Anti-ngf vaccine composition

Abstract

The present invention relates to a polypeptide comprising, or consisting of: - a first sequence consisting of at least 8 contiguous amino acids chosen from within the sequence running from amino acids 122 to 136 of the β subunit of the NGF protein and of at most 30 contiguous amino acids chosen from within the complete sequence of the β subunit of the NGF protein; and / or - a second sequence consisting of at least 8 contiguous amino acids chosen from within the sequence running from amino acids 148 to 158 of the β subunit of the NGF protein and of at most 30 contiguous amino acids chosen from within the complete sequence of the β subunit of the NGF protein.

Description

[0001] ANTI-NGF VACCINE COMPOSITION Field of the Invention The present invention relates to peptides or polypeptides useful for eliciting an immune response directed against Nerve Growth Factor (NGF). Technical Background Chronic pain (CRPD) is a huge unmet medical need and more effective safe drugs are desperately needed. Some of the most common forms or sources of chronic pain include: i) neuropathic pain (NP), associated with nerve injury in the peripheral or central nervous system; and ii) osteoarthritis (OA), a progressive degeneration of joint cartilage characterized by inflammation and pain. There is no completely effective treatment for these widespread debilitating chronic pain conditions and current treatments (NSAIDs and opioids) cause serious unwanted side effects.Recently, the NGF ligand-receptor system has emerged as a novel target for NP and OA, with significant therapeutic potential. Indeed, NGF and its receptors (TrkA and p75. NTR) appear to be the main regulators controlling both the neuropathic and inflammatory components of pain. Excessive levels of NGF, caused by tissue injury or other factors, lead to rapid sensitization of nociceptors, reducing the threshold for pain sensation and increasing the intensity of perceived pain (e.g., allodynia and hyperalgesia). Human genetic studies have validated NGF as a target, since mutations in the genes for the TrkA receptor and for NGF itself cause congenital forms of pain insensitivity (hereditary autonomic sensory neuropathy type IV, HSAN IV, and HSAN type V, respectively). Thus, blocking the NGF signaling system is a rational and well-validated approach to pain treatment. Indeed, the potent analgesic efficacy of some anti-NGF monoclonal antibodies (mAbs),such as Tanezumab (Eli Lilly and Company) and Fasinumab (Mirati Therapeutics), has been demonstrated in different preclinical models of CRLD, from PN to inflammatory models (cancer pain and osteoarthritis, interstitial cystitis, respectively), as well as in clinical trials (Gondal et al. (2022) Drugs Today (Barc.) 58:187-200. In addition, other pathologies are also linked to NGF. Indeed, NGF is widely expressed in lung tissues. In different microenvironments, NGF participates in the onset and development of lung diseases by altering protein expression levels and acting on cellular function. Thus, NGF may intervene in some underlying mechanisms in pulmonary fibrosis (PF), coronavirus disease 2019 (COVID-19), pulmonary hypertension (PH), asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. In particular,NGF is a critical mediator in the neuroimmune mechanisms of asthma and aggravates airway inflammation and remodeling (Li et al. (2009) Respirology 14:60-68). Serum NGF levels are also extremely elevated in subjects with COPD (Stabile et al. (2016) J. Biol. Chem. 397:157-163). In tumor tissues, NGF stimulates angiogenesis, including non-small cell lung cancer (NSCLC) (Lu et al. (2014) J. Huazhong Univ. Sci. Technol. Med. Sci. 34:359-362). It is also present in breast cancers and produced by tumor cells while normal epithelial cells do not, and can therefore serve as a diagnostic as well as a therapeutic target. Also the use of anti-NGF therapies could be the basis of future therapeutic strategies in the mentioned lung diseases. However,Monoclonal antibodies are affected by many well-known limitations: high cost, the need for frequent re-administration and the development of an immune reaction directed against the administered monoclonal antibodies. It is therefore an object of the present invention to overcome these drawbacks. Summary of the invention The present invention arises from the unexpected demonstration, by the inventors, that polypeptides derived from sequences extending from amino acids 122 to 136 and 148 to 158 of the β subunit of the human NGF protein (hNGF) allowed the production of antibodies, in particular neutralizing antibodies, directed against the hNGF protein. The present invention therefore relates to a polypeptide comprising, or consisting of: - a first sequence consisting of at least 8 contiguous amino acids chosen from within the sequence extending from amino acids 122 to 136, in particular,of the β subunit of the NGF protein and at most 30 contiguous amino acids selected from the complete sequence of the β subunit of the NGF protein, or a variant sequence having at least 75% identity with the first sequence; and / or - a second sequence consisting of at least 8 contiguous amino acids selected from the sequence extending from amino acids 148 to 158 of the β subunit of the NGF protein and at most 30 contiguous amino acids selected from the complete sequence of the β subunit of the NGF protein, or a variant sequence having at least 75% identity with the second sequence; provided that the polypeptide is different from the β subunit of the NGF protein and that it does not consist of a portion of more than 30 contiguous amino acids of the β subunit of the NGF protein,and provided that polypeptides respectively consisting of the variant sequences of the first and second sequences make it possible to elicit an immune response directed against the NGF protein. In a preferred embodiment, the invention relates more particularly to a polypeptide comprising, or consisting of: - a first sequence consisting of SEQ ID NO: 1, 22, 24, 26, 28 or 29, in particular SEQ ID NO: 1 or 28, or a variant sequence having at least 75% identity with the first sequence; and / or - a second sequence consisting of SEQ ID NO: 2, 23, 25 or 27, in particular SEQ ID NO: 2 or 27, or a variant sequence having at least 75% identity with the second sequence. The present invention also relates to a nucleic acid encoding a polypeptide as defined above, or the complement thereof. The present invention also relates to: - at least one polypeptide as defined above,or - at least one nucleic acid as defined above, for use as a medicament, in particular a vaccine, in particular for human or veterinary use. In a particular embodiment of the invention, the medicament, in particular the vaccine, as defined above also comprises at least one other compound intended for the prevention or treatment of a disease linked to or due to the NGF protein. The present invention also relates to a pharmaceutical composition, in particular a vaccine, comprising, as active substance: - at least one polypeptide as defined above, or - at least one nucleic acid as defined above, optionally in association with at least one pharmaceutically acceptable vehicle. In a particular embodiment of the invention, the pharmaceutical composition, in particular a vaccine,as defined above also comprises at least one other compound for the prevention or treatment of a disease related to or due to the NGF protein. The present invention also relates to the use of a polypeptide as defined above, for the preparation of an antibody, an antibody fragment or an aptamer. The present invention also relates to a method for preparing an antibody, an antibody fragment or an aptamer comprising a step of administering a polypeptide as defined above to an antibody-producing organism or a step of affinity selection of an antibody, an antibody fragment or an aptamer which binds to the polypeptide as defined above. The present invention also relates to an anti-NGF antibody, an antibody fragment, or an aptamer specifically directed against the polypeptide as defined above,provided that the polypeptide does not comprise more than two amino acid residues in addition to the first or second sequence or their respective variant sequences. The present invention also relates to an antibody, an antibody fragment, or an aptamer as defined above, for use as a medicament. In a particular embodiment of the invention, the medicament as defined above also comprises at least one other compound intended for the prevention or treatment of a disease linked to or due to the NGF protein. The present invention also relates to a pharmaceutical composition comprising, as active ingredient, an antibody, an antibody fragment, or an aptamer as defined above, optionally in association with a pharmaceutically acceptable vehicle. In a particular embodiment of the invention,the pharmaceutical composition as defined above also comprises at least one other compound for the prevention or treatment of a disease related to or due to the NGF protein. The present invention also relates to a polypeptide as defined above, a nucleic acid (RNA or DNA) as defined above, or a pharmaceutical composition as defined above, for use in a method for eliciting an immune response directed against