, and hidradenitis suppurativa (HS).

[0055] 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.

[0056] 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 is affected by atopic dermatitis.

[0057] Verneuil's disease is characterized by significant pain, significantly impacting the mobility of those affected.

[0058] c) chronic inflammatory bowel diseases

[0059] Inflammatory bowel diseases, also known as IBD, are characterized by inflammation of the lining of a part of the intestine due to dysregulation of the intestinal immune system. They include Crohn's disease and ulcerative colitis (UC).

[0060] 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 intestinal cramps and pain.

[0061] Ulcerative colitis is characterized by inflammation of the lower part of the rectum that extends more or less into the colon. The disease causes the formation of small lesions in the colon that lead to abdominal pain.

[0062] d) chronic inflammatory neurological diseases, characterized by chronic inflammation of the nerves and / or brain.

[0063] The chronic form of inflammatory nerve damage is called chronic inflammatory polyradiculoneuropathy (CIDP). This disease causes deficits in strength and sensation that can be very severe and even fatal.

[0064] Inflammatory brain diseases are diverse in terms of the tissues affected: they can affect the white matter such as multiple sclerosis, neuromyelitis optica or rhombencephalitis, but also both white and grey matter or grey only, as is the case for autoimmune encephalitis, systemic diseases with neurological involvement or vasculitis.

[0065] All these chronic inflammatory diseases are characterized by a significant presence of IL-17 at the site of inflammation.

[0066] For the purposes of the invention, the term "chronic inflammatory diseases" specifically excludes diseases such as systemic lupus erythematosus (SLE), as well as cancers.

[0067] According to a preferred embodiment, the chronic inflammatory disease under consideration is chosen from one of the following diseases: rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, psoriasis, and atopic dermatitis.

[0068] For the purposes of the 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 "to treat" or "treatment" include, in particular, 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 skilled in 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.

[0069] For the purposes of this invention, the term "prevention" or "prevent" refers to reducing the risk to an individual of 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, such 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 susceptible to contracting the disease in question. Inhibition of CD74 protein activity

[0070] According to a first aspect, the invention relates to an inhibitor of CD74 protein activity, for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease, specifically chosen from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.

[0071] For the purposes of the invention, an “inhibitor of the activity of the CD74 protein” 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 a configuration of said protein inactive; or by inhibiting its cellular transport; or by inhibiting its function according to any other molecular mechanism.

[0072] The inhibition of this activity can be quantified according to the technologies well known to the person of art.

[0073] 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) can be quantified by ELISA in the culture medium of said cells.

[0074] This inhibitor of CD74 activity may be of any molecular nature, and in particular may be chosen from a protein, a peptide, a nucleic acid, an oligonucleotide (in particular an aptamer), or any chemical compound having the function of inhibiting the activity of the CD74 protein, as may be determined by a person skilled in the art, in particular according to the measurement technique mentioned above and illustrated in the examples of the application.

[0075] 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 of said antibody.

[0076] By "antibody" we mean a protein comprising at least one binding domain for a given antigen (here, the CD74 protein) and therefore binding to said protein, and a constant domain comprising an Fc fragment capable of binding to Fc receptors (FcR).

[0077] The term "antibody" is used here 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.

[0078] 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 (RIA) and enzyme-linked immunosorbent assays (ELISA). As a rule In general, such a specific connection is at least twice the background noise and can be more than ten times the background noise.

[0079] The term "antibody fragment" refers to 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 entire antibody. Each chain of the fragment may have a length of at least 5 contiguous amino acids, preferably at least 7, 10, 15, 20, 25, 30, or more amino acids.

[0080] 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.

[0081] 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 mutations of natural origin that may be found in minimal proportions.

[0082] 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.

[0083] 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.

[0084] 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, particularly from mice, and - constant domains, derived from one or more human antibodies.

[0085] 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.

[0086] The humanized antibodies according to the invention can be prepared by techniques well known to the person of the art, as presented in the review (Almagro et al., 2008).

[0087] 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. Variable domains are involved in antigen recognition, while constant domains are involved in the biological, pharmacokinetic, and effector properties of the antibody.

[0088] The constant domains are characterized by a very similar amino acid sequence from one antibody to another, typical of the species and isotype, possibly with some somatic mutations. The Fc fragment naturally consists of the constant region of the heavy chain excluding the CH1 domain, i.e. the lower hinge region and the CH2 and CH3 or CH2 to CH4 constant domains (depending on the isotype).

