Hybrid molecule comprising an Fc fragment of antibody and at least one citrullinated fibrin-derived peptide, and its uses

Abstract

The invention relates to a hybrid molecule comprising at least one Fc fragment of an antibody covalently linked to at least one fibrin-derived peptide having at least one citrullyl residue, the uses of such a hybrid molecule, and its production process. (no figure)

Description

Description Title of the invention: Hybrid molecule comprising an Fc fragment of antibody and at least one citrullinated fibrin-derived peptide, and its uses

[0001] — The present invention relates to a hybrid molecule comprising at least one Fc fragment of antibody covalently linked to at least one fibrin-derived peptide including one or more citrully residue(s), the uses of such a molecule hybrid, as well as its production process. Context of the invention

[0002] — Rheumatoid arthritis is the most common of the inflammatory rheumatic diseases or arthritis, but also the most common autoimmune disease. The disease is ca- characterized by chronic inflammation of the synovial joints leading to irreversible joint destruction.

[0003] — The presence of class G autoantibodies directed against citrullinated proteins and called anti-citrullinated protein autoantibodies (ACPA), is highly specific to Rheumatoid arthritis. Patient sera that contain ACPA, the lymphocyte cells that express them on their membrane and the patients themselves, are said to be 'ACPA-positive'. Several studies have shown that these ACPAs are at the heart autoimmune reactions specific to rheumatoid disease and thus represent a therapeutic target of choice.

[0004] — The antigenic targets of ACPA have been characterized. They are notably directed specifically against deiminated or citrullinated forms of polypep- chains tidiques to and [3 of fibrin, a protein abundant in inflammatory synovial tissue. This citrullination corresponds to the enzymatic deimination of the arginyl residues of polypeptide chains, under the action of peptidyl-arginine deiminases (PAD).

[0005] More specifically, the immunodominant epitopes recognized by ACPA on the α and [3] fibrin polypeptide chains have been characterized and published, in particular in applications PCT / FR00 / 01857 or PCT / FR2007 / 000758. The five peptides listed below- Trullinated proteins carrying immunodominant epitopes are particularly the peptides named a36-50Cit (as represented in SEQ ID NO: 5), a171-185Cit (as as represented in SEQ ID NO: 6), a501-515Cit (as represented in SEQ ID NO: 14), a621-635Cit (as represented in SEQ ID NO: 18) and [360-74Cit (as re- presented in SEQ ID NO: 19). Sera from ACPA-positive patients recognize a or several of these five peptides.

