Composition

Abstract

Compositions comprising myelin basic protein peptides for use in the treatment or prevention of uveitis are provided. The present invention provides a composition comprising a myelin basic protein peptide (MBP) selected from the following peptides for use in treating or preventing uveitis in a subject: MBP 30-44, MBP 83-99, MBP 131-145, and MBP 140-154.

Description

Technical Field

[0001] The present invention relates to a composition comprising a peptide derived from myelin basic protein (MBP) or several kinds of peptides. The composition or peptide may be useful for the prevention and / or suppression of autoimmunity, for example, the prevention and / or suppression of effector T helper cells, and it is useful for the treatment and / or prevention of uveitis. The present invention also relates to the corresponding treatment method and the use of the peptide in the manufacture of a medicament for the treatment and / or prevention of uveitis.

Background Art

[0002] Uveitis represents a group of diseases accompanied by inflammation of the uvea. The uvea is the area of the eye located between the sclera and the retina and includes the iris, ciliary body and choroid. The uvea provides most of the blood supply to the retina. Related diseases are not limited to those directly affecting the uvea, and adjacent structures such as the retina, optic nerve, lens, vitreous body and sclera can be affected by the onset of uveitis.

[0003] All forms of uveitis are generally characterized by inflammatory cell infiltration visualized using a microscope. In 2010, it was estimated that 285 million people had visual impairment, of which 39 million were blind, and it was estimated that 10% of the causes were due to uveitis (Global data on visual impairments, The World Health Report, WHO (2010) http: / / www.who.int / blindness / GLOBALDATAFINALforweb.pdf).

[0004] Current treatments for uveitis include the use of glucocorticoid steroids and other broad-spectrum immunosuppressive agents such as methotrexate.

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, in this technical field, there is a need for alternative treatments for uveitis. The present invention addresses this need.

Means for Solving the Problem

[0006] The inventors have identified a number of peptides derived from myelin basic protein (MBP) that may be useful in the prevention and / or treatment of uveitis.

[0007] The examples of the present application demonstrate that in an in vivo model of uveitis, the MBP peptides according to the present invention can significantly reduce the clinical signs of uveitis.

[0008] That is, the present invention provides a composition comprising a myelin basic protein peptide selected from the following peptides for use in the treatment and / or prevention of uveitis in a subject: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4).

[0009] In one aspect, a composition for use in the treatment or prevention of uveitis in a subject may comprise MBP 30-44 (SEQ ID NO: 1), 83-99 (SEQ ID NO: 2), 131-145 (SEQ ID NO: 3) and 140-154 (SEQ ID NO: 4), i.e., the composition may comprise a "cocktail" of four peptides.

[0010] A composition for use in the treatment or prevention of uveitis in a subject can consist essentially of MBP 30-44 (SEQ ID NO: 1), 83-99 (SEQ ID NO: 2), 131-145 (SEQ ID NO: 3) and 140-154 (SEQ ID NO: 4).

[0011] The present invention also provides a method for treating or preventing uveitis in a subject, the method comprising the step of administering to the subject a composition as described herein.

[0012] The peptide has been found to bind to several MHC class II molecules including HLA-DR and HLA-DQ molecules, and the combination of their epitopes covers a wide range of various major histocompatibility complex (MHC) haplotypes found in uveitis patients, more so than therapy using a single peptide.

[0013] The treatment or prevention method according to the present invention can include, for example, administration of the composition to an HLA-DQ6 or HLA-DR2 positive subject or any other HLA type, such as a subject expressing DRB1, DRB3, DRB5, DQA1 or DQB1.

[0014] The present invention encompasses the use of a composition as described herein in the manufacture of a medicament for treating or preventing uveitis in a subject.

[0015] The present invention also encompasses the use of a composition as described herein in the treatment or prevention of uveitis in a subject.

[0016] The present invention also provides a kit comprising a myelin basic protein peptide selected from the following peptides for use in the treatment or prevention of uveitis in a subject: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4). In one aspect, the composition is MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4) and at this time, the MBP peptide can be for co-administration, separate administration, or sequential administration.

Brief Description of the Drawings

[0017]

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Fig. 7A

Fig. 7B

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Fig. 9

Mode for Carrying Out the Invention

[0018] Myelin basic protein Myelin basic protein (MBP) is a protein isolable from human brain white matter. The mature protein has 170 amino acids and its sequence is widely available in the literature (e.g., see Chou et al (1986) J. Neurochem. 46:47-53, FIG. 1; Kamholz et al (1986), PNAS 83:4962-4966, FIG. 2; U.S. Patent No. 5,817,629, SEQ ID NO: 1; Roth et al (1987), J. Neurosci. Res. 17:321-328, FIG. 4; Medeveczky et al (2006), FEBS Letters 580:545-552, FIG. 3). Alternative splicing variants / isoforms of MBP may be generated due to alternative splicing of MBP (e.g., see Kamholz, supra).

[0019] The compositions according to the present invention comprise an MBP peptide selected from the following peptides: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4).

[0020] The compositions may comprise MBP 30-44 (SEQ ID NO: 1), 83-99 (SEQ ID NO: 2), 131-145 (SEQ ID NO: 3) and 140-154 (SEQ ID NO: 4).

[0021] The compositions can consist essentially of MBP 30-44 (SEQ ID NO: 1), 83-99 (SEQ ID NO: 2), 131-145 (SEQ ID NO: 3) and 140-154 (SEQ ID NO: 4).

[0022] The peptides present in the composition can consist of MBP 30-44 (SEQ ID NO: 1), 83-99 (SEQ ID NO: 2), 131-145 (SEQ ID NO: 3) and 140-154 (SEQ ID NO: 4). That is, no other MBP peptides are present. The MBP peptides can thus consist of SEQ ID NOs: 1-4.

[0023] "Consisting of" means including and being limited to whatever follows the phrase "consisting of". That is, "consisting of" indicates that the recited elements are necessary or obligatory and that no other elements can be present. "Essentially consisting of" means including any of the elements recited in this phrase and being limited to other elements that do not interfere with or contribute to the activity or action specified in the present disclosure with respect to the recited elements. That is, the phrase "essentially consisting of" indicates that the recited elements are necessary or obligatory, but that other elements are optional and may or may not be present depending on whether they affect the activity or action of the recited elements.

[0024] Peptide The peptides that can be used in the compositions and kits for use according to the present invention are as follows: MBP 30-44 (SEQ ID NO: 1): H-Pro-Arg-His-Arg-Asp-Thr-Gly-Ile-Leu-Asp-Ser-Ile-Gly-Arg-Phe-NH2 MBP 83-99 (SEQ ID NO: 2): H-Glu-Asn-Pro-Val-Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro-NH2 MBP 131-145 (SEQ ID NO: 3): H-Ala-Ser-Asp-Tyr-Lys-Ser-Ala-His-Lys-Gly-Phe-Lys-Gly-Val-Asp-NH2 MBP 140-154 (SEQ ID NO: 4): H-Gly-Phe-Lys-Gly-Val-Asp-Ala-Gln-Gly-Thr-Leu-Ser-Lys-Ile-Phe-NH2

[0025] The term "peptide" is used in its ordinary sense and typically means a series of residues, typically L-amino acids, connected from one to the other by peptide bonds between the α-amino and carboxyl groups of adjacent amino acids. This term includes modified peptides and synthetic peptide analogs.

[0026] The peptides of the present invention can be produced using chemical methods (Peptide Chemistry, A practical Textbook. Mikos Bodansky, Springer-Verlag, Berlin). For example, peptides can be synthesized by solid-phase techniques (Roberge JY et al (1995) Science 269: 202-204), cleaved from the resin, and purified by preparative high-performance liquid chromatography (e.g., Creighton (1983) Proteins Structures And Molecular Principles, WH Freeman and Co, New York NY). Automated synthesis can be achieved, for example, using an ABI 431A peptide synthesizer (Perkin Elmer) according to the instructions provided by the manufacturer.

[0027] Peptides can alternatively be made by recombinant means or by cleavage from longer polypeptides. For example, peptides can be obtained by cleavage from myelin basic protein, followed by modification of one or both termini. The composition of the peptide can be confirmed by amino acid analysis or sequencing (e.g., Edman degradation).

[0028] For practical purposes, there are various other properties that a peptide can exhibit. For example, it is important for the peptide to be sufficiently stable in vivo to be therapeutically useful. The half-life of the peptide in vivo can be at least 10 minutes, 30 minutes, 4 hours, or 24 hours.