the NGF protein in an individual. In a particular embodiment of the invention, the polypeptide, nucleic acid or pharmaceutical composition is used in combination with at least one other compound useful for eliciting an immune response directed against the NGF protein. The present invention also relates to a method for eliciting an immune response directed against the NGF protein in an individual,comprising administering to the individual an effective amount of a polypeptide as defined above, a nucleic acid as defined above, or a pharmaceutical composition as defined above. In a particular embodiment of the invention, the polypeptide, nucleic acid or pharmaceutical composition is administered in combination with at least one other compound useful for eliciting an immune response directed against the NGF protein. The present invention also relates to the use of a polypeptide as defined above or a nucleic acid as defined above for the preparation of a medicament intended to elicit an immune response directed against the NGF protein in an individual. In a particular embodiment of the invention,the medicament also comprises at least one other compound useful for eliciting an immune response directed against the NGF protein. The present invention also relates to a polypeptide as defined above, a nucleic acid as defined above, a pharmaceutical composition as defined above, or an antibody, an antibody fragment or an aptamer as defined above, for use in a method of preventing or treating a disease related to or due to the NGF protein in an individual. In a particular embodiment of the invention, the polypeptide, the nucleic acid, the pharmaceutical composition, or the antibody, the antibody fragment or the aptamer is used in combination with at least one other therapy for the prevention or treatment of a disease related to the NGF protein. The present invention also relates to a method of preventing or treating a disease related to or due to the NGF protein in an individual,comprising administering to the individual an effective amount of a polypeptide as defined above, a nucleic acid as defined above, a pharmaceutical composition as defined above, or an antibody, an antibody fragment or an aptamer as defined above. In a particular embodiment of the invention, the method comprises at least one other therapy for the prevention or treatment of a disease related to the NGF protein. The present invention also relates to the use of a polypeptide as defined above, a nucleic acid as defined above, or an antibody, an antibody fragment or an aptamer as defined above, for the preparation of a medicament for the prevention or treatment of a disease related to or due to the NGF protein in an individual. In a particular embodiment of the invention,the medicament comprises at least one other compound intended for the prevention of a disease linked to or due to the NGF protein. The present invention also relates to products containing: - a polypeptide or a nucleic acid as defined above, and - at least one other compound intended for the prevention or treatment of a disease linked to or due to the NGF protein, as a combination product for simultaneous, separate or spread-out use over time for the prevention or treatment of a disease linked to or due to the NGF protein. Description of the invention, it will be recalled that the term "comprising" means "including", "containing" or "encompassing", that is to say that when an object "comprises" one or more elements, other elements than those mentioned may also be included in the object. Conversely, the expression "consisting of" means "made up of", that is to say that when an object "consists of" one or more elements, the object cannot include elements other than those mentioned. Polypeptide Definition of the NGF protein The NGF protein is Nerve Growth Factor, also called NGF, Beta-HSAN5 or NGFB, it is well known to the person skilled in the art. NGF is a multimeric protein comprising α, β and γ subunits, generally with the stoichiometry α2β2γ2. The β subunit of NGF, or β-NGF, carries the catalytic activity. NGF is sometimes used as a synonym for β-NGF. Preferred species and sequences of the β subunit ofNGF protein Preferably, the β subunit of the NGF protein according to the invention is selected from the group consisting of the β subunit of the human NGF protein, the β subunit of the mouse NGF protein, the β subunit of the rat NGF protein, the β subunit of the rabbit NGF protein, the β subunit of the monkey NGF protein, the β subunit of the dog NGF protein, the β subunit of the cat NGF protein, the β subunit of the horse NGF protein, the β subunit of the pig NGF protein, the β subunit of the sheep NGF protein, and the β subunit of the dromedary NGF protein. Particularly preferably, the NGF protein is the β subunit of the human (hNGF) or dog NGF protein. Preferably: - the β subunit of the human NGF protein (hNGF) is as described in the UniProt / Swissprot database under the reference P01138 and consists of SEQ ID NO: 3, - the β subunit of theMouse NGF (mNGF) protein is as described in the UniProt / Swissprot database under reference P01139 and consists of SEQ ID NO: 4, - the β subunit of rat NGF protein is as described in the NCBI Genbank database under reference NP_001263984.1 or in the Uniprot / SwissProt database under reference P25427 and consists of SEQ ID NO: 5 or 18, - the β subunit of rabbit NGF protein is as described in the NCBI Genbank database under reference XP_051712092.1 and consists of SEQ ID NO: 6, - the β subunit of monkey NGF protein is as described in the Genbank database under reference NP_001012439.1 or in the database Uniprot / SwissProt under the reference Q9N2F1 and consists of SEQ ID NO: 7 or 19, - the β subunit of the dog NGF protein is as described in the Uniprot / SwissProt database under the reference A0A8I3PYI3 and consists of SEQ ID NO: 8, -the β subunit of the cat NGF protein is as described in the Genbank database under reference XP_004001166.2 and consists of SEQ ID NO: 9. - the β subunit of the horse NGF protein is as described in the Genbank database under reference XP_001496237.2 and consists of SEQ ID NO: 10, - the β subunit of the pig NGF protein is as described in the Genbank database under reference XP_020945655.1 and consists of SEQ ID NO: 11, - the β subunit of the sheep NGF protein is as described in the UniProt / Swissprot database under reference A0A481MW93 or in the Genbank database under reference XP_060257455.1 and consists of SEQ ID NO: 12 or 20, - the β subunit of the dromedary NGF protein is as described in the UniProt / Swissprot database under reference A0A5N4DT36 and consists of SEQ ID NO: 13. Amino acid residue numbering As understoodherein, the amino acid residue numbering of the NGF protein β subunit begins at the first amino acid residue, usually a methionine (M), forming the N-terminus of the full-length NGF protein β subunit encoded by the open reading frame of the NGF β subunit gene (β-NGF), i.e., including its signal peptide and the constitutive pro-NGF propeptide. Furthermore, the amino acid residue numbering of the NGF protein β subunit used herein is defined with reference to the human NGF protein β subunit. It is thus easy for a person skilled in the art to determine the amino acid residue of a β subunit of the NGF protein corresponding to a position number to which reference is made according to the invention: it is sufficient to align the sequence of the β subunit of the NGF protein for which one wishes to determine the amino acid residue corresponding to a position number with a sequence of the β subunitof the human NGF protein, in particular SEQ ID NO: 3, so as to optimize the percentage of identity between the two aligned sequences, then to identify the amino acid residue corresponding to the desired position number as being that which is aligned with the amino acid residue of the sequence of the β subunit of the human NGF protein which bears this position number. First and second sequences Preferably, the first sequence and the second sequence consist of at least 9, 10, 11, 12 contiguous amino acids respectively chosen from within one of the sequences extending from amino acids 122 to 136 or 148 to 158 of the β subunit of the NGF protein, or consist respectively of at least the sequence extending from amino acids 122 to 136 or 148 to 158 of the β subunit of the NGF protein. Also preferably, the first sequence and the second sequence according to the invention are respectively made up of at most 29, 28, 27, 26, 25, 24, 23, 22, 21,20 contiguous amino acids selected from the complete sequence of the β subunit of the NGF protein, or consist of at most sequences 122 to 136 and 148 to 158, respectively, of the β subunit of the NGF protein. Preferably, the first and second sequences according to the invention are respectively constituted by (i) SEQ ID NO: 1, 22, 24, 26, 28 or 29, in particular SEQ ID NO: 1 or 28, and (ii) SEQ ID NO: 2, 23, 25 or 27, in particular SEQ ID NO: 2 or 27. SEQ ID NO: 1 and 2 respectively represent portions 122 to 136 and 148 to 158 of the β subunit of the human NGF protein, in particular represented by SEQ ID NO: 3. Sequence SEQ ID NO: Amino acid residues of β-hNGF SSSHPIFHRGEFSVC 1 122-136 TATDIKGKEVM 2 148-158 SEQ ID NO: 22 represents portion 122 to 136 of the