[0006] Secreted into the rheumatoid synovial tissue by local plasma cells, ACPAs y exhibit a high concentration, close to their main target, the fibrin ci- trullin, which is also abundant there in the form of interstitial deposits. The binding of ACPA to these deposits and therefore the formation of immobilized immune complexes, which in turn bind rheumatoid factors, other autoantibodies associated with rheumatoid arthritis and also secreted by local plasma cells, triggers a cascade of pro-inflammatory events. The stimulation of macrophage cells by these immune macro-complexes, essentially via their membrane Fegamma receptors, leads them to secrete pro-inflammatory cytokines and in particular TNF-alpha which has been identified as the main cytokine responsible for rheumatoid inflammation. Currently, there is no cure for rheumatoid arthritis. Treatments are only aimed at managing flare-ups and / or preventing their occurrence. One object of the present invention is thus to provide a treatment for rheumatoid arthritis. ACPAs are oligoclonal and therefore secreted by only a few plasmacytic clones, themselves resulting from the differentiation of a few B lymphocyte clones. In the case of rheumatoid arthritis, clones of B lymphocytes express on their membrane immunoglobulins carrying the ACPA specificity (these are ACPA-positive B lymphocytes), while the plasma cells resulting from the differentiation of ACPA-positive B lymphocyte clones (these are ACPA-positive plasma cells) secrete these same ACPAs in abundance into their microenvironment. The present invention is based on the Inventors' findings that it is possible to target and eliminate B lymphocyte clones expressing ACPA on their surface using a hybrid molecule comprising (i) at least one fibrin-derived peptide having at least one citrullyl residue and (ii) an Fc fragment of human immunoglobulin. These hybrid molecules will specifically target ACPA-positive B lymphocytes (using the fibrin-derived peptide having at least one citrullyl residue, which is recognized by said ACPA), which will then be eliminated, after binding of the Fc fragment to Fc receptors, by macrophages (via phagocytosis) and / or NK cells (via antibody-dependent cell-mediated cytotoxicity - ADCC), and / or by activation of the complement cascade. By targeting B lymphocyte clones expressing ACPAs and cells that differentiate into plasma cells that themselves secrete ACPAs, the hybrid molecules of the invention aim to eliminate ACPAs from the patients' bodies. Description of the invention M bridle according to i 1 In a first aspect, the invention relates to a hybrid molecule comprising at least one Fc fragment of an antibody covalently linked to at least one fibrin-derived peptide having at least one citrullyl residue, at least one spacer being optionally present between said Fc fragment and said peptide. The diagram of such a construct is shown in [Fig. 1]. According to the invention, a "hybrid molecule" is understood to be a molecule having at least two components of a different nature, in this case the Fc fragment of antibody and said peptide. According to the invention, an antibody "Fc fragment" is understood to be the constant region of an immunoglobulin excluding the first constant region domain of the immunoglobulin (i.e., CH1-CL). Thus, the Fc fragment refers to a homodimer, each monomer comprising the last two constant domains of IgA, IgD, IgG (i.e., CH2 and CH3), or the last three constant domains of IgE and IeM (i.e., CH2, CH3, and CH4). According to the invention, the expression "covalently bonded" means a covalent bond, that is to say, a chemical bond in which two atoms share two electrons. Said covalent bond may be polar or nonpolar. According to the invention, a "spacer" is a linker that covalently binds an Fc fragment of an antibody to a fibrin-derived peptide having at least one citrullyl residue, while simultaneously separating the Fc fragment from the peptide (thus reducing potential steric hindrance). The spacer can be any molecule, and in particular a peptide. Preferably, the spacer does not alter the physicochemical properties of the hybrid molecule. The presence of at least one spacer is advantageous: it facilitates independent accessibility of the two partners of the hybrid molecule (the Fc fragment is more easily accessible to bind to Fc receptors, as is the peptide said, which is more easily accessible to bind to ACPA-positive B lymphocytes), and / or stabilizes the hybrid molecule, and / or increases the solubility of the hybrid molecule. According to one embodiment, the hybrid molecule according to the invention may comprise one or more spacers. Preferably, the hybrid molecule comprises one or two spacers. In one embodiment, when at least one spacer is present in said hybrid molecule of the invention, said Fc fragment is covalently linked to a spacer, said spacer being itself covalently linked to said peptide. In another embodiment, when at least two spacers are present in said hybrid molecule of the invention, said Fc fragment is covalently linked to a first spacer, said first spacer being itself covalently linked to a second spacer, and the second spacer is itself covalently linked to said peptide. peptide. The link between the Fc fragment and the peptide can therefore be direct, or indirect in the presence of spacers. According to one embodiment, the hybrid molecule according to the invention may comprise at least one fibrin-derived peptide having at least one citrullyl residue. This means that the Fc fragment can be linked to one or two peptides. Indeed, the Fc fragment comprises two monomers, and the Fc fragment can thus be covalently linked to a peptide on only one of the two monomers, or the Fc fragment can be covalently linked to a peptide on each monomer. Preferably, when two peptides are linked to the Fc fragment, the two peptides are identical, for example, two peptides of SEQ ID NO: 18 or SEQ ID NO: 19. According to one embodiment, said spacer is a polymer containing one or more repeating units containing the ether group. According to a particular embodiment, said spacer is polyethylene glycol of formula PEGn, in which n represents an integer between 1 and 100, preferably between 1 and 10, and in particular 1, 2, 3, 4, or 8. According to the invention, said polyethylene glycol can be functionalized, for example, with an amine group (PEGn-amine such as PEG-NH₂). According to the invention, "an integer between 1 and 100" represents all integer values ​​between 1 and 100, i.e.; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100. According to the invention, the expression "fibrin-derived peptide having at least one citrullyl residue" means a fibrin or fibrinogen molecule in which at least one arginyl residue has been substituted by a citrullyl residue. A "fibrin-derived peptide having at least one citrullyl residue" according to the invention means a peptide recognized by ACPAs and may also be called a "citrullinated peptide." Such peptides can be obtained from natural, recombining, or synthetic fragments of fibrin or fibrinogen. Such peptides can also be directly synthesized. The amino acids constituting the peptide can be of the L or D series, preferably of the L series. This substitution can, for example, be carried out by an enzymatic deimination step under the action of peptidyl-arginine deiminases (PADs). Such a peptide can also be obtained by directly incorporating one or more citrullyl residues into the synthesized peptide. According to one embodiment, in said hybrid molecule according to the invention, said peptide is derived from all or part of the α or β chain sequence of a vertebrate fibrin, by substitution of at least one arginyl residue with a citrullyl residue. Preferably, said peptide is derived from a sequence of at least 5 amino acids. consecutive chains of the ε chain (notably represented by SEQ ID NO: 27) or B chain (notably represented by SEQ ID NO: 28), of a vertebrate fibrin. More specifically, said vertebrate fibrin is a mammalian fibrin, preferably human. According to one embodiment, in said hybrid molecule according to the invention, the peptide has a size of at least 2 consecutive amino acids, 3 consecutive amino acids, 4 consecutive amino acids, preferably 5 consecutive amino acids, and even more preferably between 5 and 25 amino acids. According to the invention, "between 5 and 25" means all the values: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25. Preferably, said peptide has a size of between 10 and 20 amino acids, more particularly 15 amino acids. According to one embodiment, in said hybrid molecule according to the invention, the peptide is linear. According to one embodiment, in said hybrid molecule according to the invention, the peptide can be modified to improve its reactivity towards ACPAs. By way of example, peptides can be cyclized, or they can be of the retro-type (the L-series amino acids are linked in a reverse sequence to that of the peptide to be reproduced), or of the retro-inverso type (the amino acids are of the D type instead of the natural L series and are linked in a reverse sequence to that of the peptide to be reproduced). In a further particular embodiment, in said hybrid molecule according to the invention, the terminal carboxyl (COOH) group of said peptide is replaced by a carboxamide (CONH) group. Preferably, in the peptide of SEQ ID NO: 12, the terminal carboxyl (COOH) group of said peptide is replaced by a carboxamide (CONH) group.As an example, the peptide p60-74Cit (as represented in SEQ ID NO: 19) advantageously exhibits such a carboxamide function. According to another embodiment, in said hybrid molecule according to the invention, the peptide can be modified to facilitate its synthesis and / or improve its stability, for example by alkylation. In a further particular embodiment, in said hybrid molecule according to the invention, the terminal amine (NH₂) group of said peptide is acetylated. Preferably, in the peptide of SEQ ID NO: 1, the terminal amine group of said peptide is acetylated. By way of example, the peptide x621-635Cit (as shown in SEQ ID NO: 18) advantageously has such an acetyl group on its terminal amine (NH₂). According to one embodiment, in said hybrid molecule according to the invention, the amine and carboxyl functions of the peptide can be in the form of the salt corresponding to the acid or the base. According to one embodiment, in said hybrid molecule according to the invention, said peptide includes at least one citrullyl residue, and is chosen from the group consisting of: a) a peptide defined by the sequence X,PAPPPISGGGYX:AX; (SEQ ID NO: 1) in which X,, X,, and X; each represent a citrullyl residue or an arginy residue], and at least one of the residues X1 or X, or X; is a citrullyl residue; b) a peptide defined by the sequence GPX,VVEX,HQSACKDS (SEQ ID NO: 2) in which X, and X, each represent a citrullyl residue or an arginyl residue, and at least one of the residues X, or X; is a citrully residue!; c) a peptide defined by the sequence SGIGTLDGFX,HX,HPD (SEQ ID NO: 3) in which X, and X, each represent a citrullyl residue or an arginyl residue, and at least one of the residues X, or X; is a citrully residue!; d) a peptide defined by the sequence VDIDIKIX,SCX,GSCS (SEQ ID NO: 4) in which X, and X, each represent a citrullyl residue or an arginyl residue, and at least one of the residues X, or X; is a citrully residue!; (e) a peptide defined by the sequence X,GHAKSX,PVX;GIHTS (SEQ ID NO: 12) in which X, X' and X' each represent a citrullyl residue or an arginyl residue, and at least one of the residues X, or X', or X' is a citrullyl residue; f) a peptide comprising at least 5 consecutive amino acids, including at least one citrullyl residue, from one of the peptides a) to e) above. According to a particular embodiment, said peptide comprises at least one citrullyl residue, and is selected from the group consisting of: - a peptide defined by the sequence SEQ ID NO: 1 in which at least one residue selected from X, or X, or X is a citrullyl residue, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residue(s); - a peptide defined by the sequence SEQ ID NO: 2 in which at least X, or X; is a citrullyl residue, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residue(s); - a peptide defined by the sequence SEQ ID NO: 3 in which at least X, or X, is a citrullyl residue, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residue(s); - a peptide defined by the sequence SEQ ID NO: 4 in which at least X, or X, is a citrullyl residue, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residue(s); - a peptide defined by the sequence SEQ ID NO: 12 in which at least one residue selected from X, or X; or X; is a citrullyl residue, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residue(s). According to a further particular embodiment, in said hybrid molecule according to the invention, said peptide comprises at least one citrullyl residue, and is chosen from the group consisting of: - a peptide defined by the sequence SEQ ID NO: 1 in which X;, X3, and X; are citrullyl residues, or a peptide of at least 15 amino acids comprising said sequence (this is a peptide of SEQ ID NO: 19); - a peptide defined by the sequence SEQ ID NO: 2 in which X, and X; are citrullyl residues, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residues (this is a peptide of SEQ ID NO: 5); - a peptide defined by the sequence SEQ ID NO: 3 in which X, and X; are citrullyl residues, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residues (this is a peptide of SEQ ID NO: 14); - a peptide defined by the sequence SEQ ID NO: 4 in which X, and X; are citrullyl residues, or a peptide comprising a fragment of at least 5 consecutive amino acids of said sequence containing said citrullyl residues (this is a peptide of SEQ ID NO: 6); - a peptide defined by the sequence SEQ ID NO: 12 in which X;, X; and X; are citrullyl residues, or a peptide comprising a fragment of at least 10 consecutive amino acids of said sequence containing said citrullyl residues (this is a peptide of SEQ ID NO: 18). According to a further particular embodiment, in said hybrid molecule according to the invention, said peptide is selected from the group consisting of: SEQ ID NO: 5 (036-SOcit:3,42), SEQ ID NO: 6 (4171-185cit,1e,181), SEQ ID NO: 7 (@183-197cit1e6,100), SEQ ID NO: 8 (a246-260cit,s3), SEQ ID NO: 9 (a259-273cit,63,271), SEQ ID NO: 10 (0366-380cit;67), SEQ ID NO: 11 (0396-410cit;0), SEQ ID NO: 13 (a411-425cit 45), SEQ ID NO: 14 (a501-515cits10,512), SEQ ID NO: 15 (0546-560cits47), SEQ ID NO: 16 (a561-575cits7;), SEQ ID NO: 17 (a588-602cits9:), SEQ ID NO: 18 (a621-635cit(21,627,600), SEQ ID NO: 19 (B60-74cit40,7274), SEQ ID NO: 20 (B210-224cit,24), SEQ ID NO: 21 (B281-295cit2g5294), SEQ ID NO: 22 (B420-434cit4>, ) and SEQ ID NO: 23 (B433-447cit,16,445), more specifically chosen from the group consisting of: SEQ ID NO: 5 (036-S50cit42,42), SEQ ID NO: 6 (0171-18Scit,78,181), SEQ ID NO: 14 (0501-515cits10512), SEQ ID NO: 18 (a621-635cits21627630) and SEQ ID NO: 19 (B60-74cit(,7274), even more particularly chosen from SEQ ID NO: 18 (a621-635cit621.627,620) and SEQ ID NO: 19 (B60-74cit60,72,74). ; According to one embodiment, in said hybrid molecule according to the invention, said Fc fragment is a human Fc fragment, in particular of IgG, more particularly of IgG1. IgG] can correspond to any allotypic variant, for example G1m3 or nGlm1. As an example, the Fc fragment of IgG1 is represented by SEQ ID NO: 24, SEQ ID NO: 25 (Fc+Qtag) or SEQ ID NO: 26 (Fc+Qtag bis). According to one embodiment, in said hybrid molecule according to the invention, said Fc fragment is wild-type or mutated. The mutation(s) may aim to increase the plasma half-life, decrease it, or modify the effector functions of the Fc fragment. According to a further specific embodiment, said mutated Fe fragment comprises at least the following mutations: - L234A and L235A (LALA), or - L234A, L235A and P329G (LALAPG), or - G236A, S239D and 1332E (GASDIE), or - G236A, S239D, A330L and 1332E (GASDALIE), or - S239D, H268F, S324T and 1332E (SDHFSTIE or SDH), The numbering is indicated in the sequence of a human IgG1 according to the EU index. Such mutations are notably described in the article by Bruhns and Jänsson, Immunol Rev. 2015 Nov;268(1):25-51. Preferably, when the hybrid molecule is used in therapy, the mutated Fc fragment includes at least the GASDIE, GASDALIE, or SDH mutations. According to one embodiment, in said hybrid molecule according to the invention, said fragment Fc exhibits a fucosylation rate of between 0% and 100% of the glycosylated forms. According to the invention, "between 0% and 100%" represents all integer values ​​between 0 and 100, i.e.; 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100%. Low fucosylation of the Fc fragment causes a strong ADCC response. Therefore, according to a particular embodiment, said Fc fragment has a fucosylation rate between 0% and 60% of the glycosylated forms, specifically 50%, 40%, 30%, 20%, 10% or 0%.According to the invention, the fucosylation rate is defined as the average proportion of fucose carried by the Fc fragment, relative to the maximum amount of fucose that an Fc fragment can carry. The Fc fragment and the peptide each have N- and C-terminal ends. The Fc fragment can therefore be linked via its N- or C-terminal end to the N- or C-terminal end of the peptide. In a preferred embodiment, in said hybrid molecule according to the invention, said covalent bond is located between the C-terminal end of said Fc fragment and the N-terminal end of said peptide, or between the N-terminal end of said Fc fragment and the N-terminal end of said peptide. In a preferred embodiment In one embodiment, when a spacer is present, the spacer can be linked to the Fc fragment via its N- or C-terminal end. In another embodiment, when two spacers are present, the first spacer can be linked to the Fc fragment via its N- or C-terminal end, and the second spacer can be linked to the peptide via its N- or C-terminal end, particularly its N-terminal end. Alternatively, the covalent bond between the Fc fragment and the peptide (optionally in the presence of one or more spacers) can be formed on all or part of the Fc fragment. According to the invention, "all or part of the Fc fragment" means that different amino acids constituting the Fc fragment can be involved in a covalent bond with the peptide. According to a preferred embodiment, when at least one spacer is present in said hybrid molecule of the invention, it allows the Fc fragment to be linked to an azide or an alkyne, which will itself be involved in the covalent bond with said peptide. In another embodiment, when at least one spacer is present in said hybrid molecule of the invention, it can also allow the peptide to be linked to an alkyne or an azide, which will itself be involved in the covalent bond with the Fc fragment. In a preferred embodiment, the hybrid molecule according to the invention comprises at least two spacers: a first spacer that allows the Fc fragment to be linked to an azide or an alkyne, and a second spacer that allows the peptide to be linked to an azide (when the Fc fragment is linked to an alkyne) or to an alkyne (when the Fc fragment is linked to an azide). According to an embodiment of the invention, in said hybrid molecule according to the invention, said fragment Fc: - is coupled to at least one azide or an alkyne, such as a cyclooctyne, and in particular DBCO, or - is linked to at least one spacer which is itself coupled to an azide or an alkyne, such as a cyclooctyne, and in particular DBCO, and said peptide is either coupled to an azide or an alkyne, such as a cyclooctyne, and in particular DBCO, or linked to a spacer which is itself coupled to an azide or an alkyne, such as a cyclooctyne, and in particular DBCO, the covalent bond between said Fc fragment and said peptide, possibly in the presence of one or more spacers, being created between the azide and the alkyne. According to an embodiment of the invention, in said hybrid molecule according to the invention, - the Fc fragment is coupled to at least one azide and said peptide is coupled to an alkyne, such as a cyclooctyne, and in particular DBCO, or - the Fc fragment is coupled to at least one alkyne, such as a cyclooctyne, and in particular DBCO, and said peptide is coupled to an azide, the covalent bond between said Fc fragment and said peptide being created between the azide and alkyne. According to an embodiment of the invention, in said hybrid molecule according to the invention: - the Fc fragment is coupled to at least one azide and said peptide is linked to a spacer, itself coupled to an alkyne, such as a cyclooctyne, and in particular DBCO or - the Fc fragment is coupled to at least one alkyne, such as a cyclooctyne, and in particular DBCO, and said peptide is linked to a spacer, itself coupled to an azide or - the Fc fragment is linked to at least one spacer, itself coupled to an azide, and said peptide is coupled to an alkyne, such as a cyclooctyne, and in particular DBCO or - the Fc fragment is linked to at least one spacer, itself coupled to an alkyne, such as a cyclooctyne, and in particular DBCO, and said peptide is coupled to an azide or - the Fc fragment is linked to at least one spacer, itself coupled to an azide, and said peptide is linked to a spacer, itself coupled to an alkyne, such as a cyclooctyne, and in particular DBCO or - the Fc fragment is linked to at least one spacer, itself coupled to an alkyne, such as a cyclooctyne, and in particular DBCO, and said peptide is linked to a spacer, itself coupled to an azide, the covalent bond between said fragment Fc and said peptide, in the presence of one or more spacers, being created between the azide and the alkyne. According to one embodiment, in the molecules described above, more particularly in paragraphs

