Anti-chemokin like receptor 1 antibodies and their therapeutic applications

Abstract

To provide novel anti-chemerin receptor antibodies having agonistic capability on chemokine-like receptor 1 (CMKLR1), and their use for treatment, particularly where the resolution of inflammation is disrupted or delayed, such as autoimmune diseases, chronic inflammatory diseases, infection diseases, cancers, and any conditions.SOLUTION: The present invention provides anti-CMKLR1 compounds having agonistic capability on the interaction between Resolvin E1 and CMKLR1, and their uses for treating or preventing diseases, particularly where the resolution of inflammation is delayed or disrupted.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the field of immunotherapy. The present invention provides novel anti-chemerin receptor antibodies with agonistic activity against chemokine-like receptor-1 (CMKLR1). The present invention also provides the use of such antibodies in therapy, particularly for treating autoimmune and chronic inflammatory diseases, infectious diseases, cancer, and any condition in which the resolution phase of inflammation is impeded or delayed. [Background technology]

[0002] The important role of the inflammatory process in health and disease has long been recognized. The detailed molecular mechanisms and biological events that regulate inflammatory progression and resolution are still of crucial importance. Recent studies have provided strong evidence that inflammatory resolution is not a passive process as previously thought. It is rather a biosynthetic active process regulated by biochemical mediators and receptor signaling pathways. Thus, resolution is driven by specialized pro-resolving mediators. Inflammation is a spontaneous mechanism that occurs upon infection, injury, or trauma. Inflammation is inevitable and usually beneficial, and the response is orchestrated by a delicate balance between positive and negative feedback loops. Inflammation is usually divided into three steps: initiation, amplification, and resolution.

[0003] The initiation step is characterized by vasodilation of blood vessels. Resident cells (dendritic cells (DCs) and macrophages) recognize pathogens or danger signals infecting the body. This step induces the secretion of cytokines, chemokines, and the production of proinflammatory lipid mediators called prostaglandins (PGs) and leukotrienes. The chemokines return to the blood circulation and induce the recruitment of cellular effectors of innate immunity. The amplification step begins with the recruitment of inflammatory cells of the immune system. The first effectors recruited to the site of infection are polymorphonuclear cells (PMNs). During the cellular phase, PMNs recognize the pathogen and are responsible for its elimination. DCs and other cells, such as the proinflammatory macrophage M1, migrate to the site of inflammation to help PMNs. DCs enter the blood circulation and reach lymph nodes to activate adaptive immunity. T and B lymphocytes reach the site of inflammation and eradicate the infected cells. Once the pathogen has been completely eliminated, it is essential that inflammation ceases in order to prevent chronic inflammation that becomes pathogenic for the organism. To do so, an active mechanism called resolution of inflammation occurs. Resolution is therefore described as the final step of inflammation.

[0004] The healing process that allows the cessation of the inflammatory response is a complex process that involves the sequential and sequential participation of cellular effectors (e.g., granulocytes or macrophages) and chemical effectors (e.g., cytokines or specialized pro-healing mediators or factors).

[0005] Lack of resolution of inflammation may result in increased infiltration of granulocytes at the site of inflammation (measured, for example, by histology, cytology, or indirect biochemical techniques such as quantification of elastase by enzyme immunoassay or molecular quantification of granulocyte receptor 1 by PCR), delayed apoptosis of such cells (measured, for example, by cytology using specific antibodies against annexin 5). Lack of resolution of inflammation may also result in persistent or increased synthesis of pro-inflammatory cytokines such as TNF-alpha, IL8, or IL12, and decreased anti-inflammatory cytokines such as IL-10 (measured, for example, by enzyme immunoassay or PCR), persistent or increased activation of transcription factors involved in the synthesis of inflammatory cytokines such as NF-kappa B (measured, for example, by nuclear translocation or Western blot and quantification of the levels of degradation of Ikappa B). It can also be measured by quantification of specific pro-resolving mediators (e.g. lipoxins, resolvins, protectins, or maresins) or their precursors (such as 17-HDOHE or 14-HDOHE) by mass spectrometry or enzyme immunoassays. Lack of recovery results in lack of synthesis of one or more of these mediators. Lack of recovery can also be due to reduced expression or internalization of the receptors of the resolving molecules (ALX / CMK1R1, GPR32, GPR18) and reduced processing of their receptors into the cytoplasm, or overexpression of some receptors or lipids of inflammatory cytokines. These conditions may be measured by histology, cytology, or PCR. Lack of recovery can also result in reduced or inhibited switch from M1 to M2 macrophages, leading to impaired phagocytosis or efferocytosis of the same cells.

[0006] It is now evident that a family of chemicals actively promotes inflammation resolution and tissue repair without compromising host defense in addition to checkpoint activators and / or inhibitors involved in such mechanisms. Events during the development of acute inflammation establish a series of biosynthetic pathways for chemical mediators that can act as antagonists as well as agonists, meaning that they do not simply inhibit inflammatory pathways, but that they influence inflammation, leading to the restoration of tissue homeostasis and function. Thus, anti-inflammatory and pro-resolving factors are not equivalent (Buckley et al., 2014) (Serhan, 2014a). The inability to resolve acute inflammation contributes to the development of chronic inflammation. Thus, anti-inflammatory compounds refer to inhibitors or blockers of inflammation resolution, as well as molecules that stop immune extravasation; whereas pro-resolving factors stimulate and / or activate specific processes, such as apoptosis or efferocytosis, that initiate or enhance inflammation resolution.

[0007] Recovery begins shortly after the initiation of the inflammatory response by PMNs, which clear pathogens and simultaneously initiate the synthesis of specialized pro-healing mediators (SPMs). These SPMs are the main actors of the recovery phase. Neutrophils govern the initiation of the recovery phase of inflammation by enabling the activation of pro-healing circuits to ensure the safe termination of the inflammatory response. During the early stages of recovery, neutrophils undergo a phenotypic switch, producing a different profile of lipid mediators depending on the cells and substances present in the nearby environment. PMN-LTs switch to the PMN-LO (lipoxygenase) pathway through the action of lipoxins and resolvins. They initiate their phenotypic change upon exposure to an autacoid gradient. Lipoxins are generated via a biosynthetic pathway that is involved during cell-cell interactions (PMN-5-LO / tissue resident cell-5-LO). It has been observed that wound healing is delayed in neutrophil-deficient models and that neutrophils release proteases that deactivate inflammatory cytokines.

[0008] Various molecules are involved in the initiation or inhibition of inflammation resolution. The following molecules are illustrative of such active molecules. COX-2 (cyclooxygenase-2), prostaglandin-endoperoxide synthase (PTGS), is an enzyme responsible for the formation of prostanoids, including thromboxanes and prostaglandins, such as prostacyclin, and has a dual role as a contributor to the initiation of inflammation and as a cofactor to later resolve the process. COX-2 inhibitors may have beneficial effects in the early phase of inflammation. COX-2 inhibitors also have adverse consequences, such as reducing early PMN migration, preventing LXA production, reducing macrophage phagocytosis, and reducing PGE2 and LXA. An anti-inflammatory prostaglandin called PGD2 / 15dPGJ is also involved in negative feedback, while other prostaglandins, such as PGE2, are involved in positive feedback during inflammation resolution.

[0009] G protein-coupled receptors (GPCRs) constitute a vast family of proteins that encompass a wide range of functions, including various autocrine, paracrine, and endocrine processes. They exhibit considerable diversity at the sequence level, on the basis of which they can be classified into different groups. Typically, GPCR activation involves a broad network of signaling pathways mediated by either G proteins or B arrestins, or both.

[0010] Chemokine-like receptor 1 (CMKLR1) and chemokine receptor-like 2 (CCRL2), also known as ChemR23, are seven-transmembrane receptors identified by their homology to known G protein-coupled receptors (AJ Kennedy and AP Davenport, 2018). Chemokine-like receptor 1 (CMKLR1; called Dez in murine animals) is an orphan G protein-coupled receptor related to GPR-1 (38% total amino acid identity), C3a receptor (38%), C5a anaphylatoxin receptor (36%), and formyl Met-Leu-Phe receptor (35%). ChemR23 is more distantly related to the chemokine receptor subfamily (Samson et al., 1998). CMKLR1 is expressed on monocytes, macrophages, dendritic cells, and NK cells, as well as adipocytes and endothelial cells. CMKLR1 expression has also been described in many cell populations other than leukocytes, including preadipocytes and adipocytes (Goralski et al., 2007; Roh et al., 2007), skeletal muscle cells (Sell et al., 2009), and endothelial cells (Kaur et al., 2010), and additional roles for the chemerin / CMKLR1 system have been proposed in the control of lipid and glucose metabolism (Bozaoglu et al., 2007; Ernst and Sinal, 2010), blood pressure (Watts et al., 2013), and angiogenesis (Kaur et al., 2010).

[0011] Recent studies have identified the ligands of these receptors and are beginning to clarify their functions. It has been shown that chemerin, a plasma protein-derived chemoattractant, is a ligand for CMKLR1, and activation of CMKLR1 by chemerin induces migration of macrophages and dendritic cells (DCs) in vitro, suggesting a proinflammatory role for chemerin. In vivo studies using CMKLR-deficient mice suggest the opposite, that these receptors may have an anti-inflammatory role, possibly by recruiting plasmacytoid DCs. Chemerin / CMKLR1 interaction also promotes adipogenesis and angiogenesis.

[0012] Chemerin acts as a chemokine during inflammation, recruiting cells to the site of infection. This ligand promotes resolution of inflammation in animal models of acute inflammation by enhancing PMN apoptosis and M2-dependent efferocytosis (non-inflammatory phagocytosis; does not release pro-inflammatory mediators), and by reducing DC migration and secretion of IL12 (a pro-inflammatory cytokine) (Serhan, 2014b).

[0013] Chemerin is abundant in inflammatory fluids, has antibacterial activity, has been shown to attract leukocytes expressing CMKLR1, and promotes macrophage adhesion to extracellular matrix proteins (Wittamer et al., 2003). In addition, chemerin was recently discovered to be an adipokine. When secreted by mature adipocytes, chemerin stimulates preadipocytes to differentiate. Increased serum levels of chemerin are associated with chronic inflammatory diseases, coronary artery disease, metabolic syndrome, and obesity. It has been shown that high chemerin production in obese adipose tissue may contribute to the increased macrophage infiltration observed in obese adipose tissue, resulting in low-level inflammation. Binding of chemerin to CMKLR1 activates two signaling pathways: the G protein signaling pathway and the β-arrestin signaling pathway.

[0014] The second ligand of CMKLR1 is resolvin E1 (RvE1), a lipid mediator belonging to the resolvin family. Resolvin E1, an anti-inflammatory lipid mediator, inhibits leukocyte infiltration and pro-inflammatory gene expression. These divergent results suggest that CMKLR1 is a multifunctional receptor. It is associated with increased PMN apoptosis and M2 efferocytosis, and decreases DC migration and secretion of pro-inflammatory cytokines such as IL12. RvE1 is produced by neutrophils and endothelial cells. It is also induced by aspirin treatment in vitro, as aspirin activates the COX-2 pathway responsible for the production of RvE1. Furthermore, neutrophils allow the conversion of 18R-HEPE to RvE1. It has been observed that macrophages have reduced phagocytosis in patients with localized aggressive periodontitis (LAP). RvE1 rescues the impaired phagocytic activity of LAP macrophages. RvE1 also promotes recovery through the reduction of IL-23 and IL-6 and the increase of IFN-γ in allergic airways in mice. RvE1 regulates natural killer cell (NK) migration and cytotoxicity. When RvE1 binds to CMKLR1, only the G protein signaling pathway is activated and the B arrestin pathway is inhibited; under certain conditions, the B arrestin pathway is inhibited.

[0015] Initially, interest in the chemerin system was focused on its role in inflammation and immune cell chemotaxis after its discovery in psoriatic disease. Recently, its potential role in cardiovascular function, in relation to its role in inflammation, obesity, metabolic syndrome, and in reproductive biology, has been explored. Thus, the chemerin system is of great importance with regard to its role in inflammatory processes, especially in the resolution of inflammation. Several diseases are associated with delayed or hindered resolution processes. Most of the currently known specialized pro-resolving factor mediators are derived from polyunsaturated fatty acids, including lipoxins, the resolvin family, including E-series resolvins and D-series resolvins, protectins, and maresins. Nevertheless, pro-resolving molecules are difficult to synthesize due to their lipid nature. Producing pro-resolving molecules in sufficient quantities, for example for clinical trials, is burdensome, and there are very few SPMs that are efficiently produced. Besides, antibodies that specifically target G protein-coupled receptors are difficult to produce. Thus, there is a need for molecules capable of initiating or enhancing the healing phase of the inflammatory response, such as pro-healing factors. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] WO2008068637 [Patent Document 2] European Patent No. 1270725 B1 [Patent Document 3] US Patent No. 8536307 B2 [Non-patent literature]

[0017] [Non-Patent Document 1] Buckley, CD, Gilroy, DW, and Serhan, CN (2014). Proresolving Lipid Mediators and Mechanisms in the Resolution of Acute Inflammation. Immunity 40, 315-327 [Non-Patent Document 2] Serhan, CN (2014a). Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92-101 [Non-Patent Document 3] AJ Kennedy and AP Davenport, 2018 [Non-Patent Document 4] Samson, M., Edinger, AL, Stordeur, P., Rucker, J., Verhasselt, V., Sharron, M., Govaerts, C., Mollereau, C., Vassart, G., Doms, RW, et al. (1998). ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. Eur. J. Immunol. 28, 1689-1700 [Non-Patent Document 5] Goralski , KB , McCarthy , TC , Hanniman , EA , Zabel , BA , Butcher , EC , Parlee , SD , ​​Muruganandan , S. , and Sinal , CJ (2007). Chemerin, a Novel Adipokine That Regulates Adipogenesis and Adipocyte Metabolism. J. Biol. Chem. 282, 28175–2

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[0018] In a first aspect, the present invention relates to an anti-CMKLR1 antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimic, or a modified antibody. In the following disclosure, the anti-CMKLR1 compound is considered to be either an anti-CMKLR1 antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimic, or a modified antibody. In a particular embodiment of the present invention, the compound is defined by the sequence of its CDRS. In a more particular embodiment of the present invention, the anti-CMKLR1 compound is an antibody defined by the sequence of its CDRs and its framework regions (FRs). The anti-CMKLR1 compound is a compound that specifically binds to chemokine-like receptor 1 (CMKLR1). In the following disclosure, the terms chemokine-like receptor 1, CMKLR1, and ChemR23 are used interchangeably and all designate receptors encoded by the gene CMKLR1 in humans or cmklr1 in non-human animals. In a particular embodiment of the present invention, the anti-CMKLR1 compound specifically binds to human CMKLR1, or in other words, the present invention relates to anti-human CMKLR1 compounds. As used herein, the term "CMKLR1" refers to chemokine-like receptor 1 protein (also called ChemR23), a member of the G protein-coupled receptor family from mammalian species, preferably human CMKLR1. The reference sequence of human CMKLR1 protein used in the examples of this application corresponds to the sequence associated with Uniprot Accession No. Q99788 (SEQ ID NO: 1).

[0019] In a second aspect, the present invention relates to an anti-CMKLR1 antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimic, or an engineered antibody, defined by at least one functional feature. In a preferred embodiment, said anti-CMKLR1 compound is defined by its ability to inhibit the secretion of pro-inflammatory cytokines, particularly IL12, and / or its ability to enhance the secretion of anti-inflammatory cytokines, particularly IL10 and / or CCL17. In a more specific embodiment, the anti-CMKLR1 compound inhibits or enhances cytokine secretion by macrophages, particularly M1 and / or M2 macrophages. In a specific embodiment, the anti-CMKLR1 compound of the present invention enhances the polarization of macrophages into anti-inflammatory macrophages, particularly M2 macrophages.

[0020] In a third aspect, the present invention relates to an anti-CMKLR1 antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimic, that has agonistic properties against resolvin E1 (RvE1), thereby mimicking the binding of RvE1 to CMKLR1 on CMKLR1-positive cells. "Agonistic properties against RvE1-CMKLR1 interaction" means that the antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimic, or an engineered antibody of the present invention that targets CMKLR1 has the effect of mimicking the binding of RvE1 to CMKLR1, thereby activating receptor signaling pathways that are normally activated by RvE1, in particular the binding of human RvE1 to human CMKLR1 in dendritic cells, monocytes, and macrophages. As a result of receptor binding and activation resulting in a biological response, the compounds of the present invention activate G protein signaling pathways, in particular Gα, without activating the β-arrestin pathway. i Signaling pathways and / or Gα oActivation of CMKLR1, in particular the compounds of the present invention may result in inhibition of the β-arrestin pathway. In particular, the binding of the compounds according to the present invention induces the activation of Akt and / or Erk proteins in vitro and / or in vivo. In other words, a resolvin-E1-like agonist antibody may be defined as an antibody capable of binding to CMKLR1 and thereby inducing phosphorylation of Akt and / or Erk proteins compared to a control antibody. The control antibody may be an antibody that does not specifically bind to CMKLR1. Protein phosphorylation may be determined according to methods well known to those skilled in the art, for example by the methods disclosed in the examples of the present invention.

[0021] In a particular embodiment, the compounds of the present invention are RvE1-like agonists, i.e., the compounds of the present invention are agonists of the CMKLR1 signaling pathway induced by RvE1. In other words, the anti-CMKLR1 compounds of the present invention are agonists of the interaction between RvE1 and CMKLR1, particularly between human RvE1 and human CMKLR1. In a particular embodiment, the compounds of the present invention enhance the activation of the G protein pathway induced by CMKLR1. In another embodiment, the compounds of the present invention do not induce the activation of the β-arrestin pathway induced by CMKLR1. In another embodiment, the compounds of the present invention inhibit the β-arrestin pathway induced by CMKLR1. In another embodiment, the compounds of the present invention are pro-restorative factors or pro-restorative mediators, since they induce at least one agonistic effect of the binding of RvE1 to CMKLR1, and since RvE1 is a pro-restorative factor or pro-restorative mediator.

[0022] In a particular embodiment, the compounds of the present invention do not interfere with the binding of chemerin to CMKLR1. Chemerin is one of the natural ligands of CMKLR1. In other words, the compounds according to the present invention are not agonists of the interaction between chemerin and CMKLR1. The absence of such agonistic potential may be assessed according to the examples of the present invention, which disclose a competition assay that measures chemerin-dependent B-arrestin recruitment by the CMKLR1 receptor in the presence of the anti-CMKLR1 antibody of the present invention. In a preferred embodiment, the anti-CMKLR1 compounds of the present invention do not compete with chemerin for binding to CMKLR1. The absence of competition between the anti-CMKLR1 compounds of the present invention and chemerin may be determined when the binding of chemerin to CMKLR1 in the presence of the CMKLR1 compounds of the present invention is at least 50%, more preferably at least 80%, even more preferably at least 90%, and most preferably similar to the binding of chemerin to CMKLR1 under the same experimental conditions but in the absence of the anti-CMKLR1 of the present invention. Alternatively, the absence of competition between the anti-CMKLR1 compounds of the invention and Chemerin may be determined according to the methods illustrated in Example 11.

[0023] In certain embodiments, anti-CMKLR1 compounds have the ability to activate at least one of Akt signaling pathway proteins (also known as PI3K-Akt pathway) and / or Erk signaling pathway proteins, preferably Akt protein and / or Erk protein, preferably both Akt and Erk protein, in vitro and / or in vivo. Pathway activation can be evaluated according to methods known in the art, in particular according to the methods disclosed in the examples of the present invention.