[0089] The variable region differs from one antibody to another. Indeed, the genes encoding the heavy and light chains of the 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 the 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.

[0090] 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 since it is located in the recombination zone. These three CDRs, and in particular CDR3, are found in the part of the antibody that will be in contact with the antigen and are therefore important for antigen recognition. CDR1, CDR2, and CDR3 are each preceded by FRI, 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.

[0091] Various methods for determining CDRs have been proposed, and the portion of the amino acid sequence of the variable region of a heavy or light chain of an antibody defined as the CDR varies depending on the method chosen.

[0092] The first method of determination is that proposed by Kabat et al. (Kabat et al., 1991). In this method, CDRs are defined by searching for the amino acids responsible for antibody-antigen binding.

[0093] A second method has been proposed by IMGT, based on the determination of hypervariable regions. In this method, a unique numbering system has been defined to compare variable regions independently of the antigen receptor, chain type, or species (Lefranc et al. 2003). This numbering system provides a standardized definition of 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 complementarity-determining regions (CDR1-IMGT: positions 27 to 38, CDR2-IMGT: positions 56 to 65, and CDR3-IMGT: positions 105 to 117).

[0094] Finally, there is also a so-called "common" numbering in which the sequence of a particular CDR corresponds to the common sequence between the Kabat numbering and the IMGT numbering.

[0095] In the present description, the CDRs were determined according to the IMGT method implemented by the BLAST software, based on a comparison of the SEQ ID NO. 6 and 7 sequences with reference sequences SEQ ID NO. 8 and 9.

[0096] These CDRs have the following sequences:

[0097] [Tables 1] SEQ ID NO. 1 CDR2 heavy chain 7 aa GMGLSWI SEQ ID NO. 2 CDR3 heavy chain 3 aa NQV SEQ ID NO. 3 CDR1 light chain 5 aa QSISD SEQ ID NO. 4 CDR2 light chain manages 12 aa PRLLIKYASQSI SEQ ID NO. 5 CDR3 light chain manages 6 aa GHSFPY

[0098] 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 an antibody fragment characterized in that it comprises at least one CDR having a sequence selected from SEQ ID NO. 1 to 5.

[0099] More specifically, 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 - a variable light chain (VL) comprising at least one CDR having a sequence chosen from SEQ ID NO. 3 to 5.

[0100] 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.

[0101] 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 SEQ ID sequence NO. 6 and 100% identity with the CDR regions of SEQ ID sequences NO. 1 to 2, 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.

[0102] 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 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.

[0103] 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 sequence, and - a variable light chain (VL) comprising a peptide sequence having 100% identity with the SEQ ID NO. 7 sequence. CD74 expression inhibitor

[0104] According to a second aspect, the present invention relates to an inhibitor of the expression of the CD74 protein for its therapeutic use in the prevention and / or treatment of a chronic inflammatory disease chosen in particular from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.

[0105] Indeed, inhibition of CD74 protein expression has the same physiological effects as inhibition of its activity.

[0106] 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 may 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 referred to in Article 10.

[0107] 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 an siRNA (silencing RNA) or an shRNA (small hairpin RNA). Pharmaceutical compositions

[0108] Whether it is a compound that inhibits the activity of CD74, or a compound that inhibits the expression of CD74, 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.

[0109] For the purposes of the present 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.

[0110] For the purposes of the invention, the term "effective quantity" means a sufficient quantity of the compound that inhibits the activity or expression of CD74, 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.

[0111] 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

[0112] 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 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 the present application.

[0113] 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.

[0114] According to one embodiment of the invention, said biological sample is that of a patient suffering from a chronic inflammatory disease, in particular chosen from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.

[0115] Quantification may be carried out on cultured cells, obtained from a biological sample, or in situ on a tissue sample.

[0116] According to a particular embodiment, the biological sample is chosen from blood, serum, synovial fluid or tissue biopsies.

[0117] Advantageously, said quantification method is implemented on a biological sample taken from a tissue subjected to chronic inflammation.

[0118] Said biological sample may be obtained by any technique well known to the person skilled in the art, this step of obtaining the sample not being included in the quantification process. Diagnostic procedure

[0119] The present invention also relates to 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 quantification method described above, in which the level obtained is compared to a reference level.

[0120] In particular, said chronic inflammatory disease is chosen from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.

[0121] Quantifying the number of cells expressing the CD74 protein on their surface allows us to obtain a "CD74 membrane expression level".