[0040] to

[0042] , the spacer used is preferably a PEGn spacer, n representing more particularly an integer between 1 and 10. When the hybrid molecule according to the invention comprises at least two PEGn spacers, the values ​​n of the two spacers may be identical or different. For example, the first spacer may be a PEG, and the second spacer may be a PEG; or PEG 4; According to a particularly preferred embodiment, in the molecules described above, more particularly in paragraphs

[0040] to

[0042] , the peptide is derived from human fibrin or fibrinogen and the Fc fragment is a human Fc, preferably from human IgG1. According to the invention, the formation of the covalent bond between the azide and the alkyne corresponds to a so-called "click chemistry" step, the N3 portion of the azide reacting with an alkyne. Azide refers to salts of hydrozotic acid (HN₂O), or organic azides in which one of the nitrogen atoms is covalently bonded to a carbon atom of an organic compound (for example, methyl azide, CH₂N₂). 3) Preferably, azide is represented by the formula N3. An alkyne is understood to be a molecule with the general formula C,H,,2, characterized by the presence of at least one triple bond. Preferably, an alkyne is a cyclooctyne, and even more preferably, a dibenzocyclooctyne (DBCO). The Fc fragment, the peptide, and optionally the spacer(s) are coupled to the alkyne or azide by any conventionally used molecular coupling technique (such as conjugation). Any technique may also be used to covalently link the Fc fragment to the spacer and / or the peptide to the spacer. More specifically, a conjugation technique refers to either enzymatic or chemical conjugation. Enzymatic conjugation, for example, involves conjugation using a transglutaminase, which catalyzes the formation of covalent bonds between free amine groups and glutamine or lysine residues, or using a transpeptidase such as sortase. For further information on enzymatic conjugation, see, for example, patent applications US20160361434 or US20170313787, or the publication Ohtsuka et al., Bioscience, Biotechnology, and Biochemistry, Volume 64, 2000 - Issue 12, "Comparison of Substrate Specificities of Transglutaminases Using Synthetic Peptides as Acyl Donors." The substrate of transglutaminase is, for example, a peptide containing a glutamy! residue. (a Qtag), as represented by SEQ ID NO: 29 (LLQG).A chemical conjugation is understood, for example, as a covalent bond between an isolated cysteine ​​or one participating in a disulfide bridge after its reduction, and, for example, a maleimide. An example of such a conjugation is shown in [Fig. 9]. In this example, the Fc fragment comprises a Qtag peptide, and said Fc fragment is linked to a spacer (itself coupled to an azide), thanks to the action of transglutaminase, which creates a covalent bond between the glutamyl residue of the Qtag and the NH group, carried by the PEGn spacer. According to the invention, the term "coupled" or "molecular coupling" refers to the establishment of a covalent bond, whereby the Fc fragment and / or the peptide and / or the spacer is covalently linked to an alkyne or an azide. The term "linked" also refers to a covalent bond. Thus, for example, the expression "the Fc fragment is coupled to an azide and said peptide is linked to a spacer, itself coupled to an alkyne, such as a cyclooctyne, and in particular DBCO" can also be read as "the Fc fragment is covalently linked to an azide and said peptide is covalently linked to a spacer, said spacer being itself covalently linked to an alkyne, such as a cyclooctyne, and in particular DBCO." According to an embodiment of the invention, said hybrid molecule is represented by: - a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself- even coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit(,72,74) where SEQ ID NO: 18 (a621-635cits21.627.620)2 - an Fc fragment comprising the mutations S239D, H268F, S324T and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit60,72,74) where SEQ ID NO: 18 (0621-635cite21,627,630), - an Fc fragment comprising the L234A, L235A and P329G mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit 672,74) Where SEQ ID NO: 18 (a621-635cite21.627.620)4 - a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself coupled to a cyclooctyne covalently linked to an azide coupled to a PEGn spacer itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cit 6.774) OR SEQ ID NO: 18 (a621-635cite21.627.620), - an Fc fragment comprising the mutations S239D, H268F, S324T and 1332E which is linked to at least one PEGn spacer which is itself coupled to a cyclooctyne covalently linked to an azide coupled to a PEGn spacer itself linked to a peptide re- represented by SEQ ID NO: 19 (B60-74cit60,1274) where SEQ ID NO: 18 (a621-63Scit 621,627,630)s - an Fc fragment comprising the L234A, L235A and P329G mutations which is linked to at least one PEGn spacer which is itself coupled to a cyclooctyne covalently linked to an azide coupled to a PEGn spacer itself linked to a peptide re- presented by SEQ ID NO: 19 (B60-74cit(,7274) OR SEQ ID NO: 18 (a621-635cit 621,627,630)s - a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cite0.72.74) OR SEQ ID NO: 18 (a621-635cite21 627.630), - an Fc fragment comprising the mutations S239D, H268F, S324T and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cit(9,72,74) or SEQ ID NO: 18 (a621-635cite21 627.620), - an Fc fragment comprising the L234A, L235A and P329G mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cite0,72,74) or SEQ ID NO: 18 (0621-635cite21,627,630), - an Fc fragment comprising the mutations G236A, S239D and 1332E, which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide re- presented by SEQ ID NO: 19 (B60-74cite9,1274) where SEQ ID NO: 18 (a621-63Scit 621,627,630). - an Fc fragment comprising the mutations G236A, S239D, A330L and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cit(,72,74) where SEQ ID NO: 18 (a621-635cits21.627.620)2 - an Fc fragment comprising the mutations G236A, S239D and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit 6.774) OR SEQ ID NO: 18 (a621-635cite21.627.620), - an Fc fragment comprising the mutations G236A, S239D, A330L and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit60,7274) or SEQ ID NO: 18 (0621-635cite21,627,630), n preferably representing an integer between | and 10, more particularly 1, 2, 3, 4 or 8. According to an embodiment of the invention, said hybrid molecule is represented by: - a wild-type Fc fragment which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cite9,72,74) or SEQ ID NO: 18 (a621-635cite21,627,630), - an Fc fragment comprising the mutations S239D, H268F, S324T and I332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cite0.7274) OR SEQ ID NO: 18 (0621-635cite21 627.630), - an Fc fragment comprising the L234A, L235A and P329G mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit 672,74) or SEQ ID NO: 18 (a621-635cite21.627.620), - a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cit6072,74) or SEQ ID NO: 18 (a621-635cite21,627,630), - an Fc fragment comprising the mutations S239D, H268F, S324T and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cit(,72,74) where SEQ ID NO: 18 (a621-635cits21.627.620)2 n preferably representing an integer between | and 10, more particularly 1, 2, 3, 4 or 8. According to a more particular embodiment of the invention, said hybrid molecule is represented by: - a wild-type Fc fragment which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cite0.72,34), - an Fc fragment comprising the mutations S239D, H268F, S324T and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit60.22.74), - an Fc fragment comprising the L234A, L235A and P329G mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74cit 60.72.74), - a wild-type Fc fragment that is linked to a PEGn spacer which is itself coupled to at least one azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cite0.72.74) OR SEQ ID NO: 18 (0621-635cite21 627.630), - an Fc fragment comprising the mutations S239D, H268F, S324T and I332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74cit(9,72,74) Or SEQ ID NO: 18 (a621-635cite21.627.630), n preferably representing an integer between 1 and 10, more particularly 1, 2, 3, 4 or 8. Use of hybrid molecules according to the invention In a second aspect, the present invention also relates to a hybrid molecule as defined above, for its use as a drug. More specifically, according to the invention, said hybrid molecules are intended to target and lyse in the body of patients, by ADCC and / or phagocytosis and / or complement activation, all "ACPA-positive" B cells (i.e. B lymphocytes that express on their surface anti-citrullinated protein (ACPA) autoantibodies). Indeed, the hybrid molecule according to the invention binds to ACPA-positive B lymphocytes via the fibrin-derived peptide having at least one citrullyl residue: this is the epitope target of said ACPA. The hybrid molecule according to the invention also binds to cells, enabling the destruction of ACPA-positive B lymphocytes, thanks to its Fc fragment, a natural ligand of Fc receptors (for example, Fc-gamma receptor (FcyR) if the Fc fragment is derived from an IgG), present notably on the surface of macrophages but also of NK (Natural Killer) cells. According to a particular embodiment, the invention relates to a hybrid molecule, as previously defined, for use in the treatment of autoimmune diseases associated with the production of anti-citrullinated protein autoantibodies, in particular Sjögren's syndrome and rheumatoid arthritis. In this embodiment, severe forms of said autoimmune diseases associated with the production of anti-citrullinated protein autoantibodies are targeted, as well as various so-called "borderline" forms with other chronic arthritis, such as psoriatic arthritis or systemic lupus erythematosus. According to one embodiment, the invention also relates to a pharmaceutical composition comprising a hybrid molecule according to any one of the preceding claims, in combination with a pharmaceutically acceptable vehicle. According to the invention, "a pharmaceutically acceptable vehicle" means any formulation that makes the composition suitable for administration to a patient, in any pharmaceutical form. As stated above, the present invention aims to destroy ACPA-positive B lymphocytes. However, ACPA-positive