subunit β of the mouse or rat NGF protein, in particular represented by SEQ ID NO: 4, 5 or 18. SEQ ID NO: 23 represents the portion 148 to 158 of the β subunit of themouse or rat NGF protein, in particular represented by SEQ ID NO: 4, 5 or 18. SEQ ID NO: 24 and 25 represent respectively portions 122 to 136 and 148 to 158 of the β subunit of the rabbit NGF protein, in particular represented by SEQ ID NO: 6. SEQ ID NO: 26 represents portion 122 to 136 of the β subunit of the monkey (chimpanzee) NGF protein, in particular represented by SEQ ID NO: 7 or 19. SEQ ID NO: 27 represents portion 148 to 158 of the β subunit of the monkey (chimpanzee), dog, cat, horse, pig, or sheep NGF protein, in particular represented by SEQ ID NO: 7 or 19, 8, 9, 10, 11, or 12 or 20, or portion 149 to 159 or of the β subunit of the dromedary NGF protein, in particular represented by SEQ ID NO: 13. SEQ ID NO: 28 represents portion 122 to 136 of the β subunit of the dog, cat, horse, pig, or sheep NGF protein, in particular represented by SEQ ID NO: 8, 9, 10, 11, or 12 or 20. SEQ ID NO: 29 representsthe portion 122 to 137 of the β subunit of the dromedary NGF protein, in particular represented by SEQ ID NO: 13. Variant sequences A variant sequence according to the invention, which has at least 75% identity with the first or second sequence presented above, preferably has at least 80%, 85%, 90%, 95% or 98% identity with the first or second sequence above. As used herein, the percentage identity between two peptide sequences can be determined by performing an optimal alignment over the entire length of the sequences, determining the number of aligned positions for which the amino acids are identical in each sequence and dividing this number by the total number of amino acids in the longer of the two sequences. The optimal alignment is that which gives the highest percentage identity between the two sequences. Also preferably, a variant sequence according to the invention has at least 75%,80%, 85%, 90%, 95% or 98% identity with SEQ ID NO: 1, 22, 24, 26, 28 or 29 or SEQ ID NO: 2, 23, 25 or 27. The variant sequence according to the invention is such that a polypeptide consisting of the variant sequence must make it possible to elicit an immune response directed against the NGF protein; that is to say that the administration of such a peptide, optionally cyclized by formation of at least one inter-cysteine ​​disulfide bridge, if necessary after addition of one or two cysteines within the peptide, and / or at its N-terminal end and / or at its C-terminal end, the peptide being optionally linked to a carrier molecule, in particular a carrier protein, such as KLH (Keyhole Limpet Hemocyanin), to an animal, such as a mouse, a rat or a rabbit, causes the production of antibodies directed against an NGF, in particular an NGF of the same species as that to which belongs the sequence with which the variant sequence has the highest percentage of identity. The man of theThe art knows well how to determine whether an antibody is directed against NGF, in particular by implementing an ELISA test. Preferably, the antibodies elicited by administration of the conjugated peptide are blocking or neutralizing, that is to say they prevent the NGF protein from exerting all or part, in particular at least 10%, 25%, 50%, 75%, of its activity, for example measured in vitro. Length of the polypeptide The polypeptide according to the invention preferably comprises at most 200, 150, 100, 90, 80, 70, 60, 50, 40 or 30 amino acid residues. It is different from the β subunit of the NGF protein and does not consist of a portion of more than 30 contiguous amino acid residues of the β subunit of the NGF protein. As the person skilled in the art will understand, this does not exclude that it may consist of two or more portions of the β subunit of the NGF protein of at most 30 contiguous amino acid residues, provided that these portions are not arranged in such a way as toreconstitute a portion of the β subunit of the NGF protein of more than 30 contiguous amino acids. As will be clear to those skilled in the art, the polypeptide according to the invention may comprise several repeats, for example 2, 3, 4, 5, 10 or 20 repeats, respectively of the first and second sequences and of the variant sequence according to the invention. Sequences in addition to the sequences of the first and second sequences and of the variant sequences Furthermore, the polypeptide according to the invention may also comprise sequences not originating from the β subunit of the NGF protein, and in particular sequences comprising epitopes belonging to other proteins, which makes it possible to elicit or generate an immune response directed against these other proteins. In addition, the polypeptide according to the invention may comprise sequences of exogenous T epitope(s), preferably universal, which makes it possible to reinforce the immunogenicity of the polypeptide according to the invention.The polypeptide according to the invention may also comprise at least one sequence of a carrier protein, for example a virus-like particle (VLP), as described in particular in international application WO 05 / 117983 for TNF. Cyclization of the polypeptide The polypeptide according to the invention may be cyclized or non-cyclized. The polypeptide according to the invention is preferably cyclized. This cyclization may be of any type known to those skilled in the art. The choice of the cyclization strategy according to the invention may in particular take into account the best antigenic presentation of the epitopes contained in the polypeptide according to the invention. Depending on the functional groups present in the polypeptide, this cyclization may be carried out in several different ways, such as for example: from its C-terminal end to its N-terminal end, from its N-terminal end to a side chain, from a side chain to its C-terminal end or between twoside chains. Among the various modalities of cyclization of polypeptides, it is possible to cite lactamization, lactonization or the formation of a disulfide bridge. In particular, during the formation of an inter-cysteine ​​disulfide bridge, that is to say between the –SH radicals of two cysteines, the cysteines may already be present in the variant sequence according to the invention or in the first and second sequences according to the invention, or else be added within these sequences, as well as at their N-terminal and / or C-terminal end. Post-translational modifications, amino acid analogues In addition, the polypeptide according to the invention may comprise post-translational modifications, such as glycosylations, methylations, acylations, in particular by fatty acids, or phosphorylations. In particular, the N-terminal end of the polypeptide according to the invention may be acetylated and the C-terminal end may be modified by amidation.The polypeptide according to the invention may also comprise one or more amino acid analogues or derivatives, including non-natural or non-standard amino acids. Carrier molecule Also preferably, the polypeptide according to the invention is attached or linked, in particular by covalent bonding, to a carrier molecule, in particular a carrier protein. In particular, the carrier molecule may be Keyhole Limpet Hemocyanin (KLH) protein, hepatitis B surface antigen (HBsAg), bovine serum albumin (BSA), tetanus toxoid (TT) and diphtheria toxoid (DT). The diphtheria toxoid (DT) according to the invention is preferably selected from the group consisting of CRM 197, CRM 176, CRM 228, CRM 45, CRM 9, CRM 102, CRM 103, and CRM 107. In a particularly preferred manner, the carrier molecule is CRM 197. The binding of the polypeptide according to the invention to a carrier molecule, in particular a carrier protein, can be carried out using a binding agent.heterobifunctional coupling, such as N-γ-maleimidobutyryl-oxysuccinimide (GMBS) ester and sulfo-GMBS derivative, m-maleimidobenzoyl-n-hydroxysuccinimide (MBS) ester and sulfo-MBS derivative, succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), a carbodiimide, bisdiazonium-benzidine (BDB) or glutaraldehyde. When glutaraldehyde is used, it is preferably attached to a lysine (K) which, if not present in a first or second sequence, or a variant sequence according to the invention, may be added, in particular at its N-terminal or C-terminal end. Furthermore, when a lysine is present in a portion according to the invention at an undesired position, it is preferable to use another conjugation technique. When BDB is used, it is preferably attached to a tyrosine (Y) which, if not present in a first or second sequence, or a variant sequence according to the invention, can beadded, in particular at its N-terminal or C-terminal end. Furthermore, when a tyrosine is present in a portion according to the invention at an undesired position, it is possible to use, instead, a variant sequence in which the tyrosine is substituted by another amino acid, such as a phenylalanine (F). When GMBS, MBS or SMCC are used, they are preferably attached to a cysteine ​​(C), which if it is not present in a first or a second sequence, or a variant sequence according to the invention, can be added, in particular at its N-terminal or C-terminal end. Furthermore, when a cysteine ​​is present in a first