[0029] The peptide can also exhibit good bioavailability in vivo. The peptide can maintain in vivo a conformation that allows it to bind to MHC molecules at the cell surface without significant interference.

[0030] In one aspect, the composition can comprise an MBP peptide having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% sequence identity to any one of SEQ ID NOs: 1-4. In a preferred aspect, the peptide has at least 80%, 90%, 95%, 97% or 99% sequence identity to any one of SEQ ID NOs: 1-4.

[0031] Sequence identity can be evaluated by any conventional method. However, to determine the degree of sequence identity between sequences, computer programs that perform multiple alignments of sequences, such as Clustal W (Thompson et al., (1994) Nucleic Acids Res., 22: 4673-4680), are useful. Programs for comparing and aligning pairs of sequences, such as ALIGN (Myers et al., (1988) CABIOS, 4: 1-17), FASTA (Pearson et al., (1988) PNAS, 85:2444-2448; Pearson (1990), Methods Enzymol., 183: 63-98), and gapped BLAST (Altschul et al., (1997) Nucleic Acids Res., 25: 3389-3402), are also useful for this purpose. In addition, the Dali server at the European Bioinformatics institute provides alignments based on the structures of protein sequences (Holm (1993) J. Mol. Biol., 233: 123-38; Holm (1995) Trends Biochem. Sci., 20: 478-480; Holm (1998) Nucleic Acid Res., 26: 316-9).

[0032] Multiple sequence alignments and percent identities can be determined using standard BLAST parameters (using sequences from all available organisms, matrix Blosum 62, gap cost: existence 11, extension 1).

[0033] Alternatively, the following programs and parameters can be used: Program: Align Plus 4, version 4.10 (Sci Ed Central Clone Manager Professional Suite). DNA comparison: Global comparison, Standard Linear Scoring matrix, Mismatch penalty = 2, Open gap penalty = 4, Extension gap penalty = 1. Amino acid comparison: Global comparison, BLOSUM 62 Scoring matrix.

[0034] That is, variants that retain the functional activity of the parent, i.e., as long as the variants are functionally equivalent, in other words, as long as the variants have or retain the activity of the parent peptide as defined herein, variants of the recited or provided sequences are included within the scope of the present invention. Such variants may include, for example, amino acid substitutions, additions or deletions (including cleavage at one or both ends) of the parent sequence at one or more positions, for example, 1 to 14 amino acids.

[0035] The substitutions can be conservative substitutions. As used herein, "conservative substitution" means changing the identity of an amino acid in order to substitute an amino acid of generally equivalent size, charge and / or polarity at a given position. Examples of natural conservative substitutions of amino acids include the following 8 groups of substitutions (represented by the conventional single-letter notation): (1) M, I, L, V; (2) F, Y, W; (3) K, R; (4) A, G; (5) S, T; (6) Q, N; (7) E, D; and (8) C, S.

[0036] Functionally equivalent derivatives in which one or more amino acids are chemically derivatized (e.g., substituted with a chemical group) are also included.

[0037] The peptides for use according to the present invention can comprise a portion or fragment of SEQ ID NOs: 1-4, provided that the peptides retain the necessary activity. The portion or fragment of SEQ ID NOs: 1-4 can be, for example, 6 to 16 residues in length, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 residues in length.

[0038] The peptides for use according to the present invention can also be included within longer peptides, i.e., peptides comprising any one of SEQ ID NOs: 1-4. The peptides for use according to the present invention can thus comprise 8 to 30 amino acids, for example, 8 to 25 amino acids, 8 to 20 amino acids, 8 to 15 amino acids or 8 to 12 amino acids. In one embodiment, the peptides of the present invention can be, i.e., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids in length.

[0039] The peptide compositions for use according to the present invention can comprise the amino acid sequences according to the present invention as described herein. In one embodiment, the peptide composition comprises only the amino acid sequences according to the present invention as described herein, i.e., it does not contain additional peptides other than those according to the present invention.

[0040] The peptides can be formulated in the composition in a neutralized form or in a salt form. Pharmaceutically acceptable salts include acid addition salts (formed using the free amino groups of the peptides), for example, those formed using inorganic acids such as hydrochloric acid or phosphate, or organic acids such as acetic acid, tartaric acid or malic acid. Salts formed using free carboxyl groups can also be derived from, for example, inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine and procaine.

[0041] Apitope In the adaptive immune response, T lymphocytes can recognize internal epitopes of protein antigens. APCs take up protein antigens and degrade them into short peptide fragments. The peptides can bind to major histocompatibility complex (MHC class II) inside the cell and be transported to the cell surface. When presented on the cell surface together with MHC molecules, the peptides can be recognized by T cells (via the T cell receptor (TCR)), and in that case, the peptides are T cell epitopes.

[0042] Thus, an epitope is a peptide derivable from an antigen that can bind to the peptide-binding groove of an MHC molecule and be recognized by a T cell.

[0043] The minimal epitope is the shortest fragment derivable from an epitope that can bind to the peptide-binding groove of an MHC class I or II molecule and be recognized by a T cell. For a given immunogenic region, it is typically possible to generate an "nested" set of overlapping peptides that act as epitopes, all of which contain the minimal epitope but differ in their flanking regions.

[0044] Similarly, it is possible to identify the minimal epitope for a particular MHC molecule:T cell combination by measuring the response to truncated peptides. For example, if the response is obtained to a peptide containing residues 1 - 15 in an overlapping library, the minimal epitope can be identified using sets truncated at both ends (i.e., 1 - 14, 1 - 13, 1 - 12, etc. and 2 - 15, 3 - 15, 4 - 15, etc.).

[0045] The inventors have previously identified a correlation between the ability of a peptide to bind to MHC molecules and be presented to T cells without further processing, and its ability to induce antigen-specific immune tolerance in vivo (WO02 / 16410). If a peptide is too long to bind to the peptide-binding groove of MHC molecules without further processing (e.g., trimming), or binds in an inappropriate conformation, it is not tolerogenic in vivo. On the other hand, if a peptide binds directly to the MHC peptide-binding groove and is of an appropriate size and conformation to be presented to T cells, this peptide can be predicted to be useful for tolerance induction.

[0046] Therefore, it is possible to examine the tolerogenic ability of a peptide by investigating whether it can bind to MHC molecules and be presented to T cells in vitro without further antigen processing.

[0047] The MBP epitope (antigen processing-independent epitope) can bind to MHC molecules and stimulate a response from MBP-specific T cells without further antigen processing. Such an epitope can be predicted to cause tolerance to MBP according to the rule-based method described in WO02 / 16410.

[0048] Peptides that bind to MHC class I molecules are typically 7 - 13, more usually 8 - 10 amino acids in length. Peptide binding is stabilized at its two ends by contacts between the peptide backbone and atoms in invariant sites in the peptide-binding grooves of all MHC class I molecules. There are invariant sites at both ends of the groove that bind to the amino and carboxy termini of the peptide. Variations in peptide length are accommodated by kinks, often at proline or glycine residues that confer flexibility in the peptide backbone.

[0049] Peptides that bind to MHC class II molecules are typically 8 - 20 amino acids in length, more usually 10 - 17 amino acids in length, and can be longer (e.g., up to 40 amino acids). These peptides adopt an extended conformation along the MHC II peptide-binding groove, which is open at both ends (unlike the MHC class I peptide-binding groove). The peptide is held in place mainly by backbone atom contacts with conserved residues lining the peptide-binding groove.

[0050] In a preferred embodiment, peptides derived from MBP are capable of binding to MHC class II molecules without further processing.

[0051] A portion The peptides of the present invention may comprise all or a portion of the MBP-derived peptides shown as SEQ ID NOs: 1 - 4.

[0052] The term "a portion" refers to a peptide derived from SEQ ID NOs: 1 - 4 and containing at least a minimal epitope, i.e., the peptide is capable of binding to the peptide-binding groove of MHC class I or II molecules and being recognized by T cells to induce tolerance.

[0053] Uveitis Clinically, uveitis is generally classified as one of the following, mainly based on the part of the eye affected: anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis.

[0054] Anterior uveitis includes iridocyclitis and iritis. Iritis is an inflammation of the anterior chamber and iris, and iridocyclitis includes inflammation within the ciliary body.

[0055] Intermediate uveitis (pars planitis) generally refers to vitritis, which is an inflammation of the cells in the vitreous cavity and is accompanied by the deposition of inflammatory substances on the pars plana of the ciliary body. Inflammatory vitreous, or bleeding or protein deposition caused by inflammation, is characteristic of intermediate uveitis. In these experiments, the symptoms of intermediate uveitis are incorporated into the scoring using TEFI images. As shown in Example 3, a score of 4 (×2), which can total up to 8 at most, is caused by whiteout. In Figure 4, the TEFI image regarding the highest score reflects intermediate uveitis. In one aspect of the present invention, the uveitis is intermediate uveitis.