[0024] In certain embodiments, the antibodies, antigen-binding fragments thereof, antigen-binding antibody mimics, or modified antibodies of the invention enhance RvE1-induced secretion of IL10 cytokines in vitro and / or in vivo, in particular secretion of IL10 cytokines by macrophages. In certain embodiments, the antibodies, antigen-binding fragments thereof, antigen-binding antibody mimics, or modified antibodies of the invention enhance RvE1-induced secretion of IL10 and CCL17 cytokines in vitro and / or in vivo, in particular secretion of IL10 and CCL17 by macrophages. In certain embodiments, the antibodies, antigen-binding fragments thereof, antigen-binding antibody mimics, or modified antibodies of the invention inhibit secretion of IL12 cytokines in vitro and / or in vivo, in particular secretion of IL12 by macrophages. The inhibition may be partial, i.e., the secretion level of IL12 in the presence of the anti-CMKLR1 compound is reduced from the baseline level (i.e., the level in the absence of RvE1 or the anti-CMKLR1 compound), or the inhibition may be complete (no secretion of IL12). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] As used herein, the term "antibody" includes polyclonal, monoclonal, or recombinant antibodies. As used herein, "monoclonal antibody" is intended to refer to a preparation of antibody molecules to obtain antibodies sharing a common heavy chain and a common light chain amino acid sequence, as opposed to "polyclonal" antibody preparations that contain a mixture of antibodies of different amino acid sequences. Monoclonal antibodies can be produced by several known techniques, such as phage, bacterial, yeast, or ribosome display, as well as by classical methods exemplified by hybridoma-derived antibodies. They may also be synthesized using the amino acid sequences of the present disclosure as a reference. Thus, the term "monoclonal" is used to refer to all antibodies derived from a single nucleic acid clone.

[0026] The antibody of the present invention includes recombinant antibodies. As used herein, the term "recombinant antibody" refers to an antibody that is produced, expressed, generated, or isolated by recombinant means, such as an antibody expressed using a recombinant expression vector transfected into a host cell; an antibody isolated from a recombinant combinatorial antibody library; an antibody isolated from an animal (e.g., a mouse) that is transgenic with human immunoglobulin genes; or an antibody that is produced, expressed, generated, or isolated in any other manner in which a particular immunoglobulin gene sequence (e.g., a human immunoglobulin gene sequence) is assembled with other DNA sequences. Recombinant antibodies include, for example, chimeric and humanized antibodies.

[0027] As used herein, a "chimeric antibody" refers to an antibody in which variable domain sequences derived from the germline of a mammalian species, e.g., a mouse, have been grafted onto constant domain sequences derived from the germline of another mammalian species, e.g., a human.

[0028] As used herein, "humanized antibody" refers in a first embodiment to an antibody in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human or humanized framework sequences. In a further embodiment, "humanized antibody" refers to an antibody in which at least one CDR and all or part of the framework sequences have been humanized.

[0029] As used herein, "antigen-binding fragment of an antibody" refers to a molecule corresponding to a part of an antibody, i.e., a part of the structure of an antibody of the present invention, which possibly exhibits the antigen-binding ability of its native form CMKLR1; such fragments in particular exhibit the same or substantially the same antigen-binding specificity for said antigen compared to the antigen-binding specificity of the corresponding four-chain antibody. Advantageously, the antigen-binding fragment has a similar binding affinity to the corresponding four-chain antibody. However, antigen-binding fragments with reduced antigen-binding affinity with respect to the corresponding four-chain antibody are also encompassed by the present invention. Antigen-binding ability can be determined by measuring the affinity between the antibody and the target fragment. These antigen-binding fragments can also be referred to as "functional fragments" of antibodies.

[0030] The antigen-binding fragment of an antibody is a fragment that includes its hypervariable domain called CDR (complementarity determining region) or a part thereof that includes the recognition site of the antigen, i.e., the extracellular domain of CMKLR1, in particular the third loop (called EL3) of the extracellular domain of CMKLR1, thereby defining the antigen recognition specificity. EL3 is located between amino acid residues 283 and 300 of SEQ ID NO:1. EL3 corresponds to the amino acid residues of SEQ ID NO:2. EL3 is also included within the polypeptide of SEQ ID NO:18.

[0031] Each light and heavy chain variable domain (VL and VH, respectively) of a four-chain immunoglobulin has three CDRs, designated VLCDR1, VLCDR2, and VLCDR3 for the light chain variable domain; and VHCDR1, VHCDR2, and VHCDR3 for the heavy chain variable domain. Each light and heavy chain variable domain of a four-chain immunoglobulin has four framework regions (FRs), designated LFR1, LFR2, LFR3, and LFR4 for the light chain variable domain; and HFR1, HFR2, HFR3, and HFR4 for the heavy chain variable domain.

[0032] The skilled artisan is able to determine the location of the various regions / domains of an antibody by reference to standard definitions in this regard, including by reference to the reference numbering system, the KABAT numbering system, or by application of the IMGT "collier de perle" algorithm. In this regard, it should be noted that, with respect to the definition of the sequences of the present invention, the boundaries of the regions / domains may differ from each other depending on the reference system. Thus, the regions / domains defined in the present invention encompass sequences that exhibit approximately ±10% variation in length or position of the corresponding sequence within the full-length sequence of the variable domain of an antibody.

[0033] Based on the four-chain immunoglobulin structure, antigen-binding fragments can thus be defined by comparison with the sequences of antibodies in available databases and in the prior art, in particular by comparing the location of the functional domains in these sequences, it being noted that the locations of the framework and constant domains are well defined for the various classes of antibodies, in particular for IgG, and in particular for mammalian IgG. Such a comparison also requires data on the three-dimensional structure of the antibody.

[0034] For the purposes of illustrating certain embodiments of the invention, antigen-binding fragments of an antibody containing a variable domain comprising the CDRs of said antibody include Fv, dsFv, scFv, Fab, Fab', F(ab')2. Fv fragments consist of the VL and VH domains of an antibody associated together by hydrophobic interactions; in dsFv fragments, the VH:VL heterodimer is stabilized by disulfide bonds; in scFv fragments, the VL and VH domains are connected to each other via a flexible peptide linker, thus forming a single-chain protein. Fab fragments are monomeric fragments obtainable by papain digestion of antibodies; they contain the VH-CH1 fragments of the complete L chain and H chain linked together through disulfide bonds. F(ab')2 fragments can be produced by pepsin digestion of an antibody below the hinge disulfide; they contain two Fab' fragments and also a part of the hinge region of the immunoglobulin molecule. Fab' fragments can be obtained from F(ab')2 fragments by cleaving the disulfide bond in the hinge region. F(ab')2 fragments are bivalent, i.e. they contain two antigen-binding sites like native immunoglobulin molecules; whereas Fv (VHVL dimers constituting the variable part of Fab), dsFv, scFv, Fab, and Fab' fragments are monovalent, i.e. they contain a single antigen-binding site. These basic antigen-binding fragments of the invention can be combined together to obtain multivalent antigen-binding fragments, such as diabodies, tribodies, or tetrabodies. These multivalent antigen-binding fragments are also part of the present invention.

[0035] As used herein, the term modified antibody includes "bispecific" antibodies and refers to antibodies that recognize two different antigens by having at least one region specific for a first antigen (e.g., derived from the variable region of a first antibody) and at least a second region specific for a second antigen (e.g., derived from the variable region of a second antibody). Bispecific antibodies specifically bind to two target antigens and are thus a type of multispecific antibody. Multispecific antibodies that recognize two or more different antigens include, but are not limited to, antibodies that can be produced by recombinant DNA methods or produced chemically by any conventional method. Bispecific antibodies include all antibodies or conjugates of antibodies capable of recognizing two different antigens, or polymeric antibodies. Bispecific antibodies include antibodies that have been reduced and altered to retain their bivalent character, and antibodies that have been chemically coupled so that they can have several antigen recognition sites for each antigen, e.g. BiME (Bispecific Macrophage Enhancing antibodies), BiTE (bispecific T cell engager), DART (Dual affinity retargeting); DNL (Dock and Lock), DVD-Ig (Dual Variable Domain Immunoglobulin), HAS (Human Serum Albumin), kih (knobs into holes).

[0036] Antigen-binding antibody mimetics are organic compounds that specifically bind to antigens but are not structurally related to antibodies. They are usually artificial peptides or small proteins with molar masses of about 3-20 kDa. Nucleic acids and small molecules are sometimes considered to be antibody mimetics as well, but not artificial antibodies, antibody fragments, and antibody proteins composed of them. Common advantages over antibodies are good solubility, tissue penetration, stability to heat and enzymes, and relatively low production costs. Antibody mimetics are being developed as therapeutic and diagnostic agents. Antigen-binding antibody mimetics may also be selected from the group including affibodies, affilins, affimers, affitins, DARPins, and Monobodies.

[0037] The antigen-binding antibody mimics are more preferentially selected from the group comprising affitins and anticalins. Affitins are artificial proteins with the ability to selectively bind antigens. They are structurally derived from the DNA-binding protein Sac7d found in Sulfolobus acidocaldarius, a microorganism belonging to the Archaea domain. By randomizing the amino acids on the binding surface of Sac7d, for example by generating variants corresponding to random substitutions of 11 residues of the binding interface of Sac7d, an affitin library can be generated and the resulting protein library can be subjected to a round of ribosome display, thereby directing the affinity to various targets such as peptides, proteins, viruses, and bacteria. Affitins are antibody mimics and have been developed as tools in biotechnology. They are also used as specific inhibitors of various enzymes (Krehenbrink et al., J. mol. Biol., 383:5, 2008). A person skilled in the art can easily develop affitins with the required binding properties using methods known in the art, in particular the generation of phage display and / or ribosome display libraries and screening thereof using the antigens disclosed herein, as disclosed in patent application WO2008068637 and the publications cited above. Anticalins are artificial proteins capable of binding either antigens, proteins or small molecules. They are antibody mimics derived from the human lipocalin, a family of proteins that naturally bind. Anticalins are about 8 times smaller, with a size of about 180 amino acids and a mass of about 20 kDa (Skerra, Febs J., 275:11, 2008). Anticalin phage display libraries have been generated that allow the screening and selection of anticalins with particularly specific binding properties.The skilled artisan can easily develop anticalins with the required binding properties using methods known in the art, in particular those disclosed in EP 1270725 B1, US 8536307 B2, Schlehuber and Skerra, Biophys. Chem., 96:2-3, 2002, and the publications cited above, in particular the generation of phage display and / or ribosome display libraries and screening thereof using the antigens disclosed herein. Both anticalins and affitins can be produced in a number of expression systems, including bacterial expression systems. Thus, the present invention includes the use of affitins, anticalins, and other similar antibody mimetics having the characteristics of the antibodies described herein, in particular for their binding ability to CMKLR1, their agonistic ability to the binding between RvE1 and CMKLR1, their ability to induce or inhibit the secretion of certain cytokines described herein, their use in the treatment or prevention of diseases described herein, all of which are contemplated as mimetics according to the present invention.

[0038] As used herein, "modified antibody" refers to an antibody whose amino acid sequence has been modified by mutation of at least one amino acid residue. Thus, "modified antibody" encompasses chimeric or humanized antibodies as defined herein, and "modified antibody" may also correspond to a molecule comprising an antibody or an antigen-binding fragment thereof, but said monoclonal antibody or functional fragment thereof relates to a functionally distinct molecule. The modified antibody of the present invention may be either a fusion chimeric protein or a conjugate resulting from any suitable form of binding, including covalent binding, grafting, chemical binding, with chemical or biological groups or molecules, such as PEG polymers or other protective groups or molecules suitable for protection against protease cleavage in vivo, to improve the stability and / or half-life of the antibody or functional fragment. By similar techniques, in particular by chemical coupling or grafting, modified antibodies can be prepared with biologically active molecules, said active molecules being selected, for example, from toxins, in particular Pseudomonas exotoxin A, the plant toxin ricin A chain or saporin toxin, in particular therapeutic active principles, vectors (including in particular protein vectors) suitable for targeting the antibody or functional fragment to specific cells or tissues of the human body, or, in particular when using fragments of antibodies, may be associated with a label or a linker. PEGylation of antibodies or functional fragments thereof is a particularly interesting embodiment, since it improves the conditions for delivery of active substances to the host, in particular for therapeutic applications. PEGylation can be site-specific and can be carried out by high molecular weight PEG to prevent interference with the recognition site of the antibody or functional fragment. PEGylation can be achieved through free cysteine ​​residues present in the sequence of the antibody or functional fragment, or through additional free cysteine ​​residues in the amino acid sequence of the antibody or functional fragment. When the term "antibody" is used according to the present invention, this means either an antibody, an antigen-binding fragment thereof, an antigen-binding antibody mimic, or a modified antibody.

[0039] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab')2, or other target-binding subsequences of antibodies) that contain minimal sequence derived from a non-human immunoglobulin. Generally, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, with all CDR regions corresponding to those of a non-human immunoglobulin and / or its humanized form, and all or substantially all of the FR regions being those of a human immunoglobulin template sequence. A humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically of a selected human immunoglobulin template. In certain embodiments, the invention relates to an antibody comprising a heavy chain variable region as disclosed herein and a light chain variable region as disclosed herein, the heavy chain variable region and the light chain variable region further comprising a constant region, in particular an Fc region.

[0040] The terms "specific binding" and "specifically bind" refer to binding between an antibody, antigen-binding fragment thereof, antigen-binding antibody mimetic, or modified antibody of the invention to at least 1×10 -6 M, 1×10 -7 M, 1×10 -8 M, 1×10 -9 M, 1×10 -10 M, 1×10 -11 M, 1×10 -12 It refers to the ability to bind to CMKLR1 with an affinity of M or higher, and / or the ability to bind to CMKLR1 with an affinity at least 2-fold higher than its affinity for a non-specific target (e.g., another protein other than CMKLR1). Affinity can be evaluated according to various methods well known to those skilled in the art. These methods include, but are not limited to, Biacore analysis, Blitz analysis, and biosensors such as Scatchard plots.

[0041] The term "therapeutically effective amount" is used to refer to an amount of any given compound as defined herein sufficient to at least improve the clinical or physiological condition of the patient being treated. The therapeutically effective amount of an antibody, antigen-binding fragment thereof, antigen-binding antibody mimetic, or modified antibody according to the invention to be administered will be governed by considerations such as the disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0042] All embodiments disclosed herein relating to antibodies or antigen-binding fragments thereof may be substituted mutatis mutandis for the macromolecules of the invention, in particular antigen-binding antibody mimetics and engineered antibodies.

[0043] In a first aspect, the present invention relates to a polypeptide comprising the amino acid residues of SEQ ID NO: 2, and more particularly an epitope located within SEQ ID NO: 2, or an epitope located within the EL3 loop of CMKLR1, and an antibody, antigen-binding fragment thereof, antigen-binding antibody mimetic, or modified antibody, which specifically binds to CMKLR1, in particular the EL3 loop of CMKLR1, and which consists of the sequence of amino acid residues "AMPGS" (SEQ ID NO: 152), comprising: - a heavy chain variable domain comprising HCDR1, HCDR2, and HCDR3; a light chain variable domain comprising LCDR1, LCDR2, and LCDR3 The present invention relates to an antibody, an antigen-binding fragment thereof, an antigen-binding antibody mimetic, or an engineered antibody comprising:

[0044] In another aspect, the present invention provides an anti-CMKLR1 compound selected from the group of antibodies, or antigen-binding fragments thereof, or antigen-binding antibody mimetics, or chimeric or humanized antibodies that specifically bind to CMKLR1: - an antibody heavy chain variable domain comprising three CDRs, VHCDR1, VHCDR2 and VHCDR3: VHCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:4 or a variant thereof in which amino acid residues have been substituted; VHCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:6 or a variant thereof in which amino acid residues have been substituted; an antibody heavy chain variable domain, the VHCDR3 of which comprises or consists of the amino acid sequence set forth in SEQ ID NO: 8 or a variant thereof in which amino acid residues have been substituted such that the amino acid residues at positions 1 and 2 of SEQ ID NO: 8 are L and I or L, respectively; and - an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2 and VLCDR3: VLCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof in which amino acid residues have been substituted; VLCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14 or a variant thereof in which amino acid residues have been substituted; an antibody light chain variable domain, wherein VLCDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 15 or a variant thereof in which amino acid residues are substituted; Including, the anti-CMKLR1 compound is an RvE1-like agonist of CMKLR1, and in particular the anti-CMKLR1 compound is a recovery promoter, particularly in myeloid cell lineages; In particular, the present invention relates to an anti-CMKLR1 compound, wherein the anti-CMKLR1 compound is an anti-human CMKLR1 compound.

[0045] In another aspect, the present invention provides an anti-CMKLR1 compound selected from the group of antibodies, or antigen-binding fragments thereof, or antigen-binding antibody mimics, or chimeric or humanized antibodies, that specifically bind to CMKLR1, comprising an antibody heavy chain variable domain comprising a VHCDR3 that comprises or consists of the amino acid sequence set forth in SEQ ID NO:8, or a variant thereof in which amino acid residues have been substituted such that amino acid residues at positions 1 and 2 of SEQ ID NO:8 are L and I or L, respectively; the anti-CMKLR1 compound specifically binds to an epitope located within the third extracellular loop (EL3) of CMKLR1, in particular the compound specifically binds to a polypeptide comprising or consisting of the amino acid residues of the sequence of SEQ ID NO: 2 or SEQ ID NO: 152; the anti-CMKLR1 compound is a resolvin E1-like agonist of CMKLR1, and in particular the anti-CMKLR1 compound is a pro-restorative factor, particularly in myeloid cell lineages; The present invention relates to an anti-CMKLR1 compound, which competes with an antibody comprising a heavy chain variable domain corresponding to SEQ ID NO: 9 and a light chain variable domain corresponding to SEQ ID NO: 16, more particularly with antibody 2G1, for binding to a polypeptide comprising or consisting of amino acid residues of the sequence of SEQ ID NO: 2 or SEQ ID NO: 152, or a polypeptide comprising or consisting of the third loop (EL3) of the extracellular domain of CMKLR1.

[0046] In another aspect, the present invention provides an anti-CMKLR1 compound selected from the group of antibodies, or antigen-binding fragments thereof, or antigen-binding antibody mimetics, or chimeric or humanized antibodies that specifically bind to CMKLR1: - an antibody heavy chain variable domain comprising three CDRs, VHCDR1, VHCDR2 and VHCDR3: VHCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:4 or a variant thereof in which amino acid residues have been substituted; VHCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:6 or a variant thereof in which amino acid residues have been substituted; VHCDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO:8 or a variant thereof in which amino acid residues have been substituted such that the amino acid residues at positions 1 and 2 of SEQ ID NO:8 are L and I or L, respectively; An antibody heavy chain variable domain; and - an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2 and VLCDR3: VLCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof in which amino acid residues have been substituted; VLCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14 or a variant thereof in which amino acid residues have been substituted; comprising an antibody light chain variable domain, wherein VLCDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 15 or a variant thereof in which amino acid residues have been substituted, the anti-CMKLR1 compound is an RvE1-like agonist of CMKLR1, and in particular the anti-CMKLR1 compound is a recovery-promoting factor, particularly in myeloid cell lineages; The present invention relates to an anti-CMKLR1 compound, which is a compound that competes with an antibody comprising a heavy chain variable domain corresponding to SEQ ID NO: 9 and a light chain variable domain corresponding to SEQ ID NO: 16, more particularly with antibody 2G1, for binding to a polypeptide (or antigen) comprising or consisting of amino acid residues of SEQ ID NO: 2 and / or SEQ ID NO: 152, and / or for binding to the third extracellular loop of CMKLR1 (i.e., cross-competes with the amino acid residues of SEQ ID NO: 2 and / or SEQ ID NO: 152, or cross-competes with the third extracellular loop of CMKLR1). Binding to a polypeptide comprising or consisting of amino acid residues of SEQ ID NO: 2 and / or SEQ ID NO: 152, and / or binding to the third extracellular loop of CMKLR1 can be evaluated by binding affinity analysis by ELISA assay, in particular the examples disclosed in Example 9. To determine whether a test antibody can compete for binding to the same antigen or third loop as the epitope bound by the 2G1 antibody (or an antigen-binding fragment comprising a heavy chain variable domain corresponding to SEQ ID NO: 9 and a light chain domain corresponding to SEQ ID NO: 16), a cross-blocking assay (e.g., competitive ELISA assay) can be performed. In an exemplary competitive ELISA assay, a polypeptide comprising or consisting of the epitope or third loop can be coated onto the wells of a microtiter plate and pre-incubated in the presence or absence of a candidate competing antibody, followed by the addition of a biotin-labeled 2G1 antibody of the present invention. The amount of labeled anti-2G1 antibody bound to the polypeptide comprising or consisting of SEQ ID NO: 2 or SEQ ID NO: 152 or the third loop polypeptide of CMKLR1 in the wells is measured using an avidin-peroxidase conjugate and an appropriate substrate. The antibody can be labeled with a radioactive or fluorescent label, or some other detectable and measurable label.The amount of labeled anti-2G1 antibody bound to SEQ ID NO:2 or SEQ ID NO:152, or the third loop, has an indirect correlation to the ability of a candidate competing antibody to compete for binding to the same epitope or the same loop, i.e. the higher the affinity of the test antibody for the same epitope, the less labeled 2G1 antibody will bind to the antigen-coated well. A candidate competing antibody is considered to be an antibody that competes with the 2G1 antibody of the invention for binding to the same polypeptide or third loop if the candidate antibody is able to block the binding of the 2G1 antibody by at least at least 20%, preferably at least 20-50%, and even more preferably at least 50%, compared to a control run simultaneously in the absence of the candidate competing antibody (but which may be in the presence of a known non-competing antibody). It is understood that variations of this assay can be performed to arrive at the same quantitative value.