[0122] In the diagnostic process of the invention, this expression rate is then compared to a reference expression rate.

[0123] The value of this reference rate may be the mean or median of several values ​​determined on several samples obtained from a plurality of healthy subjects and / or patients with chronic inflammatory diseases, the nature and severity of which are known.

[0124] According to one embodiment of the invention, the reference value is representative of the absence of a chronic inflammatory disease. Such a reference value is obtained by means of the quantification method described above, implemented on biological samples obtained from healthy subjects, not exhibiting clinical signs of the chronic inflammatory disease in question.

[0125] 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.

[0126] 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.

[0127] 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, representative of the "boundary" between the "healthy" status and the "disease" status.

[0128] This "threshold" reference value can be easily determined by persons in the art using their general knowledge.

[0129] 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".

[0130] The present invention also relates to a biomarker of the presence and / or severity of a chronic inflammatory disease, consisting of an 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.

[0131] 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 presented above, in order to obtain a diagnostic conclusion regarding the presence and / or severity of a chronic inflammatory disease. Isolated anti-CD74 antibody

[0132] The present invention also relates to an isolated anti-CD74 antibody or fragment thereof comprising at least one CDR having a sequence selected from the SEQ ID NO. 1 to 5 sequences.

[0133] 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.

[0134] 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 - a variable light chain (VL) comprising at least one CDR having a sequence chosen from SEQ ID NO. 3 to 5.

[0135] 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.

[0136] 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 sequence SEQ ID NO. 6 and 100% identity with the CDR regions of sequences SEQ ID NO. 1 to 2, and - a variable light chain (VL) exhibiting at least 90%, 95%, 96%, 97%, 98% or 99% identity with the frame regions (FR) of sequence SEQ ID NO. 7 and 100% identity with the CDR regions of sequences SEQ ID NO. 3 to 5.

[0137] 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 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.

[0138] 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 sequence, and - a variable light chain (VL) comprising a peptide sequence having 100% identity with the SEQ ID NO. 7 sequence.

[0139] According to a particular embodiment, this antibody comprises a heavy chain (VH) comprising a peptide sequence as shown in SEQ ID NO. 6 and a light chain (VL) comprising a peptide sequence as shown in SEQ ID NO. 7.

[0140] Advantageously, the antibody according to the invention "blocks" the inflammatory biological effects of CD74, in particular strongly inhibits the secretion of IL-17, but has little effect on the secretion of IL-10, a cytokine with anti-inflammatory properties (as illustrated in [Fig.2]).

[0141] 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.

[0142] This antibody can be used in all fields, and in particular in the pharmaceutical and cosmetic fields.

[0143] The invention also relates to this antibody, for its use as a medicinal product.

[0144] 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.

[0145] The invention also relates to this antibody, for its therapeutic use in the prevention and / or treatment of cancer.

[0146] The invention also relates to the cosmetic, non-therapeutic use of this antibody to treat inflammatory conditions of keratinous materials, in particular of the skin, hair and nails. EXAMPLES

[0147] 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, which opens up numerous avenues for the therapy of chronic inflammatory diseases associated with high IL-17 secretion.

[0148] Example 2 illustrates the functional characterization of this identified antibody.

[0149] Example 3 relates to the structural characterization of this antibody, in particular its peptide sequence and its hypervariable parts (CDRs) by alignment with reference sequences.

[0150] Example 1. Screening of a library of 75 anti-synoviocyte antibodies and selection of an antibody of interest

[0151] 75 anti-synoviocyte antibodies were obtained by immunization of BALBc mice with synoviocytes. Samples

[0152] 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 of L-glutamine and 100 mL / ml penicillin / streptomycin (complete DMEM). Cells were maintained at 37°C in a 5% carbon dioxide humidified incubator 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. Obtaining anti-synoviocyte antibodies

[0153] Germline BALB / c mice were immunized by three successive intraperitoneal injections of Freund's adjuvant (Sigma Chemical Co.) and PR synoviocyte lysate (1xlO6 cells / 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 precipitation of the supernatants with sodium sulfate, the monoclonal antibodies (mAbs) were purified by anion exchange chromatography on Q Ceramic HyperD (Pall Corporation, New York, NY, USA). Screening

[0154] These 75 antibodies were tested and selected on co-culture of synoviocytes and PBMCs (peripheral blood mononuclear cells), according to the protocol shown below.