[0056] Posterior uveitis (choroiditis) is an inflammation of the retina and choroid regions.

[0057] Panuveitis is a general term meaning an inflammation that invades all layers of the uvea.

[0058] In one aspect, the uveitis is idiopathic uveitis.

[0059] In a preferred embodiment of the present invention, the uveitis is posterior uveitis. In another aspect of the present invention, the uveitis is anterior uveitis. In another aspect of the present invention, the uveitis is intermediate uveitis.

[0060] Uveitis can also be classified as either infectious or non - infectious, and also as uveitis associated with autoimmune diseases (i.e., mainly non - infectious), which is more common in developed countries. Common animal models used to study uveitis are also driven by autoimmunity and show a clear correlation between the two. It is predicted that 25 - 30% of uveitis is associated with systemic autoimmune or autoinflammatory diseases.

[0061] The uveitis according to the present invention described herein is preferably non - infectious uveitis, and even more preferably autoimmune uveitis.

[0062] Tolerance T cell epitopes play a central role in the adaptive immune response to any antigen, whether self or foreign. The central role played by T cell epitopes in hypersensitivity diseases (including allergies, autoimmune diseases and transplant rejection) has been demonstrated by the use of experimental models. Injection of self-antigens or synthetic peptides (based on the structure of T cell epitopes) in combination with adjuvants can induce inflammatory or allergic diseases.

[0063] In contrast, it has been shown that administration of peptide epitopes in soluble form can induce immunogenic tolerance to specific antigens. Administration of soluble peptide antigens has been demonstrated as an effective means of inhibiting disease in experimental autoimmune encephalomyelitis (EAE - a model for multiple sclerosis (MS)) (Metzler and Wraith (1993) Int. Immunol. 5:1159 - 1165; Liu and Wraith (1995) Int. Immunol. 7:1255 - 1263; Anderton and Wraith (1998) Eur. J. Immunol. 28:1251 - 1261) and experimental models of arthritis, diabetes, and uveoretinitis (reviewed in Anderton and Wraith (1998) supra). This has also been demonstrated as a means of treating ongoing disease in EAE (Anderton and Wraith (1998) supra).

[0064] Tolerance is the failure to respond to an antigen. Tolerance to self-antigens is an important feature of the immune system, and loss of this can lead to autoimmune disease. The adaptive immune system must maintain the ability to respond to a vast variety of infectious agents while avoiding autoimmune attack on self-antigens contained within its own tissues. This is controlled to a large extent by the sensitivity of immature T lymphocytes to apoptotic cell death in the thymus (central tolerance). However, not all self-antigens are detected in the thymus, and thus death of autoreactive thymocytes remains incomplete. Therefore, there are also mechanisms by which tolerance can be acquired by mature autoreactive T lymphocytes in peripheral tissues (peripheral tolerance). An overview of the mechanisms of central and peripheral tolerance is given by Anderton et al (1999) (Immunological Reviews 169: 123-137).

[0065] Available data suggest that uveitis can arise from reactive T cells that are generated by retinal proteins, drive inflammation, and mimic the effects of chronic infection. The compositions according to the invention are capable of inducing tolerance to self-antigens such as MBP, and thereby, when administered to a subject, can restore tolerance to the MBP protein and reduce the pathogenic immune response.

[0066] Composition A composition comprising one or more peptides according to the invention may be for prophylactic or therapeutic use in a patient having uveitis.

[0067] When administered for prophylactic use, the composition may reduce or prevent the development of an immune response to MBP. The level of the immune response is less than would be obtained if the patient had not been treated with the composition. The term "reduce" indicates that a partial reduction in the immune response is observed, e.g., a 50%, 70%, 80% or 90% reduction in the response observed if the patient had not been treated with the composition (or in the response observed in untreated patients over the same period). The term "prevent" indicates that no perceivable immune response to MBP is observed.

[0068] When administered for therapeutic use, the composition may suppress an already ongoing immune response to MBP. The term "suppress" indicates a reduction in the level of the ongoing immune response compared to the level before peptide treatment or the level that would have been observed at the same time if no treatment had been given.

[0069] Treatment with the composition according to the invention may cause a reduction at any or all of the following levels: (i) MBP autoantibodies (ii) Inflammatory CD4+ T cells specific for MBP (iii) B cells that secrete MBP autoantibodies.

[0070] Detection of all of these elements can be carried out by techniques known in the art such as ELISA, flow cytometry, etc.

[0071] Treatment with the compositions of the invention can further, or alternatively, induce anergy in CD4+ T cells specific for MBP. Anergy can be detected, for example, by subsequent in vitro administration of MBP. Treatment with the compositions of the invention can result in the generation of antigen-specific regulatory T cells, characterized, for example, by the transcription factors c-Maf and NFIL3, and the negative costimulatory molecules LAG-3, TIGIT, PD-1 and TIM-3 (see Burton et al. Nature Communications (2014) Article number 4741).

[0072] Formulation Compositions according to the invention as described herein can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, a liquid prior to injection can also be prepared. The preparations can also be emulsified or the peptides can be encapsulated in liposomes. The peptides can alternatively be encapsulated in a carrier (e.g., nanoparticles) or can be bound to the surface of a carrier. The active ingredient can be mixed with pharmaceutically acceptable and compatible additives. Suitable additives are, for example, water, saline (e.g., phosphate buffered saline), dextrose, glycerol, ethanol, and the like, and combinations thereof.

[0073] In addition, if desired, the compositions can contain minor amounts of auxiliary substances such as wetting or emulsifying agents and / or pH buffering agents. Buffering salts include, for example, phosphates, citrates, acetates. Hydrochloric acid and / or sodium hydroxide can be used for pH adjustment. Disaccharides such as sucrose or trehalose can be used for stabilization.

[0074] After formulation, the compositions can be incorporated into sterile containers and then sealed and stored at a low temperature, for example 4°C, or they can be lyophilized.

[0075] Conveniently, the composition is prepared as a freeze-dried powder. Freeze-drying enables long-term storage in a stabilized form. Freeze-drying procedures are well known in the art; see, for example, http: / / www.devicelink.com / ivdt / archive / 97 / 01 / 006.html. Bulking agents such as mannitol, dextran or glycine are generally used prior to freeze-drying.

[0076] The composition can be administered in a convenient manner, such as by oral, intravenous (if water-soluble), intramuscular, subcutaneous, sublingual, intranasal, intradermal or suppository routes, or by implantation (e.g., using a sustained-release molecule or device).

[0077] The composition can advantageously be administered via the intranasal, subcutaneous or intradermal routes. In a preferred embodiment, the administration is by intradermal administration.

[0078] The methods and pharmaceutical compositions for use according to the present invention can be used to treat human subjects. Typically, a physician will determine the actual dosage most suitable for an individual subject, which will vary depending on the age, weight and response of the particular patient.

[0079] The compositions as described herein are typically administered in an "effective amount"; that is, an amount effective, inter alia, to produce one or more of a therapeutic or prophylactic effect. One of ordinary skill in the art could determine, by conventional experimental techniques, the effective non-toxic amount to be included in a pharmaceutical composition or to be administered for a desired outcome. Generally, the compositions disclosed herein can be administered in a manner that is compatible with the route of administration and the physical characteristics of the recipient (including state of health), and in a manner that produces the desired effect (i.e., therapeutically effective and / or prophylactic). For example, the appropriate dosage of a composition can depend on a variety of factors including, but not limited to, the physical characteristics of the subject (e.g., age, weight, sex), and other factors that can be recognized by one of ordinary skill in the art. Other exemplary examples of general considerations that can be taken into account in determining the appropriate dosage of a composition are discussed by Gennaro (2000, "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams, & Wilkins; and Gilman et al., (Eds), (1990), "Goodman And Gilman's: The Pharmacological Bases of Therapeutics", Pergamon Press).

[0080] It is expected that said amount will fall within a relatively broad range that can be determined through methods known to those of ordinary skill in the art, taking into account some of the considerations outlined above.

[0081] The peptides and compositions of the present invention can be used to treat human subjects. Subjects according to the present invention preferably have posterior uveitis. The subject can have T cells specific for MBP.