[0047] In another aspect, the present invention provides an antibody, an antigen-binding fragment thereof, an antigen-binding antibody mimetic, or a chimeric or humanized antibody that specifically binds to CMKLR1, particularly human CMKLR1, comprising: - an antibody heavy chain variable domain comprising three CDRs, VHCDR1, VHCDR2 and VHCDR3: VHCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:62; SEQ ID NO:63; SEQ ID NO:64, or SEQ ID NO:65; VHCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:66; SEQ ID NO:67; SEQ ID NO:68; SEQ ID NO:69; SEQ ID NO:70; SEQ ID NO:71, or SEQ ID NO:72; an antibody heavy chain variable domain, the HCDR3 of which comprises or consists of the amino acid sequence set forth in SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:73; SEQ ID NO:74; SEQ ID NO:75; SEQ ID NO:144; SEQ ID NO:145; SEQ ID NO:146; SEQ ID NO:147; SEQ ID NO:148; SEQ ID NO:149; SEQ ID NO:150 or SEQ ID NO:151, and / or - an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2 and VLCDR3: VLCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:76; SEQ ID NO:77; SEQ ID NO:78; SEQ ID NO:79, or SEQ ID NO:80; VLCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:81; SEQ ID NO:82; SEQ ID NO:83; SEQ ID NO:84; SEQ ID NO:85; SEQ ID NO:86; SEQ ID NO:87, or SEQ ID NO:88; an antibody light chain variable domain, wherein VLCDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 89; The present invention relates to an antibody, an antigen-binding fragment thereof, an antigen-binding antibody mimetic, or a chimeric or humanized antibody comprising:

[0048] In certain embodiments, the present invention provides an antibody, an antigen-binding fragment thereof, an antigen-binding antibody mimetic, or an engineered antibody that specifically binds to CMKLR1, particularly human CMKLR1, comprising: - an antibody heavy chain variable domain comprising three CDRs, VHCDR1, VHCDR2 and VHCDR3: VHCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:4; SEQ ID NO:62, or SEQ ID NO:63; VHCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 67; SEQ ID NO: 70, or SEQ ID NO: 72; an antibody heavy chain variable domain, the VHCDR3 of which comprises or consists of the amino acid sequence set forth in SEQ ID NO: 8; SEQ ID NO: 144 or SEQ ID NO: 148; and / or - an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2 and VLCDR3: - VLCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 77; - VLCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14; SEQ ID NO: 81 or SEQ ID NO: 84; an antibody light chain variable domain, wherein VLCDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 89; The present invention relates to an antibody, an antigen-binding fragment thereof, an antigen-binding antibody mimetic, or a chimeric or humanized antibody comprising:

[0049] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO:4; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO:67, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO:144 or SEQ ID NO:148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO:144.

[0050] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 4; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 70, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144.

[0051] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO:4; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO:72, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO:144 or SEQ ID NO:148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO:144.

[0052] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 62; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 67, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144.

[0053] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 62; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 70, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144.

[0054] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 62; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 72, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144.

[0055] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 63; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 67, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144.

[0056] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 63; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 70, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144.

[0057] In a particular embodiment of the invention, the antibody heavy chain variable domain comprises a VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 63; a VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 72, and a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148, more particularly a VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 144.

[0058] In a specific embodiment of the invention, the antibody light chain variable domain comprises a VLCDR1 having the amino acid sequence set forth in SEQ ID NO:77; a VLCDR2 having the amino acid sequence set forth in SEQ ID NO:14; and a VLCDR3 having the amino acid sequence set forth in SEQ ID NO:15.

[0059] In a specific embodiment of the invention, the antibody light chain variable domain comprises a VLCDR1 having the amino acid sequence set forth in SEQ ID NO:77; a VLCDR2 having the amino acid sequence set forth in SEQ ID NO:14; and a VLCDR3 having the amino acid sequence set forth in SEQ ID NO:89.

[0060] In a specific embodiment of the invention, the antibody light chain variable domain comprises a VLCDR1 having the amino acid sequence set forth in SEQ ID NO:77; a VLCDR2 having the amino acid sequence set forth in SEQ ID NO:81; and a VLCDR3 having the amino acid sequence set forth in SEQ ID NO:15.

[0061] In a specific embodiment of the invention, the antibody light chain variable domain comprises a VLCDR1 of the amino acid sequence set forth in SEQ ID NO:77; a VLCDR2 of the amino acid sequence set forth in SEQ ID NO:81; and a VLCDR3 of the amino acid sequence set forth in SEQ ID NO:89.

[0062] In a specific embodiment of the invention, the antibody light chain variable domain comprises a VLCDR1 having the amino acid sequence set forth in SEQ ID NO:77; a VLCDR2 having the amino acid sequence set forth in SEQ ID NO:84; and a VLCDR3 having the amino acid sequence set forth in SEQ ID NO:15.

[0063] In a specific embodiment of the invention, the antibody light chain variable domain comprises a VLCDR1 of the amino acid sequence set forth in SEQ ID NO:77; a VLCDR2 of the amino acid sequence set forth in SEQ ID NO:84; and a VLCDR3 of the amino acid sequence set forth in SEQ ID NO:89.

[0064] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic or modified antibody is a humanized antibody of a murine antibody, in particular wherein at least one framework region (FR1 and / or FR2 and / or FR3 and / or FR4) of the antibody light and / or heavy chain variable domain is derived from a human chain framework region, said light and / or heavy chain further comprising any combination of CDRs described herein or wild-type CDRs.

[0065] Wild-type antibodies, referred to in this disclosure as 2G1 and 2G4 (having the same variable region but different heavy chain constant regions), are defined and synthesized starting from multiple choices in the amino acid sequence of the third CDR of the heavy chain. Several putative antibody sequences have been generated accordingly, synthesized, and tested for their binding properties and their biological properties. In several newly synthesized antibodies, it has been determined that the presence of the amino acid residues "5'RLIY 3'" or "5'RLLY 3'" sequence in the third CDR of the heavy chain variable domain (according to IMGT) is highly related to the agonistic properties of the antibody against RvE1-CMKLR1 interaction. Antibodies with different amino acid residue sequences (such as "5'RIIY 3'", "5'RILY 3'") were less obvious as being agonistic of RvE1 binding to CMKLR1.

[0066] Thus, the synthesized wild-type anti-CMKLR1 antibodies (referred to as 2G1 and 4G1 in this disclosure) are chimeric antibodies with mouse variable regions and human constant regions (human IgG1 for 2G1 or human IgG4 for 2G4). 2G1 has the following amino acid sequence in its variable region: Heavy Chain:

[0067] [ka]

[0068] where the signal peptide is in lower case and the CDRs are in bold (according to Kabat) or underlined (according to IMGT). The complete sequence of the heavy chain with signal peptide corresponds to SEQ ID NO: 10, whereas SEQ ID NO: 9 corresponds to the heavy chain without the signal peptide. CDR1, CDR2 and CDR3 according to Kabat correspond to SEQ ID NO: 4, SEQ ID NO: 6 and SEQ ID NO: 144, respectively, whereas CDR1, CDR2 and CDR3 according to IMGT correspond to SEQ ID NO: 3, SEQ ID NO: 5 and SEQ ID NO: 7, respectively. CDR3 can be modified by substituting the amino acid residue ILE in the second position with the amino acid residue LEU (second position according to Kabat numbering) to give a heavy chain of the sequence:

[0069] [ka]

[0070] Light chain

[0071] [ka]

[0072] where the signal peptide is in lower case and the CDRs are in bold (according to Kabat) or underlined (according to IMGT). The complete sequence of the light chain with signal peptide corresponds to SEQ ID NO: 17, whereas SEQ ID NO: 16 corresponds to the heavy chain without the signal peptide. CDR1, CDR2 and CDR3 according to Kabat correspond to SEQ ID NO: 12, SEQ ID NO: 14 and SEQ ID NO: 15, respectively, whereas CDR1, CDR2 and CDR3 according to IMGT correspond to SEQ ID NO: 11, SEQ ID NO: 13 and SEQ ID NO: 15, respectively.

[0073] As known in the art and as exemplified for the chimeric antibodies of the invention, both the heavy and light chain variable domains comprise three CDRs (CDR1, CDR2, and CDR3, respectively, from the 5' to the 3' end) and four framework regions (FR1, FR2, FR3, and FR4, respectively, from the 5' to the 3' end). Humanization of a murine antibody may consist of humanizing at least one framework region in the light chain variable region or in the heavy chain variable region, or in both. In certain embodiments, some framework regions may be humanized, in particular in the heavy and light chain variable regions. The wild-type CDRs may be preserved, but the CDRs may also be exchanged for CDRs already described herein. Thus, the anti-CKLMR1 compounds according to the invention may comprise at least one, or at least two, or at least three, or at least four, or at least five, or six wild-type CDRs, if the framework regions are humanized. In other words, the anti-CMKLR1 compound is a humanized version of the parent chimeric antibody 2G1, in which at least one framework region is humanized, in particular at least one framework region and at least one CDR are humanized. In a particular embodiment of the present invention, the variable region of the antibody can be associated with an antibody constant region, such as the antibody constant region described in SEQ ID NO: 134 (encoded by the nucleotide sequence of SEQ ID NO: 133); SEQ ID NO: 136 (encoded by the nucleotide sequence of SEQ ID NO: 135); SEQ ID NO: 138 (encoded by the nucleotide sequence of SEQ ID NO: 137); SEQ ID NO: 139; SEQ ID NO: 140, and SEQ ID NO: 141. Such a combination is illustrated by the light chain of SEQ ID NO: 142 and the heavy chain of SEQ ID NO: 143.

[0074] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises at least one humanized framework region within its antibody heavy chain variable domain: An antibody heavy chain variable domain comprises four framework regions, HFR1, HFR2, HFR3, and HFR4: HFR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 90; SEQ ID NO: 91; SEQ ID NO: 92 or SEQ ID NO: 93; and / or HFR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 94; SEQ ID NO: 95; SEQ ID NO: 96; SEQ ID NO: 97; SEQ ID NO: 98; SEQ ID NO: 99, or SEQ ID NO: 100; and / or HFR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 101; SEQ ID NO: 102; SEQ ID NO: 103; SEQ ID NO: 104; SEQ ID NO: 105, or SEQ ID NO: 106; and / or HFR4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 107 or SEQ ID NO: 108.

[0075] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises at least one humanized framework region within its antibody light chain variable domain: The antibody light chain variable domain comprises four framework regions LFR1, LFR2, LFR3, and LFR4: LFR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 109; SEQ ID NO: 110; SEQ ID NO: 111 or SEQ ID NO: 112; and / or LFR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 113; SEQ ID NO: 114; SEQ ID NO: 115; SEQ ID NO: 116 or SEQ ID NO: 117; and / or LFR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 118; SEQ ID NO: 119; SEQ ID NO: 120; SEQ ID NO: 121; SEQ ID NO: 122 or SEQ ID NO: 132; and / or LFR4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 123 or SEQ ID NO: 124.

[0076] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises at least one humanized framework region within its antibody light chain variable region and within its antibody heavy chain variable region: The antibody heavy chain variable domain comprises four framework regions HFR1, HFR2, HFR3, and HFR4: HFR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 90; SEQ ID NO: 91; SEQ ID NO: 92 or SEQ ID NO: 93; and / or HFR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 94; SEQ ID NO: 95; SEQ ID NO: 96; SEQ ID NO: 97; SEQ ID NO: 98; SEQ ID NO: 99, or SEQ ID NO: 100; and / or HFR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 101; SEQ ID NO: 102; SEQ ID NO: 103; SEQ ID NO: 104; SEQ ID NO: 105, or SEQ ID NO: 106; and / or HFR4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 107 or SEQ ID NO: 108; The antibody light chain variable domain comprises four framework regions LFR1, LFR2, LFR3, and LFR4: LFR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 109; SEQ ID NO: 110; SEQ ID NO: 111 or SEQ ID NO: 112; and / or LFR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 113; SEQ ID NO: 114; SEQ ID NO: 115; SEQ ID NO: 116 or SEQ ID NO: 117; and / or LFR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 118; SEQ ID NO: 119; SEQ ID NO: 120; SEQ ID NO: 121; SEQ ID NO: 122 or SEQ ID NO: 132; and / or LFR4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 123; SEQ ID NO: 124.

[0077] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable region comprising HFR1 of SEQ ID NO: 91; HFR2 of SEQ ID NO: 95; HFR3 of SEQ ID NO: 102, and HFR4 of SEQ ID NO: 108 Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0078] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable region comprising HFR1 of SEQ ID NO: 92; HFR2 of SEQ ID NO: 96; HFR3 of SEQ ID NO: 103, and HFR4 of SEQ ID NO: 108 Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0079] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable region comprising HFR1 of SEQ ID NO: 92; HFR2 of SEQ ID NO: 98; HFR3 of SEQ ID NO: 106, and HFR4 of SEQ ID NO: 108 Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0080] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable region comprising HFR1 of SEQ ID NO: 93; HFR2 of SEQ ID NO: 96; HFR3 of SEQ ID NO: 104, and HFR4 of SEQ ID NO: 108 Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0081] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a light chain variable region comprising: LFR1 of SEQ ID NO: 111; LFR2 of SEQ ID NO: 115; LFR3 of SEQ ID NO: 120, and LFR4 of SEQ ID NO: 124 Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0082] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a light chain variable region comprising: LFR1 of SEQ ID NO: 110; LFR2 of SEQ ID NO: 114; LFR3 of SEQ ID NO: 119, and LFR4 of SEQ ID NO: 124 Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0083] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a light chain variable region comprising: LFR1 of SEQ ID NO: 110; LFR2 of SEQ ID NO: 114; LFR3 of SEQ ID NO: 122, and LFR4 of SEQ ID NO: 124 Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0084] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: a light chain variable region comprising: LFR1 of SEQ ID NO: 112; LFR2 of SEQ ID NO: 116; LFR3 of SEQ ID NO: 121, and LFR4 of SEQ ID NO: 124; Such an antibody may comprise the CDRs of the parent chimeric antibody (i.e., HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6; HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15).

[0085] In certain embodiments, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a humanized antibody light chain variable domain and a humanized antibody heavy chain variable domain: Antibody heavy chain variable domains: a VHCDR1 having the amino acid sequence as set forth in SEQ ID NO: 4; a VHCDR2 having the amino acid sequence as set forth in SEQ ID NO: 67, and a VHCDR3 having the amino acid sequence as set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or a VHCDR1 having the amino acid sequence as set forth in SEQ ID NO: 4; a VHCDR2 having the amino acid sequence as set forth in SEQ ID NO: 70, and a VHCDR3 having the amino acid sequence as set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or a VHCDR1 having the amino acid sequence as set forth in SEQ ID NO: 4; a VHCDR2 having the amino acid sequence as set forth in SEQ ID NO: 72, and a VHCDR3 having the amino acid sequence as set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or a VHCDR1 having the amino acid sequence as set forth in SEQ ID NO: 62; a VHCDR2 having the amino acid sequence as set forth in SEQ ID NO: 67, and a VHCDR3 having the amino acid sequence as set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 62; VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 70, and VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or a VHCDR1 having the amino acid sequence as set forth in SEQ ID NO: 62; a VHCDR2 having the amino acid sequence as set forth in SEQ ID NO: 72, and a VHCDR3 having the amino acid sequence as set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or a VHCDR1 having the amino acid sequence as set forth in SEQ ID NO: 63; a VHCDR2 having the amino acid sequence as set forth in SEQ ID NO: 67, and a VHCDR3 having the amino acid sequence as set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 63; VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 70, and VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; or VHCDR1 of the amino acid sequence set forth in SEQ ID NO: 63; VHCDR2 of the amino acid sequence set forth in SEQ ID NO: 72, and VHCDR3 of the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148; and The antibody light chain variable domain is: VLCDR1 having the amino acid sequence as set forth in SEQ ID NO: 77; VLCDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and VLCDR3 having the amino acid sequence as set forth in SEQ ID NO: 15; or VLCDR1 having the amino acid sequence as set forth in SEQ ID NO: 77; VLCDR2 having the amino acid sequence as set forth in SEQ ID NO: 14, and VLCDR3 having the amino acid sequence as set forth in SEQ ID NO: 89; or VLCDR1 of the amino acid sequence set forth in SEQ ID NO: 77; VLCDR2 of the amino acid sequence set forth in SEQ ID NO: 81, and VLCDR3 of the amino acid sequence set forth in SEQ ID NO: 15; or VLCDR1 of the amino acid sequence set forth in SEQ ID NO: 77; VLCDR2 of the amino acid sequence set forth in SEQ ID NO: 81, and VLCDR3 of the amino acid sequence set forth in SEQ ID NO: 89; or VLCDR1 having the amino acid sequence as set forth in SEQ ID NO: 77; VLCDR2 having the amino acid sequence as set forth in SEQ ID NO: 84, and VLCDR3 having the amino acid sequence as set forth in SEQ ID NO: 15; or VLCDR1 having the amino acid sequence set forth in SEQ ID NO: 77; VLCDR2 having the amino acid sequence set forth in SEQ ID NO: 84; and VLCDR3 having the amino acid sequence set forth in SEQ ID NO: 89. Includes.