B lymphocytes that have differentiated into ACPA-secreting plasma cells are no longer targeted by the previously described hybrid molecules. According to a particular embodiment, the present invention thus relates to a hybrid molecule as previously described, for use as a drug, in combination with a second hybrid molecule, said second hybrid molecule comprising at least one fibrin-derived peptide having at least one citrullyl residue, said peptide being covalently linked to at least one antibody or at least one antibody fragment, said antibody or fragment being capable of binding to CD38 and / or CD138, one or more spacers being optionally present between said peptide and said antibody or fragment.Such combination therapy makes it possible to specifically target and destroy ACPA-positive plasma and B lymphocyte clones, thereby eliminating ACPA from the patient's body. The antibody used is preferably a monoclonal antibody. According to a particular embodiment, in this second hybrid molecule, the fragment means a portion of antibody comprising an antigen-binding site or a variable region of the antibody. Examples of such antibody fragments include Fab, F(ab”)2, Fv, dsFv, scFv, single-chain fragments such as isolated VH or VL fragments, camelid VHHs, cartilaginous fish VNARs, and multispecific antibodies composed of different fragments, such as bispecific antibodies, nanobodies, diabodies, triabodies, tetrabodies, or tandem scFvs. These fragments are well known to those skilled in the art. Further information concerning these fragments and constructs is described, for example, in International Patent WO2017137579, Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883, or Nelson, mAbs 2:1. 77-83; January / February 2010. Preferably the fragment is a Fab or F(ab')2. According to a particular embodiment, in this second hybrid molecule, said antibody or fragment F(ab*)2 is a bispecific antibody or fragment F(ab”)2 directed against CD38 and another plasma cell target. Alternatively, in this second hybrid molecule, said antibody or fragment F(ab”)2 is a bispecific antibody or fragment F(ab”)2 directed against CD138 and another plasma cell target. According to the invention, an “other plasma cell target” means any molecule expressed on the surface of plasma cells. According to another particular embodiment, in this second hybrid molecule said antibody or fragment F(ab') is a bispecific antibody or fragment F(ab') directed against CD38 and CD138. According to this particular embodiment of the invention, the first and second hybrid molecules are administered simultaneously, separately or spread out over time. According to another embodiment, the hybrid molecule according to the invention can be coupled to at least one radioisotope or to at least one fluorochrome, such as A488 or A647. Such molecules can advantageously be used as molecular tracer tools. According to another embodiment, the invention relates to the in vitro or ex vivo use of a hybrid molecule comprising at least one Fc fragment of an antibody covalently linked to at least one fibrin-derived peptide having at least one citrullyl residue, optionally at least one spacer being present between said Fc fragment and said peptide, as a molecular tool. Such constructs can, in particular, be used to analyze the binding of hybrid molecules to ACPAs and Fc receptors of macrophages and NK cells, as well as to analyze the reactivity of macrophages and NK cells to the binding of the hybrids followed by their bridging by ACPAs. The radioisotopes and / or fluorochromes are preferably coupled to the Fc fragment, even more particularly at the level of the Qtag (if present) or at the level of the lysines. Method for producing hybrid molecules according to the invention In another aspect, the invention also relates to a process for obtaining a hybrid molecule as defined above. According to one embodiment, the invention thus relates to a process for producing a hybrid molecule as defined above, comprising the following steps: - (D) obtaining an azide coupled to an Fc fragment or obtaining an alkyne coupled to an Fc fragment, - (ii) obtaining an alkyne coupled to a peptide or obtaining an azide coupled to a peptide, - (iii) formation of the covalent bond between the azide and the alkyne, - step (i) can be carried out before or after step (ii), or concurrently. According to one embodiment, the invention thus relates to a process for producing a hybrid molecule as defined above, comprising the following steps: - (D) coupling of at least one azide and one Fc fragment, possibly in the presence of at least one spacer, or coupling of at least one alkyne and at least one Fc fragment, possibly in the presence of a spacer, - (ii) coupling of an alkyne and a peptide, possibly in the presence of a spacer, or coupling of an azide and a peptide, possibly in the presence of a spacer, - (iii) formation of the covalent bond between the azide and the alkyne, - step (i) can be carried out before or after step (ii), or concurrently. According to another embodiment, the invention thus relates to a process for producing a hybrid molecule as defined above, comprising the following steps: - () coupling of at least one azide to each monomer of the Fc fragment, possibly in the presence of at least one spacer, or coupling of at least one alkyne to each monomer of the Fc fragment, possibly in the presence of a spacer, - (ii) coupling of an alkyne and a peptide, possibly in the presence of a spacer, or coupling of an azide and a peptide, possibly in the presence of a spacer, - (iii) formation of the covalent bond(s) between the azide and the alkyne, - step (i) can be carried out before or after step (ii), or in such a way concomitant. The sequences of the invention are represented in Table 1 << [Table 1] |Sequence |XPAPPPISGGGYX;AX; |GPX,VVEX;HQSACKDS |VDIDIKIX,SCX;GSCS Sequence Number / Sequence Name if applicable SEQ ID NO: |XPAPPPISGGGYX:AX; 1 SEQ ID NO: |GPX,VVEX:HQSACKDS 2 SEQ ID NO: |SGIGTLDGFX,HX;HPD 3 SEQ ID NO: |VDIDIKIX;SCX;GSCS 4 SEQ ID NO: |XGHAKSX,PVX,GIHTS 12 SEQ ID NO: |GPXVVEXHQSACKDS, X representing a citrullyl residue 5 / a36-50citas,| 4 SEQ ID NO: |VDIDIKIXSCXGSCS, X representing a citrullyl residue 6 / a171-185cit.7s,| 181 SEQ ID NO: |SCSXALAXEVDLKDY, X representing a citrullyl residue 7 / a183-197cit1g6, | bind 190 SEQ ID NO: |PEWKALTDMPQMXME, X representing a citrullyl residue, | 258 SEQ ID NO: |MELEXPGGNEITXGG, X representing a citrullyl residue, | 271 SEQ ID NO: |EXGSAGHWTSESSVS, X representing a citrullyl residue 10 / a366-380cits67 SEQ ID NO: |DSPGSGNAXPNNPDW, X representing a citrullyl residue 11 / 0396-410cit404 SEQ ID NO: |GTFEEVSGNVSPGTX, X representing a citrullyl residue 13 / a411-425cit;s SEQ ID NO: |SGIGTLDGFXHXHPD, X representing a citrullyl residue 14 / a501-515citsio, | Les 512 SEQ ID NO: |SXGSESGIFTNTKES, X representing a citrullyl residue 184 a546-560cits47 SEQ ID NO: |SSHHPGIAEFPSXGK, X representing a citrullyl residue 16 / a561-575cits73 SEQ ID NO: |SYNXGDSTFESKSYK, X representing a citrullyl residue 17 / a588-602citso1 SEQ ID NO: |XGHAKSXPVXGIHTS, X representing a citrullyl residue 18 / a621-635cite1, | 627,630 SEQ ID NO: |XPAPPPISGGGYXAX, X representing a citrullyl residue 19 / B60-74cit 60,72,74 SEQ ID NO: |QKLESDYSAQMEYCX, X representing a citrullyl residue 20 / P210-224cit224 SEQ ID NO: |VIQNXQDGSVDFGXK, X representing a citrullyl residue 21; p281-295citrgs, | 294 SEQ ID NO : |PXKQCSKEDGGGWWY, X représentant un résidu citrullyl 22 / p420-434cit41 SEQID NO : |\WYNXCHAANPNGXYY, X représentant un résidu citrullyl 23 / p433-447cit4s6, | 445 SEQ ID NO : APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDYSHEDPEVK | 24 / Fragment |ENWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL Fe NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK SEQID NO : |LLQGARSDATHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP 25 / Fragment |EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS Fc + Qtag TYRVVSVLTVLHQODWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK SEQ ID NO : |AHGHGHGLLQGARSDATHTCPPCPAPELLGGPSVFLFPPKPKD 26 / Fragment |TLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKP Fc + Qtag bis |JREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: |GPRVVERHQSACKDSDWPFCSDEDWNYKCPSGCRMKGLIDE 27 / Fibrin chain "to |VNQDFTNRINKLKNSLFEYQKNNKDSHSLTTNIMEILRGDFSS ANNRDNTYNRVSEDLRSRIEVLKRKVIEKVQHIQLLQKNVRA QLVDMKRLEVDIDIKIRSCRGSCSRALAREVDLKDYEDQQKQ LEQVIAKDLLPSRDRQHLPLIKMKPVPDLVPGNFKSQLQK VPP EWKALTDMPQMRMELERPGGNEITRGGSTSYGTGSETESPRN PSSAGSWNSGSSGPGSTGNRNPGSSGTGGTATWKPGSSGPGST GSWNSGSSGTGSTGNQNPGSPRPGSTGTWNPGSSERGSAGHW TSESSVSGSTGQWHSESGSFRPDSPGSGNARPNNPDWGTFEEV SGNVSPGTRREYHTEKLVTSKGDKELRTGKEKVTSGSTTTRR SCSKTVTKTVIGPDGHKEVTKEVVTSEDGSDCPEAMDLGTLSG IGTLDGFRHRHPDEAAFFDTASTGKTFPGFFSPMLGEFVSETES RGSESGIFINTKESSSHHPGIAEFPSRGKSSSYSKQFTSSTSYNR GDSTFESKSYKMADEAGSEADHEGTHSTKRGHAKSRPVRGIH TS SEQID NO: |GHRPLDKKREEAPSLRPAPPPISGGGYRARPAKAAATQKKVER 28 / Chaine B_|KAPDAGGCLHADPDLGVLCPTGCQLQEALLQQERPIRNSVDE of fibrine | |LNNNVEAVSQTSSSSEQYMYLLKDLWQKRQKQVKDNENVVN EYSSELEKHQLYIDETVNSNIPTNLRVLRSILENLRSKIQKLESD VSAQMEYCRTPCTVSCNIPVVSGKECEENRKGGETSEMYLIQP DSSVKPYRVYCDMNTENGGWTVIQNRQDGSVDFGRKWDPY KQGFGNVATNTDGKNYCGLPGEYWLGNDKISQLTRMGPTEL LIEMEDWKGDKVKAHYGGFTVQNEANKYQISVNKYRGTAGN ALMDGASQLMGENRTMTIHNGMFFSTYDRDNDGWLTSDPRK QCSKEDGGGWWYNRCHAANPNGRY YWGGQOYTWDMAKHG TDDGVVWMNWKGSWYSMRKMSMKIRFFPQQ |SEQ IDNO: |LLQG SEQID NO: |LLQG 29 (Exemple de Qtag) SEQ ID NO : |MFSMRIVCLVLSVYVGTAWTADSGEGDFLAEGGGVRGPRVVE 30 RHQSACKDSDWPFCSDEDWNY KCPSGCRMKGLIDEVNQDFT Chaine à de (i|NRINKLKNSLFEYQKNNKDSHSLTTNIMEILRGDFSSANNRDN brinogène TYNRVSEDLRSRIEVLKRKVIEKVQHIQLLQKNVRAQLVDMK RLEVDIDIKIRSCRGSCSRALAREVDLKDYEDQQKQLEQVIAK DLLPSRDRQHLPLIKMKPYVPDLVPGNFKSQLQK VPPEWKALT DMPQMRMELERPGGNEITRGGSTSYGTGSETESPRNPSSAGSW NSGSSGPGSTGNRNPGSSGTGGTATWKPGSSGPGSTGSWNSGS SGTGSTGNQNPGSPRPGSTGTWNPGSSERGSAGHWTSESSVSG STGQWHSESGSFRPDSPGSGNARPNNPDWGTFEEVSGNVSPGT RREYHTEKLVTSKGDKELRTGKEKVTSGSTTTTRRSCSKTVTK TVIGPDGHKEVTKEVYVTSEDGSDCPEAMDLGTLSGIGTLDGFR HRHPDEAAFFDTASTGKTFPGFFSPMLGEFVSETESRGSESGIF TNTKESSSHHPGIAEFPSRGKSSSYSKQFTSSTSYNRGDSTFESK SYKMADEAGSEADHEGTHSTKRGHAKSRPVRGIHTS SEQ ID NO: |MKRMVSWSFHKLKTMKHLLLLLLCVFLVKSQGVNDNEEGFF 31 SARGHRPLDKKREEAPSLRPAPPPISGGGYRARPAKAAATQKK Chaine B de fi-VERKAPDAGGCLHADPDLGVLCPTGCQLQEALLQQERPIRNS brinogène VDELNNNVEAVSQTSSSSFQYMYLLKDLWQKRQKQVKDNEN VVNEYSSELEKHQLYIDETVNSNIPTNLRVLRSILENLRSKIQKL