[0082] In a preferred embodiment, it may be according to a "dose escalation" protocol in which multiple doses are administered to the patient at increasing concentrations. Such an approach has been used, for example, for phospholipase A2 peptides in immunotherapy applications for bee venom allergy (Muller et al (1998) J. Allergy Clin Immunol. 101:747-754 and Akdis et al (1998) J. Clin. Invest. 102:98-106).

[0083] Kit Peptides derived from MBP can be administered together in the form of a mixed composition or cocktail. However, there may be situations where it is preferred to provide the peptides separately in the form of a kit for simultaneous, separate, sequential or combined administration.

[0084] For example, the kit can contain three types of peptides in separate containers. The contents of the containers can be combined before administration or not.

[0085] The kit can also include means for mixing and / or administration (e.g., a vapouriser for intranasal administration, or a syringe and needle or other medical device for subcutaneous / intradermal administration). The kit can also include instructions for use.

[0086] The compositions / kits of the present invention can be used to suppress or prevent the production of MBP autoantibodies in vivo. In particular, the compositions / kits can be used to treat and / or prevent uveitis in a subject.

[0087] Animal model The present invention also encompasses an animal model of uveitis. As described in the examples, the animal model according to the present invention provides the advantage of inducing uveitis without inducing encephalomyelitis (EAE).

[0088] That is, in a further aspect, the present invention provides an animal model of uveitis, which animals contain elevated levels of myelin basic protein (MBP) and interphotoreceptor retinoid-binding protein (IRBP) compared to control animals.

[0089] The term "elevated levels of MBP and IRBP" is intended to encompass elevated levels of either the full-length MBP or IRBP sequences (e.g., MBP or IRBP peptides).

[0090] In one aspect, MBP is from or derived from human or guinea pig (gpMBP). The sequences of human and guinea pig MBP are described below: TIFF0007679346000001.tif35158

[0091] Other isoforms of MBP are also known, e.g., UniProtKB, P02686-3, P02686-4, P02686-5 and P02686-6. TIFF0007679346000002.tif25157

[0092] In one aspect of the invention, IRBP is human IRBP or is derived from human IRBP. The sequence of human IRBP is described below (UniProtKB entry P10745): TIFF0007679346000003.tif92155

[0093] In one aspect, IRBP is bovine IRBP (SEQ ID NO: 8) (UniProtKB entry P12661): TIFF0007679346000004.tif89121TIFF0007679346000005.tif125121

[0094] In one aspect, IRBP is a peptide derived from IRBP, preferably IRBP 1177-1191 ADGSSWEGVGVVPDV (SEQ ID NO: 9).

[0095] The levels of MBP and IRBP are elevated relative to a suitable control animal, e.g., an animal not administered exogenous or transgenic MBP and IRBP.

[0096] The levels of MBP and IRBP can be elevated in an animal by any suitable means. For example, this can be by immunizing the animal with MBP and IRBP, as described in the examples herein.

[0097] Alternatively, the elevation can be achieved by administering one or more vectors comprising one or more nucleic acid molecules encoding MBP and / or IRBP. In a preferred embodiment, the vector is a viral vector.

[0098] In a further embodiment, the invention provides a method for creating an animal model of uveitis, the method comprising the step of elevating the levels of MBP and IRBP in the animal body.

[0099] In a preferred embodiment, the method comprises the step of elevating the levels of MBP and IRBP by administering MBP and IRBP to the animal, which can be by immunizing the animal with MBP and IRBP, as described in the examples herein.

[0100] This animal model has characteristics associated with uveitis. For example, in the animal model, the clinical signs of uveitis may be increased compared to equivalent control animals in which the levels of MBP and IRBP are not elevated.

[0101] MBP and / or IRBP can be human MBP and / or IRBP.

[0102] As long as the required functions are retained in the animal model, MBP or IRBP may be MBP or a part or fragment or portion of IRBP. In one aspect, IRBP can be the IRBP 1177-1191 peptide (ADGSSWEGVGVVPDV (SEQ ID NO: 9), also referred to as R16).

[0103] MBP and / or IRBP can be administered to the animal in any suitable manner, such as, for example, orally, intravenously (if water-soluble), intramuscularly, subcutaneously, sublingually, intranasally, intradermally or by suppository route or implantation (e.g., using a sustained-release molecule).

[0104] In one aspect, the administration is subcutaneous administration.

[0105] Suitable dosages of MBP to be administered to the animal can be about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400 or 500 μg. In one aspect, about 100 μg of MBP is administered.

[0106] Suitable dosages of IRBP to be administered to the animal can be about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90 or 100 μg. In one aspect, about 20 μg of IRBP is administered.

[0107] In one aspect, MBP and / or IRBP is administered together with an adjuvant (e.g., Freund's adjuvant).

[0108] Nucleic acids encoding MBP and / or IRBP can be provided using methods well known to those skilled in the art, for example, based on the MBP and / or IRBP sequences described herein.

[0109] The nucleic acid can be natural, synthetic or recombinant. The nucleic acid can be double-stranded or single-stranded, and can be DNA or RNA or a combination thereof. The nucleic acid can be, for example, cDNA, a PCR product, a genomic sequence or mRNA.

[0110] The nucleotide sequence can be codons optimized for production in a selected host / host cell.

[0111] Delivery of the nucleotide sequence encoding MBP and / or IRBP can be mediated by viral infection. Suitable viral vectors are well known in the art. For example, the viral vector can be an adenovirus, a retrovirus or a lentivirus.

[0112] Generation of the animal model may involve multiple administrations of the vector.

[0113] The vector (e.g., adenovirus) can be administered at 3-week intervals. For example, the vector can be administered at intervals of 18 - 25, 18 - 23, 19 - 23 or 20 - 22 days. The vector can be administered at intervals of 20, 21 or 22 days.

[0114] The animal model involves administering the adenovirus vector at at least two time points. For example, the adenovirus vector can be administered at 2 or 3 time points.

[0115] The vector (e.g., adenovirus) can be administered at a dose of 10 9 ~10 11 viral particles per administration. In particular, the adenovirus can be administered at a dose of 10 8 ~10 11 viral particles per administration. The adenovirus can be administered at a dose of 10 9 viral particles per administration.

[0116] The vector can be administered by any suitable means. For example, in the case of an adenovirus vector, the vector can be administered by intramuscular injection.

[0117] The animal can be a mammal. For example, the animal can be a mouse, rat, rabbit, guinea pig or primate. Preferably, the animal is a rat.

[0118] In one embodiment, the animal is a Lewis rat, preferably a female Lewis rat.

[0119] For example, the model described in the examples herein was prepared by subcutaneous injection of 200 microliters of an emulsion containing 20 micrograms of IRBP1177 - 1191 and 100 micrograms of human (huMBP) or guinea pig myelin basic protein (gpMBP) in incomplete Freund's adjuvant supplemented with 5 mg / mL of Mycobacterium tuberculosis H37Ra. As discussed herein, the model according to the present invention offers the advantage of inducing uveitis with minimal induction of encephalomyelitis.

[0120] Here, the present invention will be described with reference to the following examples.

Examples

[0121] Example 1 This study aimed to investigate the effect of immunization with guinea pig myelin basic protein (gpMBP), human myelin basic protein (huMBP) and / or interphotoreceptor retinoid-binding protein on the development of encephalomyelitis (EAE) and / or uveitis (EAU) in Lewis rats.

[0122] Experimental overview Adult female Lewis rats were randomly assigned to experimental groups and allowed to acclimatize for one week. On day 0, the animals were administered, by subcutaneous injection, 200 μl of an emulsion containing 20 μg of IRBP1177-1191 (Cambridge Bioscience, UK) and / or 100 μg of human (Fitzgerald Industries International, MA, US) or guinea pig myelin basic protein (gpMBP) in incomplete Freund's adjuvant (Sigma, UK) supplemented with 5 mg / mL of Mycobacterium tuberculosis H37Ra (500 μg / rat) (Becton Dickenson, UK). From day 0 until the end of the experiment, the body weight of the animals was measured daily. From day 0 until the end of the experiment, the animals were scored daily for clinical signs of experimental autoimmune encephalomyelitis, including limpness, paresis and / or paralysis of the tail, hindlimbs and / or forelimbs. From day 0 until the end of the experiment, the animals were scored twice weekly for clinical signs of uveitis. On day 21 (groups 1, 2, and 3) or day 28 (groups 4 and 5), the animals were culled and the following samples were excised by dissection and stored in tissue fixative for optional histopathological analysis: brain, spinal cord, right and left eyes.