[0086] These combinations of CDRs (VH CDRs and VL CDRs) are combined with humanized framework regions as described herein, in particular the following framework regions: - HFR1 of SEQ ID NO: 91; HFR2 of SEQ ID NO: 95; HFR3 of SEQ ID NO: 102, and HFR4 of SEQ ID NO: 108; or - HFR1 of SEQ ID NO: 92; HFR2 of SEQ ID NO: 96; HFR3 of SEQ ID NO: 103, and HFR4 of SEQ ID NO: 108; or - HFR1 of SEQ ID NO: 92; HFR2 of SEQ ID NO: 98; HFR3 of SEQ ID NO: 106, and HFR4 of SEQ ID NO: 108; or - HFR1 of SEQ ID NO: 93; HFR2 of SEQ ID NO: 96; HFR3 of SEQ ID NO: 104, and HFR4 of SEQ ID NO: 108; and - a light chain variable region comprising an LFR1 of SEQ ID NO: 111; an LFR2 of SEQ ID NO: 115; an LFR3 of SEQ ID NO: 120, and an LFR4 of SEQ ID NO: 124; or - a light chain variable region comprising: LFR1 of SEQ ID NO: 110; LFR2 of SEQ ID NO: 114; LFR3 of SEQ ID NO: 119, and LFR4 of SEQ ID NO: 124; or - a light chain variable region comprising: LFR1 of SEQ ID NO: 110; LFR2 of SEQ ID NO: 114; LFR3 of SEQ ID NO: 122, and LFR4 of SEQ ID NO: 124; or a light chain variable region comprising: LFR1 of SEQ ID NO: 112; LFR2 of SEQ ID NO: 116; LFR3 of SEQ ID NO: 121, and LFR4 of SEQ ID NO: 124; It should be noted that it may be combined with

[0087] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41 or SEQ ID NO:42; in particular the heavy chain variable domain comprises or consists of the amino acid sequence set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; or SEQ ID NO:39.

[0088] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47; SEQ ID NO:48; SEQ ID NO:49; SEQ ID NO:50; SEQ ID NO:51; SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59; SEQ ID NO:60 or SEQ ID NO:61; in particular the light chain variable domain comprises or consists of the amino acid sequence set forth in SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:51; SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59 or SEQ ID NO:60.

[0089] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic or modified antibody is: - a heavy chain variable domain comprising an HCDR1 of SEQ ID NO: 4; an HCDR2 of SEQ ID NO: 6, an HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148, an HFR1 of SEQ ID NO: 90; an HFR2 of SEQ ID NO: 94; an HFR3 of SEQ ID NO: 101, and an HFR4 of SEQ ID NO: 107; and a light chain variable domain comprising: LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, LCDR3 of SEQ ID NO: 15, LFR1 of SEQ ID NO: 109, LFR2 of SEQ ID NO: 113; LFR3 of SEQ ID NO: 118, and LFR4 of SEQ ID NO: 123; Includes.

[0090] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain of SEQ ID NO:10 and a light chain variable domain of SEQ ID NO:17.

[0091] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41 or SEQ ID NO:42; in particular the heavy chain variable domain comprises or consists of the amino acid sequence set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; or SEQ ID NO:39; - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61; in particular the light chain variable domain comprises or consists of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59 or SEQ ID NO: 60.

[0092] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and HFR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 19 (E / Q VQLV A / E / Q SG G / A / SGL / EV / LQ / KP / K PG G / ASL / VK / R / VL / V SC A / K AS).

[0093] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and HFR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 125 (WVR Q / A TP D / GR / KR / G / Q LELVA).

[0094] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and HFR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 126 (RF / VT / VIS / TRDN A / SK / T / VN / STLY L / MQ / EM / L / ISSL K / RS / AEDTA M / V YYCPR).

[0095] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and HFR4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 127 (WGQGT T / LL / V TVSS).

[0096] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and LFR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 128 (Q / A / EIV / Q LTQSP A / S / DI / S / F / TM / L / QSA / S / LS / VP / V / TG / PE / D / KK / RV / ATM / I / L TC).

[0097] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and LFR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 129 (WYQQK S / PG / DT / KS / APK / R RWIY).

[0098] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and LFR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 130 (GV / IPA / S RFSGSGSGT F / DYS / T LTI S / NSM / LE / QA / P ED A / FAT / V YYC).

[0099] In a particular embodiment of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises a heavy chain variable domain, and LFR4 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 131 (FG P / G GTK L / VEL / I KR).

[0100] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 20; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0101] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 21; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0102] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 22; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0103] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0104] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0105] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 25; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0106] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 26; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0107] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 27; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0108] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 28; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0109] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 29; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0110] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 30; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0111] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 31; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0112] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 32; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0113] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 33; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0114] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 34; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0115] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 35; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0116] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 36; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0117] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 37; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0118] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 38; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0119] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 39; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0120] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 40; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0121] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 41; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0122] In certain embodiments of the invention, the antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody is: - a heavy chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 42; and - a light chain variable domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61 Includes.

[0123] The present invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of diseases in which the resolution of inflammation is delayed or impeded, and / or of diseases selected from the group consisting of inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, for example sepsis, peritonitis; degenerative diseases; wound healing disorders, dry eye syndrome; cancer diseases, in particular solid and hematological cancers, metastatic cancers, in particular carcinomas, in particular breast cancer or colon cancer, or lung cancer or bone marrow cancer, in particular leukemia, in particular cancers in which the cancer cells express CMKLR1, or cancers in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1. In a particular embodiment, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of diseases in which the resolution of inflammation is delayed or prevented and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, such as sepsis, peritonitis; degenerative diseases; wound healing disorders and dry eye syndrome. In another particular embodiment of the invention, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of cancer, in particular solid and hematological cancers, metastatic cancers, in particular carcinomas, in particular breast or colon cancer, or lung or bone marrow cancers, in particular leukemias, in particular cancers in which the cancer cells express CMKLR1 or in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1.

[0124] In a particular embodiment, the present invention relates to a method for treating diseases in which the resolution of inflammation is delayed or prevented, and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, such as sepsis, peritonitis; degenerative diseases; wound healing disorders, dry eye syndrome; 1. An anti-CMKLR1 compound selected from the group of antibodies that specifically bind to anti-CMKLR1, or antigen-binding fragments thereof, or antigen-binding antibody mimics, or modified antibodies, for use in the prevention and / or treatment of a disease selected from the group of cancer diseases, in particular solid and hematological cancers, metastatic cancers, in particular carcinomas, in particular breast or colon cancer, or lung or bone marrow cancer, in particular leukemias, in particular cancers in which the cancer cells express CMKLR1, or in which the tumor microenvironment is infiltrated by cells that express or overexpress CMKLR1, comprising: - an antibody heavy chain variable domain comprising three CDRs, VHCDR1, VHCDR2 and VHCDR3: VHCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:62; SEQ ID NO:63; SEQ ID NO:64, or SEQ ID NO:65; VHCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:66; SEQ ID NO:67; SEQ ID NO:68; SEQ ID NO:69; SEQ ID NO:70; SEQ ID NO:71, or SEQ ID NO:72; an antibody heavy chain variable domain, the VHCDR3 of which comprises or consists of the amino acid sequence set forth in SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:73; SEQ ID NO:74, SEQ ID NO:75; SEQ ID NO:144; SEQ ID NO:145; SEQ ID NO:146; SEQ ID NO:147; SEQ ID NO:148; SEQ ID NO:149; SEQ ID NO:150, or SEQ ID NO:151; and / or - an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2 and VLCDR3: VLCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:76; SEQ ID NO:77; SEQ ID NO:78; SEQ ID NO:79, or SEQ ID NO:80; VLCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:81; SEQ ID NO:82; SEQ ID NO:83; SEQ ID NO:84; SEQ ID NO:85; SEQ ID NO:86; SEQ ID NO:87, or SEQ ID NO:88; an antibody light chain variable domain, wherein VLCDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 89; The present invention relates to an anti-CMKLR1 compound comprising the compound: In a particular embodiment, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of diseases in which the resolution of inflammation is delayed or prevented and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, such as sepsis, peritonitis; degenerative diseases; wound healing disorders and dry eye syndrome. In another particular embodiment of the invention, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of cancer, in particular solid and hematological cancers, in particular carcinomas, in particular breast or colon cancer, or bone marrow cancers, in particular leukemias, in particular cancers in which the cancer cells express CMKLR1 or in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1.

[0125] In a particular embodiment of the invention, the present invention relates to a therapeutic agent for treating diseases in which the resolution of inflammation is delayed or prevented, and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, such as sepsis, peritonitis; degenerative diseases, such as inflammatory bowel disease ... The antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimetic, or a modified antibody for use in the therapeutic treatment and / or prevention of a disease selected from the group of: diseases; wound healing disorders, dry eye syndrome; cancer diseases, particularly solid and hematological cancers, metastatic cancers, particularly carcinomas, particularly breast or colon cancer, or lung or bone marrow cancer, particularly leukemia, particularly a cancer in which the cancer cells express CMKLR1, or a cancer in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1, comprising: - a heavy chain variable domain comprising an HCDR1 of SEQ ID NO: 4; an HCDR2 of SEQ ID NO: 6, an HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148, an HFR1 of SEQ ID NO: 90; an HFR2 of SEQ ID NO: 94; an HFR3 of SEQ ID NO: 101, and an HFR4 of SEQ ID NO: 107; and a light chain variable domain comprising: LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, LCDR3 of SEQ ID NO: 15, LFR1 of SEQ ID NO: 109, LFR2 of SEQ ID NO: 113; LFR3 of SEQ ID NO: 118, and LFR4 of SEQ ID NO: 123; Includes. In a particular embodiment, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of diseases in which the resolution of inflammation is delayed or prevented and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, such as sepsis, peritonitis; degenerative diseases; wound healing disorders and dry eye syndrome. In another particular embodiment of the invention, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of cancer, in particular solid and hematological cancers, in particular carcinomas, in particular breast or colon cancer, or bone marrow cancers, in particular leukemias, in particular cancers in which the cancer cells express CMKLR1 or in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1.

[0126] In particular embodiments of the invention, the present invention is directed to diseases in which the resolution of inflammation is delayed or impeded and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases such as sepsis, peritonitis; degenerative diseases; wound healing disorders, dry eye syndrome; The antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimetic, or a modified antibody for use in the prevention and / or treatment of a disease selected from the group of cancer diseases, particularly solid and blood cancers, metastatic cancers, particularly carcinomas, particularly breast cancer or colon cancer, or lung cancer or bone marrow cancer, particularly leukemia, particularly a cancer in which the cancer cells express CMKLR1, or a cancer in which the tumor microenvironment is infiltrated by cells that express or overexpress CMKLR1, comprises a heavy chain variable domain of SEQ ID NO: 10 and a light chain variable domain of SEQ ID NO: 17. In a particular embodiment, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of diseases in which the resolution of inflammation is delayed or prevented and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, such as sepsis, peritonitis; degenerative diseases; wound healing disorders and dry eye syndrome. In another particular embodiment of the invention, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of cancer, in particular solid and hematological cancers, in particular carcinomas, in particular breast or colon cancer, or bone marrow cancers, in particular leukemias, in particular cancers in which the cancer cells express CMKLR1 or in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1.

[0127] In certain embodiments of the invention, the antibody or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody comprises: - HCDR1 of SEQ ID NO: 4; HCDR2 of SEQ ID NO: 6, HCDR3 of SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148, and HFR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 91; SEQ ID NO: 92 or SEQ ID NO: 93; and HFR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 95; SEQ ID NO: 96; SEQ ID NO: 97; SEQ ID NO: 98; SEQ ID NO: 99 or SEQ ID NO: 100; and HFR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 102; SEQ ID NO: 103; SEQ ID NO: 104; SEQ ID NO: 105 or SEQ ID NO: 106; and HFR4 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 108 a heavy chain variable domain comprising: - LCDR1 of SEQ ID NO: 12; LCDR2 of SEQ ID NO: 14, LCDR3 of SEQ ID NO: 15; and LFR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 110; SEQ ID NO: 111 or SEQ ID NO: 112; and LFR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 114; SEQ ID NO: 115; SEQ ID NO: 116 or SEQ ID NO: 117; and an LFR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 119; SEQ ID NO: 120; SEQ ID NO: 121; SEQ ID NO: 122 or SEQ ID NO: 132; and LFR4 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 124 A light chain variable domain comprising Includes.

[0128] In particular embodiments of the invention, the present invention is directed to diseases in which the resolution of inflammation is delayed or prevented and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases such as sepsis, peritonitis; , wound healing disorders, dry eye syndrome; cancer diseases, in particular solid and hematological cancers, metastatic cancers, in particular carcinomas, in particular breast, lung or colon cancer or bone marrow cancers, in particular leukemias, in particular cancers in which the cancer cells express CMKLR1 or in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1, comprising: - a heavy chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41 or SEQ ID NO:42; in particular a heavy chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; or SEQ ID NO:39; - a light chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61; in particular a light chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59 or SEQ ID NO: 60 Includes. In a particular embodiment, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of diseases in which the resolution of inflammation is delayed or prevented and / or inflammatory diseases, in particular acute inflammatory diseases, chronic inflammatory diseases, such as asthma, keratoconjunctivitis, periodontal disease, eczema, inflammatory bowel disease, in particular Crohn's disease or colitis, in particular ulcerative colitis or spontaneous colitis; autoimmune diseases, such as diabetes, in particular type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, myasthenia gravis; infectious diseases, such as sepsis, peritonitis; degenerative diseases; wound healing disorders and dry eye syndrome. In another particular embodiment of the invention, the invention relates to any of the compounds of the invention as defined above for use in the prevention and / or treatment of cancer, in particular solid and hematological cancers, in particular carcinomas, in particular breast or colon cancer, or bone marrow cancers, in particular leukemias, in particular cancers in which the cancer cells express CMKLR1 or in which the tumor microenvironment is infiltrated by cells expressing or overexpressing CMKLR1.

[0129] In certain embodiments of the invention, an antibody, or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody for use in treating colitis or Crohn's disease in a subject refractory to corticosteroid and / or immunosuppressive treatment comprises: - a heavy chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41 or SEQ ID NO:42; in particular a heavy chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; or SEQ ID NO:39; and - a light chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60 or SEQ ID NO: 61; in particular a light chain variable domain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 43; SEQ ID NO: 44; SEQ ID NO: 45; SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59 or SEQ ID NO: 60 has.

[0130] In another aspect, the present invention relates to anti-CMKLR1 compounds as defined herein, which enhance the secretion of anti-inflammatory cytokines, in particular IL10, by macrophages. In another aspect, the present invention relates to anti-CMKLR1 compounds as defined herein, which enhance the secretion of anti-inflammatory cytokines, in particular CCL17, by macrophages. In another aspect, the present invention relates to anti-CMKLR1 compounds as defined herein, which enhance the secretion of anti-inflammatory cytokines, in particular IL10 and / or CCL17, by macrophages. The present invention also relates to anti-CMKLR1 compounds as defined herein, which inhibit the secretion of pro-inflammatory cytokines, in particular IL12, by macrophages. Cytokine secretion may be assessed by methods known in the art or by methods disclosed in the examples of the present invention.

[0131] In another aspect, the present invention relates to an anti-CMKLR1 compound as defined herein that inhibits proliferation and / or activation of dendritic cells, in particular human dendritic cells. Proliferation and / or activation of dendritic cells may be assessed by the methods disclosed in the examples of the present invention.

[0132] In another aspect, the present invention relates to a composition comprising an anti-CMKLR1 compound as described herein, in particular a pharmaceutical composition comprising an anti-CMKLR1 compound according to the present invention and a further therapeutic agent or a pharma- ceutically acceptable carrier. In a particular embodiment, the present invention relates to a composition comprising an anti-CMKLR1 compound according to the present invention and a therapeutic agent selected from the group consisting of an immunomodulator, an immune checkpoint blocker, an immune checkpoint activator, an antibody, in particular an anti-CD137 antibody (which targets the TNF receptor superfamily member 4-1BB, also known as CD137), or an anti-SIRPa antibody (P84-Merck Millipore's anti-mouse SIRPa).

[0133] In another aspect, the present invention relates to a combination of compounds comprising the anti-CMKLR1 compounds described herein, in particular a pharmaceutical composition comprising an anti-CMKLR1 compound according to the present invention and an anti-PD1 or anti-PDL1 compound, in particular an anti-PD1 compound; such compounds are in particular selected from the group consisting of small molecules such as antibodies, antigen-binding antibody fragments, antigen-binding antibody mimetics, aptamers or peptides, modified antibodies such as, but not limited to, humanized or chimeric antibodies capable of binding to PD1 or PDL1.

[0134] In another aspect, the present invention relates to a combination of compounds comprising the anti-CMKLR1 compounds described herein, in particular a pharmaceutical composition comprising an anti-CMKLR1 compound according to the present invention and an anti-SIRPa compound; such compounds are in particular selected from the group consisting of small molecules such as antibodies, antigen-binding antibody fragments, antigen-binding antibody mimetics, aptamers or peptides, modified antibodies such as, but not limited to, humanized or chimeric antibodies capable of binding to SIRPa, in particular human SIRPa.

[0135] In another aspect, the present invention relates to the therapeutic use of the anti-CMKLR1 compounds of the present invention for the treatment of diseases in which prolonged inflammation or prolonged resolution of inflammation is pathological, in particular for inducing and / or enhancing resolution of inflammation, in particular when said resolution is delayed or hindered.

[0136] In certain embodiments of the invention, the anti-CKLMR1 compounds bind to CMKLR1 with an affinity (KD value) of at least 10E-8M, more preferably with an affinity of at least 10E-9M. Specific binding between an antibody of the invention, or an antigen-binding fragment thereof, or an antigen-binding antibody mimetic, or an engineered antibody, and CMKLR1 (or a region of CMKLR1 comprising the third extracellular loop, comprising the amino acid sequences set forth in SEQ ID NOs: 2 and 18) implies that the antibody exhibits an appreciable affinity for CMKLR1. "Appreciable affinity" refers to an affinity of at least about 10 -8 M(KD) or stronger. Preferably, the binding is with a binding affinity of 10 -8 M~10-12 Optionally, 10 for M -9 M~10 -10 During M, especially at least 10 -9 M. Whether a binding domain specifically reacts with or binds to a target can be easily tested by, among other things, comparing the reaction of the binding domain with a target protein or antigen to the reaction of the binding domain with a protein or antigen other than the target protein. Such an antibody of the present invention specifically binds to CMKLR1 and has an agonistic effect on the interaction between RvE1 and CMKLR1. Methods for determining antibody specificity and affinity by competitive inhibition are known in the art (e.g., Harlow et al., "Antibodies: A Laboratory Manual", Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1998); Colligan et al., "Current Protocols in Immunology", Green Publishing Assoc., NY (1992; 1993); Muller, Meth. Enzym., 92:589-601 (1983)). These methods include, but are not limited to, Biacore analysis, Blitz analysis, flow cytometry, and ELISA assays.

[0137] In certain embodiments of the present invention, the anti-CMKLR1 compounds specifically bind to an epitope located within the third extracellular loop of CMKLR1, particularly an epitope located within the amino acid residue sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 18, particularly SEQ ID NO: 2. Anti-CMKLR1 compounds that bind within this specific region of CMKLR1 can have agonistic properties for CMKLR1, thereby mimicking the binding of RvE1 to CMKLR1.

[0138] In another aspect, the present invention relates to an anti-CMKLR1 antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimetic, or a modified antibody as defined herein above, having agonistic ability on the interaction between RvE1 and CMKLR1 for use as a medicament.

[0139] In another aspect, the present invention relates to an anti-CMKLR1 antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimic, or a modified antibody, as defined herein above, capable of inducing the activation of Akt and / or Erk proteins in vitro and / or in vivo. The activation of these proteins may be evaluated by the methods described in the examples of the present invention. In particular, the anti-CMKLR1 antibody, or an antigen-binding fragment thereof, or an antigen-binding antibody mimic, or a modified antibody, has the ability to activate either or both of Akt and / or Erk proteins in macrophages, particularly human macrophages.

[0140] The present invention also relates to a method of treatment in a subject in need thereof, comprising administering to said subject an effective amount of an anti-CMKLR1 antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimic as defined above, which has agonistic ability for the interaction between RvE1 and CMKLR1, or in other words is an RvE1 agonist-like factor or modulator.