[0155] Synoviocytes were cultured in 96-well plates at a concentration of 2 x 10⁴ cells / well overnight to form a cell mat. The following day, PBMC cells were added at a PBMC / synoviocyte ratio of 5:1, with stimulation by phytohemaglutinin (PHA, 5 pg / ml) in the presence of a separate antibody (5 pg / ml) in each well.

[0156] The co-culture plate is placed for 48 hours in an incubator at 37 °C and 5% CO2. After 48 hours of incubation, the culture supernatants (SN) are recovered by centrifugation and the concentration of IL-17 and IL-6 is measured by ELISA (Enzyme-Linked Immuno Assay) according to the distributor's instructions (DIACLONE, France). Results of the first screening step

[0157] 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.

[0158] Based on the effect on IL-17 production, a first selection of 15 antibodies was made. Second screening stage: dose-response effect

[0159] In order to confirm the role of these 15 selected antibodies, different antibody concentrations were used (from 10 pg / ml to 0.1 pg / ml) to determine the dose-response of the cells in culture.

[0160] Figures IA and IB represent the percentages of inhibition obtained on the production of IL-17 and IL-6 compared to the control.

[0161] 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). Synoviocytes were cultured for 48 hours, with or without stimulation. After 48 hours, they were incubated with the 15 preselected antibodies and then with a secondary antibody coupled to FITC (fluorescein isothiocyanate) for analysis by flow cytometry.

[0162] As observed in Figure IC, 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 may be expressed intracellularly in the absence of cell interaction, or by immune cells present in co-cultures.

[0163] The 7 antibodies boxed in [Fig.1] were retained for subsequent experiments, aimed at identifying their targets. Expression cloning

[0164] For this purpose, a cloning technique by adapted expression of the technique described in the article (Valladeau et al., 2000) was implemented.

[0165] The protocol comprises 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 by the NucleoBond® PC kit (Macherey Nagel) 3. production of said plasmids by bacteria (Top 10, Invitrogen) transformed by electroporation; 4. transfection of HEK 293 cells with 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 plasmids; 6. Transfection of the bacteria with the extracted plasmids, returning to step 3.

[0166] 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.

[0167] After three cloning cycles, 3 plasmids were sequenced for identification of the target expressed by positive cells. One of the plasmids contains a sequence that was identified using BLAST software (NCBI) as the CD74 protein.

[0168] Example 2. Functional characterization of antibody 8350

[0169] The specific antibody for this identified target was confirmed by immunolabeling on HEK 293 cells expressing said target after transfection: antibody 8350 (see [Fig.1]) is able to bind to cells expressing this target, both on the membrane surface and intracellularly.

[0170] To confirm the biological effects of the selected antibody 8350, its effects on the secretion of interleukins and interferon were compared to the effects obtained with a commercial anti-CD74 antibody (obtained from Thermo Fisher, reference 14-0747-82).

[0171] As illustrated in Fig. 2A, these two antibodies inhibit IL-17 secretion in co-cultures of immune and stromal cells.

[0172] An opposite effect on IFN-gamma production is also observed (Figure 2B).

[0173] 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.

[0174] Finally, it is likely that the antibody identified here exhibits additional functionalities to those of already known anti-CD74 antibodies, making it a good candidate for therapeutic use.

[0175] Example 3. Structural characterization of the identified anti-CD74 antibody

[0176] Antibody 8350 was sequenced according to the following protocol: - Extraction of RNA from the cells producing said antibody; - Performing RT-PCR amplification on RNA (qPCRBIO) SyGreen 1-Step Go, Eurobio) - New PCR amplification (REDTaq ReadyMix PCR reaction, Sigma) - The PCR products obtained were purified (MinElute PCR Purification Kit, Qiagen) and sent for sequencing to the company MicroSynth France-Biofidal.

[0177] The obtained sequences (SEQ ID NO.6 and 7) were then aligned with reference sequences (SEQ ID NO.8 and 9) using the online tool BLAST (NCBI). The results are presented in [Fig.3].

[0178] For the heavy chain (SEQ ID NO.6), a match has been established with a Immunoglobulin heavy chain as defined on BLAST:

[0179] >Chain H, F AB [Mus musculus] Sequence ID: 2J88_H Length: 191 - Range 1: 21 to 129

[0180] 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 of the reference sequence.

[0181] For the light chain (SEQ ID NO.7), a correspondence was established with an immunoglobulin light chain defined as follows on BLAST:

[0182] >immunoglobulin light chain variable region, partial [Mus musculus] Sequence ID: AAO60121.1 Length: 121 - Range 1:17 to 115

[0183] 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 of the reference sequence.