ESDVSAQMEYCRTPCTVSCNIPVVSGKECEEIIRKGGETSEMYL IQPDSSVKPYRVYCDMNTENGGWTVIQNRQDGSVDFGRKWD PYKQGFGNVATNTDGKNYCGLPGEYWLGNDKISQLTRMGPT ELLIEMEDWKGDKVKAHYGGFTVQNEANKYQISVNKYRGTA GNALMDGASQLMGENRTMTIHNGMFFSTYDRDNDGWLTSDP RKQCSKEDGGGWWYNRCHAANPNGRYYWGGQYTWDMAK HGTDDGVVWMNWKGSWYSMRKMSMKIRPFFPQQ Summary table of the invention sequences Other features, details and advantages of the invention will become apparent from the accompanying Figures and examples which illustrate the invention and are in no way intended to limit it. In the exemplified hybrid molecules, it is the N-terminal end of the Fc fragment that is linked to a PEGn spacer (except in the case indicated by Cter-PEG (see [Fig. 4])), and it is always the N-terminal end of said peptide that is linked to cycloctyn DBCO or to a second PEGn spacer as appropriate. Furthermore, in the exemplified hybrid molecules, in the PEGn spacer linked to the Fc fragment, n most commonly represents 3 or 4, and in the PEGn spacer linked to the peptide, the PEGn spacer represents 3 or 8, although any other value of n, particularly between 1 and 10, can be used. Brief description of the Figures Fig.1 [Fig.1] represents the diagram of an example of a hybrid molecule according to the invention. An optional spacer is shown between the Fc fragment of the antibody and the fibrin-derived peptide with a citrullyl residue (called the "citrullinated peptide"). Fig. 2 [Fig.2] represents a B lymphocyte expressing on its surface trans-membrane ACPAs linked to a hybrid molecule according to the invention, said hybrid molecule being itself linked by the Fe fragment to an NK cell. The NK cell can thus destroy the B lymphocyte via ADCC. More specifically, this figure shows a B cell (or B lymphocyte) expressing an ACPA-type BCR on its surface, which interacts specifically with the citrullinated peptide carried by the hybrid molecule. Engagement of the Fc fragment carried by the same hybrid molecule with FcyRITIa (CD16a) expressed on the surface of an NK cell activates ADCC and induces the specific destruction of the ACPA-positive B lymphocyte. (ACPA, Anti-Citrullinated Protein Autoantibodies; ADCC: Antibody-Dependent Cell Cytotoxicity; BCR, B-Cell Receptor; FcyR, Fc-gamma Receptor; NK cell, Natural Killer cell). Fig. 3 [Fig.3] represents a B lymphocyte expressing on its surface trans-membrane ACPAs linked to a hybrid molecule according to the invention, said hybrid molecule being itself linked by the Fc fragment to a macrophage. The macrophage can then destroy the B lymphocyte by phagocytosis. More specifically, this figure shows B cells (or B lymphocytes) that express an ACPA-type BCR on their surface and interact specifically with citrullinated peptides carried by hybrid molecules. The engagement of the Fc fragments carried by these same hybrid molecules with different FcyRs expressed on the surface of a macrophage will activate ADP, i.e., phagocytosis, and induce the specific destruction of ACPA-positive B lymphocytes. (ACPA, Anti-Citrullinated Protein Autoantibodies; ADP, Antibody-Dependent Phagocytosis; BCR, B-Cell Receptor; FcyR, Fc-gamma Receptor). Fig. 4 [Fig.4] represents the reactivity of several hybrid molecules including the SEQ ID NO peptide: 19 (P60-74cit:072,74) towards ACPA. B60-74 represents the peptide of SEQ ID NO: 19. Fc-WT-B60-74 represents a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO which is coupled to a peptide represented by SEQ ID NO: 19 (B60-74:160,72,4). Fc-LALA-B60-74 represents an Fc fragment comprising the L234A, L235A and P329G mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO which is coupled to a peptide represented by SEQ ID NO: 19. Fc-SDH-B60-74 represents an Fc fragment comprising the S239D, H268F, S324T and 1332E mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO coupled to a peptide represented by SEQ ID NO: 19.Fc-WT-PEG-B60-74 represents a wild-type Fc fragment that is linked to at least one PEGn spacer, which is itself coupled to an azide covalently linked to a cyclooctyne DBCO coupled to a PEGn spacer, which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74.160,7,74). Fc-SDH-PEG-B60-74 represents an Fc fragment comprising the S239D, H268F, S324T, and 1332E mutations, which is linked to at least one PEGn spacer, which is itself coupled to an azide covalently linked to a cyclooctyne DBCO coupled to a PEGn spacer, which is itself linked to a peptide represented by SEQ ID NO: 19 (B60-74.160,72,74). Fc-SDH(Cter)-PEG-B60-74 corresponds to Fc-SDH-PEG-B60-74, except that in the hybrid Fc-SDH(Cter)-PEG-B60-74, the first PEGn is . fixed at the C-terminal end of the Fc fragment, unlike the other examples where the first PEGn is fixed at the N-terminal end. n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4, or 8. Fig. 5 [Fig.5] represents the reactivity of a hybrid molecule comprising the SEQ ID NO peptide: 18 (0621-635cit421,627,630) towards ACPA. 621-635 represents the peptide of SEQ ID NO: 18. Fc-W'T-PEG-a621-635 re- presents a wild-type (WT) Fc fragment that is linked to at least one PEGn spacer, which is itself coupled to an azide covalently linked to a cyclooctyne DBCO coupled to a PEGn spacer, which is itself linked to a peptide represented by SEQ ID NO: 18. Fc-SDH-PEG-0621-635 represents an Fc fragment comprising the mutations S239D, H268F, S324T, and 1332E, which is linked to at least one PEGn spacer, which is itself coupled to an azide covalently linked to a cyclooctyne DBCO coupled to a PEGn spacer, which is itself linked to a peptide represented by SEQ ID NO: 18. n represents a number between | and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4 or 8. Fig. 6 [Fig.6] represents the reactivity of a recombinant human monoclonal ACPA (clone 2H06), comprising an unmodified Fc or one modified with SDH-type mutations, towards hybrid molecules comprising the SEQ ID NO peptide: 18. FcWT-PEG-a621-635 represents a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 18. FESDH-PEG-a621-635 represents an Fc fragment comprising the mutations S239D, H268F, S324T and 1332E, which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 18. n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4 or 8. Fig. 7 [Fig.7] represents a method for manufacturing a hybrid molecule according to the invention, comprising the scheme for derivation and conjugation of the Fc fragments. Fig. 8 [Fig. 8] represents the evolution of the percentage of phagocytosis and lymphocytes B in the presence of hybrid molecules Fc-WT-PEG-0w621-635arg and Fc-WT-PEG-a621-635cit. The results of the 6 experiments presented in Example 6 are shown (N=6). The P value is as follows: * < 0.05 ** < 0.01 *** < 0.001. Fig. 9 [Fig.9] represents the lysis by human NK cells of transduced human malignant plasmablastic B cell line expressing a recombinant monoclonal ACPA on its membrane, in the presence of FcWT-N3-DBCO-PEG3-a621-635Cit and FeSDH-N3-DBCO-PEG3-a621-635Cit hybrids. Nalm6 represents the case where only Nalm6 cells were incubated; Nalm6+NK the case where Nalm6 cells were incubated with NK cells; WTaCIT the case where the WTaCIT hybrid was incubated with Nalm6 cells and NK cells; WTaArg the case where the WTaArg hybrid was incubated with Nalm6 cells and NK cells; SDHaCIT the case where the SDHaCIT hybrid was incubated with Nalm6 cells and NK cells; and SDHaArg the case where the SDHaArg hybrid was incubated with Nalm6 cells and NK cells. Examples Example 1: Example of the production of a hybrid molecule according to the invention The hybrid molecule described here comprises the following construct: an Fc fragment covalently linked to at least one PEGn spacer, itself coupled to an azide, said azide being covalently linked to an alkyne, which is itself coupled to a PEGn spacer linked to a citrullinated peptide. Such a molecule can be read as: Fc-PEGn-N3-DBCO-PEGn-citrullinated peptide. The two PEGn subunits may be identical or different (for example, the first PEGn subunit is PEG; and the second PEGn subunit is PEG;). 1. Synthesis of an NH2-PEGn-N; (Le. a spacer coupled to an azide at one end and possessing a free amine function at the other end). 2. NH₃-PEGn-N₃ is reacted with an Fc fragment possessing a Qtag and transglutaminase, preferably for 16 hours at 37°C. This "derivatization" step is preferably performed with 20 times more moles of NH₃-PEGn-N₃ than moles of Fc fragment. Transglutaminase is used at a concentration of 1 SU / µmol per Qtag present (on one or both monomers). Optionally, desalting can be performed to remove excess spacer not bound to the Fc fragment after this step. An Fc-PEGn-N₃ is thus obtained. If the Fc fragment has two Qtags (one on each monomer), then the Fc fragment can carry two PEGn-N₃. 3. Synthesis of a citrullinated Cys-PEGn-peptide (i.e., a spacer bound to a peptide at one end and possessing a free cysteine ​​at the other end). An alkyne, for example a DBCO, is then coupled to the citrullinated Cys-PEGn-peptide at the cysteine, and a citrullinated DBCO-PEGn-peptide is thus obtained. 4. "Click" reaction: coupling between N and DBCO. DBCO-PEGn-citrullinated peptide is reacted with Fc-PEGn-N, preferably with 10 times more moles of DBCO-PEGn-citrullinated peptide than moles of Fc-PEGn-N. The click reaction occurs primarily at room temperature and is almost complete after 4 hours. 