[0141] Modification of macrophage polarization in favor of anti-inflammatory cells may be useful in many disease states or situations. As described above, this modification is particularly useful in the context of diseases selected from the group of inflammatory diseases including, but not limited to, acute and chronic inflammatory diseases, inflammatory bowel disease, Crohn's disease, asthma, keratoconjunctivitis, periodontal disease, eczema, colitis, especially ulcerative colitis or spontaneous colitis, diabetes, especially type I diabetes, peritonitis, psoriasis, carcinoma, especially breast cancer or colon cancer, cancer, metastatic cancer, lung cancer, degenerative diseases, infectious diseases, especially sepsis, autoimmune diseases.

[0142] The present invention also relates to the use of an anti-CMKLR1 antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic as defined above, having agonistic potential for the interaction between RvE1 and CMKLR1, in the manufacture of a medicament.

[0143] In another aspect, the present invention relates to an engineered antibody, such as an anti-CMKLR1 antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic or a humanized or chimeric antibody as defined herein, but not limited to, for use in the treatment of chronic inflammatory diseases, in particular for treating chronic colitis.

[0144] In another aspect, the present invention relates to an anti-CMKLR1 antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic as defined above having agonistic activity against the interaction between RvE1 and CMKLR1 for use in the treatment of inflammatory conditions, in particular delayed or hindered recovery of inflammatory diseases whose recovery is delayed or hindered, and / or in the treatment or prevention of a disease selected from the group of inflammatory diseases including, but not limited to, acute and chronic inflammatory diseases, inflammatory bowel disease, Crohn's disease, asthma, keratoconjunctivitis, periodontal disease, eczema, colitis, in particular ulcerative colitis or spontaneous colitis, diabetes, in particular type I diabetes, peritonitis, psoriasis, carcinoma, in particular breast cancer or colon cancer, cancer, degenerative diseases, infectious diseases, in particular sepsis, autoimmune diseases.

[0145] A "delayed or impeded resolution of an inflammatory condition" as defined herein occurs when the resolution of inflammation is delayed or impeded compared to normal resolution (i.e., the resolution that occurs in patients who experience normal recovery after an inflammatory event). A delayed or poor resolution may result in an increased infiltration of granulocytes at the inflammatory site. A delayed or poor resolution may thereby be assessed by quantification of granulocytes at the inflammatory site. Granulocyte population may be measured by histological, cytometric or indirect biochemical techniques, such as, for example, elastase quantification by enzyme immunoassay or molecular quantification by PCR of granulocyte receptor 1). A delayed or poor resolution may also be assessed by determining a delay in granulocyte apoptosis, measured, for example, by cytological diagnosis using specific antibodies against annexin 5. A poor or delayed resolution of inflammation may also be determined by assessing the quantification of the synthesis of pro-inflammatory cytokines, such as TNF-alpha, IL8 or IL12, and anti-inflammatory cytokines, such as IL10. Cytokine secretion may be assessed by enzyme immunoassay or by PCR. A poor or delayed resolution of inflammation can also be determined by evaluating the activation of transcription factors involved in the synthesis of inflammatory cytokines, such as NFkappaB, which can be measured, for example, by nuclear translocation or by Western blot and / or by quantifying the degradation level of IkappaB. A poor or delayed resolution of inflammation can also be determined by quantifying specialized pro-resolving mediators (e.g. lipoxins, resolvins, protectins or maresins) or their precursors (e.g. 17-HDOHE or 14-HDOHE) by mass spectrometry or enzyme immunoassay. A poor or delayed resolution then results in a poor synthesis of one or more of these mediators. A poor or delayed resolution can also be determined if the expression of receptors of the resolving molecules is reduced. These receptors can be selected from the group including ALX, CMK1R1, GPR32 or GPR18. Alternatively or complementary, the internalization and processing of these receptors into the cytoplasm can also be evaluated.Alternatively or complementary, the expression of some receptors of inflammatory cytokines or lipids can also be evaluated, and overexpression compared to normal conditions is important for delayed or poor recovery of inflammation. These conditions can be measured by histology, cytology or PCR. Poor recovery can also result in reduced or inhibited switching from M1 to M2 macrophages, impaired phagocytosis or efferocytosis of the same cells. Thus, delayed or poor recovery can be evaluated by analyzing the switching from M1 to M2 macrophages in specific conditions compared to normal conditions, as illustrated in the examples of the present invention.

[0146] According to specific embodiments, the anti-CMKLR1 compounds may be used to treat individuals having cancer selected from the group consisting of breast cancer, particularly breast cancer, melanoma, colon cancer, particularly colon cancer, leukemia, particularly acute myeloid leukemia, particularly leukemia where the cancer cells overexpress CMKLR1.

[0147] In one embodiment, the present invention relates to an anti-human CMKLR1 antibody or its antigen-binding fragment or antigen-binding antibody mimic or modified antibody as defined above for the use as defined above, wherein said anti-human CMKLR1 antibody or its antigen-binding fragment or antigen-binding antibody mimic or modified antibody of the present invention is administered to a patient presenting with a CMKLR1-positive tumor.

[0148] The antibody or antigen-binding fragment thereof of the present invention may be administered to a subject by various suitable routes, for example, intravenously (IV), subcutaneously (SC) or intramuscularly (IM). The anti-CMKLR1 compound may be administered alone or in combination with another therapeutic agent, for example, a second human monoclonal antibody or antigen-binding fragment thereof. In another example, the antibody is administered in combination with another agent, for example, an immunosuppressant, an erythropoietin stimulating agent (ESA), a therapeutic cell composition, etc. In one embodiment, the present invention relates to an anti-CMKLR1 compound or antigen-binding fragment thereof or an antigen-binding antibody mimic for use as defined above, wherein the anti-CMKLR1 antibody or antigen-binding fragment is combined with a second therapeutic agent.

[0149] The administration of the second therapeutic agent may or may not be simultaneous with the administration of the anti-CMKLR1 compound. Depending on the nature of the second agent, the simultaneous administration may be prepared in the form of a combination drug (product), also known as a "combo". A combo is a fixed-dose combination that contains two or more active pharmaceutical ingredients combined in a single dosage form that is manufactured and distributed in a fixed dose. However, the dosage regimen and / or the route of administration may be different.

[0150] In preferred embodiments, the second therapeutic agent is selected from the group consisting of chemotherapeutic agents, radiotherapeutic agents, immunotherapeutic agents, cellular therapeutic agents (such as CAR-T cells), antibiotics, and probiotics.

[0151] In particular, immunotherapeutic agents useful in the context of the present invention are selected from the group consisting of therapeutic vaccines (DNA, RNA or peptide vaccines), immune checkpoint blockers or activators, especially of adaptive immune cells (T or B lymphocytes), or immunoconjugates such as antibody drug conjugates.

[0152] As used herein, the term "immunotherapeutic agent" refers specifically to agents whose interesting biological phenomena make them effective therapeutic agents for cancer vaccines, including T cell growth factors that increase the number and repertoire of naive T cells, growth factors that increase the number of dendritic cells (DCs), agonists that activate DCs and other antigen presenting cells (APCs), adjuvants that enable and augment cancer vaccines, agonists that activate and stimulate T cells, inhibitors of T cell checkpoint blockade, T cell growth factors that increase the proliferation and survival of immune T cells, and agents that inhibit, block or neutralize cancer cell and immune cell derived immunosuppressive cytokines.

[0153] Numerous immune checkpoint blockers or activators are known in the art. In the context of the present invention, examples of immune checkpoint blockers or activators of adaptive immune cells (B or T lymphocytes) that may be useful are anti-PDL1, anti-PD1, anti-CTLA4, anti-SIRPa; anti-CD137, anti-CD2, anti-CD28, anti-CD40, anti-HVEM, anti-BTLA, anti-CD160, anti-TIGIT, anti-TIM-1 / 3, anti-LAG-3, anti-2B4 and anti-OX40, anti-CD40 agonists, CD40-L, TLR agonists, anti-ICOS, ICOS-L and B cell receptor agonists, in particular anti-CD137 and anti-SIRPa. In a specific embodiment of the present invention, the second therapeutic agent is an anti-PDL1 or anti-PD1 compound, in particular an anti-PD1 compound, more particularly an anti-PD1 antibody. In a specific embodiment of the present invention, the second therapeutic agent is an anti-SIRPa compound, in particular an anti-SIRPa antibody.

[0154] The immunotherapeutic agent may also be an antibody targeting a tumor antigen, in particular an antibody selected from the group consisting of anti-Her2, anti-EGFR, anti-CD20, anti-CD19, anti-CD52.

[0155] Antibodies may be provided at an effective dose of about 1 ng / kg body weight to about 30 mg / kg body weight or more, in particular embodiments, dosages may range from 1 μg / kg to about 20 mg / kg, optionally from 10 μg / kg to 10 mg / kg or from 100 μg / kg to 5 mg / kg.

[0156] The term "effective dose" or "effective dosage" or "effective amount" is defined as an amount sufficient to achieve or at least partially achieve a desired effect. The term "effective dose" is meant to encompass an amount sufficient to cure or at least partially halt the disease and its complications or to alleviate the symptoms of the disease in a patient already suffering from the disease. The amount or dose effective for this use will depend on the condition being treated, the antibody construct being delivered, the therapeutic context and purpose, the severity of the disease, previous therapies, the patient's medical history and response to the therapeutic agent, the route of administration, the size (weight, body surface area or organ size) and / or condition (age and general health) of the patient, and the general state of the patient's own immune system. The appropriate dose may be administered to the patient once or over a series of administrations, and may be adjusted to obtain the optimal therapeutic effect.

[0157] Dosing for such purposes may be repeated as necessary, for example daily, twice weekly, weekly, twice monthly, monthly or as needed upon recurrence.

[0158] In another aspect, the present invention relates to a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof as defined above and a pharma- ceutically acceptable carrier.

[0159] As used herein, "pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject or patient, such as a mammal, particularly a human. Generally, a "pharmaceutical composition" is sterile and usually free of contaminants that may induce an undesirable response in a subject (e.g., the compounds in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be designed for administration to a subject or patient in need thereof via a number of different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intracheal, and the like.

[0160] As used herein, "pharmaceutically acceptable carrier" is meant to encompass excipients, diluents, carriers, and adjuvants that are generally safe, non-toxic, and not biologically or otherwise undesirable, and are useful for preparing pharmaceutical compositions, including excipients, diluents, carriers, and adjuvants that are acceptable for veterinary and human pharmaceutical use. As used herein, "pharmaceutically acceptable carrier" includes one or more of such excipients, diluents, carriers, and adjuvants.

[0161] In particular, the present invention relates to a pharmaceutical composition comprising an active ingredient as defined above, an antibody or an antigen-binding fragment thereof and a pharma- ceutically acceptable carrier.

[0162] In another aspect, the present invention relates to a therapeutic means, in particular a combination product means, comprising as active ingredients: an anti-SIRPα antibody or an antigen-binding fragment thereof or an antigen-binding antibody mimetic as defined above and a second therapeutic agent, wherein said active ingredients are formulated for separate, sequential or combined therapy, in particular for combined or sequential use.

[0163] In particular, the present invention relates to a combination product comprising an anti-CMKLR1 compound as defined above and a second therapeutic agent for simultaneous, separate or sequential pharmaceutical use.

[0164] In one embodiment, the invention relates to a combination product as defined above, wherein the second therapeutic agent is selected from the group consisting of chemotherapeutic agents, radiotherapeutic agents, cellular therapeutic agents, immunotherapeutic agents, antibiotics and probiotics.

[0165] In one embodiment, the invention relates to a combination product as defined above, wherein said immunotherapeutic agent is selected from the group consisting of therapeutic vaccines, immune checkpoint blockade or activators, in particular of adaptive immune cells (T and B lymphocytes) and antibody drug conjugates.

[0166] In one embodiment, the invention relates to a combination product as defined above, wherein said immune checkpoint blockade or activator of adaptive immune cells (T and B lymphocytes) is selected from the group consisting of anti-PDL1, anti-PD1, anti-SIRPA, anti-CTLA4, anti-CD137, anti-CD2, anti-CD28, anti-CD40, anti-HVEM, anti-BTLA, anti-CD160, anti-TIGIT, anti-TIM-1 / 3, anti-LAG-3, anti-2B4 and anti-OX40, anti-CD40 agonists, CD40-L, TLR agonists, anti-ICOS, ICOS-L and B cell receptor agonists, in particular selected from the group consisting of anti-PDL1, anti-PD1 and anti-CD137. In a specific embodiment of the invention, the second therapeutic agent is an anti-PDL1 or anti-PD1 compound, in particular an anti-PD1 compound and more particularly an anti-PD1 antibody. In a specific embodiment of the invention, the second therapeutic agent is an anti-SIRPa compound, in particular an anti-SIRPa antibody.

[0167] In one embodiment, said immunotherapeutic agent is an antibody targeting a tumor antigen, in particular selected from the group consisting of anti-Her2, anti-EGFR, anti-CD20, anti-CD19, anti-CD52.

[0168] In one aspect, the present invention relates to a combination product as defined above for simultaneous, separate or sequential use in the treatment of any condition susceptible to amelioration or prevention by altering macrophage polarization towards anti-inflammatory macrophages.

[0169] In one embodiment, the present invention relates to a method for the treatment of any condition susceptible to amelioration or prevention by altering macrophage polarization towards anti-inflammatory macrophages in a subject in need thereof comprising simultaneously, separately or sequentially administering to the subject an effective amount of a combination product as defined above.

[0170] In one embodiment, the invention relates to the use of a combination product as defined above in the manufacture of a medicament for the treatment of any condition susceptible to amelioration or prevention by altering macrophage polarization towards anti-inflammatory macrophages.

[0171] In one aspect the invention relates to a combination product as defined above for simultaneous, separate or sequential use in the treatment of a condition selected from the group consisting of inflammatory diseases, including but not limited to acute inflammatory diseases and chronic inflammatory diseases, inflammatory bowel disease, Crohn's disease, asthma, keratoconjunctivitis, periodontal disease, eczema, colitis, particularly ulcerative or spontaneous colitis, diabetes, particularly type I diabetes, peritonitis, psoriasis, cancer, particularly breast or colon cancer, cancer, metastatic cancer, lung cancer, degenerative diseases, infectious diseases, particularly sepsis, autoimmune diseases or for use in vaccination.

[0172] In one embodiment the invention relates to a method for the treatment of a condition selected from the group of inflammatory diseases, including but not limited to acute inflammatory diseases and chronic inflammatory diseases, inflammatory bowel disease, Crohn's disease, asthma, keratoconjunctivitis, periodontal disease, eczema, colitis, particularly ulcerative colitis or spontaneous colitis, diabetes, particularly type I diabetes, peritonitis, psoriasis, cancer, particularly breast cancer or colon cancer, cancer, metastatic cancer, lung cancer, degenerative diseases, infectious diseases, particularly sepsis, autoimmune diseases, in a subject in need thereof comprising simultaneously, separately or sequentially administering to the subject an effective amount of a combination product as defined above.

[0173] In one embodiment the invention relates to the use of a combination product as defined above in the manufacture of a medicament for the treatment of a condition selected from the group of: inflammatory diseases, including but not limited to acute inflammatory diseases and chronic inflammatory diseases, inflammatory bowel disease, Crohn's disease, asthma, keratoconjunctivitis, periodontal disease, eczema, colitis, particularly ulcerative colitis or spontaneous colitis, diabetes, particularly type I diabetes, peritonitis, psoriasis, cancer, particularly breast cancer or colon cancer, cancer, metastatic cancer, lung cancer, degenerative diseases, infectious diseases, particularly sepsis, autoimmune diseases.

[0174] The present invention provides a method for selecting an anti-CMKLR1 compound, comprising: a) providing a compound selected from the group of antibodies or antigen-binding fragments thereof, or chimeric or humanized antibodies, said compound being: - an antibody heavy chain variable domain comprising three CDRs, VHCDR1, VHCDR2 and VHCDR3: VHCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:4 or a variant thereof in which amino acid residues have been substituted; VHCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:6 or a variant thereof in which amino acid residues have been substituted; an antibody heavy chain variable domain, the VHCDR3 of which comprises or consists of the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 144 or SEQ ID NO: 148, or a variant thereof in which amino acid residues have been substituted such that the amino acid residues at positions 1 and 2 of SEQ ID NO: 8 become L and I, respectively; and - an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2 and VLCDR3: VLCDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof in which amino acid residues have been substituted; VLCDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14 or a variant thereof in which amino acid residues have been substituted; an antibody light chain variable domain, wherein VLCDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 15 or a variant thereof in which amino acid residues are substituted; A process comprising: b) testing the ability of the compound to be an RvE1-like agonist of CMKLR1, particularly testing the ability of the compound to favor the amelioration of inflammation in myeloid cells; and optionally c) testing the binding ability of the compound to an epitope located in the third loop E3 ​​of CMKLR1 by BLITZ analysis or biosensor, in particular the binding ability of the compound to a polypeptide comprising the amino acid residues of SEQ ID NO: 2 or SEQ ID NO: 152; and optionally d) testing that the compound is unable to compete with the binding of chemerin to CMKLR1; e) if the binding capacity of the compound tested in step c) is at least 10E-8KD; i) testing the ability of the compound to induce phosphorylation of Akt and / or phosphorylation of Erk following binding of the compound to CMKLR1, in particular phosphorylation of Akt and phosphorylation of Erk; ii) testing the ability of the compound to enhance the secretion of anti-inflammatory cytokines, in particular IL10, more particularly IL10 and CCL17; and / or the ability of the compound to inhibit or reduce the secretion of pro-inflammatory cytokines, in particular IL12, especially in myeloid cells expressing CMKLR1; and / or iii) testing the ability of the compound to enhance macrophage polarization in favor of anti-inflammatory M2-type macrophages; in particular the ability of the compound to enhance the secretion of the phenotypic marker CD200R; and / or iv) testing the ability of the compound to inhibit dendritic cell activation and / or proliferation.

[0175] The potency of the compounds can be tested by the examples disclosed in the examples of this disclosure.

[0176] The present invention also relates to polynucleotides encoding the anti-CMKLR1 compounds defined herein. For this purpose, the present invention also relates to a nucleic acid molecule, or a group of nucleic acid molecules, more particularly isolated and / or recombinant nucleic acid molecules, encoding any of the anti-CMKLR1 compounds according to the present disclosure, more particularly encoding a heavy chain variable domain comprising or consisting of the amino acid residues of the sequence set forth in SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28: SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41 or SEQ ID NO:42, and / or a light chain variable domain comprising or consisting of the amino acid residues of the sequence set forth in SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47; SEQ ID NO:48; SEQ ID NO:49; SEQ ID NO:50; SEQ ID NO:51: SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59; SEQ ID NO:60 or SEQ ID NO:61. The nucleic acid molecule may further comprise regulatory sequences, such as, but not limited to, enhancers, silencers, promoters, in particular expression promoters, signal peptides, for the transcription and expression of the encoded heavy chain variable domain and / or light chain variable domain.

[0177] The present invention also relates to vectors comprising the polynucleotides disclosed herein or comprising the nucleic acid molecules disclosed herein. As used herein, a vector is a nucleic acid molecule used as a vehicle to transfer genetic material into a cell, and in a preferred embodiment allows for the expression of a polynucleotide inserted into the vector. The term vector encompasses plasmids, viruses, cosmids, and artificial chromosomes. A vector generally comprises an origin of replication, a multiple cloning site, and a selectable marker. The vector itself is generally a nucleotide sequence, usually a DNA sequence, that contains the inserted (transgene) and a larger sequence that serves as the "backbone" of the vector. Current vectors may include additional features beyond the transgene insert and backbone: promoters, genetic markers, antimicrobial resistance, reporter genes, targeting sequences, protein purification tags. In particular, vectors referred to as expression vectors (expression constructs) are for the expression of a transgene in a target cell and generally have regulatory sequences.