or a second sequence, according to the invention at an undesired position, it is possible to use, instead, a variant sequence in which the cysteine ​​is substituted by another amino acid, such as a serine. In a very particularly preferred manner, the polypeptide according tothe invention is attached to the carrier protein CRM197 according to a construct represented by a formula selected from the group consisting of the following formulas: Polypeptide SEQ ID NO: [cycloS-S(Acetyl+CSSSHPIFHRGEFSVC)EGE–Ahx-C]n–CRM19714 [cycloS-S(CTATDIKGKEVMC)EGE–Ahx-C]n–CRM19715 [cycloS-S(Acetyl+CSSSHPIFHRGEFSVCEGE–K)]n–KLH 16 [cycloS-S(CTATDIKGKEVMCEGE–Ahx-C)]n–CRM 197 17 [Acetyl-SSSHPIFHRGEFSVEGE-C]n– CRM197 21 [cycloS-S(CTATDIKGKEVMCEGE–Ahx-C)]n–CRM 197 30 [Acetyl-SSTHPVFHMGEFSVEGE-C]n– CRM197 31 [Acetyl-SSSHPVFHRGEFSVEGE-C]n– CRM197 32 where: - CRM197 denotes the carrier protein, - Acetyl+ indicates that the N-terminus is acetylated, - cycloS-S() indicates a cyclization by disulfide bridge between the sulfhydryl groups of the cysteines present in the C-terminus and in the N-terminus, - Ahx indicates a non-natural amino acid of the amino-hexanoic acid type, - the brackets ([X]n) indicate that one or more polypeptides are attached to the carrier protein and - the partunderlined and in bold represents the first or second sequence according to the invention Preparation of the polypeptide The polypeptide according to the invention can be prepared by any method known in the state of the art and in particular by chemical synthesis. It is also possible to prepare it by expression of the nucleic acid according to the invention in eukaryotic or prokaryotic cells. Activity of the polypeptide The polypeptide according to the invention, if necessary linked to a carrier molecule, is immunogenic, that is to say it can elicit, or provoke, an immune reaction, in particular of the humoral type, that is to say the production of antibodies, by an individual, in particular of the mammalian type, to which it is administered. In particular, the polypeptide according to the invention makes it possible to elicit an immune response directed against the NGF protein, in particular anti-NGF antibodies, preferably blocking or neutralizing anti-NGF antibodies, that is to say they prevent the NGF protein from exertingall or part, in particular at least 5%, 10%, 25%, 50%, 75%, of its activity, for example measured in vitro. Nucleic acid The nucleic acid according to the invention is RNA or DNA, preferably DNA. It is preferred that the nucleic acid according to the invention is operatively linked to a prokaryotic and / or eukaryotic promoter sequence, in particular mammalian or viral. Furthermore, the nucleic acid according to the invention may be included in a vector, such as a plasmid or a virus. Antibodies, antibody fragments and aptamers The antibodies, antibody fragments, and aptamers according to the invention are said to be specifically directed against a polypeptide as defined above when they exhibit essentially no binding to another polypeptide, which does not comprise the polypeptide defined above, under conditions allowing the binding of the antibodies, antibody fragment, and aptamers according to the invention to the polypeptides against which they are specifically directed.directed. The antibody according to the invention may be polyclonal or monoclonal, preferably monoclonal. Furthermore, as used herein, the "antibody fragments" comprise at least one antigen-binding portion of the antibody from which they are derived, and are in particular of the Fab, Fab', F(ab')2, disulfide-stabilized Fv (dsFv), dimerized (diabody), trimerized, tetramerized or pentamerized region V, single-chain Fv (scFv), complementarity determining region (CDR) type. The antibodies may be of any species, in particular human, mouse, rat, rabbit or camelid. Furthermore, when they are not human, they may also be humanized, that is to say that the constant portions of these antibodies are partially or completely replaced by corresponding human constant portions. The antibodies according to the invention can be obtained by immunizing an animal using a polypeptide according to the invention according to well-known techniques ofthose skilled in the art. As used herein, aptamers are nucleic acids, in particular RNAs, capable of specifically binding to a molecular target, such as a protein. Aptamers may in particular be obtained by implementing the SELEX technique well known to those skilled in the art, from the polypeptides according to the invention. Therapeutic use Diseases Various diseases, human or veterinary, may be treated according to the invention, and in particular chronic pain. Other examples of conditions or disorders include asthma, psoriasis, osteoarthritis, and arthritis. The invention is useful for the treatment or prevention of chronic pain or general or localized recurrent pain, which is often linked to the activity of NGF. The invention may be used for prevention, symptomatic treatment, or even treatment of the disease itself. The invention may be used for the treatment of asthma andother disorders associated with airway hyperresponsiveness, typically characterized by episodes of coughing and / or breathing problems. The invention is also useful in the management of other inflammatory conditions, such as multiple sclerosis, colitis, chronic inflammatory bowel disease, including Crohn's disease or ulcerative colitis, bladder cystitis, eczema, contact dermatitis, arthritis, including chronic arthritis and rheumatoid arthritis, and psoriasis. The invention is also useful in the treatment of diseases that may be associated with increased levels of NGF, including, for example, osteoarthritis, lupus erythematosus, but also chronic obstructive pulmonary disease (COPD), lung cancer, hyperalgesia, chronic pain, and general or localized recurrent pain. Individual The individual(s) according to the invention are animals, preferably mammals ormarsupials, more preferably humans, horses, cattle, pigs, sheep, goats, dromedaries, dogs or cats, most preferably humans or dogs. Administration Preferably, the polypeptide, pharmaceutical composition, medicament or product according to the invention is administered in a form that can be administered orally, mucosally, in particular sublingually, parenterally, intraperitoneally, transcutaneously, intradermally, subcutaneously, intramuscularly, intravenously or intra-arterially. Doses In the context of the invention, the polypeptide according to the invention can be administered at doses ranging, for example, from 1 ng to 1 g, preferably from 1 µg to 1 mg. Pharmaceutically acceptable vehicle As used herein, a “pharmaceutically acceptable vehicle” includes all the compounds, in particular the excipients, that can be administered to an individual in conjunction with a pharmacological active ingredient. Adjuvant In addition,in particular when used in a vaccine or prophylactic context, the polypeptide according to the invention may be associated or combined with an adjuvant, or the pharmaceutical composition, the medicament or the product according to the invention may comprise an adjuvant. The adjuvant may be of any type suitable for increasing the immune response of an individual, animal or human, to the administration of a polypeptide. It may thus be complete or incomplete Freund's adjuvant, Montanide ISA51 VG, alum or calcium phosphate for example, Montanide ISA51 VG and alum being preferred. The adjuvant may be associated with the polypeptide according to the invention by making a 1 / 1 mixture by volume of an adjuvant solution and a solution comprising the polypeptide. Other therapy As used herein, the term “other therapy” means a pharmacological therapy with at least one other compound different from the polypeptide according to the invention or a non-pharmacological therapy such as in thecase of the treatment of asthma of the use of anti-IgGE antibodies. Other compound Another compound, useful for eliciting an immune response directed against the NGF protein according to the invention, may in particular be a polypeptide different from that of the invention and also derived from the NGF protein. In addition, in particular when used in a vaccine context or when it is included in a vaccine or a vaccine composition, the polypeptide according to the invention may be combined with other antigens intended to elicit an immune response against a target different from the NGF protein. This type of combination is useful for the preparation of multivalent vaccines. As understood herein, the expression "in combination" or "combination product" means that the polypeptide as defined above and the other compound as defined above may be combined within the same pharmaceutical composition or the same medicament, and therefore be administered together, or beadministered separately, i.e., by separate routes of administration and / or separate administration regimens, provided that when administered separately, the periods of prophylactic or therapeutic activity of the polypeptide as defined above and of the other compound as defined above overlap in whole or in part. Thus, when the polypeptide and the other compound are administered separately, the polypeptide as defined above will preferably be administered within 24 hours, more