5. Preparation of the hybrid molecule: Fc-PEGn-N;-DBCO-PEGn-citrullinated peptide. This embodiment is illustrated in [Fig.7]. Similarly, an Fc-PEGn-DBCO and an N,-PEGn-citrullinated peptide can be obtained and then coupled to obtain Fc-PEGn-DBCO-N,-PEGn-citrullinated peptide. Likewise, an Fc-PEGn-DBCO and an N-citrullinated peptide can be obtained, or an Fc-PEGn-N and a DBCO-citrullinated peptide, and then coupled to obtain Fc-PEGn-DBCO-Nz-citrullinated peptide or Fc-PEGn-N,-DBCO-citrullinated peptide, respectively. Example 2: Reactivity of ACPA purified by affinity chromatography on citrullinated peptides and eluted at pH 3 (pH 3 fraction), towards the hybrid molecules according to the invention The ACPAs (here ACPA, pH3 fraction) used are ACPAs obtained from serum of ACPA-positive rheumatoid arthritis patients. Such ACPAs were obtained by a classic column affinity chromatography method known to those skilled in the art, using as bound antigens one or more of the five immunodominant peptides of the invention (see SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 14, SEQ ID NO: 18 or SEQ ID NO: 19). a. Examples with hybrid molecules containing the B60-74cit peptide. ELISA microtiter plate wells were coated by passive adsorption with 100 µL of a solution containing either the B60-74cit peptide (SEQ ID NO: 19, also known as fB60-74), or a hybrid molecule: Fc-WT-B60-74cit, Fc-LALA-B60-74cit, Fc-SDH-B60-74cit, Fc-WT-PEG-B60-74cit, Fc-SDH-PEG-B60-74cit, or Fc-SDH(Cter)-PEG-B60-74cit. Each of these solutions was used at a concentration of 5 µg / mL in PBS (Phosphate Buffered Saline) buffer and incubated overnight at 4°C. The non-citrullinated peptide and hybrid molecules constructed with the non-citrullinated peptide (B60-74arg, corresponding to a SEQ ID NO: 19 peptide in which the citrullyl residues have been replaced by arginyl residues) were used at the same concentration as negative controls. The wells were then saturated with 2% BSA (Bovine Serum Albumin) for 1 h at 4°C.After washing, the purified ACPAs were incubated at 1, 0.5, or 0.25 µg / mL, diluted in 2% PBS BSA 2M NaCl buffer for 1 h at 4°C. After washing, the reactivity of the ACPAs was detected using a secondary anti-Fab antibody of human IgG diluted 1 / 2500 in 2% PBS BSA buffer. The results are expressed as ADO (Optical Delta Density). corresponding to the DO obtained with peptide B60-74cit or with hybrid molecules constructed with peptide B60-74cit, subtracted respectively from the DO obtained with peptide B60-74arg or with the corresponding hybrid molecules constructed with peptide B60-74arg. The results are presented in [Fig. 4]. They show a dose-dependent reactivity of ACPA purified on B60-74cit peptide towards the hybrid molecules Fc-WT-B60-74cit, Fc-LALA-B60-74cit, Fc-SDH-B60-74cit, Fc-WT-PEG-B60-74cit, Fc-SDH-PEG-B60-74cit, or Fc-SDH(Cter)-PEG-B60-74cit. They show that, when included in the different hybrids, the citrullinated peptides remain fully reactive with ACPA. b. Examples with hybrid molecules containing the peptide a621-635cit ELISA plate wells were coated with 100 jL of a solution containing the peptide a621-635cit (SEQ ID NO: 18, also known as a621-635) or a hybrid molecule Fc-WT-PEG-a621-635cit or Fc- SDH-PEG-a621-635cit, at a concentration of 5 µg / mL in PBS (Phosphate Buffered Saline), was incubated overnight at 4°C. The non-citrullinated peptide a621-635arg and the corresponding hybrid molecules constructed with the non-citrullinated peptide (a621-63Sarg, corresponding to a peptide of SEQ ID NO: 18 in which the citrullyl residues have been replaced by arginyl residues) were used at the same concentration as negative controls. The wells were then saturated with 2% BSA (Bovine Serum Albumin) in PBS buffer for 1 h at 4°C. After washing, the purified ACPAs were incubated at 4, 2, and 1 µg / mL diluted in PBS 2% BSA 2M NaCl buffer for 1 h at 4°C. After washing, ACPA reactivity was detected using a secondary anti-Fab antibody of human IgG diluted 1 / 2500 in 2% BSA PBS buffer.The results are expressed in ADO (Optical Delta Density), corresponding to the OD obtained with the peptide a621-63Scit or with the hybrid molecules constructed with the peptide œ621-63Scit, subtracted respectively from the OD obtained with the peptide a621-635arg or with the hybrid molecules constructed with the peptide a621-635arg. . The results are presented in [Fig. 5]. They show a strong dose-dependent reactivity of ACPAs purified on the α621-635cit peptide towards the hybrid molecules Fc-WT-PEG-α621-635cit and Fc-SDH-PEG-α621-635cit. The reactivity of the ACPAs towards the hybrid molecules is comparatively higher, while their epitope density is lower than that of the α621-635cit peptide. Example 3: Reactivity of recombinant monoclonal 2H06 ACPAs in wild type (WT) or mutated form (SDH mutation) towards the hybrid molecules according to the invention The ACPA used here is a recombinant monoclonal human ACPA (clone 022014CCP14CFCT2H06, also known as 2H06). Such an ACPA can be obtained as described in Titcombe PJ, Wigerblad G., Sippl N., Zhang N., Shmagel AK, Sahlstrôm P., Zhang Y., Barsness LO, Ghodke-Puranik Y., Baharpoor A. et al. Pathogenic Citrulline-Multispecific B Cell Receptor Clades in Rheumatoid Arthritis. Arthritis & Rheumatology 2018, 70 (12), 1933-1945. https: / / doi.org / 10.1002 / art.40590. The ACPA VH 2H06 has the accession number MH629710.1 under Genbank, and the VL has the accession number MH629700.1. ELISA plate wells were coated with 100 jL of a solution containing either the hybrid molecule Fc-WT-PEG-a621-635cit or Fc-SDH-PEG-a621-635cit, used at a concentration of 5 µg / mL in PBS (Phosphate Buffered Saline) buffer and incubated overnight at 4°C. Hybrid molecules constructed with a non-citrullinated peptide (a621-635arg) were used at the same concentration as negative controls. The wells were then saturated with 2% BSA (Bovine Serum Albumin) PBS buffer for 1 h at 4°C. After washing, the recombinant monoclonal ACPAs 2H06, WT and SDH, were incubated at 40, 20 and 10 µg / mL, diluted in 2% PBS BSA 2M NaCl buffer for 1 h at 4°C. After washing, their reactivities were detected using a secondary anti-Fab antibody of human IgG diluted 1 / 2500 in 2% PBS BSA buffer.The results are expressed in ADO (Delta-Optical Density), corresponding to the OD obtained with the hybrid molecules constructed with the peptide a621-635cit subtracted from the OD obtained with the hybrid molecules constructed with the negative control peptide a621-63Sarg. The hybrid molecules Fc-WT-PEG-a621-635cit and Fc-SDH-PEG-a621-635cit are identical to those used in Example 2. The results are presented in [Fig.6]. The results show a strong dose-dependent reactivity of monoclonal WT and SDH ACPAs towards the hybrid molecules Fc-WT-PEG-a621-635cit and Fc-SDH-PEG-a621-635cit. Example 4: Binding of hybrid molecules to macrophages at 2h and 20h, at physiological temperature Human macrophages, differentiated in vitro in the presence of M-CSF (100 ng / mL) from CD14+ monocytes isolated from the peripheral blood of a healthy subject, were incubated at 500,000 cells / well in the presence of hybrid molecules at 5 µg / mL: FcWT-N3-DBCO-B60-74Cit (a wild-type Fc fragment linked to a PEGn spacer, which is itself coupled to an azide covalently linked to cyclooctyne DBCO, which is coupled to a peptide represented by SEQ ID NO: 19, referred to as WT in Tables 2 and 3), and FeSDHFSTIE-N3-DBCO-B60-74Cit (an Fc fragment containing the S239D, H268F, S324T, and I332E mutations, linked to a PEGn spacer, which is itself coupled to an azide). covalently linked to a DBCO which is coupled to a peptide represented by SEQ ID NO: 19, referred to as SDH in Tables 2 and 3) or FcLALAPG-N3-DBCO-B60-74Cit (an Fc fragment comprising the L234A mutations, L235A and P329G, which is linked to a PEGn spacer that is itself coupled to an azide covalently linked to a cyclooctyne DBCO, which is coupled to a peptide represented by SEQ ID NO: 19 (designated LALAPG in Tables 2 and 3), for 2 h or 20 h at 37°C. The binding of the hybrid molecules to the surface of macrophages is demonstrated and quantified by cytofluorimetry (FACS Canto IT) after incubation of the macrophages with an anti-Fc antibody coupled to FITC, used at a concentration of 1 / 1000. In the constructs, n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4, or 8. The results are presented in Tables 2 and 3 below. "NM" and "ANTI FC" represent the well containing macrophages incubated without antibodies or with the anti-Fc antibody alone, respectively. [Tables 2] Results at 2 a.m. [Tables 3] Macrophages 275 1003 404 1457 Results at 8pm The results presented in Tables 2 and 3 show that the hybrid molecules FcWT-N3-DBCO-B60-74Cit and FESDHFSTIE-N3-DBCO-B60-74Cit, at a physiological temperature of 37°C, bind to the macrophage membrane as early as the second hour and are still present 20 hours later. These results also show that the binding of the FESDHFSTIE-N3-DBCO-B60-74Cit hybrid is greater than that of the wild-type FcWT-N3-DBCO-B60-74Cit. Example 5: Phagocytosis induced by the Fc-SDH hybrid B60citrullinated peptide when B lymphocytes are armed via their FcyRIIb (CD32b) with purified ACPA. Freshly purified human B lymphocytes from peripheral blood of healthy donors by CD19+ magnetic sorting were labeled with PKH-67 green (Paul Karl Horan / fluorescent lipid marker) and then incubated with purified ACPA (pH3 fraction, obtained as in Example 2) on B60-74cit peptide (SEQ ID NO: 19) at a concentration of 5 ug / mL for 30 min at 37°C. Subsequently, the cells were washed and then placed in the presence of the FOSDHFSTIE-N3-DBCO-PEG3-B60-74Cit hybrid (an Fc fragment comprising the S239D, H268F, S324T and 1332E mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO which is coupled to a PEGn spacer itself linked to a peptide represented by SEQ ID NO: 19). This construct is referred to as CIT in Table 4 below).The cells were also treated with the FcSDHFSTIE-N3-DBCO-PEG-B60-74Arg hybrid (which corresponds to the FcSDHFSTIE-N3-DBCO-PEG3-B60-74Cit construct in which the B60-74 peptide is not citrullinated). This construct is referred to as NCIT in Table 4 below. The cells were treated with the hybrids at 10 µg / mL for 30 min at 37°C. After washing, the cells were incubated with macrophages (labeled with PKH-26 red) at a ratio of 1 B lymphocyte per macrophage for 2 h at 37°C. The cells were then detached and analyzed by flow cytometry. Cells exhibiting dual fluorescence (PKH-67 green / PKH-26 red) correspond to macrophages that phagocytosed lymphocytes. The different cell populations are expressed as a percentage of the total cell population: percentage of phagocytosis and percentage of B lymphocytes.In the constructions, n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4 or 8. The results are presented in Table 4 in four rows which correspond to four independent experiments, . [Tables 4] % Phagocytosis [NCIT CcIT % (ACIT-NCI | T) | - 40% - 40% 33% -16% -12% % Population B % NCIT — joT (ACIT-NCI T) [+91 46.1 329 +26% = |405 30.5 +46% | |77.1 66.7 +#2% |M73 69.3 Percentage of phagocytosis and percentage of B lymphocytes The results obtained confirm that phagocytosis activity is increased in the presence of citrullinated hybrids (increased phagocytosis associated with a decrease in the B lymphocyte population). Indeed, in the 4 independent experiments, a significant increase in the percentage of phagocytosis, always associated with a significant decrease in the B lymphocyte population, was