[0123] Treatment groups and dosages Groups 1, 2 and 3: n = 8 / group Groups 4 and 5: n = 14 / group. TIFF0007679346000006.tif89169

[0124] Measured values Non-specific clinical findings From day 0 until the end of the experiment, the animals were checked daily for non-specific clinical signs, including abnormal posture (curling of the body), abnormal hair condition (piloerection) and abnormal activity level (decrease or increase in activity).

[0125] Body weight From day 0 until the end of the experiment, the body weight of the animals was measured daily.

[0126] Clinical score (uveitis) From day 0 until the end of the experiment, the clinical signs of anterior uveitis were visually scored in the animals twice a week using the following scoring system. The maximum score assumed was 3. The data were graphed (mean ± SEM).

[0127] TIFF0007679346000007.tif35132

[0128] From day 0 until the end of the experiment, the animals were scored twice a week for the clinical signs of intermediate and posterior uveitis. Retinal images were acquired using TEFI in restrained animals after mydriasis with 1% tropicamide and subsequently 2.5% phenylephrine hydrochloride under non - anesthesia. The retinal images were scored using the following system. The maximum score assumed was 6. The data were graphed (mean ± SEM). The TEFI images show the symptoms of both intermediate and posterior uveitis.

[0129] TIFF0007679346000008.tif61166

[0130] Results Non - specific clinical findings From day 0 until the end of the experiment, the animals showed no non - specific clinical signs such as abnormal posture (curling of the body), abnormal hair condition (piloerection) or abnormal activity level (decrease or increase in activity). In the animals administered gpMBP, a significant weight loss was observed from day 11 until the end of the experiment on day 21 compared to the IRBP - administered group (p < 0.0001).

[0131] In animals administered with IRBP and gpMBP, significant weight loss was observed from day 11 to the end of the experiment on day 21 compared to the IRBP-administered group (p < 0.05 on day 11, p < 0.001 on day 12, p < 0.0001 from day 13 to day 20, p < 0.001 on day 21). There was no difference in the amount of weight loss between animals administered with only gpMBP and those administered with IRBP and gpMBP. No significant weight loss was observed in animals administered with only IRBP, human MBP, or human MBP + IRBP.

[0132] Clinical score: Uveitis Animals that had an average score of greater than 0.5 for both eyes in at least two consecutive TEFI sessions (see Figure 2) or a score of greater than 1.0 at any time point were considered to have clinical signs of posterior uveitis.

[0133] Based on this criterion, the incidence of EAU was as follows: TIFF0007679346000009.tif42118

[0134] Due to the lack of pigment formation in the retina of Lewis rats, the following scoring system was used. This was due to the inability to identify the area of infiltration causing turbidity and the cell infiltration on the bright background. The inflammation of the optic disc could not be clearly identified and was therefore not scored, and no structural damage was observed. The infiltration of retinal blood vessels could be identified from the congested appearance with a score of 0 - 3 from mild to severe. Retinal inflammation could also be identified with a score of 0 - 3 from the appearance of redness in small areas to large areas caused by the increase in angiogenesis, with an assumed total score of 6.

[0135] TIFF0007679346000010.tif60111

[0136] The incidence of clinical signs of posterior uveitis was highest in all experimental groups administered IRBP alone or in combination with gpMBP or huMBP. Clinical signs of EAU were also observed in 50% of the animals administered gpMBP and 100% of the animals administered huMBP without IRBP (see Figure 1).

[0137] The onset of clinical signs of EAU did not differ statistically between experimental groups.

[0138] The severity of clinical signs of EAU was significantly lower in animals administered gpMBP compared to the experimental groups administered IRBP (p < 0.001), IRBP and gpMBP (p < 0.01), IRBP and huMBP (p < 0.01), or huMBP (p < 0.05).

[0139] Clinical signs of anterior uveitis were also observed during the experiment.

[0140] Data collected up to day 21 were analyzed by two-way analysis of variance and subsequently by Dunnett's post-test for multiple comparisons between experimental groups.

[0141] In animals administered IRBP, clinical signs were observed from day 11. The signs were significantly higher than those in the gpMBP-administered group on days 11, 14, and 18 (p < 0.0001) (Figure 3).

[0142] In animals administered IRBP & gpMBP, signs of anterior uveitis were also observed from day 11 compared to the gpMBP-administered group (p < 0.0001 on day 11, p < 0.01 on days 14 and 18, p < 0.05 on day 21).

[0143] In animals administered IRBP & huMBP, signs of anterior uveitis were observed on days 11 and 14 compared to the gpMBP-administered group (p < 0.0001).

[0144] In the huMBP-administered animals, signs of anterior uveitis were observed on day 14 (p < 0.0001) and day 18 (p < 0.01) compared to the gpMBP-administered group.

[0145] Murine MBP induces experimental autoimmune encephalomyelitis (EAE) in Lewis rats, a model of multiple sclerosis (MS). In this experiment, Lewis rats immunized with gpMBP alone (incidence 8 / 8 rats; mean maximum score 3.5) or in combination with IRBP peptide (incidence 8 / 8 rats; mean maximum score 3.9) developed severe EAE, and the scores were obtained using the following scoring system for paralytic symptoms: (0) no abnormality, (0.5) partial tail weakness, (1) complete tail weakness, (2) sensory abnormality in one hind limb, (2.5) sensory abnormality in two hind limbs, (3) paralysis of one hind limb, (4) paralysis of two hind limbs, (5) incontinence, and (6) moribund. In contrast to the gpMBP-immunized rats, very mild symptoms were shown in other groups: immunization with IRBP alone (incidence 2 / 8, mean maximum score 1.0); immunization with huMBP (incidence 3 / 14, mean maximum score 1.0) and combination of huMBP and IRBP peptide (incidence 3 / 14, mean maximum score 1.0).

[0146] Conclusion Administration of huMBP produced signs of both anterior and posterior uveitis.

[0147] When administered simultaneously with IRBP, the clinical signs of both anterior uveitis and intermediate / posterior uveitis increased, providing a robust model for testing the efficacy against autoimmune uveitis.

[0148] In addition to the very low incidence and severity of EAE that developed after immunization with human MBP, as described in Example 2, in order to study the effect of the MBP peptide according to the present invention, it was determined to use a model of uveitis with immunization with human MBP alone or with the addition of IRBP peptide.

[0149] Example 2 This example details the study of the effect of ATX-UV-3 in a Lewis rat model of human myelin basic protein (huMBP) and interphotoreceptor retinoid-binding protein (IRBP)-induced uveitis as described in Example 1.

[0150] ATX-UV-3 contains the following sequences: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4).

[0151] Methods Experimental outline Adult female Lewis rats were randomly assigned to the experimental groups and acclimated for one week. On day 0, the animals were administered a 200-μL emulsion containing 100 μg of human myelin basic protein (MBP) (Fitzgerald Industries International, MA, US) in incomplete Freund's adjuvant (Sigma, UK) supplemented with 5 mg / mL of human-type Mycobacterium tuberculosis H37Ra (500 μg / rat) (Becton Dickenson, UK) and 20 micrograms of IRBP 1177-1191 (Cambridge Bioscience, UK) by subcutaneous injection. From day 0 until the end of the experiment, the animals were scored twice weekly for clinical signs of uveitis. On day 21, the clinical scores were analyzed and the study was extended until day 35. On day 35, the animals were culled and the eyes (right and left) were excised by dissection and stored in a tissue fixative for histopathological analysis.

[0152]

Table 1

[0153] Non-specific clinical findings From day 0 until the end of the experiment, animals were checked daily for nonspecific clinical signs, including abnormal posture (curling of the body), abnormal hair coat condition (ruffling), and abnormal activity levels (decrease or increase in activity).

[0154] Clinical score (uveitis) From day 0 until the end of the experiment, animals were scored twice weekly for clinical signs of ocular inflammation (anterior uveitis) using the following scoring system: (0) normal, (1) some iris vascular dilation and iris stromal thickening, a few scattered inflammatory cells, or both, (2) vascular congestion within the iris, abnormal pupil constriction, and (3) anterior chamber turbidity. Data were graphed (mean ± SEM).

[0155] [Table 2]

[0156] From day 0 until the end of the experiment, animals were scored twice weekly for clinical signs of uveitis. Retinal images were acquired using TEFI on restrained animals under non - anesthesia, after dilation with 1% tropicamide and subsequently 2.5% phenylephrine hydrochloride. Retinal images were scored using the following modified scoring system, where the assumed maximum score is 10. Data were graphed (mean ± SEM).