preferably within 2 hours, and even more preferably within 1 hour, following the administration of the other compound as defined above, and its administration will possibly be continued on the following days. Conversely, the other compound as defined above will preferably be administered within 24 hours, more preferably within 2 hours, and even more preferably within 1 hour, following the administration of thepolypeptide as defined above, and its administration will optionally be continued on subsequent days. In another preferred embodiment of the invention, when the polypeptide as defined above and the other compound as defined above are administered separately, they are administered essentially simultaneously. Table 1 SEQ ID NO: Name Sequences 1 PPV-11-13 SSSHPIFHRGEFSVC 2 PPV-11-18 TATDIKGKEVM 3 Beta-nerve >sp|P01138|NGF_HUMAN|1-241 growth factor MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRR [Homo ARSAPAAAIAARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAA sapiens] DTQDLDFEVGGAAPFNRTHRSKRSSSHPIFHRGEFSVCDSVSVWVG Human DKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSGCRG IDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAV RRA 4 Beta-nerve >sp|P01139|NGF_MOUSE|1-241 growth factor MSMLFYTLITAFLIGVQAEPYTDSNVPEGDSVPEAHWTKLQHSLDTALR [Mus musculus] RARSAPTAPIAARVTGQTRNITVDPRLFKKRRLHSPRVLFSTQPPPTSSDT Mouse LDLDFQAHGTIPFNRTHRSKRSSTHPVFHMGEFSVCDSVSVWVGDKTTATDIKGKEVTVLAEVNINNSVFRQYFFETKCRASNPVESGCRGIDSKH WNSYCTTTHTFVKALTTDEKQAAWRFIRIDTACVCVLSRKATRRG 5 Beta-nerve >NCBI Reference Sequence NP_001263984.1|1-241 growth factor MSMLFYTLITAFLIGVQAEPYTDSNVPEGDSVPEAHWTKLQHSLDTALR precursor RARSAPAEPIAARVTGQTRNITVDPKLFKKRRLRSPRVLFSTQPPPTSSD [Rattus TLDLDFQAHGTISFNRTHRSKRSSTHPVFHMGEFSVCDSVSVWVGDKT norvegicus] TATDIKGKEVTVLGEVNINNSVFKQYFFETKCRAPNPVESGCRGIDSK Rat HWNSYCTTTHTFVKALTTDDKQAAWRFIRIDTACVCVLSRKAARRG 18 Beta-nerve >sp|P25427|NGF_RAT|1-241 growth factor MSMLFYTLITAFLIGVQAEPYTDSNVPEGDSVPEAHWTKLQHSLDTALR [Rattus RARSAPAEPIAARVTGQTRNITVDPKLFKKRRLRSPRVLFSTQPPPTSSD norvegicus] TLDLDFQAHGTISFNRTHRSKRSSTHPVFHMGEFSVCDSVSVWVGDKT Rat TATDIKGKEVTVLGEVNINNSVFKQYFFETKCRAPNPVESGCRGIDSK HWNSYCTTTHTFVKALTTDDKQAAWRFIRIDTACVCVLSRKAARRG 6 >NCBI Reference Sequence XP_051712092.1|1-241 Beta-nerve MSMLFYTLITALLIGIQAEPHADSNVPAGHALPQAHWTKLQHSLDTAL growth factor RRARAAPAVAIAARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPLA [OryctolagusAVDFEELDLEVDVGSPSNRTYRSKRSAPHPVFHMGEFSVCDSVSVW cuniculus] VGDKTTATDIKGNEVKVLGEVNINNSVFKQYFFETKCRDPNPVESGC Lapin RGIDAKHWNSYCTTTHTFVKALTTDDKQAAWRFIRIDTACVCVLSRKA SRRG Beta-nerve >NCBI Reference Sequence NP_001012439.1|122-241 growth factor MSMLFYTLITAFLIGTQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALR precursor [Pan RARSAPAAAIAARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPPEA troglodytes] ADTQDLDFEVGGAAPFNRTHRSKRSSSHPIFHRGEFSVCDSVSVWV Chimpanzé GDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSGCR GIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKA VRRA Beta-nerve sp|Q9N2F1|NGF_PANTR|1-241 growth factor MLFYTLITAFLIGTQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRA [Pan RSAPAAAIAARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPPEAADT troglodytes] QDLDFEVGGAAPFNRTHRSKRSSSHPIFHRGEFSVCDSVSVWVGDKT Chimpanzé TATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSGCRGIDS KHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAVRRA Beta-nerve >tr|A0A8I3PYI3|A0A8I3PYI3_CANLF|1-241 growth factor MSMLFYTLITALLIGIRAEPHPESHVPAGHAIPHAHWTKLQHSLDTALRR [Canis lupusARSAPAGAIAARVTGQTRNITVDPKLFKKRRLRSPRVLFSTHPPPVAA familiaris] DAQDLDLEAGSTASVNRTHRSKRSSSHPVFHRGEFSVCDSVSVWVG Chien DKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPTPVDSGCRGI DSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAG RRA Beta-nerve >NCBI Reference Sequence XP_004001166.2|1-241 growth factor MSMLSYTLITALLIGIQAEPHPESNVPAGHTIPQAHWTKLQHSLDTALR [Felis catus] RARSTPAGAIAARVAGQTRNITVDPKLFKKRRLRSPRVLFSTHPPPVAA Chat DTQGLDLEAGGAASFNRTHRSKRSSSHPVFHRGEFSVCDSVSVWVG DKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPTPVDSGCRGI DSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAG RRA Beta-nerve >NCBI Reference Sequence XP_001496237.2|1-241 growth factor MSMLFYTLITALLIGTQAEPHTESNVPAGHAIPQAHWTKLQHSLDTALR [Equus RARSAPARAIAARVAGQTRNITVDPKLFKKRRLRSPRVLFSTQPPPVA caballus] ADTQDLDFEAGGAASFNRTHRSKRSSSHPVFHRGEFSVCDSVSVWV Cheval GDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSGCR GIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKT GRKA Beta-nerve >NCBI Reference Sequence XP_020945655.1|1-241 growth factorMSMLFYTLITALLIGVQAEPHTESNVPAGHAIPQAHWTKLQHSLDTAL [Sus scrofa] RRAHSAPAGAIAARVAGQTRNITVDPKLFKKRRLRSPRVLFSTQPPPV Cochon AADTQDPDLEASGAASFNRTHRSKRSSSHPVFHRGEFSVCDSVSVW VGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSG CRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSR KAGRRA Beta-nerve >tr|A0A481MW93|A0A481MW93_SHEEP|1-220 growth factor ITALLIGIQAAPHTESNVPAGHAIPQAHWIKLQHYLDTVLRRAHSAQA [Ovis aries] GPIAARVAGQTHNITVDPKLFKKRRLRSPRVLFSTQPPPVAADTQDLD Mouton FEAGGAASFNRTHRSKRSSSHPVFHRGEFSVCDSVSVWVGDKTTATD IKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSGCRGIDAKHW NSYCTTTHTFVKALTMDGKQAAWRFIRIDTA Beta-nerve >NCBI Reference Sequence XP_060257455.1|1-241 growth factor MSMLFYTLITALLIGIQAAPHTESNVPAGHAIPQAHWIKLQHSLDTVLR RAHSAQAGPIAARVAGQTHNITVDPKLFKKRRLRSPRVLFSTQPPPVA [Ovis aries] ADTQDLDFEAGGAASFNRTHRSKRSSSHPVFHRGEFSVCDSVSVWV Mouton GDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSGCR GIDAKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKT GRRA Beta-nerve >tr|A0A5N4DT36|A0A5N4DT36_CAMDR|1-242 growth factorDromedary VADKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPDESGC RGIDSKHWNSYCTTTHTFVRALTMDGKQAAWRFIRIDTACVCVLSRK AGRRA [cycloS-S(Acetyl+CSSSHPIFHRGEFSVC)EGE–Ahx-C]n–CRM197 [cycloS-S(CTATDIKGKEVMC)EGE–Ahx-C]n–CRM197 [cycloS-S(Acetyl+CSSSHPIFHRGEFSVCEGE–K)]n–KLH [cycloS-S(CTATDIKGKEVMCEGE–Ahx-C)]n–CRM 197 [Acetyl-SSSHPIFHRGEFSVEGE-C]n– CRM197 First SSTHPVFHMGEFSVC mouse or rat sequence Second TATDIKGKEVT mouse or rat sequence First SAPHPVFHMGEFSVC rabbit sequence Second TATDIKGNEVK rabbit sequence First SSSHPIFHRGEFSVC chimpanzee sequence Second TATDIKGKEVM chimpanzee, dog, cat, horse, pig, sheep, dromedary sequence First SSSHPVFHRGEFSVC dog, cat, horse, pig, sheep sequence First SAPSHPIFHRGEFSVC dromedary sequence[cycloS-S(CTATDIKGKEVMCEGE–Ahx-C)]n–CRM 197 [Acetyl-SSTHPVFHMGEFSVEGE-C]n– CRM197 [Acetyl-SSSHPVFHRGEFSVEGE-C]n– CRM197 Sequence Listing The invention is further illustrated using the following non-limiting figures and examples. Description of the figures Figure 1 Figure 1 represents the anti-hNGF antibody titres50 (y-axis) measured from the sera of six SWISS mice immunized with the conjugated PPV-11-13 peptide (derived from SEQ ID NO: 1 of Example 1). The x-axis corresponds to the time of sera collection in days before or after the first immunization (D0). Figure 2 Figure 2 represents the anti-hNGF antibody titers50 (y-axis) measured from the sera of six SWISS mice immunized with the PPV-11-18 peptide (derived from SEQ ID NO: 2 of Example 2) conjugated. The x-axis corresponds to the time of sera collection in days before or after the first immunization (D0). Figure 3 Figure 3 represents theAnti-hNGF antibody titers50 (y-axis) measured from sera of five rabbits immunized against the conjugated peptide derived from SEQ ID NO: 1 of Example 3, as a function of serum collection time in days (x-axis). The red arrows represent the days of immunization (D0, D28 and D119). Figure 4 Figure 4 represents the percentages of inhibition of 8 ng / mL of hNGF to its receptor hTrkA, by the purified antibodies diluted 1 / 2, at D45, D80, D110, D136, D180 and D209, of five rabbits immunized against the conjugated peptide derived from SEQ ID NO 1 of Example 3. Figure 5 Figure 5 represents the titres50 of anti-hNGF antibodies (y-axis) measured from the sera of five rabbits immunized with the conjugated peptide derived from Seq ID NO 2 of Example 4, as a function of the time of collection of the sera in days (x-axis). The red arrows represent the days of immunization (D0, D28 and D119). Figure 6 Figure 6 represents the percentagesinhibition of 8 ng / mL of hNGF to its receptor hTrkA, by purified antibodies diluted 1 / 2, at D45, D80, D110, D136, D180 and D209, of five rabbits immunized with the conjugated peptide derived from SEQ ID NO: 2 of Example 4. Figure 7 Evaluation of the analgesic activity of peptides derived from β-hNGF in a model of osteoarthritis induced by monosodium iodoacetate, in rats. Figure 7 represents the weight balance between ipsilateral (MIA) and contralateral paws in percentage (y-axis), calculated as [(weight supported by the ipsilateral paw / sum of weight supported by the ipsilateral and contralateral paws) * 100], measured in rats at different times per day (x-axis), after intra-articular injection of MIA (1 mg / rat). G1: vehicle group, rats immunized subcutaneously with 0.1 mL of PBS emulsified in Montanide ^ ISA 51 VG adjuvant (n = 12, 6 males + 6 females). G2: test group, rats immunized subcutaneously with 0.1 mL of 25 µgof peptide equivalent of SEQ ID NO: 22 of Example 5, emulsified in Montanide ^ ISA 51 VG adjuvant (n = 12, 6 males + 6 females) G3: test group, rats immunized subcutaneously with 0.1 mL of 25 µg of peptide equivalent of SEQ ID NO: 23 of Example 5, emulsified in Montanide ^ ISA 51 VG adjuvant (n = 12, 6 males + 6 females). *p < 0.05, **p < 0.01, ***p < 0.001 compared to the control group (receiving only the PBS emulsion, G1). One-way ANOVA followed by a Tukey post hoc test. EXAMPLES The following examples show how all the peptides of the invention, derived from the NGF sequences of several different animals, induce the production of antibodies capable of neutralizing the activity of homologous or heterologous β-NGF proteins: Example 1: Recognition of the β subunit of the human NGF protein (β-hNGF) by sera from mice immunized with a peptide derived from β-hNGF A peptide comprising the sequence 122-136 of the β subunit of the proteinHuman NGF (PPV-11-13, see Table 2) was synthesized by solid-phase chemical synthesis according to standard methods well known to those skilled in the art, then cyclized by formation of a disulfide bridge between two cysteines of the peptide. It was then coupled to a carrier protein, KLH (Keyhole Limpet Hemocyanin), using the coupling agent glutaraldehyde. Specific pathogen-free SWISS mice (Janvier Labs, Le Genest-Saint-Isle, France) were immunized subcutaneously with 25 µg of PPV-11-13 peptide equivalent emulsified in Montanide ISA 51 VG adjuvant (n = 6). The mice received three subcutaneous injections (D0, D28 and D84). Table 2 Amino acid residues SEQ ID Peptide Construction of β-hNGF NO: PPV-11-13 122-136 [cycloS-S(Acetyl+CSSSHPIFHRGEFSVCEGE–K)]n–KLH 16 The amino acids underlined in bold correspond to amino acid residues 122-136 of the human NGF protein β-subunit sequence (Swissprot P01138)Peptide PPV-11-13 derived from the β subunit of the human NGF protein used for immunization The relative quantity of anti-β-hNGF antibodies is evaluated in mouse sera at D-4 (pre-immune), D56, D98 and D126 by ELISA. It is observed that all immunized mice produced antibodies recognizing the β-hNGF protein (Figure 1). The conjugated PPV-11-13 peptide makes it possible to induce an immune response against the β subunit of the human NGF protein in mice. Example 2: Recognition of the β subunit of the human NGF protein (β-hNGF) by sera from mice immunized with a peptide derived from β-hNGF A peptide comprising the sequence 148-158 of the β subunit of the human NGF protein (PPV-11-18, see Table 3) was synthesized by solid-phase chemical synthesis according to standard methods well known to the person skilled in the art, then cyclized by formation of a disulfide bridge between two cysteines of the peptide. It was then coupled to a proteincarrier, CRM 197, using the maleimide coupling agent. Specific pathogen-free SWISS mice (Janvier Labs, Le Genest-Saint-Isle, France) were immunized subcutaneously with 25 µg of PPV-11-18 peptide equivalent emulsified in Montanide ISA 51 VG adjuvant (n = 6). Mice received three subcutaneous injections (D0, D28, and D84). Table 3 SEQ ID Amino acid residues Peptide Constructi n ID of β-hNGF NO: PPV-11-18 148-158 [cycloS-S(CTATDIKGKEVMCEGE–Ahx-C)]n–CRM 197 17 The amino acids underlined in bold correspond to amino acid residues 148-158 of the sequence of the β subunit of the human NGF protein (Swissprot P01138) Peptide PPV-11-18 derived from the β subunit of the human NGF protein used for immunization The relative quantity of anti-β-hNGF antibodies is evaluated in the sera of mice at D-4 (pre-immune), D56, D98 and D126 by ELISA. It is observed that all the immunized mice produced antibodiesrecognizing the β-hNGF protein (Figure 2). The conjugated PPV-11-18 peptide can induce an immune response against the β subunit of the human NGF protein in mice Example 3: Production of antibodies neutralizing the β subunit of the human NGF protein (β-hNGF) in rabbits immunized with a peptide derived from β-hNGF. A peptide comprising the sequence 122-135 of the β subunit of the human NGF protein (derived from SEQ ID NO: 1, see Table 4) was synthesized by solid-phase chemical synthesis according to standard methods well known to those skilled in the art. It was then coupled to a carrier protein, CRM 197, using the coupling agent maleimide. New Zealand rabbits (Agro-Bio, La Ferté-SFranceubin, France) were immunized subcutaneously with 25 µg of peptide equivalent emulsified in Montanide ^ ISA 51 VG adjuvant (n = 5). Rabbits received three subcutaneous injections (D0, D28 and D119). Table 4 SEQ Peptide Acid ResidueConstruction ID derived from amino acids of β-hNGF NO SEQ ID NO: 1 122-135 [Acetyl-SSSHPIFHRGEFSVEGE-C]n– CRM197 15 The amino acids underlined in bold correspond to amino acid residues 122-135 of the sequence of the β subunit of the human NGF protein (Swissprot P01138). Peptide derived SEQ ID NO: 1 from the β subunit of the human NGF protein used for immunization. The relative quantity of anti-β-hNGF antibodies is evaluated in rabbit sera at D-10 (pre-immune), D45, D80, D110, D136, D180 and D209 by ELISA. It is observed that all immunized rabbits produced antibodies recognizing the β-hNGF protein, from D45 (Figure 3). Antibodies recognizing the β-hNGF protein are present at all sampling times in the sera of the five immunized rabbits. The peak in the level of antibodies recognizing the β-hNGF protein is observed at D180, after the 2 èmebooster (D119). The neutralizing capacity of the antibodies purified from the sera of each rabbit was evaluated in an ELISA-type test for inhibition of the binding of the β-hNGF protein to its hTrkA receptor. It was observed that the antibodies produced neutralized 80% or more of 8 ng / mL of the β-hNGF protein, from D45, in the five immunized rabbits (Figure 4). At D209, the antibodies produced neutralized 100% of 8 ng / mL of the β-hNGF protein, in the five immunized rabbits (Figure 4). The conjugated peptide allows the induction of neutralizing antibodies against the β subunit of the human NGF protein in rabbits. Example 4: Production of antibodies neutralizing the β subunit of the human NGF protein (β-hNGF) in rabbits immunized with a peptide derived from β-hNGF.A peptide comprising the sequence 148-158 of the β subunit of the human NGF protein (derived from SEQ ID NO: 2, see Table 3) was synthesized by solid-phase chemical synthesis according to standard methods well known to the person skilled in the art, then cyclized by formation of a disulfide bridge between two cysteines of the peptide. It was then coupled to a carrier protein, CRM 197, using the coupling agent maleimide. New Zealand rabbits (Agro-Bio, La Ferté-St Aubin, France) were immunized subcutaneously with 25 µg of peptide equivalent emulsified in Montanide ^ ISA 51 VG adjuvant (n = 5). The rabbits received three subcutaneous injections (D0, D28 and D119). The relative amount of anti-β-hNGF antibodies was evaluated in rabbit sera at D-9 (pre-immune), D46, D80, D110, D136, D180 and D209 by ELISA. It was observed that all immunized rabbits produced antibodies recognizing the β-hNGF protein, from D45 (Figure 5).Antibodies recognizing the β-hNGF protein were present at all sampling times in the sera of the five immunized rabbits. The peak level of antibodies recognizing the β-hNGF protein was observed at D180, after the 2nd. èmereminder (J119). The neutralizing capacity of the antibodies purified from the sera of each rabbit was evaluated in an ELISA-type test for inhibition of the binding of the β-hNGF protein to its hTrkA receptor. It was observed that the antibodies produced had a neutralizing capacity for the binding of the β-hNGF protein to its hTrkA receptor, for four of the 5 immunized rabbits (Figure 6). The conjugated peptide thus made it possible to induce neutralizing antibodies against the β subunit of the human NGF protein in rabbits. Example 5: Evaluation of the analgesic activity of peptides derived from β-hNGF in a model of osteoarthritis induced by monosodium iodoacetate in rats. Several experimental animal models of various species have been developed for human osteoarthritis and used to study the preclinical efficacy of candidate drugs modifying the disease and the symptoms of osteoarthritis.One such model is chemically induced by intra-articular injection of monosodium iodoacetate (MIA) into the rat knee. Intra-articular MIA disrupts chondrocyte glycolysis by inhibiting glyceraldehyde-3-phosphate dehydrogenase. This results in chondrocyte death and damage throughout the joint space, and causes symptoms of osteoarthritis, including joint pain similar to that observed in human patients. Eight- to ten-week-old Sprague Dawley rats (Cellvax, Institut Gustave Roussy, Hôpital Paul Brousse, Villejuif, France) were randomly divided into three groups of 12 rats (6 females and 6 males per group), designated G1, G2, and G3. G1 rats (vehicle group) were immunized subcutaneously with 0.1 mL of PBS emulsified in Montanide ^ ISA 51 VG adjuvant (n = 12).G2 rats were immunized subcutaneously with 0.1 mL of 25 µg of peptide equivalent SEQ ID NO: 23 (see Table 5) emulsified in Montanide ^ ISA 51 VG adjuvant (n = 12). G3 rats were immunized subcutaneously with 0.1 mL of 25 µg of peptide equivalent SEQ ID NO: 22 (see Table 5) emulsified in Montanide ^ ISA 51 VG adjuvant (n = 12). These peptides are derived from rat β-NGF sequences at the two targeted peptide regions. Rats received three subcutaneous injections (D0, D28 and D126). The injection of 1 mg of MIA was performed in the right knee 13 days after the third injection (D139).