[0178] In another aspect, the present invention relates to a cell, an isolated cell, a host cell, an isolated host cell or a cell line comprising a vector as defined above. As used herein, these terms relating to cells are intended to include any individual cell or cell culture that may be or has been a recipient of vectors, exogenous nucleic acid molecules and polynucleotides encoding the antibody construct of the present invention; and / or of the antibody construct itself. The introduction of the respective material into the cell may be performed by methods such as transformation, transfection, etc. These terms are also intended to include the progeny or potential progeny of a single cell. Suitable host cells include prokaryotic or eukaryotic cells, including but not limited to bacteria, yeast cells, fungal cells, plant cells, and animal cells such as insect cells and mammalian cells, e.g., mouse, rat, rabbit, macaque or human cells.

[0179] The following figures and examples are provided to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are the only ones performed. Although the invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various modifications may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition, method, method step or steps, within the objective, spirit and scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto. [Brief description of the drawings]

[0180] [Figure 1A] Figure 1 shows the effect of anti-CMKLR1 variant 1G1, 2G1, 3G1 and 4G1 chimeric antibodies on DC maturation and differentiation. Mouse dendritic cells were incubated with vehicle or RvE1 or anti-CMKLR1 antibody variants (mutations at positions 1 and 2 of SEQ ID NO: 8, VH-CDR3: corresponding to 1G1(LL), 2G1(LI), 3G1(IL) or 4G1(II) or isotype control (hIgG1 or mIgG)) during the maturation phase (24 hours or 48 hours) followed by the differentiation phase. Cells were then stained for FACS analysis using cell marker antibody: A.CD80-PE. The mean fluorescence was determined in each condition. [Figure 1B]Figure 1 shows the effect of anti-CMKLR1 variant 1G1, 2G1, 3G1 and 4G1 chimeric antibodies on DC maturation and differentiation. Mouse dendritic cells were incubated with vehicle or RvE1 or anti-CMKLR1 antibody variants (mutations at positions 1 and 2 of SEQ ID NO: 8, VH-CDR3: corresponding to 1G1(LL), 2G1(LI), 3G1(IL) or 4G1(II) or isotype control (hIgG1 or mIgG)) during the maturation phase (24 hours or 48 hours) followed by the differentiation phase. Cells were then stained for FACS analysis using cell marker antibody: B.CD86-FITC; Mean fluorescence was determined in each condition. [Figure 1C] Figure 1 shows the effect of anti-CMKLR1 variant 1G1, 2G1, 3G1 and 4G1 chimeric antibodies on DC maturation and differentiation. Mouse dendritic cells were incubated with vehicle or RvE1 or anti-CMKLR1 antibody variants (mutations at positions 1 and 2 of SEQ ID NO: 8, VH-CDR3: corresponding to 1G1(LL), 2G1(LI), 3G1(IL) or 4G1(II) or isotype control (hIgG1 or mIgG)) during the maturation phase (24 hours or 48 hours) followed by the differentiation phase. Cells were then stained for FACS analysis using cell marker antibody: C.CD103-PerCPCy5.5; The mean fluorescence was determined in each condition. [Figure 1D] Figure 1 shows the effect of anti-CMKLR1 variant 1G1, 2G1, 3G1 and 4G1 chimeric antibodies on DC maturation and differentiation. Mouse dendritic cells were incubated with vehicle or RvE1 or anti-CMKLR1 antibody variants (mutations at positions 1 and 2 of SEQ ID NO: 8, VH-CDR3: corresponding to 1G1(LL), 2G1(LI), 3G1(IL) or 4G1(II) or isotype control (hIgG1 or mIgG)) during the maturation phase (24 hours or 48 hours) followed by the differentiation phase. Cells were then stained for FACS analysis using cell marker antibodies: DI / Ab-APC. The mean fluorescence was determined in each condition. [Figure 1E]Figure 1 shows the effect of anti-CMKLR1 variant 1G1, 2G1, 3G1 and 4G1 chimeric antibodies on DC maturation and differentiation. Mouse dendritic cells were incubated with vehicle or RvE1 or anti-CMKLR1 antibody variants (mutations at positions 1 and 2 of SEQ ID NO: 8, VH-CDR3: corresponding to 1G1(LL), 2G1(LI), 3G1(IL) or 4G1(II) or isotype control (hIgG1 or mIgG)) during the maturation phase (24 hours or 48 hours) followed by the differentiation phase. E represents the cell viability measured by FACS using the LIVE / DEAD® kit from Life Technologies for each condition after 24 hours of maturation. [Figure 1F] Figure 1 shows the effect of anti-CMKLR1 variant 1G1, 2G1, 3G1 and 4G1 chimeric antibodies on DC maturation and differentiation. Mouse dendritic cells were incubated with vehicle or RvE1 or anti-CMKLR1 antibody variants (mutations at positions 1 and 2 of SEQ ID NO: 8, VH-CDR3: corresponding to 1G1(LL), 2G1(LI), 3G1(IL) or 4G1(II) or isotype control (hIgG1 or mIgG)) during the maturation phase (24 hours or 48 hours) followed by the differentiation phase. F represents the cell viability measured by FACS using the LIVE / DEAD® kit from Life Technologies for each condition after 48 hours of maturation. [Figure 2A] Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse acute inflammatory colitis model induced by DSS. Mice were injected with isotype control hIgG1 (10 μg per mouse) (x), RvE1 (1 μg per mouse) daily (●), or 2G1 antibody (10 μg per mouse) three times (□) for 5 days 6 days after DSS induction. Untreated wild type mice are represented by ▽. A. Animal weight loss. [Figure 2B]Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse acute inflammatory colitis model induced by DSS. Mice were injected with isotype control hIgG1 (10 μg per mouse) (x), RvE1 (1 μg per mouse) daily (●), or 2G1 antibody (10 μg per mouse) three times (□) for 5 days after 6 days of DSS induction. Untreated wild-type mice are represented by ▽. B. Animal fecal scores. [Figure 2C] Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse acute inflammatory colitis model induced by DSS. Mice were injected with isotype control hIgG1 (10 μg per mouse) (x), RvE1 (1 μg per mouse) daily (●), or 2G1 antibody (10 μg per mouse) three times (□) for 5 days 6 days after DSS induction. Untreated wild type mice are represented by ▽. C. Colon length. [Figure 2D] Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse acute inflammatory colitis model induced by DSS. Mice were injected with isotype control hIgG1 (10 μg per mouse) (x), RvE1 (1 μg per mouse) daily (●), or 2G1 antibody (10 μg per mouse) three times (□) for 5 days 6 days after DSS induction. Untreated wild type mice are represented by ▽. D. Recovery index. [Diagram 3] Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse acute inflammatory colitis model induced by TNBS. Mice received 200 μL of the haptenating agent TNBS, 5% in 50% ethanol, on day 0 and were then injected with isotype control hIgG1 (10 μg per mouse) (x), RvE1 (1 μg per mouse) daily (●) or 2G1 antibody (10 μg per mouse) three times (□) for 5 days, or were left untreated (wild type animals) (△). Mice were sacrificed and colon length was measured in each condition. [Figure 4]Figure 1 shows the effect of anti-CMKLR1 antibody in IL10 KO mouse chronic inflammatory colitis model. IL10 KO mice develop spontaneous inflammatory colitis. They were treated intraperitoneally (25 μg / injection, 3 times a week) with anti-CMKLR1 antibody (2G1) (□) or isotype control (hIgG1) (x). A. Animal weight loss during and after treatment, B. Animal fecal score. [Diagram 5] Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse type 1 non-obese diabetes model. Mice develop spontaneous diabetes. When blood glucose was between 180 and 234 mg / dL, they were treated intraperitoneously with anti-CMKLR1 antibodies (□ in A and B, ◆ in C) or isotype control antibodies (x in A and B; □ in C) at 20 μg / injection, three times a week, for 2 weeks. A. Percentage of survival, B. Individual representation of blood glucose concentration in mg / dL, C. Pooled representation of blood glucose concentration in mg / dL. [Figure 6] FIG. 1 shows the effect of Resolvin E1 in autoimmune disease, including a mouse psoriasis model. Mice treated with Aldara for six consecutive days were injected intraperitoneally with: RvE1 (1 μg) (●) and PBS daily, as well as isotype control antibody (10 μg) (x) on days 0, 2, and 4. A. Ear thickness and B. skin thickness were measured daily until recovery. [Figure 7A] Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse peritonitis model. Anti-CMKLR1 prophylaxis was administered prior to Zymosan A injection (1 mg per mouse in 1 mL): RvE1 (1 μg per mouse) (●), 2G1 antibody (10 μg per mouse) (□) or isotype control antibody (x). A. PMNs counted in the first 50 hours after Zymosan A injection. [Figure 7B]Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse peritonitis model. Anti-CMKLR1 prophylaxis was administered prior to Zymosan A injection (1 mg per mouse in 1 mL): RvE1 (1 μg per mouse) (●), 2G1 antibody (10 μg per mouse) (□) or isotype control antibody (x). B. Macrophages counted during the first 50 hours after Zymosan A injection. [Figure 7C] Figure 1 shows the effect of anti-CMKLR1 antibodies in a mouse peritonitis model. Anti-CMKLR1 prophylaxis was administered prior to Zymosan A injection (1 mg per mouse in 1 mL): RvE1 (1 μg per mouse) (●), 2G1 antibody (10 μg per mouse) (□) or isotype control antibody (x). C. Recovery index. [Figure 8] Figure 1 shows the effect of anti-CMKLR1 antibodies in a 4T1 breast tumor model. Mice were inoculated into the mammary gland with 4T1 cells (250,000 cells). Anti-CMKLR1 antibody (2G1) (A.□B.●) or anti-41BB antibody (3H3) (●) or both antibodies (△) were then injected twice on days 4 and 7 (10 μg / injection) or a control antibody (IgG1 isotype antibody clone 3G8) (x A. and B.) was injected three times a week for three weeks. A. Tumor area was measured 8 days after tumor injection and then every two days. B. Tumor lung metastasis was measured by bioluminescence imaging (BLI) in animals (n=4) treated with isotype control and anti-CMKLR1 antibody. [Figure 9] Figure 1 shows the effect of anti-CMKLR1 antibodies in two different colon cancer mouse models. Two mouse models were studied, with animals receiving isotype control antibody (3G8) (x) or anti-CMKLR1 (2G1) (□) at 20 μg / ip for 3 weeks. A-C. Results in the CT26 colon cancer model comparing single treatment with p84 (A) and 2G1 (B) with combination therapy with both antibodies (C). D: Results in the MC38 colon cancer model. [Figure 10]Figure 1 shows the expression of CMKLR1 in ulcerative colitis (UC) or Crohn's disease patient biopsies before and after anti-TNFa treatment. x represents control; □ represents CMKLR1 expression in patients responsive to corticosteroid treatment and / or immunosuppressive treatment before infliximab treatment; ◆ represents CMKLR1 expression in patients unresponsive to corticosteroid treatment and / or immunosuppressive treatment before infliximab treatment; Δ represents CMKLR1 expression in patients responsive to corticosteroid treatment and / or immunosuppressive treatment after infliximab treatment; △ represents CMKLR1 expression in patients unresponsive to corticosteroid treatment and / or immunosuppressive treatment after infliximab treatment. A. CMKLR1 transcript expression in ulcerative colitis patients before and after infliximab treatment, B. CMKLR1 transcript expression in Crohn's disease patients before and after infliximab treatment in inflammatory colon biopsies. [Figure 11] Figure 1 shows expression of CMKLR1 in UC patient biopsies before and after anti-α4β7 (VDZ) treatment. A. CMKLR1 (CMKLR1) transcript expression in ulcerative colitis patients before and after vedolizumab treatment in inflammatory colon biopsies. R corresponds to patients responsive to VDZ treatment and NR corresponds to patients unresponsive to VDZ treatment. [Figure 12] Figure 1 shows binding analysis of anti-CMKLR1 antibodies with CMKLR1 peptide by ELISA. Binding of 2G1 antibody (□) to the CMKLR1 EL3 loop (SEQ ID NO: 18) was compared to an isotype control antibody (3G8) (x) by measuring OD at 450 nm by ELISA. [Figure 13] Figure 1 shows the study of CMKLR1 expression in various cell lines by FACS and Western blot. A. Protein expression on the cell surface of CMKLR1 was determined in two different human T cell lines Thp1 and U937 at various concentrations (ng / ml) using 2G1 antibody. B. CMKLR1 protein expression was examined by Western blot for CMKLR1 in T cell lines (Thp1 and U937), fibroblast cell line MRC5, NK cell line NKL, and negative and transduced CHO cells. [Figure 14]Figure 1 shows the expression of CMKLR1 in mouse myeloid cells by FACS. After differentiation, mouse myeloid cell lines were analyzed for their CMKLR1 expression on the cell surface. A. Expression on macrophage monocytes (M0). B and C. Expression on macrophages (mM1 and mM2). D and E. Expression on dendritic cells (mDC and iDC). [Figure 15] Figure 1 shows a study of inflammatory cytokine secretion by human macrophages upon CMKLR1 activation. After differentiation of human macrophages M1 or M2, cells were incubated in the presence of medium, isotype control, anti-CMKLR1 antibodies (H6 and BZ194), C15 peptide, 2G1 anti-CMKLR1 antibody or RvE1. Secretion of IL10, CCL17 and IL12p40 was assessed by ELISA. Cytokine secretion is measured in the supernatant using ELISA kits from BD. Supernatants were diluted 1 / 10 for IL10 cytokines, 1 / 50 for CCL17 cytokines and 1 / 100 for IL12p40 cytokines. A. IL10 cytokine secretion by M2 cells. B. CCL17 cytokine secretion by M2 cells. C. IL12 cytokine secretion by M1 cells. [Figure 16] Figure 1 shows the study of inflammatory cytokine secretion by human macrophages upon CMKLR1 activation. After differentiation of human monocytes, cells were incubated in the presence of various isotype controls (mlgG4; hlgG4 or hlgG1, 2 μg / ml); C7 commercial anti-CMKLR1 antibody (2 μg / ml); 2G4 or 2G1 antibody (2 μg / ml), or other commercial anti-CMKLR1 antibodies (H6 (2 μg / ml), BZ332 (2 μg / ml) or 84939 (2 μg / ml), C15 peptide (10 nM) or RvE1 (10 ng / ml). A. Expression of CD200R marker measured by FACS. B. IL10 cytokine secretion by M2 cells. C. CCL17 cytokine secretion by M2 cells. D. IL12 cytokine secretion by M1 cells. Secretion of IL10, CCL17 and IL12p40 was evaluated by ELISA. [Figure 17]Figure 1 shows the study of myeloid cell activation markers after CMKLR1 pathway activation. Dendritic cells incubated with vehicle, RvE1, 2G1 or isotype control (hIgG1) were then stained for FACS analysis with marker antibodies: A. CD80-PE, B. CD86-FITC, C. CD103-PerCPCy5.5, D. CD40-PeCy7, EI / Ab-APC. The mean fluorescence was determined for each condition. [Figure 18] Figure 1: CMKLR1 pathway activation: Akt and Erk phosphorylation study. Western blot analysis of ERK and AKT activation pathways after 5, 10 and 30 min incubation of mouse M1 cells with 2G1 or RvE1. Phosphorylated proteins Akt or Erk were assessed using P-Akt or P-Erk antibodies (p44 / 42). A. Erk and Akt activation with RvE1. B. Erk and Akt activation with 2G1. [Figure 19] Figure 1 shows the expression of CMKLR1 in human monocytes and mouse bone marrow cells stimulated with pro-inflammatory stimuli. After 16 or 48 hours of stimulation of cells with LPS, TNFa or IL6, the expression of CMKLR1 (ChemR23) was measured by FACS. A. Results in human blood monocytes, B. and C. Results in myeloid and neutrophilic cells derived from mouse bone marrow. [Figure 20] Figure 1: Competition studies on chemerin-CMLKR1 interaction using anti-CMKLR1 antibodies. A. Inhibition of cAMP by chemerin from two different suppliers was tested from DiscoverX (●) or R&D Systems (△), or in combination with anti-CMKLR1 antibody (2G1) alone (◇) or in combination with chemerin from DiscoverX (□). B. Beta-arrestin activation in the presence of various concentrations of anti-CMKLR1 antibodies from 1 μM to 1 nM and chemerin at 2 nM (◇) or 6 nM (●). [Figure 21]FIG. 1 shows the effect of anti-CMKLR1 antibody in a mouse model of chronic colitis transferred with CD45Rbhigh T cells. The weight changes of treated animals were observed up to 60 days. Animals were treated with isotype control hIgG1(x) or anti-CMKLR1 antibody (◆). [Figure 22] Figure 1 shows the effect of anti-CMKLR1 antibody in hepatocellular carcinoma mouse model (HCC model). Antitumor effect of anti-CMKLR1 antibody (2G1, 0.8 mg / kg) ip administration 3 times per week for 2 weeks, in combination (△) or not (●) with 2 injections of anti-PD1 mAb (RMP1-14 clone, 8 mg / kg) on ​​days 4 and 8, or with injections of anti-PD-1 antibody alone (Δ) (twice per week). Mice were treated with an orthotropic model of mouse hepatocellular carcinoma for 2 weeks (2.5x106 Hepa 1.6 cells injected through the portal vein on day 0). Isotype control antibody was used at 0.8 mg / kg 3 times per week for 2 weeks. Mice responses were considered partial (PR) if they survived several days to one month after treatment was stopped, or complete (CR) if they survived for more than one month or were cured by surviving more than three times the time required for all control mice to die. EXAMPLES

[0181] Production and selection of anti-CMKLR1 antibodies Several antibodies were synthesized with different CDR sequences in their heavy and light chain variable domains. The different antibodies were tested for their ability to induce dendritic cell maturation and differentiation towards pro-inflammatory or anti-inflammatory pathways. In view of the diverse results, the inventors compared the amino acid sequences of the heavy and light chain variable domains obtained and determined that amino acid differences in HCDR3 may be important for the experimental results. They selected antibody 2G1 (SEQ ID NO: 10 and SEQ ID NO: 17) to evaluate its properties in resolving inflammatory situations that at least affect the situation in the recovery phase.

[0182] As shown in Figure 1, the detection level of CD103 and IAb expressing DCs treated with 2G1 was lower than that of DC cells treated with C7 antibody, indicating that 2G1 and 1G1 (another synthetic antibody) antibodies could inhibit DC activation and / or maturation in a more potent manner than other synthetic antibodies (3G1 and 4G1) could direct cells to pro-inflammatory pathways (the method used in this assay is described in Example section 10.2). As shown in Figure 1E and Figure 1F, cell viability is enhanced after treatment with 1G1 or 2G1 antibodies compared to cells treated with C7 or other antibodies including Resolvin E1.

[0183] 2G1 was humanized using computer CDR grafting. Methods of humanization are well known in the art. The humanized sequences generated from the CDR and FR regions and from the variable heavy and light chains are listed in the table below.

[0184] [Table 1]

[0185] [Table 2]

[0186] [Table 3]

[0187] [Table 4]

[0188] [Table 5]

[0189] [Table 6]

[0190] Examples of therapeutic efficacy of anti-CMKLR1 antibody treatment in preclinical models of autoimmune and inflammatory diseases Example 1 Induction of colitis by DSS Colitis was induced in 8-10 week old C57Bl / 6 male mice by adding 2% (wt / vol) DSS to sterile drinking water ad libitum for 6 days. Treatments were intraperitoneally injected: isotype control hIgG1 (10 μg per mouse), RvE1 (1 μg per mouse) daily, or 2G1 antibody (10 μg per mouse) three times for 5 days. Colitis follow-up consisting of weight and stool score (0: normal stool; 4: blood in stool) parameters was performed daily. When mice were euthanized, colon length, which represents the severity of the disease, was measured. Recovery index was determined in different conditions as described by Bannenberg et al., 2005.