observed when the B lymphocytes were coated with the FcSDHFSTIE-N3-DBCO-PEG3-B60-74Cit (CIT) hybrid versus FOSDHFSTIE-N3-DBCO-PEG3-B60-74Arg (NCIT) hybrid. Example 6: Phagocytosis of B lymphocytes loaded with recombinant human monoclonal ACPA 2H06 mutated SDH, by macrophages armed with the Fc-WT-PEG-0621-635cit hybrid. Freshly purified human B lymphocytes from peripheral blood of healthy donors by CD19+ magnetic sorting were labeled with PKH-67 green (Paul Karl Horan / fluorescent lipid marker) and then incubated for 1h at 37°C with recombinant human monoclonal ACPA 2H06 with SDH-mutated Fc, at a concentration of 10 ug / mL. Such antibodies can be obtained as in Example 3. In parallel, macrophages labeled with PKH-26 red were exposed to the hybrids Fc-WT-PEG-a621-635cit (a wild-type Fc fragment which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a DBCO which is coupled to a PEGn spacer which is itself linked to the peptide re- presented by SEQ ID NO: 18) and Fc-WT-PEG-a621-635arg (this is the hybrid Fc-WT-PEG-a621-635cit, except that the peptide is not citrullinated), at 5 pg / mL for | h at 37°C.After washing, the cells were incubated at a ratio of 1 B lymphocyte per macrophage for 2 hours at 37°C. The cells were then detached and analyzed by flow cytometry. The percentage of phagocytosis corresponds to the percentage of cells labeled with the two fluorochromes (PKH-67 green / PKH-26 red). In the constructs, n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4, or 8. The results are presented in Table 5 in six rows which correspond to five independent experiments. NCIT represents the result with the peptide Fc-WT-PEG-a621-635arg, CIT represents the result with the peptide Fc-WT-PEG-0621-635cit, and (ACIT-NCIT) represents the difference between the OD obtained in the presence of Fc-WT-PEG-a621-635cit and the OD obtained in the presence of Fc-WT-PEG-0621-635arg, divided by the OD obtained in the presence of Fc-WT-PEG-0621-635arg. [Tables 5] % Phagocytosis NCIT CIT % (ACIT-NCIT) +63% +21% +58% +42% |+ 27% +28% % (ACIT-NCIT) -8% |-3% - 15% -12% -17% -12% Percentage of phagocytosis and percentage of B lymphocytes The results show that phagocytic activity is increased in the presence of citrullinated hybrids: phagocytosis increased (from 21% to 63%), associated with a decrease in the B lymphocyte population (from 3% to 17%). In each of the six experiments, the percentage of double-positives was higher, indicating that phagocytosis was increased and the B lymphocyte population decreased when macrophages were armed with Fc-WT-PEG-a621-635cit (CIT) hybrids versus Fc-WT-PEG-a621-635arg (NCIT) hybrids. The results are also presented in Figures 8A and 8B. Example 7: Stability of binding of Fc-SDH A488 and citrullinated Fc-SDH B60 peptide hybrids to NK cells after 30 min, 24 h, and 48 h at physiological temperature NK cells were incubated for 30 min, 24 h, or 48 h at 37°C in the presence of FcSDHFSTIE-N3-DBCO-A488 (an Fc fragment containing the mutations S239D, H268F, S324T, and 1332E, which is linked to at least one PEGn spacer, which is itself coupled to an azide covalently linked to a DBCO, the molecule being labeled with fluorochrome A488) or of FESDHFSTIE-N3-DBCO-PEG3-B60-74cit-lysineA488 (an Fc fragment comprising the S239D, H268F, S324T, and I332E mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a DBCO which is coupled to a PEGn spacer linked to a peptide of SEQ ID NO: 19, the molecule being labeled with fluorochrome A488 which is linked to the molecule via a lysine). The binding of these two fluorescent probes to NK cells was analyzed by cytofluorimetry. In the constructions, n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4 or 8. The results are presented in Tables 6 (30 minutes), 7 (24 hours), and 8 (48 hours) below. NM represents unlabeled NK cells, without antibodies. [Table 6] RATIO / 8.163 MFI [NM 562 FeSDHFSTIE-N3-DBCO-PEG |4588 3-B60-74cit-lysineA488 ps 2973 -|5.289 Results in 30 minutes [Tables 7] RATIO / 7.324 4,212 MFI NM 558 FeSDHFSTIE-N3-DBCO-PEG [4091 3-B60-74cit-lysineA488 FeSDHFSTIE-N3-DBCO-A488|2353 Results in 24 hours [Tables 8] RATIO / 8.77 MFI NM 494 a rn 4336 3-B60-74cit-lysineA488 |FeSDHFSTIE-N3-DBCO-A488 1710 3,460 Results in 48 hours The results presented in Tables 6 to 8 show that FcSDHFSTIE-N3-DBCO-A488 and FESDHFSTIE-N3-DBCO-PEG3-B60-74cit-lysine A488 remain attached to the membrane of NK cells for at least 48 hours at physiological temperature and that the attachment of the peptide to the Fc fragment does not prevent its interaction with the Fc gamma receptors of NK cells. Example 8: Binding on NK cells of the various forms of Fc (WT, SDH and LALAPG) labeled with the fluorochrome A647. NK cells were incubated for 30 min at 37°C in the presence of the FcSDHFSTIE-N3-DBCO-A647 fragment (an Fc fragment containing the S239D, H268F, S324T, and 1332E mutations, which is linked to at least one PEGn spacer that is itself coupled to an azide covalently linked to a DBCO, the molecule being labeled with the fluorochrome A647) at 10 µg / mL. This construct is referred to as SDH in Table 9 below. The experiment was also carried out with the following hybrids: FcWT-N3-DBCO-A647 (a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a DBCO, the molecule being labeled with the fluorochrome A647), or FcLALAPG-N3-DBCO-A647 (an Fc fragment comprising the L234A, L235A and P329G mutations that is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a DBCO, the molecule being labeled with the fluorochrome A647), at the same concentrations.These two constructs are respectively designated WT and LALAPG in Table 9 below. In the constructs, n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4 or 8. The analysis of the binding of Fc fragments to NK cells was performed by cytofluorometry. The results are presented in Table 9. [Tables 9] MFI RATIO 212.08 / 1105.89 5.21 38545.45 |181.74 450.43 2.12 NE WT 10 pg / mL |sDH 10 pg / mL LALAPG 10 pg / mL Results The results presented in Table 9 show that the FcWT-N3-DBCO-A647 and FeSDHFSTIE-N3-DBCO-A647 fragments bind to the NK cell membrane. FeSDHFSTIE-N3-DBCO-A647 binds much more strongly than FcWT-N3-DBCO-A647. Example 10: Binding of the Fc-SDH fragment labeled with fluorochrome A647 onto NK cells compared to the binding of the same hybrids in the presence of human IgG at increasing concentrations, up to the physiological serum concentration. NK cells were incubated for 30 min at 37°C either in the presence of the FcSDHFSTIE-N3-DBCO-A647 fragment (an Fc fragment comprising the S239D, H268F, S324T and 1332E mutations which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a DBCO, the molecule being labeled with the fluorochrome A647) at 10 µg / mL, or in the presence of this same FcSDHFSTIE-N3-DBCO-A647 fragment at 10 µg / mL, co-incubated with human IgG at increasing concentrations (1, 10, 100, 1,000, 10,000 µg / mL). In the constructs, n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4 or 8. The binding of the FcSDHFSTIE-N3-DBCO-A647 fragment (called SDH) to NK cells was analyzed by cytofluorometry. The results are presented in Table 10. [Tables 10] [NEG SDH 10 ug / mL SDH (1pg / mL 1gG) SDH (10pg / mL IgG) SDH (100pg / mL IgG) SDH (1000pg / mL IgG) SDH (10000pg / mL IgG) MFI RATIO 21208 3854545 |181.74 [37899.98 |178.70 (3877143 [182.81 36270.21 |171.02 (2926.19 |139.22 2048626 |96.59 Results The results show a dose-dependent decrease in the binding of FeSDHFSTIE-N3-DBCO-A647 to NK cells from 100 ug / mL of IgG, but this remains effective and high, even in the presence of an IgG concentration 1,000 times greater than that of the Fc fragment (10,000 ug / mL) which corresponds to the physiological serum concentration of IgG in humans. Example 11: Lysis by human NK cells of cells from a malignant human B cell line with plasmablasts expressing a recombinant monoclonal ACPA on its membrane, in the presence of FcWT- hybrids N3-DBCO-PEG3-a621-635Cit and FeSDH-N3-DBCO-PEG3-0621-635Cit. WToaCIT represents the hybrid comprising a wild-type Fc fragment that is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO which is coupled to a PEGn spacer which is itself linked to the peptide represented by SEQ ID NO: 18; WTaArg corresponds to the WTaCIT hybrid except that the peptide of SEQ ID NO: 18 is not citrullinated; SDHaCIT represents an Fc fragment comprising the mutations S239D, H268F, S324T and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne DBCO which is coupled to a PEGn spacer which is itself linked to the peptide represented by SEQ ID NO: 18; and SDHaArg corresponds to the SDHoCIT hybrid except that the peptide of SEQ ID NO: 18 is not citrullinated. In the constructions, n represents a number between 1 and 10 when a PEGn spacer is used, preferably 1, 2, 3, 4 or 8. The experiment was performed in 96-well round-bottom plates. Nalmé cell lines (transduced for membrane expression of recombinant human monoclonal ACPA 2H06) were used as target cells. 100,000 cells / well were incubated in the presence of, on the one hand, WTaCit or SDHaCit hybrid molecules at 15 µg / mL and, on the other hand, freshly purified NK cells (labeled with purple cell tracker) used as effector cells, also at 100,000 cells / well, for 17 h at 37°C. WTaArg and SDHaArg hybrid molecules, used as specificity controls, were incubated under the same conditions. As negative controls, Nalm6 cells were incubated in the absence of hybrids, alone or in the presence of NK cells. Cell lysis was measured by flow cytometry using the fluorescent probe 7-AAD. The results show the percentage of cells positive for this marker (% of dead cells).(%) (ACIT-Arg) represents the difference between the percentages of dead 7-AAD-positive cells in the presence of WT and SDH citrullinated peptide hybrids versus their non-citrullinated homologs, divided by the percentage of 7-AAD-positive cells in the presence of the corresponding non-citrullinated hybrid. The results are presented in [Fig.9] and in Table 11. [Tables 11] % (A CIT-Arg) _ |+ 62% |55 |+83% % 7-AAD + Nalm6 8 Nalm6+NK |45 Nalmé + 65 NK + WT oCIT Nalm6 + NK 40 + WT oArg Nalm6 +NK | |s5 + SDH aCIT Nalmé + NK po + SDH aArg Results The results show that citrullinated hybrids (WT and SDH) are able to specifically enhance ADCC lysis of Nalm6 ACPA-positive target cells, induced by NK cells. This increase in mortality is 62% for WT hybrids and 83% for SDH hybrids.