[0157] [Table 3]

[0158] Results Nonspecific clinical findings From day 0 until the end of the experiment, animals showed no nonspecific clinical signs such as abnormal posture (curling of the body), abnormal hair coat condition (ruffling), or abnormal activity levels (decrease or increase in activity).

[0159] Clinical score (uveitis) Posterior uveitis Animals that had an average score of greater than 0.5 for both eyes in at least two consecutive TEFI sessions or a score greater than 1.0 at any time point were considered to have clinical signs of posterior uveitis (Figure 5).

[0160]

Table 4

[0161] Clinical scores were analyzed by two-way ANOVA followed by Tukey's post-test for multiple comparisons between experimental groups on each experimental day (Figure 5).

[0162] In the huMBP and IRBP challenge groups, the ATX peptide significantly decreased the clinical score on day 10 (p < 0.0001), day 14 (p < 0.01), and day 17 (p < 0.05) compared to the vehicle-treated group.

[0163] The clinical scores were further analyzed by calculating the area under the curve (AUC) values and comparing the AUC for each experimental group by one-way ANOVA followed by Sidak's post-test for multiple comparisons between all experimental groups (Figure 6).

[0164] In the huMBP and IRBP challenge groups, the ATX peptide significantly decreased the clinical score compared to the vehicle-treated group (p < 0.001).

[0165] Example 3 To examine the efficacy of ATX-UV-3 in an animal model of uveitis, further studies were conducted. Cyclosporin A was included as a positive control (using a high dose of cyclosporin A that would not be a physiological dose for humans but was selected for the purpose of validating the model).

[0166] Experimental outline Adult female Lewis rats were randomly assigned to the experimental groups and acclimated for one week. Treatments were performed according to the following schedule. On day 0, animals were administered 200 microliters of an emulsion containing 100 micrograms of human myelin basic protein (MBP) in incomplete Freund's adjuvant supplemented with 5 mg / mL of Mycobacterium tuberculosis H37Ra (500 micrograms / rat) and / or 20 micrograms of IRBP1177 - 1191 by subcutaneous injection. From day 0 until the end of the experiment, animals were scored twice a week for clinical signs of anterior and posterior uveitis. On day 28, animals were sacrificed, eyes (right and left) were excised by dissection, transferred into tissue fixative for optional histopathological analysis, and subsequently processed for paraffin embedding and stored in paraffin blocks.

[0167] Treatment groups and dosages All experimental groups had n = 12. The administration volume was 5 mL / kg for PO administration and a fixed volume of 100 microliters per rat for SC administration.

[0168]

Table 5

[0169] Measured values Non - specific clinical findings From day 0 until the end of the experiment, animals were checked daily for non - specific clinical signs including abnormal posture (curling of the body), abnormal hair condition (piloerection), and abnormal activity level (decrease or increase in activity). If non - specific clinical signs were judged to be too severe, animals were sacrificed before the end of the scheduled study.

[0170] Body weight From day 0 until the end of the experiment, the body weight of animals was measured daily.

[0171] Clinical score (uveitis) From day 0 until the end of the experiment, the clinical signs of ocular inflammation (anterior uveitis) were scored twice a week by one observer blinded to the treatment in the animals using the following scoring system: (0) normal, (1) some iris vascular dilation and iris stromal thickening, a few scattered inflammatory cells, or both, (2) vascular congestion within the iris, abnormal pupillary constriction, and (3) anterior chamber turbidity. Data were graphed (mean ± SEM).

[0172]

Table 6

[0173] From day 0 until the end of the experiment, the clinical signs of posterior uveitis were scored twice a week by one observer blinded to the treatment in the animals. Retinal images were obtained using TEFI in restrained animals after mydriasis with 1% tropicamide and subsequently 2.5% phenylephrine hydrochloride under non - anesthesia. The retinal images were scored using the following modified scoring system with an assumed maximum score of 10. Data were graphed (mean ± SEM).

[0174]

Table 7

[0175] Results Non - specific clinical findings - From day 22 until the end of the experiment, the animals showed no non - specific clinical signs.

[0176] Body weight The weights for the huMBP model and the huMBP+IRBP model, expressed as a percentage of the initial (-22nd day) weight, were analyzed by two-way ANOVA and subsequently by Dunnett's post-test for multiple comparisons between the experimental and vehicle groups. Two-way ANOVA revealed significant effects of time and treatment in both the huMBP model and the huMBP+IRBP model (all p<0.0001). In the huMBP model, Dunnett's post-test revealed significant increases in weight at days 22, 24, and 28 compared to the vehicle group in the cyclosporine A group (all p<0.05) and the ATX peptide group (p<0.05, p<0.05, and p<0.01, respectively). In the huMBP+IRBP model, Dunnett's post-test revealed significant increases in weight at days 13, 15, 22, 24, and 28 compared to the vehicle group in the cyclosporine A group (p<0.05, p<0.05, p<0.05, p<0.01, and p<0.01, respectively).

[0177] Anterior uveitis clinical score Animals that had an average total score (average of left eye + right eye) of 1 at two consecutive time points or had an average total score exceeding 1 after any TEFI session were considered to have clinical signs of anterior uveitis. The anterior uveitis clinical scores were analyzed by two-way analysis of variance and subsequently by Dunnett's post-test for multiple comparisons between the experimental and vehicle groups. In the huMBP model, all mice did not show clinical signs of anterior uveitis throughout the study period. In the huMBP+IRBP model, two-way analysis of variance revealed significant effects of time and treatment (both p < 0.0001). Dunnett's post-test showed significant improvements in the clinical scores in the cyclosporine A group at days 7, 10, 14, 17, 21, and 28 (p < 0.05, p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001, and p < 0.05, respectively) and in the ATX peptide group at day 10 (p < 0.0001) compared to the vehicle group (Figure 7A). Unpaired two-sided Student's t-test of the area under the curve (AUC) analysis of the anterior uveitis clinical score data revealed significant effects of cyclosporine A (p < 0.0001) and ATX peptide (p < 0.05) compared to vehicle (Figure 7B).

[0178] Posterior / intermediate uveitis clinical score Animals that had an average total score (average of left eye + right eye) greater than 1 at two consecutive time points or had an average total score greater than 1 after any TEFI session were considered to have clinical signs of posterior uveitis. The posterior uveitis clinical scores were analyzed by two-way analysis of variance and subsequently by Dunnett's post-test for multiple comparisons between the experimental and vehicle groups. In the huMBP model, two-way analysis of variance revealed significant effects of time and treatment (both p < 0.0001). Dunnett's post-test showed significant improvements in clinical scores in the cyclosporine A group at days 7, 10, 14, 17, 21, 24, and 28 (p < 0.05, p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001, p < 0.01, and p < 0.05, respectively) and in the ATX peptide group at days 7, 10, 14, 17, 21, 24, and 28 (p < 0.05, p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001, p < 0.01, and p < 0.05, respectively) compared to the vehicle group (Figure 8A). In the huMBP model, unpaired two-sided Student's t-tests of the area under the curve (AUC) analysis of the posterior uveitis clinical score data revealed significant effects of cyclosporine A (p < 0.0001) and ATX peptide (p < 0.0001) compared to vehicle (Figure 8B).

[0179] In the huMBP+IRBP model, a significant effect of time and treatment was revealed by two-way ANOVA (both p<0.0001). By Dunnett's post hoc test, significant improvements in clinical scores were revealed in the cyclosporine A group on days 7, 10, 14, 17, and 21 (p<0.05, p<0.0001, p<0.0001, p<0.0001, and p<0.05, respectively) and in the ATX peptide group on day 10 (p<0.01) compared to the vehicle group (Figure 8C). By unpaired two-tailed Student's t-test of the area under the curve (AUC) analysis of posterior uveitis clinical score data, a significant effect of cyclosporine A (p<0.0001) compared to vehicle was revealed (Figure 8D). By unpaired one-tailed Student's t-test of the area under the curve (AUC) analysis of posterior uveitis clinical score data, a significant effect of ATX peptide (p<0.05) compared to vehicle was revealed (Figure 8D).

[0180] Incidence of posterior / intermediate uveitis Animals with a mean total score (left eye + right eye) greater than 1 at two consecutive time points or greater than 1 after any TEFI session were considered to have clinical signs of posterior uveitis.

[0181] In the huMBP model, the incidence was reduced in animals treated with cyclosporine A and ATX peptide compared to vehicle-treated animals (Figure 9A). Only one animal treated with cyclosporine A and three animals treated with ATX peptide developed clinical signs of EAU (see Table 8).