[0002] Table 5 SEQ Peptide Amino acid residues Constructi n ID derived from β-hNGF NO SEQ ID 148-157 [cycloS-S(CTATDIKGKEVMCEGE–Ahx-C)]n–CRM 197 3 NO: 23 SEQ ID 122-135 [Acetyl-SSTHPVFHMGEFSVEGE-C]n–CRM197 31 NO: 22 Amino acids underlined in bold correspond to amino acid residues 148-157 or 122-135 of the rat NGF protein β-subunit sequence Assessment of weight balance between ipsilateral (MIA) and contralateral paw. The weight balance of each paw (left and right) of MIA-treated rats was analyzed using an incapacitometer. After acclimating the rats for 5 minutes in the incapacitometer, both feet of the rat were fixed on the pad and the weight balance was measured for 5 seconds. Three measurements were repeated in the same manner.Changes in body weight distribution between the two hind limbs were calculated as [(weight supported by the ipsilateral paw (MIA) / sum of weights supported by the ipsilateral and contralateral paws)*100]. The values ​​in % were measured post MIA at D14, D20, D27, D34 and D42. It is observed that the weight balance between the ipsilateral paw (MIA) and the contralateral paw is significantly improved at D20, D34 and D42 for the groups immunized with the 2 peptides (Figure 7) which confirms an analgesic activity linked to the anti-NGF responses developed for each of the groups immunized against the 2 peptides tested derived from SEQ ID NO: 22 and SEQ ID NO: 23 (first and second rat NGF sequences). Example 6: Production in dogs of antibodies neutralizing the β subunit of the NGF protein (β-hNGF) by immunization against a peptide derived from canine β-NGF.A peptide comprising the sequence 122-135 of the β subunit of the canine NGF protein (SEQ ID NO: 28, see Table 6) was synthesized by solid-phase chemical synthesis according to standard methods well known to those skilled in the art. It was then coupled to a carrier protein, CRM 197, using the coupling agent maleimide. Two dogs were immunized subcutaneously with 25 µg of peptide equivalent emulsified in Montanide ^ ISA 51 adjuvant. The dogs received two subcutaneous injections on Day 0 and Day 28. Table 6 SEQ Peptide Amino Acid Residue Construct ID Derived from β-cNGF NO SEQ ID NO: 122-135 [Acetyl-SSSHPVFHRGEFSVEGE-C]n– CRM197 32 28 The amino acids underlined in bold correspond to amino acid residues 122-135 of the canine NGF protein β-subunit sequence. Peptide derived from the canine NGF protein β-subunit SEQ ID NO: 25 used for immunization.By comparing the samples taken at D-2 and D42, it was observed that the two dogs produced antibodies recognizing the human β-hNGF protein as well as the canine peptide by ELISA at D42 (data not shown). The neutralizing capacity of the antibodies was measured from the dogs' sera. This evaluation was carried out in an ELISA-type test, of inhibition of the binding of the human β-hNGF protein (added at 8 ng / mL) to its hTrkA receptor fixed at the bottom of the well. It is possible to use the human NGF protein in this inhibition test because the sequence of the targeted peptide (SEQ ID NO: 28) has a single amino acid difference between human NGF and canine NGF. The inhibition percentages were calculated by taking as a reference of 100% neutralization an antibody serving as a positive control, known for its neutralizing effect. In the experiment, it was observed that the sera of the immunized dogs (taken on day 42) neutralized at approximately 50%.the β-hNGF protein, whereas the sera of the same dogs before immunization (D-2) have no neutralizing activity (Table 7). In addition to showing that the dog immunized with the canine NGF peptide can produce neutralizing antibodies, this result is interesting because it confirms that a variant sequence can indeed induce antibodies neutralizing the cytokine of another species (here the dog peptide induces antibodies neutralizing human NGF). Table 7 Neutralization rate of hNGF binding to its hTrkA receptor (%) by dog ​​sera D-2 D42 Dog 1 -0.5% 46.7% Dog 2 6.5% 56.5%.