[0191] Results: The DSS animal model shown in Figure 2 is an acute inflammation model. Figure 1 shows a better overall condition of animals treated with anti-CMKLR1 antibody than that of animals receiving control antibody or resolvin RvE1. Anti-CMKLR1 treated mice lost significantly less weight (Figure 2A) and had significantly better stool scores (Figure 2B). With regard to colon length and recovery index (Figures 2C and 2D), animals receiving anti-CMKLR1 or RvE1 displayed similar results.

[0192] Example 2 Induction of colitis by TNBS Colitis was induced in 8-10 week old C57Bl / 6 male mice by intrarectal injection of 200 μL of 5% haptenizing agent TNBS in 50% ethanol on day 0. Treatments were intraperitoneally injected; RvE1 (1 μg per mouse) daily for 3 days or 2G1 antibody (10 μg per mouse) twice for 3 days. Colitis follow-up consisting of weight and stool score (0: normal stool; 4: blood in stool) parameters was performed daily (data not shown). When mice were euthanized, colon length, which represents the severity of the disease, was measured.

[0193] Results: TNBS-induced colitis is another model of acute inflammation. Figure 3 shows that animals treated with anti-CMKLR1 or RvE1 had the same colon length as normal animals (wt). However, those treated with isotype control exhibited a shorter colon length. These results confirmed the therapeutic potential of anti-CMKLR1 antibodies that act similarly to RvE1 in acute inflammation mouse models.

[0194] Example 3 IL-10-KO model - Spontaneous colitis model IL-10KO mice develop spontaneous colitis from 20 weeks of age, mainly due to the lack of regulatory T cell function through IL10 secretion in the intestine. IL-10KO mice were followed up for their weight loss and stool consistency, which are clinical hallmarks of this condition, three times a week from the age of 18 weeks. Anti-CMKLR1 antibody (2G1) or isotype control (hIgG1) was injected intraperitoneally (25 μg / injection, three times a week) when weight loss exceeded 5% and stool score was equal to or exceeded 1 for 2 weeks.

[0195] Results: A chronic inflammation model was used to study the efficacy of anti-CMKLR1 antibody treatment. Figure 4 shows the analysis of the percentage of weight loss (Figure 4A) and stool score (Figure 4B) when animals were treated with isotype control or anti-CMKLR1 antibody. The results show that animals treated with anti-CMKLR1 antibody lost less weight and had better stool scores than those receiving isotype control. Therefore, it is believed that anti-CMKLR1 antibody showed therapeutic potential for chronic inflammatory diseases.

[0196] Example 4 Preclinical models of type 1 diabetes: the mouse NOD model Eight-week-old NOD female mice were obtained from Charles River laboratory. These mice develop spontaneous type 1 diabetes at ages between 12 and 20 weeks. The onset of diabetes can be measured by elevated blood glucose. Anti-CMKLR1 and isotype controls were given intraperitoneally at 20 μg / injection three times a week for 2 weeks when blood glucose was between 180 and 234 mg / dL. Mice were euthanized when blood glucose exceeded 600 mg / dL, corresponding to irreversible diabetes.

[0197] Results: This type 1 diabetes model is also considered a mouse autoimmune disease model. Results shown in Figures 5A-5C indicate that animals treated with anti-CMKLR1 antibodies exhibited a better survival percentage and near-normoglycemia as shown by measuring blood glucose levels. This recovery appeared to be stable over time, indicating the possibility of complete recovery of previously sick animals. Anti-CMKLR1 antibodies restored a glucose tolerant state.

[0198] Example 5 Imiquimod-induced psoriasis-like dermatitis Aldara® cream, known to induce psoriasis in mice, was used on male C57Bl / 6 mice (8-10 weeks old). Mice received a daily topical dose of Aldara on the shaved back and left ear for 6 consecutive days. Treatments were injected intraperitoneally: RvE1 (1 μg per mouse) and PBS daily. Ear (FIG. 6A) and back (FIG. 6B) thickness was measured daily until recovery.

[0199] Results: Animals treated with resolvin RvE1 had thinner ears and skin compared to animals treated with the control molecule. These results suggest the potential application of agonistic anti-CMKLR1 antibody therapy to a mouse model of psoriasis, an example of an autoimmune disease.

[0200] Example 6 Preclinical models of sepsis: Therapeutic efficacy of anti-CMKLR1 antibodies in a mouse peritonitis model General peritonitis is induced by intraperitoneal injection of Zymosan A® (1 mg per mouse in 1 mL). Prophylactic injection of anti-CMKLR1 was performed 5 min before Zymosan A injection: RvE1 (1 μg per mouse), 2G1 antibody (10 μg per mouse). Mouse peritoneal polymorphonuclear neutrophils (PMN) and macrophages were collected 2-4-8-16-24 and 48 hours after Zymosan A injection and counted by flow cytometry analysis to determine the recovery index (Bannenberg et al., 2005).

[0201] Results: The results shown in Figure 7 for PMN (7A) and macrophage (7B) numbers and for the recovery index (7C) showed that animals treated with RvE1 or anti-CMKLR1 antibody showed the same results and slightly fewer PMN and macrophage cells with a better recovery index compared to the isotype control. In sepsis, even small differences can be important for therapy. Therefore, these results are very informative about the applicability of anti-CMKLR1 antibody in sepsis.

[0202] Example 7 Therapeutic efficacy of anti-CMKLR1 antibody treatment in preclinical models of cancer: Example 7.1 Effect of anti-CMKLR1 antibody on the growth of primary tumors and their development of lung metastasis in an orthotopic breast cancer model Mice were anesthetized with 3% isoflurane. The abdomen of the mice was shaved, and 4T1 cells (250,000 cells) were injected into the mammary gland in 50 μL of PBS using an insulin syringe (30 gauge). Anti-CMKLR1 antibody (2G1) or anti-41BB antibody (3H3) or both antibodies were injected twice on days 4 and 7 (10 μg / injection); control antibody was injected intraperitoneally in PBS three times a week for three weeks (100 μg / injection). In a second study to measure lung metastasis following breast cancer development, animals were treated with anti-CMKLR1 antibody at 0.8 mg / kg or with control antibody (100 μg / injection) three times a week for three weeks.

[0203] Results: As shown in FIG. 8A, animals treated with a single compound (2G1 or 3H3) did not show any improvement in tumor growth compared to animals receiving an isotype control antibody. However, animals treated with a combination of anti-CMKLR1 and anti-41BB antibodies show a significant (p<0.01) reduction in tumor growth in the breast cancer model. The results seem to be clear, since this model of breast cancer is a fairly aggressive model. As shown in FIG. 8B, which illustrates the effect of anti-CMKLR1 compounds on lung metastasis by bioluminescence imaging, it seems that anti-CMKLR1 treatment reduces lung metastasis compared to animals treated with a control antibody. Analysis of lymph node metastasis shows that none of the animals treated with anti-CMKLR1 compounds had metastasis, while two animals in the control had metastasis (data not shown). These results indicate that anti-CMLKR1 antibodies with agonistic activity mimicking RvE1 have a metastasis suppression effect. In this model, the antibodies of the present invention do not show any significant efficacy on primary tumor development. However, the results show improvement when animals are treated with a combination of anti-CMKLR1 and anti-41BB antibodies.

[0204] Example 7.2 Therapeutic effects on tumor growth in a colon cancer model Eight-week-old C57bl / 6J male mice were anesthetized with 3% isoflurane. The flanks of the mice were shaved and transfected with MC38 cells (0.5 × 10 cells per mouse). 6 The cell lines were injected subcutaneously in 50 μL of PBS using an insulin syringe (30 gauge). Another model was used in which 8-week-old Balb / c male mice were anesthetized with 3% isoflurane. The flanks of the mice were shaved and CT26 cells (1 × 10 cells per mouse) were injected. 6 ) was injected subcutaneously in 50 μL of PBS using an insulin syringe (30 gauge).

[0205] Agonistic anti-CMKLR1 antibody (2G1) or anti-SIRPa antibody (p84 anti-mouse SIRPa, from Merck Millipore) (SIRPa is a novel checkpoint inhibitor) were injected intraperitoneally once a week (20 μg / injection) for 3 weeks starting 4 days after tumor inoculation, either alone or in combination.

[0206] Results: As shown in Figures 9A-9C, in the CT26 carcinoma model, anti-CMKLR1 antibody by itself (Figure 9B) did not demonstrate a clinical effect on tumor progression compared to the control group, nor did anti-SIRPa alone (Figure 9A). However, surprisingly, the combination of both compounds allowed inhibition of tumor growth in a timely manner (Figure 9C). In another mouse colon cancer model shown in Figure 9D, anti-CMKLR1 showed efficacy in inhibiting tumor growth compared to the isotype control. Together, these results for two different colon cancer models indicate that agonistic anti-CMKLR1 antibody by itself or in combination with another therapeutic agent can prevent tumor progression.

[0207] Example 8 Meta-analysis of CMKLR1 expression in biopsies from human patients with UC or CD treated with anti-TNFα or anti-α4β7 antibody therapy The signaling networks that sustain chronic gastrointestinal inflammation in the two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), remain unclear in humans. Through analysis of nearly 500 patients with IBD and 100 controls, we report here that CMKLR1 transcripts accumulate in inflamed colonic tissues of severe IBD patients who have failed to respond to immunosuppressive / corticosteroids and immunotherapies such as anti-TNFα (infliximab) or anti-α4β7 integrin (vedolizumab) therapy.

[0208] We first analyzed mucosal CMKLR1 transcript expression in patients refractory to corticosteroids and / or immunosuppression by performing a meta-analysis of three cohorts of UC patients in which colonic mucosal biopsies were performed (within 1 week) before anti-TNF treatment: GSE16879 (Arijs et al., 2009a) and GSE12251 (Arijs et al., 2009b) and publicly available transcriptional datasets of GSE73661. In these three cohorts, anti-TNF response was defined as histological healing analyzed 4-6 weeks after their first anti-TNF infusion (combined: n=18 non-IBD controls, n=41 UC non-responders and n=28 UC responders).

[0209] Results: The analysis shows that CMKLR1 transcript expression is significantly increased in colonic biopsies of primary UC refractory patients before and after treatment with anti-TNF therapy compared to non-IBD controls or patients who had UC before anti-TNF and would respond to anti-TNF therapy (Figure 10A). Mucosal CMKLR1 expression is also significantly increased in colonic or ileal biopsies of Crohn's disease patients before and after anti-TNF therapy in patients who do not respond to anti-TNF compared to non-IBD controls or future responders (n=24 non-IBD controls, n=17 CD refractory and n=20 CD responder; GSE16879 (Arijs et al., 2009a)) (Figure 10B). Finally, colonic mucosal gene expression analysis in a cohort of UC patients treated with anti-α4β7 (vedolizumab) therapy (GSE7366146) confirmed that CMKLR1 expression was also significantly increased in non-responders before and after treatment with vedolizumab (Figure 11).

[0210] Together, the meta-analysis shows that CMKLR1 is overexpressed in inflamed tissues of IBD patients, especially those who do not respond to current immunosuppression or immunotherapy, even before the start of treatment. Our meta-analysis provides evidence that CMKLR1 expression in the colon from treatment-resistant UC or CD patients, or rather in the ileum for CD, in contrast, can qualify these patients as responsive to agonistic anti-CMKLR1 antibody treatment, such as the antibody of the present invention.

[0211] Example 9 CMKLR1 expression and antibody binding studies - ELISA binding CMKLR1 (Figure 12) CMKLR1 peptide (273NH2-PYHTLNLLELHHTAMPGSVFSLGLPLATALAIA-COOH305) (SEQ ID NO: 18) (5 μg / ml) was coated overnight in borate buffer. Saturation was performed with PBS-Tween 0.1%-gelatin 0.25% for 2 hours at 37°C. 2G1 or hIgG1 antibodies were then added at various concentrations for 2 hours at 37°C. Peroxidase-conjugated secondary antibodies (0.8 μg / ml) were then added for 1 hour at 37°C and revealed by TMB substrate. The colorimetric reaction was read using a TECAN.

[0212] - CMKLR1 expression by FACS (Figure 13A) Cells were resuspended in PBS-FBS-EDTA and incubated with Fc block (1 / 50) for 30 min on ice. Staining for monocytes, macrophages and dendritic cells was performed using A488-labeled 2G1 (5 μg) or A488-labeled hIgG1 (5 μg).

[0213] - Western blot analysis CMKLR1 (Figure 13B) After protein transfer and translocation as described above, 2G1 antibody (10 μg / membrane) was incubated overnight at 4° C. and revealed with peroxidase-conjugated secondary antibody (1:2000). CMKLR1 expression was then detected by using chemiluminescence and an image reader. Western blot images were quantified by Multigauge software.

[0214] Results: The results illustrated in Figure 12 confirm that the anti-CMKLR1 antibody clone 2G1 can bind to the polypeptide that forms the loop EL3 of CMKLR1. Expression of CMKLR1 in various cell lines assessed using the 2G1 antibody by FACS and Western blot shows that human tumor T cell lines Trp1 and U937 express CMKLR1, as do transduced CMKLR1 CHO cells and the human lung fibroblast cell line MRC5 and the human NK cell line NKL (Figure 13).

[0215] Example 10 Study of CMKLR1 expression in myeloid cell lineages (Example 10.1.) Human monocyte differentiation and polarization Monocytes were collected from PBMCs of buffy coats of healthy donors and isolated by magnetic separation or by elutriation. They were then cultured with different cytokine cocktails to generate differentiated non-polarized or polarized macrophages. This protocol allowed the generation of polarized and differentiated macrophages with pro-inflammatory (M1) or anti-inflammatory (M2) macrophages in different wells. Monocytes were cultured at 0.5 × 10 cells. 6The cells were plated at 100 cells / mL in complete RPMI (RPMI with 10% FBS, 1% glutamine, 1% antibiotics) and 500 μL of cell suspension was plated per well in a 24-well plate. 100 ng / mL M-CSF was added to the medium for differentiation of the cells. The cells were incubated for 5 days and the medium was replaced on day 3 with fresh medium supplemented with 100 ng / mL M-CSF. For the polarization phase, a solution of LPS-IFNg at 100 ng / mL LPS and 20 ng / mL IFNg was supplemented with isotype control (mIgG1 or hIgG4) (2 μg / ml) or anti-CMKLR1 antibody (2 μg / ml) (2G1 or 2G4, H6, BZ332 or 84939) or C15 peptide (10 nM) or RvE1 (10 ng / ml) for 3 days to generate M1 macrophages. M1-IFNg macrophages could also be generated by adding only IFNg (20 ng / mL) in the culture medium. For M2 polarization, cells were incubated with IL4 at 20 ng / mL. Following differentiation and / or polarization, phenotype and functional cytokine / chemokine release were studied by FACS analysis, ELISA and Western blot.

[0216] (Example 10.2.) Murine macrophage and DC isolation and differentiation - Isolation of mouse bone marrow-derived macrophages Bone marrow cells were harvested and cultured in RPMI medium supplemented with 10% FBS, glutamine, and antibiotics and containing macrophage colony-stimulating factor (M-CSF) at 100 ng / ml for 5 days to induce macrophage differentiation. Macrophages were harvested and cultured for 2 days with either IFNg (20 ng / ml) and LPS (100 ng / ml) to induce M1 polarization, or with IL4 (20 ng / ml) to induce M2 polarization. Treatments were added at 2 μg / ml during macrophage polarization.

[0217] - Generation of bone marrow-derived dendritic cells Bone marrow cells were harvested and cultured in RPMI medium supplemented with 10% FBS, glutamine and antibiotics, and dendritic cell differentiation was induced with GM-CSF, 20 ng / ml, for 7 days. Immature dendritic cells (iDCs) were then harvested and cultured for 24 hours with LPS (100 ng / ml) to induce maturation of iDCs to mDCs. Treatment was added at 2 μg / ml during differentiation and maturation.

[0218] After mouse M1 or M2 differentiation as described above, cells were incubated in the presence of medium, isotype control, anti-CMKLR1 antibodies: clones H6 and BZ194, C15 peptide, 2G1 targeted anti-CMKLR1 antibody or RvE1 were used. IL10, CCL17 and IL12p40 secretion was then assessed by ELISA. Cytokine secretion was measured in the supernatants using ELISA kits from BD. Supernatants were diluted 1 / 10 for IL10 cytokine, 1 / 50 for CCL17 cytokine and 1 / 100 for IL12p40 cytokine.

[0219] - ELISA cytokine secretion studies Cytokine secretion was detected by ELISA according to the BD manufacturer's instructions. Briefly, the supernatant was diluted in the appropriate buffer and incubated for 2 hours after overnight coating and saturation with capture antibody. Cytokine was then revealed using detection biotin-conjugated antibody and the signal was amplified using a biotin-streptavidin-conjugated peroxidase system. TMB supplied by BD Bioscience was used as substrate and the colorimetric reaction was read using a TECAN.

[0220] - Activated cell markers analyzed by FACS Dendritic cells were resuspended in PBS-FBS-EDTA and incubated with LIVE / DEAD Fixable Dead Cell Stains Yellow (Life Technologies) for 30 min on ice. Staining for CD11c-BV711, CD11b-APCCy7, I / Ab-APC, CD103-PerCPCy5.5, CCR7-V450, CD40-PeCy7, CD80-PE, CD86-FITC (all supplied by BD Pharmingen) was performed.

[0221] - Western blot analysis ERK / Akt Murine proinflammatory macrophages (M1) were generated from bone marrow with M-CSF and polarized with IFN gamma (IFNg) and LPS. Briefly, bone marrow cells were harvested by flushing femurs, cultured with 100ng / mL mM-CSF for 5 days, and then polarized with 20ng / mL IFNg and 100ng / mL LPS for 24 hours. They were then starved of FBS for 24 hours with RPMI FBS 2% medium. Finally, mouse M1 were treated with 2μg / mL 2G1 antibody for various times: 5, 10 and 30 minutes. Cells were harvested in RIPA buffer. Protein concentration was measured by BCA protein kit assay. Proteins were denatured by heating at 95°C for 5 minutes and diluted in DTT and Laemmli solution. After transfer and migration, nitrocellulose membranes were blocked with 5% BSA in TBS-T for 2 hours. Anti-phosphorylated ERK and anti-phosphorylated Akt antibodies (1:1000) were incubated with the membranes overnight at 4° C. and revealed with peroxidase-conjugated secondary antibodies (1:2000). Western blot images were quantified by Multigauge software.

[0222] Example 10.3 CMLKR1 expression after inflammatory stimulation in human blood monocytes and myeloid and neutrophilic cells of mouse bone marrow Human monocytes were collected from PBMCs of buffy coats of healthy donors and isolated by magnetic separation or by elutriation. Monocytes (CD14 positive cells) were then cultured in culture medium and treated with various pro-inflammatory stimuli for 16 or 48 hours: LPS (100 ng / ml), TNFα (10.000 U / ml), or IL6 (20 ng / ml).

[0223] Mouse monocytes (CD11b+ Ly6G- SSClow) and neutrophils (CD11b+ Ly6G- SSClow) were obtained from bone marrow cells harvested and cultured in RPMI medium supplemented with 10% FBS, glutamine and antibiotics. The cells were then cultured in medium and treated with various pro-inflammatory stimuli for 16 or 48 hours: LPS (100ng / ml), TNFa (10.000U / ml) or IL6 (20ng / ml).

[0224] The expression of CMLKR1 was measured by FACS using commercially available anti-CMKLR1 antibodies (human anti-ChemR23: clone 84939 and mouse anti-ChemR23: clone 477806).