Claims

Demands

1. Hybrid molecule comprising at least one Fc fragment of a bound antibody covalently to at least one fibrin-derived peptide having at minus a citrullyl residue, at least one spacer being optional present between said Fc fragment and said peptide.

2. Hybrid molecule according to the preceding claim, wherein said peptide is derived from all or part of the sequence of the chain at or B of a vertebrate fibrin, by substitution of at least one arginyl residue by a citrullyl residue, said vertebrate fibrin being preferably a mammalian fibrin, more specifically human.

3. Hybrid molecule according to any one of the preceding claims preceding, wherein said spacer is a polymer containing a or several repeating patterns containing the ether group, said spacer being preferably polyethylene glycol of formula PEGn, in which n represents an integer between 1 and 100, preferably- tiellement entre | et 10 et particulier 1, 2, 3, 4or 8.

4. Hybrid molecule according to any one of the preceding claims preceding, in which said peptide comprises at least one residue citrullyl, and is chosen from the group consisting of: a) a peptide defined by the sequence X,PAPPPISGGGYX:AX; (SEQ ID NO: 1) in which X, X, and X; each represent a residue citrullyl or an arginyl residue, and at least one of the residues X, or X, or X 3 is a citrullyl residue; b) a peptide defined by the sequence GPX,VVEX;HQSACKDS (SEQ ID NO: 2) in which X, and X; each represent a citrullyl residue or an arginyl residue, and at least one of the residues X, or X; is a residue citrullyl; c) a peptide defined by the sequence SGIGTLDGFX,HX:HPD (SEQ ID NO: 3) in which X, and X; each represent a citrullyl residue or an arginyl residue, and at least one of the residues X, or X; is a residue citrullyl; d) a peptide defined by the sequence VDIDIKIX,SCX,GSCS (SEQ ID NO: 4) in which X, and X; each represent a citrullyl residue or an arginyl residue, and at least one of the residues X, or X; is a residue citrullyl; €) a peptide defined by the sequence X,GHAKSX,PVX;-GIHTS (SEQ ID NO: 12) in which X, X, and X each represent a residue citrullyl or an arginyl residue, and at least one of the residues X, or X, or X 3 is a citrullyl residue; (f) a peptide comprising at least 5 consecutive amino acids, of which at less one citrullyl residue, of one of the peptides a) to e) above.

5. Hybrid molecule according to any one of claims 1-3, in which peptide is chosen from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22 and SEQ ID NO: 23, more specifically chosen from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 14, SEQ ID NO: 18 and SEQ ID NO:

19.

6. Hybrid molecule according to any one of the preceding claims preceding, in which said fragment Fc is a human fragment Fc, particularly IgG, more specifically IgG1.

7. Hybrid molecule according to any one of the preceding claims preceding, in which said fragment Fc is of wild type or mutated, said mutated fragment Fc preferably comprising at least the The following mutations: - L234A and L235A, or - L234A, L235A and P329G, or - G236A, S239D and I332E, or - G236A, S239D, A330L and I332E, or - S239D, H268F, S324T and I332E, the numbering being indicated in the sequence of a human IgG1 according to the EU index.

8. Hybrid molecule according to any one of the preceding claims preceding, in which: - the Fc fragment is coupled to at least one azide and said peptide is coupled to an alkyne, such as a cyclooctyne, and in particular DBCO, or - the Fc fragment is coupled to at least one alkyne, such as a cyclooctyne, and in particular DBCO, and said peptide is coupled to an azide, or - the Fc fragment is coupled to at least one azide and said peptide is bound to a spacer itself coupled to an alkyne, such as a cyclooctyne, and in in particular the DBCO or - the Fc fragment is coupled to at least one alkyne, such as a cyclooctyne, and in particular DBCO, and said peptide is linked to a spacer itself coupled with an azide or - the Fc fragment is linked to at least one spacer, itself coupled to a azide, and said peptide is coupled to an alkyne, such as a cyclooctyne, and in particular the DBCO or - the Fc fragment is linked to at least one spacer, itself coupled to a alkyne, such as cyclooctyne, and in particular DBCO, and said peptide is coupled to an azide or - the Fc fragment is linked to at least one spacer, itself coupled to a azide, and said peptide is linked to a spacer, itself coupled to a alkyne, such as a cyclooctyne, and in particular DBCO or - the Fc fragment is linked to at least one spacer, itself coupled to a alkyne, such as cyclooctyne, and in particular DBCO, and said peptide is linked to a spacer, itself coupled to an azide, the covalent bond between said Fc fragment and said peptide, possibly temporarily in the presence of one or more spacers, being created between azide and alkyne. [Claim: Hybrid molecule according to any one of the preceding claims] preceding, the said molecule being represented by: - a wild-type Fc fragment that is linked to at least one spacer PEGn which is itself coupled to an azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 or SEQ 1D NO: 18, - an Fc fragment containing the S239D, H268F, S324T mutations and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently bonded to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 or SEQ ID NO: 18, - an Fc fragment containing the L234A, 235A and P329G mutations which is linked to at least one PEGn spacer which is itself coupled to a azide covalently linked to a cyclooctyne which is coupled to a peptide represented by SEQ ID NO: 19 or SEQ ID NO: 18, - a wild-type Fc fragment that is linked to a PEGn spacer that is itself coupled to at least one azide covalently linked to a cy- clooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 or SEQ ID NO: 18, - an Fc fragment containing the S239D, H268F, S324T mutations and 1332E which is linked to at least one PEGn spacer which is itself coupled to an azide covalently linked to a cyclooctyne coupled to a PEGn spacer which is itself linked to a peptide represented by SEQ ID NO: 19 or SEQ ID NO: 18, n preferably representing an integer between | and 10, more particularly- 1, 2, 3 or 4.

10. | Hybrid molecule according to any one of the preceding claims previous, for its use as a medicine, in particular for its use in the treatment of autoimmune diseases associated with production of anti-citrullinated protein autoantibodies, in particular the Gougerot-Sjögren syndrome and rheumatoid arthritis.

11. | Hybrid molecule according to any one of the preceding claims previous, for its use as a medicinal product, in combination with a second hybrid molecule, said second hybrid molecule comprising at least one fibrin-derived peptide having at least one citrullyl residue, said peptide being covalently linked to at least one antibody or at least one fragment of antibody, said antibody or fragment being capable of binding to CD38 and / or CD138, one or more spacers being optionally present between said peptide and said antibody or said fragment.