Claims

CLAIMS 1. Polypeptide comprising, or consisting of: - a first sequence consisting of at least 8 contiguous amino acids chosen from the sequence extending from amino acids 122 to 136 of the β subunit of the NGF protein and at most 30 contiguous amino acids chosen from the complete sequence of the β subunit of the NGF protein, or a variant sequence having at least 75% identity with the first sequence; and / or - a second sequence consisting of at least 8 contiguous amino acids chosen from the sequence extending from amino acids 148 to 158 of the β subunit of the NGF protein and at most 30 contiguous amino acids chosen from the complete sequence of the β subunit of the NGF protein,or a variant sequence having at least 75% identity with the second sequence; provided that the polypeptide is different from the β subunit of the NGF protein and that it does not consist of a portion of more than 30 contiguous amino acids of the β subunit of the NGF protein, and provided that polypeptides respectively consisting of the variant sequences of the first and second sequences make it possible to elicit an immune response directed against the NGF protein.

2. Polypeptide according to claim 1, in which the first sequence and the second sequence consist of at least 12 contiguous amino acids respectively chosen from within the sequence extending from amino acids 122 to 136, 148 to 158 of the β subunit of the NGF protein.

3. Polypeptide according to claim 1 or 2, in which the first sequence and the second sequence are respectively made up of at most amino acids 122 to 136,148 to 158 of the β subunit of the NGF protein.

4. Polypeptide according to one of claims 1 to 3, in which the β subunit of the NGF protein is selected from the group consisting of the β subunit of the human NGF protein (hNGF), the β subunit of the mouse NGF protein, the, β-subunit of rat NGF protein, β-subunit of rabbit NGF protein, β-subunit of monkey NGF protein, β-subunit of dog NGF protein, β-subunit of cat NGF protein, β-subunit of horse NGF protein, β-subunit of pig NGF protein, β-subunit of sheep NGF protein and β-subunit of dromedary NGF protein.

5. Polypeptide according to one of claims 1 to 4, in which the β-subunit of the NGF protein is the β-subunit of human NGF protein (hNGF) or dog NGF protein.

6. Polypeptide according to one of claims 1 to 5, in which the first sequence and the second sequence are respectively constituted: - of the sequence SSSHPIFHRGEFSVC (SEQ ID NO: 1) and of the sequence TATDIKGKEVM (SEQ ID NO: 2), or - of the sequence SSSHPVFHRGEFSVC (SEQ ID NO: 28) and of the sequence TATDIKGKEVM (SEQ ID NO: 27). 7.Polypeptide according to one of claims 1 to 6, in which the polypeptide is in cyclized form.

8. Polypeptide according to one of claims 1 to 7, in which the polypeptide is linked to a carrier molecule.

9. Nucleic acid coding for a polypeptide as defined in one of claims 1 to 8, or the complement thereof.

10. Pharmaceutical composition comprising, as active substance: - at least one polypeptide as defined in one of claims 1 to 8, or - at least one nucleic acid as defined in claim 9, optionally in association with at least one pharmaceutically acceptable vehicle.

11. Use of a polypeptide as defined in one of claims 1 to 8, for the preparation of an antibody, an antibody fragment or an aptamer.

12. Anti-NGF antibody, antibody fragment, or aptamer specifically directed against the polypeptide as defined in one of claims 1 to 8, provided that the polypeptide does not comprise more than two amino acid residues in addition to the first, or the second or their respective variant sequences.

13. Antibody, antibody fragment, or aptamer according to claim 12, for use as a medicament.

14. Polypeptide as defined in one of claims 1 to 8, nucleic acid as defined in claim 9, or pharmaceutical composition as defined in claim 10, for use in a method for eliciting an immune response directed against the NGF protein in an individual. 15.A polypeptide as defined in any one of claims 1 to 8, a nucleic acid as defined in claim 9, a pharmaceutical composition as defined in claim 10, or an antibody, antibody fragment or aptamer as defined in claim 13, for use in a method of preventing or treating a disease related to or due to the NGF protein in an individual. 16.A polypeptide, nucleic acid, pharmaceutical composition, or antibody, antibody fragment, or aptamer for use according to claim 15, wherein the disease related to or due to the NGF protein is selected from the group consisting of: - allergic diseases, asthma, disorders associated with hyperresponsiveness of the airways, typically characterized by episodes of coughing and / or breathing problems; - multiple sclerosis, colitis, chronic inflammatory bowel disease, bladder cystitis, eczema, contact dermatitis, arthritis, including chronic arthritis and rheumatoid arthritis, and psoriasis;. - osteoarthritis, lupus erythematosus, chronic obstructive pulmonary disease (COPD), lung cancer, hyperalgesia, chronic pain, and general or localized recurrent pain.

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