[0225] Results: Analysis of the expression of CMKLR1 in mouse myeloid cell lines, illustrated in Figure 14, revealed good expression of the protein in monocytes and macrophages from types 1 and 2, as well as dendritic cells. Figure 19 illustrates the expression of CMKLR1 in human monocytes and mouse bone marrow myeloid and neutrophil cells. This expression was clearly increased by inflammatory stimuli such as LPS, TNFa, or IL6 (at least 2-fold compared to control after 48 hours), confirming that CMKLR1 expression in myeloid cell lines and overexpression during inflammation may represent a therapeutic approach to downregulate inflammation and / or induce recovery. Study of inflammatory cytokines secreted by mouse M1 or M2 macrophages, illustrated in Figure 15, revealed that only the 2G1 clone, an anti-CMKLR1 antibody, induced anti-inflammatory cytokines IL10 and CCL17 by M2 macrophages (Figures 15A and 15B) and reduced pro-inflammatory cytokines from M1 macrophages (Figure 15C). The results were different for cells treated with RvE1 or with the C15 peptide derived from the C-terminal part of Chemerin (Cash et al., 2008) or even with other commercially available anti-CMKLR1 antibodies, showing very interesting characteristics of the 2G1 antibody as an anti-inflammatory compound. We then studied cytokine expression in human myeloid cells obtained from donors and incubated with various compounds. The results shown in Figure 16 show that 2G4 induces M2 polarization of cells compared to the control and the commercially available CMKLR1 antibody C7, confirming the results obtained in mouse cells. Only the 2G1 antibody was able to induce the anti-inflammatory cytokines IL10 and CCL17 by M2-type macrophages (Figures 16A and 16B) and reduce the secretion of the IL12p40 cytokine by M1-type macrophages (Figure 16C). Finally, DC activation markers were analyzed by FACS, and the results illustrated in Figure 17 show a sharp decrease in expression of CD80, CD86, CD103, CD40, and IAb when cells were treated with RvE1 lipid or with 2G1 antibody compared to vehicle or isotype control. These results indicate that the 2G1 antibody is active in the CMKLR1 pathway of DCs, similar to RVE1.The present inventors analyzed the CMKLR1 activation pathway in mouse macrophages by Western blot. Figure 18 shows that anti-CMKLR1 antibody 2G1 can induce the activation of both Akt and Erk proteins after 10 to 30 minutes of incubation. These results indicate that 2G1 antibody can exhibit agonistic properties against the CMKLR1 receptor, as does RvE1 lipid. (Example 11) Competition study on chemerin-induced CMKLR1 activation with anti-CMKLR1 antibody.

[0226] method Competitive assay to measure chemerin-dependent B-arrestin recruitment by the CMKLR1 receptor in the presence of anti-CMKLR1 antibody: The day before the assay, CHO-K1 CMKLR1 cells (Discover'X ref 93-0313E2) were plated in pre-warmed cell reagent, then cells (Discover'X ref 15-103) were plated in 100 μl / well in a 96-well plate and incubated for 48 hours at 37°C in a 5% CO2 humidified incubator. Anti-CMLKR1 antibodies were diluted (22-fold, 7-point series of 3-fold dilutions from 1 μM to 1 nM) and cells were incubated with the antibodies for 30 minutes at 37°C. Cells were then stimulated with Chemerin (2 or 6 nM) for 90 minutes at 37°C according to the supplier's protocol (Discover'x ref 92-1036). After addition of Working Detection Solution to the cells, luminescence was measured using a plate reader with 0.5 second integration.

[0227] Measurement of competition between anti-CMKLR1 antibody and chemerin in the production of AMPc by the CMKLR1 receptor: The day before the experiment, CHO-K1 CMKLR1 Gi cells (Discover'X ref 95-0080C2) were plated in pre-warmed cell reagent, then cells (Discover'X ref 15-103) were plated at 100 μl / well in a 96-well plate and incubated for 24 hours at 37°C in a 5% CO2 humidified incubator. Chemerin agonist (6x, 10 -7 µM to 10 -10 A mixture of 200 μM (7-point series of 3-fold dilutions from 1 μM to 1 nM) (Discover'x ref 92-1036 or 2324-CM-025, from R&D Systems) and forskolin (40 μM) (cAMP activator) (Discover'x ref 92-0005) was added to the cells for 30 min at 37° C.; or cells were preincubated with anti-CMKLR1 antibody (serial dilution: 6-fold, 7-point series of 3-fold dilutions from 1 μM to 1 nM) for 30 min at 37° C. Then a mixture of chemerin (2 nM) + forskolin (60 nM) was added to the cells for 30 min at 37° C. For cAMP detection, antibody reagent and cAMP working detection solution were added to the plate for 1 h at room temperature, then cAMP solution A was added and cells were incubated for 3 h at room temperature in the dark. Bioluminescence was read using a plate reader with 0.5 s integration.

[0228] Results: Two assays were performed to test whether the antibodies of the present invention are antagonists of chemerin-induced CMKLR1 activation. The results are shown in Figure 20. Chemerin-induced inhibition of forskolin-dependent cAMP production is shown in Figure 20A (closed circle or open square); the anti-CMLKR1 antibodies of the present invention were unable to reverse this inhibition of production (closed circle or open square) compared to the control (grey diamond). Chemerin-induced activation of beta-arrestin shown in Figure 20B shows that the anti-CMKLR1 antibodies of the present invention did not significantly alter the chemerin-dependent activation of beta-arrestin (open circle compared to black diamond). The antibodies of the present invention do not have antagonist activity of CMLKR1-chemerin interaction. Furthermore, the antibodies of the present invention are unable to induce the chemerin-induced CMKLR1 signaling pathway, confirming that these antibodies are not agonists of chemerin in the CMLKR1 pathway.

[0229] Example 12 CD45Rb high Chronic colitis mouse model with T cell transfer Method: CD45Rb highCD4 T cells were isolated from the spleens of naive mice and sorted on an ARIA FACS after negative selection of CD4 T cells by magnetic sorting, then 0.5 × 10 cells in 100 μL of PBS were sorted. 6 The mice were intraperitoneally injected with 1000x1000 cells / mL of CD45Rb cells into 6-week-old female Rag1 knockout mice. Anti-CMKLR1 antibody (2G1) or isotype control was administered intraperitoneally to CD45Rb cells. high Mice were dosed at 1 mg / kg, 3 times per week for 3 weeks, starting 32 days after CD4 T cell transfer. Body weight follow-up was assessed 3 times per week and weight change was determined relative to initial body weight. *p<0.05, **p<0.01.

[0230] Results: Figure 21 shows the percentage weight change over time after antibody administration for animals treated with anti-CMLKR1 antibody or isotype control. Both groups showed the same initial weight evolution for the first 30 days after treatment and started to differ from day 35. Mice treated with anti-CMLKLR1 continued to gain weight, whereas control mice started to lose weight, indicating the development of chronic colitis as expected in this control group. In a third model of colitis, a chronic model of inflammation, the inventors have confirmed that the anti-CMLKLR1 antibody of the invention may be interesting for treating chronic inflammatory and autoimmune diseases such as colitis.

[0231] Example 13 Antitumor effects on overall survival in a mouse hepatocellular carcinoma tumor model Methods: Mice were anesthetized with a cocktail of xylazine / ketamine. After laparotomy, tumor Hepa 1.6 cells were injected in PBS through the portal vein (2.5 × 10 cells). 6 500 / 100μL). Treatment was started 4 days after tumor injection. Anti-CMKLR1 antibody (2G1 clone) and hIgG1 isotype control were injected at 0.8mg / kg 3 times a week for 2 weeks. Anti-PD1 monoclonal antibody was injected intraperitoneally in PBS twice a week for 2 weeks (8mg / kg). Combination of anti-CMKLR1 and anti-PD1 antibodies was tested similarly (0.8mg / kg and 8mg / kg, respectively). Overall survival was followed up for 60 days and percentage of survival in each condition is reported in Figure 22.

[0232] Results: As shown in Figure 22, animals treated with anti-CMKLR1 or anti-PD1 antibodies showed an extended survival rate in only one of seven treated animals (15% of treated animals), indicating a partial response (PR). However, animals treated with a combination of anti-PD1 and anti-CMKLR1 antibodies showed a complete response (CR), with the animals surviving for 60 days after treatment, allowing a significant increase in survival rate (from 15% to 45%). This result shows the unexpected efficacy of the therapeutic combination (anti-PD1 / anti-CMKLR1 antibodies) in the HCC tumor model.

Claims

1. An anti-CMKLR1 compound selected from an antibody that specifically binds to CMKLR1, or an antigen-binding fragment thereof, or a chimeric, humanized or modified antibody, - an antibody heavy chain variable domain comprising three CDRs, VHCDR1, VHCDR2 and VHCDR3, VHCDR1 comprises the amino acid sequence set forth in SEQ ID NO:4, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64 or SEQ ID NO:65; VHCDR2 comprises the amino acid sequence set forth in SEQ ID NO:6, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 or SEQ ID NO:72; an antibody heavy chain variable domain, wherein VHCDR3 comprises the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:73, SEQ ID NO:74 or SEQ ID NO:75, and - an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2 and VLCDR3, VLCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 12, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79 or SEQ ID NO: 80; VLCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87 or SEQ ID NO: 88; an antibody light chain variable domain, wherein VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 89 2. An anti-CMKLR1 compound comprising:

2. The anti-CMKLR1 compound of claim 1, which is a resolvin E1-like agonist of CMKLR1.

3. An anti-CMKLR1 compound according to claim 1 or 2, which is a recovery promoting factor.

4. An anti-CMKLR1 compound as described in claim 3, which is a recovery-promoting factor in myeloid cell lineage.

5. A CMKLR1 compound described in any one of claims 1 to 4, which is an anti-human CMKLR1 compound.

6. An anti-CMKLR1 compound according to any one of claims 1 to 5, which specifically binds to an epitope located within the third extracellular loop (EL3) of CMKLR1.

7. An anti-CMKLR1 compound described in claim 6, which specifically binds to a polypeptide comprising amino acid residues of the sequence of SEQ ID NO:

2.

8. An anti-CMKLR1 compound according to any one of claims 1 to 7, wherein VHCDR3 comprises an amino acid sequence as set forth in SEQ ID NO:144 or SEQ ID NO:

148.

9. - VHCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4, SEQ ID NO: 62, or SEQ ID NO: 63, VHCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 67, SEQ ID NO: 70 or SEQ ID NO: 72; VHCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 144 or SEQ ID NO: 148; The anti-CMKLR1 compound according to any one of claims 1 to 8.

10. VLCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 77, VLCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 81 or SEQ ID NO: 84; VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 89; The anti-CMKLR1 compound according to any one of claims 1 to 9.

11. An anti-CMKLR1 compound described in any one of claims 1 to 10, which enhances secretion of anti-inflammatory cytokines in vitro and / or in vivo and / or inhibits or reduces secretion of pro-inflammatory cytokines in vitro and / or in vivo.

12. The anti-CMKLR1 compound of any one of claims 1 to 11, wherein the anti-inflammatory cytokine comprises IL10 and / or CCL17.

13. An anti-CMKLR1 compound according to any one of claims 1 to 12, wherein the pro-inflammatory cytokine comprises IL12.

14. An anti-CMKLR1 compound according to any one of claims 11 to 13, wherein the secretion is by a myeloid cell expressing CMKLR1.

15. An anti-CMKLR1 compound according to any one of claims 1 to 14, which enhances macrophage polarization in favour of anti-inflammatory M2-type macrophages.

16. An anti-CMKLR1 compound according to any one of claims 1 to 15, which inhibits the activation and / or proliferation of dendritic cells.

17. An anti-CMKLR1 compound according to any one of claims 1 to 16, having the ability to induce phosphorylation of Akt and / or Erk following activation of CMKLR1 in vitro and / or in vivo.

18. The anti-CMKLR1 compound of claim 17, wherein the phosphorylation is phosphorylation of both Akt and Erk induced following activation of CMKLR1.

19. An anti-CMKLR1 compound according to any one of claims 1 to 18, which does not compete with chemerin for binding to CMKLR1 or does not interfere with the binding of chemerin to CMKLR1.

20. An anti-CMKLR1 compound selected from an antibody, an antigen-binding fragment thereof, or a chimeric, modified, or humanized antibody that specifically binds to CMKLR1, comprising an antibody heavy chain variable domain comprising a VHCDR3 having an amino acid sequence as set forth in SEQ ID NO:8, wherein amino acid residues at positions 1 and 2 of SEQ ID NO:8 have been substituted such that they are L and I, or L, respectively; The anti-CMKLR1 compound specifically binds to an epitope located within the third extracellular loop (EL3) of CMKLR1; the anti-CMKLR1 compound is a resolvin E1-like agonist of CMKLR1; An anti-CMKLR1 compound, wherein the compound competes for binding to an antibody comprising a heavy chain variable domain corresponding to SEQ ID NO:9 and a light chain variable domain corresponding to SEQ ID NO:16, a polypeptide comprising amino acid residues of the sequence of SEQ ID NO:2, or a polypeptide comprising the third loop (EL3) of the extracellular domain of CMKLR1.

21. The anti-CMKLR1 compound of claim 20, wherein the compound specifically binds to a polypeptide comprising amino acid residues of the sequence of SEQ ID NO:

2.

22. The anti-CMKLR1 compound of claim 20 or 21, wherein the anti-CMKLR1 compound is a recovery promoting factor.

23. The anti-CMKLR1 compound according to any one of claims 20 to 22, wherein the anti-CMKLR1 compound is a recovery-promoting factor in myeloid cell lineage.

24. The antibody heavy chain variable domain comprises three CDRs, VHCDR1, VHCDR2, and VHCDR3; VHCDR1 comprises the amino acid sequence set forth in SEQ ID NO:4, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64 or SEQ ID NO:65; VHCDR2 comprises the amino acid sequence set forth in SEQ ID NO:6, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 or SEQ ID NO:72; VHCDR3 comprises the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:73, SEQ ID NO:74 or SEQ ID NO:75; an antibody light chain variable domain comprising three CDRs, VLCDR1, VLCDR2, and VLCDR3; VLCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 12, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79 or SEQ ID NO: 80; VLCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87 or SEQ ID NO: 88; VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 89; The anti-CMKLR1 compound according to any one of claims 20 to 23.

25. A nucleic acid molecule or a set of nucleic acid molecules encoding an anti-CMKLR1 compound according to any one of claims 1 to 24.

26. A nucleic acid molecule or set of nucleic acid molecules according to claim 25 which is an isolated nucleic acid molecule and / or a recombinant nucleic acid molecule.

27. A nucleic acid molecule or set of nucleic acid molecules as described in claim 25 or 26, further comprising regulatory sequences for transcription and expression of the encoded heavy chain variable domain and / or light chain variable domain.

28. A vector comprising an operably linked nucleic acid molecule or set of nucleic acid molecules according to any one of claims 25 to 27.

29. The vector of claim 28, which is a recombinant vector and / or an isolated vector.

30. The vector of claim 28 or 29, which is a plasmid, an artificial chromosome, a cosmid, or a viral vector.

31. A host cell comprising a nucleic acid molecule according to any one of claims 25 to 27, or a vector according to any one of claims 28 to 30.

32. The host cell of claim 31, which is a mammalian cell.

33. The host cell of claim 32, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell.

34. A pharmaceutical composition for use in the prevention and / or treatment of an inflammatory disease, acute inflammatory disease, or chronic inflammatory disease in a subject, comprising an anti-CMKLR1 compound selected from an anti-CMKLR1 described in any one of claims 1 to 24, a nucleic acid molecule or a set of nucleic acid molecules described in any one of claims 25 to 27, a vector described in any one of claims 28 to 30, and / or a host cell described in any one of claims 31 to 33.

35. The pharmaceutical composition described in claim 34, wherein the inflammatory disease is asthma, keratoconjunctivitis, periodontal disease, eczema, or inflammatory bowel disease.

36. The pharmaceutical composition of claim 35, wherein the inflammatory bowel disease is Crohn's disease, colitis, ulcerative colitis, or spontaneous colitis.

37. A pharmaceutical composition described in any one of claims 34 to 36, wherein the subject's recovery from inflammation is delayed or prevented.

38. The pharmaceutical composition of claim 35 for the treatment of colitis or Crohn's disease in a subject whose myeloid cells overexpress CMKLR1.

39. The pharmaceutical composition of claim 38, wherein the subject is refractory to corticosteroid and / or immunosuppressive treatment.

40. A pharmaceutical composition according to claim 38 or 39 for the sustained treatment of colitis and / or the treatment of advanced colitis.

41. A pharmaceutical composition for use in the prevention and / or treatment of an autoimmune disease or an infectious disease in a subject, comprising an anti-CMKLR1 compound selected from an anti-CMKLR1 described in any one of claims 1 to 24, a nucleic acid molecule or a set of nucleic acid molecules described in any one of claims 25 to 27, a vector described in any one of claims 28 to 30, and / or a host cell described in any one of claims 31 to 33.

42. The pharmaceutical composition of claim 41, wherein the autoimmune disease is diabetes, type I diabetes, psoriasis, lupus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, celiac disease, vasculitis, or myasthenia gravis.

43. The pharmaceutical composition described in claim 41, wherein the infectious disease is sepsis, peritonitis, a degenerative disease, a wound healing disorder, or dry eye syndrome.

44. A pharmaceutical composition described in any one of claims 41 to 43, wherein the subject's recovery from inflammation is delayed or prevented.

45. A pharmaceutical composition for use in the prevention and / or treatment of cancer in a subject, comprising an anti-CMKLR1 compound selected from the group consisting of an anti-CMKLR1 described in any one of claims 1 to 24, a nucleic acid molecule or a set of nucleic acid molecules described in any one of claims 25 to 27, a vector described in any one of claims 28 to 30, and / or a host cell described in any one of claims 31 to 33.

46. The pharmaceutical composition described in claim 45, wherein the cancer is a metastatic cancer, a solid cancer, or a blood cancer.

47. The pharmaceutical composition described in claim 46, wherein the cancer is carcinoma, lung cancer, or myeloid cancer.

48. A pharmaceutical composition described in any one of claims 45 to 47, wherein cancer cells express CMKLR1 or the tumor microenvironment is infiltrated by cells that express or overexpress CMKLR1.

49. A pharmaceutical composition described in any one of claims 45 to 48, wherein the subject's recovery from inflammation is delayed or prevented.

50. The pharmaceutical composition of any one of claims 45 to 49, wherein the cancer is carcinoma, hepatocellular carcinoma, breast cancer, colon cancer, lung cancer, myeloid cancer, or leukemia.

51. An agonist compound of CMKLR1 having RvE1-like agonistic ability, wherein the agonist compound induces phosphorylation of Akt and / or phosphorylation of Erk after binding of the agonist compound to CMKLR1, and the agonist compound specifically binds to the third loop E3 ​​of CMKLR1; The agonist compound is an antibody, an antigen-binding antibody, an antigen-binding antibody mimetic, an engineered antibody, an extracellular ligand, a peptide, or a polypeptide.

52. The agonist compound of claim 51, wherein the agonist compound induces phosphorylation of Akt and / or phosphorylation of Erk following binding of the agonist compound to CMKLR1 in myeloid cells.

53. An agonist compound described in claim 51 or 52, which specifically binds to an epitope located within the third loop E3 ​​and contained within the amino acid residues of the sequence of SEQ ID NO: 2 or SEQ ID NO:

152.

54. An agonist compound according to any one of claims 51 to 53, which enhances macrophage polarization in favour of anti-inflammatory M2-type macrophages, inhibits dendritic cell proliferation and activation, enhances secretion of anti-inflammatory cytokines in vitro and / or in vivo, and / or inhibits or reduces secretion of pro-inflammatory cytokines in vitro and / or in vivo.

55. The agonist compound of any one of claims 51 to 54, wherein the anti-inflammatory cytokine comprises IL10 and / or CCL17.

56. An agonist compound described in any one of claims 51 to 55, wherein the pro-inflammatory cytokine comprises IL12.

57. An agonist compound described in any one of claims 51 to 56, wherein secretion is by a myeloid cell expressing CMKLR1.

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