[0182]

Table 8

[0183] Conclusion Administration of huMBP alone or in combination with IRBP induced clinical signs of posterior uveitis, resulting in vasodilation, retinal inflammation, and cellular infiltration as predicted in these models of EAU. Clinical signs of posterior uveitis were less severe in the huMBP model compared to animals administered huMBP+IRBP.

[0184] Clinical signs of anterior uveitis were observed in the huMBP+IRBP model but not in the huMBP model. Clinical signs of anterior uveitis in the huMBP+IRBP model included increased iris neovascularization, cellular infiltration of the anterior chamber, and abnormal pupillary constriction.

[0185] Overall, in the huMBP+IRBP model, cyclosporine A and the ATX peptide significantly reduced clinical signs of anterior uveitis.

[0186] In the huMBP model, cyclosporine A and the ATX peptide decreased the incidence of posterior uveitis compared to vehicle-treated animals.

[0187] Cyclosporine A and the ATX peptide significantly delayed the onset of posterior uveitis in the huMBP+IRBP model when compared to the vehicle-treated group.

[0188] Overall, in the huMBP model and the huMBP+IRBP model, cyclosporine A and the ATX peptide significantly reduced clinical signs of posterior / intermediate uveitis.

[0189] All publications mentioned above are hereby incorporated by reference into this specification. Various modifications and variations of the described methods and systems of the present invention will be apparent to those skilled in the art without departing from the spirit of the invention. While the invention has been described in connection with specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the molecular biology, cellular immunology or related fields are intended to fall within the scope of the following claims. The present invention also provides the following aspects. [1] A composition comprising a myelin basic protein peptide selected from the following peptides for use in the treatment or prevention of uveitis in a subject: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4). [2] A composition for use according to [1], comprising the following peptides: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4). [3] A composition for use according to [1], wherein the uveitis is posterior uveitis, anterior uveitis or intermediate uveitis. [4] Use of a composition as defined in [1] or [2] in the manufacture of a medicament for the treatment and / or prevention of uveitis in a subject. [5] Use according to [4], wherein the uveitis is posterior uveitis, anterior uveitis or intermediate uveitis. [6] A method for treating or preventing uveitis in a subject, comprising the step of administering to the subject a composition as defined in [1] or [2]. [7] The method according to [8], wherein the uveitis is posterior uveitis, anterior uveitis, posterior uveitis or intermediate uveitis. [8] A kit comprising a myelin basic protein peptide selected from the following peptides for use in the treatment or prevention of uveitis in a subject: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4). [9] A kit for use according to [8], comprising the following peptides: MBP 30-44 (SEQ ID NO: 1); MBP 83-99 (SEQ ID NO: 2); MBP 131-145 (SEQ ID NO: 3); and MBP 140-154 (SEQ ID NO: 4).

[10] The kit for use according to [9], wherein the MBP peptide is for co-administration, separate administration or sequential administration.

[11] An animal model of uveitis, wherein the animal is immunized with human MBP and photoreceptor-intermediate retinoid-binding protein (IRBP) peptide.

[12] The animal model according to

[11] , wherein the uveitis is posterior uveitis, anterior uveitis, posterior uveitis or intermediate uveitis.

[13] The animal model according to

[11] or

[12] , wherein MBP is human MBP and IRBP is bovine IRBP.

[14] The animal model according to any one of

[11] to

[13] , wherein MBP and IRBP are administered by subcutaneous injection.

[15] The animal model according to any one of

[11] to

[14] , wherein the animal is a rat.

[16] The animal model according to

[15] , wherein the rat is a Lewis rat.

[17] The animal model according to

[16] , wherein the Lewis rat is a female Lewis rat.