[0184] [Tables2] Design Taille Sequence SEQ ID NO. 1 CDR2 chain price 7 aa GMGLSWI SEQ ID NO. 2 CDR3 series each 3 aa NQV SEQ ID NO. 3 CDR1 chained to 5 aa QSISD SEQ ID NO. 4 CDR2 series only 12 aa PRLLIKYASQSI SEQ ID NO. 5 CDR3 series available 6 aa GHSFPY SEQ ID NO. 6 Chain Lourde Ac 8350 111 aa TCSFSGFSLSTSGMGLSWIRQPSGKGLEWL AHIYWDDDKRYNPSLKSRLTISRDTSSNQ VFLKITSVDTADTATYYCARRDFYGGLDY WGQGTSVTVSSAKTTPPSVYPLA SEQ ID NO. 7 Chain cable Ac 8350 99 aa DGVSFSCRASQSISDFLHWYQQKSHESPRL LIKYASQSISGIPSRFSGSGSGSDFTLIISSVE PEDVGVYYCQNGHSFPYTFGGGTKLEVKR ADAAPTV SEQ ID NO. 8 chain of transmission (aa 21 to 129) 109 aa TCSFSGFSLSTSGMGVSWIRQPSGKGLEWL AHIYWDDDKRYNPSLKSRLTISKDTSRNQ VFLKITSVDTADTATYYCTLYYGSVDYWG QGTSVTVSSAKTTPPSVYPLA SEQ ID NO. 9 Chain remote control (aa 17 to 115) 99 aa DRVSLSCRASQIISDYLHWYQQKSHESPRL LIKYASQSISGIPSRFSGSGSGSDFTLSINSV EPEDVGVYYCQNGHSFPFTFGSGTKLEIKR ADAAPTV Tableau 2. Séquences citées dans la demande REFERENCES BIBLIOGRAPHIQUES BREVETS

[0185] EP 2 198 879

[0186] WO 2016 / 014434

[0187] US 10,322,176 REFERENCES BIBLIOGRAPHIQUES

[0188] Benedetti G, Miossec P. Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis. Eur J Immunol2Q14-, 44(2):339-347.

[0189] Hot A, Lenief V, Miossec P. Combination of IL-17 and TNFalpha induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothélial cells. Ann Rheum Dis2Q12, 71(5):768-776.

[0190] 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.

[0191] 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.

[0192] Su Y, Wang Y, Zhou Y, Zhu Z, Zhang Q, Zhang X, Wang W, Gu X, Guo A, Wang Y. Macrophage migration inhibitory factor activâtes inflammatory responses of astrocytes through interaction with CD74 receptor. Oncotarget. 2017 Jan 10;8(2):2719-2730. (2017a)

[0193] 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)

[0194] Almagro JC, Fransson J. Humanization of antibodies. Front Biosci. 2008 Jan 1;13:1619-33.

[0195] Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md. (1991)

[0196] 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(l):55-77.

[0197] 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 spécifie to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity. 2000 Jan;12(l):71-81.

Claims

Demands

1. 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 selected from: chronic inflammatory rheumatism, 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. CD74 protein activity inhibitor for its therapeutic use according to claim 2, characterized in that the anti-CD74 antibody is a humanized monoclonal antibody.

4. CD74 protein activity inhibitor for its therapeutic use according to claim 2 or 3, characterized in that said antibody or antibody fragment comprises at least one CDR having a sequence selected from SEQ ID NO. 1 to 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. 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 claim A

7. *T. 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 with a chronic inflammatory disease chosen from: chronic inflammatory rheumatism, chronic inflammatory dermatoses, chronic inflammatory bowel diseases and chronic inflammatory neurological diseases.

8. Method for quantifying cells expressing the CD74 protein on their surface according to claim 6 or 7, characterized in that the biological sample is chosen 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 rate obtained is compared to a reference rate.

10. Anti-CD74 antibody isolated or fragment thereof comprising at least one CDR having a sequence selected from SEQ ID NO. 1 to 5, and preferably comprising a heavy chain comprising the 2 CDRs of sequence SEQ ID NO. 1 to 2 and a light chain comprising the 3 CDRs of sequence SEQ ID NO. 3 to 5.

11. Anti-CD74 antibody isolated according to claim 10, comprising a heavy chain including a peptide sequence SEQ ID NO. 6 and a light chain including a peptide sequence SEQ ID NO. 7.

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