[0190] [Sequence Listing] <110> WORG PHARMACEUTICALS(HANGZHOU) CO., LTD. <120> COMPOSITION <130> PA22-577 <140> JP 2022-185229 <141> 2018-01-04 <150> GB 1700095.1 <151> 2017-01-04 <160> 9 <170> PatentIn version 3.5 <210> 1 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 1 Pro Arg His Arg Asp Thr Gly Ile Leu Asp Ser Ile Gly Arg Phe 1 5 10 15 <210> 2 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 2 Glu Asn Pro Val Val His Phe Phe Lys Asn Ile Val Thr Pro Arg Thr 1 5 10 15 Pro <210> 3 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 3 Ala Ser Asp Tyr Lys Ser Ala His Lys Gly Phe Lys Gly Val Asp 1 5 10 15 <210> 4 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 4 Gly Phe Lys Gly Val Asp Ala Gln Gly Thr Leu Ser Lys Ile Phe 1 5 10 15 <210> 5 <211> 304 <212> PRT <213> Homo sapiens <400> 5 Met Gly Asn His Ala Gly Lys Arg Glu Leu Asn Ala Glu Lys Ala Ser 1 5 10 15 Thr Asn Ser Glu Thr Asn Arg Gly Glu Ser Glu Lys Lys Arg Asn Leu 20 25 30 Gly Glu Leu Ser Arg Thr Thr Ser Glu Asp Asn Glu Val Phe Gly Glu 35 40 45 Ala Asp Ala Asn Gln Asn Asn Gly Thr Ser Ser Gln Asp Thr Ala Val 50 55 60 Thr Asp Ser Lys Arg Thr Ala Asp Pro Lys Asn Ala Trp Gln Asp Ala 65 70 75 80 His Pro Ala Asp Pro Gly Ser Arg Pro His Leu Ile Arg Leu Phe Ser 85 90 95 Arg Asp Ala Pro Gly Arg Glu Asp Asn Thr Phe Lys Asp Arg Pro Ser 100 105 110 Glu Ser Asp Glu Leu Gln Thr Ile Gln Glu Asp Ser Ala Ala Thr Ser 115 120 125 Glu Ser Leu Asp Val Met Ala Ser Gln Lys Arg Pro Ser Gln Arg His 130 135 140 Gly Ser Lys Tyr Leu Ala Thr Ala Ser Thr Met Asp His Ala Arg His 145 150 155 160 Gly Phe Leu Pro Arg His Arg Asp Thr Gly Ile Leu Asp Ser Ile Gly 165 170 175 Arg Phe Phe Gly Gly Asp Arg Gly Ala Pro Lys Arg Gly Ser Gly Lys 180 185 190 Asp Ser His His Pro Ala Arg Thr Ala His Tyr Gly Ser Leu Pro Gln 195 200 205 Lys Ser His Gly Arg Thr Gln Asp Glu Asn Pro Val Val His Phe Phe 210 215 220 Lys Asn Ile Val Thr Pro Arg Thr Pro Pro Pro Ser Gln Gly Lys Gly 225 230 235 240 Arg Gly Leu Ser Leu Ser Arg Phe Ser Trp Gly Ala Glu Gly Gln Arg 245 250 255 Pro Gly Phe Gly Tyr Gly Gly Arg Ala Ser Asp Tyr Lys Ser Ala His 260 265 270 Lys Gly Phe Lys Gly Val Asp Ala Gln Gly Thr Leu Ser Lys Ile Phe 275 280 285 Lys Leu Gly Gly Arg Asp Ser Arg Ser Gly Ser Pro Met Ala Arg Arg 290 295 300 <210> 6 <211> 167 <212> PRT <213> Cavia porcellus <400> 6 Ala Ser Gln Lys Arg Pro Ser Gln Arg His Gly Ser Lys Tyr Leu Ala 1 5 10 15 Thr Ala Ser Thr Met Asp His Ala Arg His Gly Phe Leu Pro Arg His 20 25 30 Arg Asp Thr Gly Ile Leu Asp Ser Ile Gly Arg Phe Phe Gly Ser Asp 35 40 45 Arg Ala Ala Pro Lys Arg Gly Ser Gly Lys Asp Ser His His Ala Ala 50 55 60 Arg Thr Thr His Tyr Gly Ser Leu Pro Gln Lys Ser Gln Arg Ser Gln 65 70 75 80 Asp Glu Asn Pro Val Val His Phe Phe Lys Asn Ile Val Thr Pro Arg 85 90 95 Thr Pro Pro Pro Ser Gln Gly Lys Gly Arg Gly Leu Ser Leu Ser Arg 100 105 110 Phe Ser Trp Gly Ala Glu Gly Gln Lys Pro Gly Phe Gly Tyr Gly Gly 115 120 125 Arg Ala Asp Tyr Lys Ser Lys Gly Phe Lys Gly Ala His Asp Ala Gln 130 135 140 Gly Thr Leu Ser Lys Ile Phe Lys Leu Gly Gly Arg Asp Ser Arg Ser 145 150 155 160 Gly Ser Pro Met Ala Arg Arg 165 <210> 7 <211> 1247 <212> PRT <213> Homo sapiens <400> 7 Met Met Arg Glu Trp Val Leu Leu Met Ser Val Leu Leu Cys Gly Leu 1 5 10 15 Ala Gly Pro Thr His Leu Phe Gln Pro Ser Leu Val Leu Asp Met Ala 20 25 30 Lys Val Leu Leu Asp Asn Tyr Cys Phe Pro Glu Asn Leu Leu Gly Met 35 40 45 Gln Glu Ala Ile Gln Gln Ala Ile Lys Ser His Glu Ile Leu Ser Ile 50 55 60 Ser Asp Pro Gln Thr Leu Ala Ser Val Leu Thr Ala Gly Val Gln Ser 65 70 75 80 Ser Leu Asn Asp Pro Arg Leu Val Ile Ser Tyr Glu Pro Ser Thr Pro 85 90 95 Glu Pro Pro Pro Gln Val Pro Ala Leu Thr Ser Leu Ser Glu Glu Glu 100 105 110 Leu Leu Ala Trp Leu Gln Arg Gly Leu Arg His Glu Val Leu Glu Gly 115 120 125 Asn Val Gly Tyr Leu Arg Val Asp Ser Val Pro Gly Gln Glu Val Leu 130 135 140 Ser Met Met Gly Glu Phe Leu Val Ala His Val Trp Gly Asn Leu Met 145 150 155 160 Gly Thr Ser Ala Leu Val Leu Asp Leu Arg His Cys Thr Gly Gly Gln 165 170 175 Val Ser Gly Ile Pro Tyr Ile Ile Ser Tyr Leu His Pro Gly Asn Thr 180 185 190 Ile Leu His Val Asp Thr Ile Tyr Asn Arg Pro Ser Asn Thr Thr Thr 195 200 205 Glu Ile Trp Thr Leu Pro Gln Val Leu Gly Glu Arg Tyr Gly Ala Asp 210 215 220 Lys Asp Val Val Val Leu Thr Ser Ser Gln Thr Arg Gly Val Ala Glu 225 230 235 240 Asp Ile Ala His Ile Leu Lys Gln Met Arg Arg Ala Ile Val Val Gly 245 250 255 Glu Arg Thr Gly Gly Gly Ala Leu Asp Leu Arg Lys Leu Arg Ile Gly 260 265 270 Glu Ser Asp Phe Phe Phe Thr Val Pro Val Ser Arg Ser Leu Gly Pro 275 280 285 Leu Gly Gly Gly Ser Gln Thr Trp Glu Gly Ser Gly Val Leu Pro Cys 290 295 300 Val Gly Thr Pro Ala Glu Gln Ala Leu Glu Lys Ala Leu Ala Ile Leu 305 310 315 320 Thr Leu Arg Ser Ala Leu Pro Gly Val Val His Cys Leu Gln Glu Val 325 330 335 Leu Lys Asp Tyr Tyr Thr Leu Val Asp Arg Val Pro Thr Leu Leu Gln 340 345 350 His Leu Ala Ser Met Asp Phe Ser Thr Val Val Ser Glu Glu Asp Leu 355 360 365 Val Thr Lys Leu Asn Ala Gly Leu Gln Ala Ala Ser Glu Asp Pro Arg 370 375 380 Leu Leu Val Arg Ala Ile Gly Pro Thr Glu Thr Pro Ser Trp Pro Ala 385 390 395 400 Pro Asp Ala Ala Ala Glu Asp Ser Pro Gly Val Ala Pro Glu Leu Pro 405 410 415 Glu Asp Glu Ala Ile Arg Gln Ala Leu Val Asp Ser Val Phe Gln Val 420 425 430 Ser Val Leu Pro Gly Asn Val Gly Tyr Leu Arg Phe Asp Ser Phe Ala 435 440 445 Asp Ala Ser Val Leu Gly Val Leu Ala Pro Tyr Val Leu Arg Gln Val 450 455 460 Trp Glu Pro Leu Gln Asp Thr Glu His Leu Ile Met Asp Leu Arg His 465 470 475 480 Asn Pro Gly Gly Pro Ser Ser Ala Val Pro Leu Leu Leu Ser Tyr Phe 485 490 495 Gln Gly Pro Glu Ala Gly Pro Val His Leu Phe Thr Thr Tyr Asp Arg 500 505 510 Arg Thr Asn Ile Thr Gln Glu His Phe Ser His Met Glu Leu Pro Gly 515 520 525 Pro Arg Tyr Ser Thr Gln Arg Gly Val Tyr Leu Leu Thr Ser His Arg 530 535 540 Thr Ala Thr Ala Ala Glu Glu Phe Ala Phe Leu Met Gln Ser Leu Gly 545 550 555 560 Trp Ala Thr Leu Val Gly Glu Ile Thr Ala Gly Asn Leu Leu His Thr 565 570 575 Arg Thr Val Pro Leu Leu Asp Thr Pro Glu Gly Ser Leu Ala Leu Thr 580 585 590 Val Pro Val Leu Thr Phe Ile Asp Asn His Gly Glu Ala Trp Leu Gly 595 600 605 Gly Gly Val Val Pro Asp Ala Ile Val Leu Ala Glu Glu Ala Leu Asp 610 615 620 Lys Ala Gln Glu Val Leu Glu Phe His Gln Ser Leu Gly Ala Leu Val 625 630 635 640 Glu Gly Thr Gly His Leu Leu Glu Ala His Tyr Ala Arg Pro Glu Val 645 650 655 Val Gly Gln Thr Ser Ala Leu Leu Arg Ala Lys Leu Ala Gln Gly Ala 660 665 670 Tyr Arg Thr Ala Val Asp Leu Glu Ser Leu Ala Ser Gln Leu Thr Ala 675 680 685 Asp Leu Gln Glu Val Ser Gly Asp His Arg Leu Leu Val Phe His Ser 690 695 700 Pro Gly Glu Leu Val Val Glu Glu Ala Pro Pro Pro Pro Pro Ala Val 705 710 715 720 Pro Ser Pro Glu Glu Leu Thr Tyr Leu Ile Glu Ala Leu Phe Lys Thr 725 730 735 Glu Val Leu Pro Gly Gln Leu Gly Tyr Leu Arg Phe Asp Ala Met Ala 740 745 750 Glu Leu Glu Thr Val Lys Ala Val Gly Pro Gln Leu Val Arg Leu Val 755 760 765 Trp Gln Gln Leu Val Asp Thr Ala Ala Leu Val Ile Asp Leu Arg Tyr 770 775 780 Asn Pro Gly Ser Tyr Ser Thr Ala Ile Pro Leu Leu Cys Ser Tyr Phe 785 790 795 800 Phe Glu Ala Glu Pro Arg Gln His Leu Tyr Ser Val Phe Asp Arg Ala 805 810 815 Thr Ser Lys Val Thr Glu Val Trp Thr Leu Pro Gln Val Ala Gly Gln 820 825 830 Arg Tyr Gly Ser His Lys Asp Leu Tyr Ile Leu Met Ser His Thr Ser 835 840 845 Gly Ser Ala Ala Glu Ala Phe Ala His Thr Met Gln Asp Leu Gln Arg 850 855 860 Ala Thr Val Ile Gly Glu Pro Thr Ala Gly Gly Ala Leu Ser Val Gly 865 870 875 880 Ile Tyr Gln Val Gly Ser Ser Pro Leu Tyr Ala Ser Met Pro Thr Gln 885 890 895 Met Ala Met Ser Ala Thr Thr Gly Lys Ala Trp Asp Leu Ala Gly Val 900 905 910 Glu Pro Asp Ile Thr Val Pro Met Ser Glu Ala Leu Ser Ile Ala Gln 915 920 925 Asp Ile Val Ala Leu Arg Ala Lys Val Pro Thr Val Leu Gln Thr Ala 930 935 940 Gly Lys Leu Val Ala Asp Asn Tyr Ala Ser Ala Glu Leu Gly Ala Lys 945 950 955 960 Met Ala Thr Lys Leu Ser Gly Leu Gln Ser Arg Tyr Ser Arg Val Thr 965 970 975 Ser Glu Val Ala Leu Ala Glu Ile Leu Gly Ala Asp Leu Gln Met Leu 980 985 990 Ser Gly Asp Pro His Leu Lys Ala Ala His Ile Pro Glu Asn Ala Lys 995 1000 1005 Asp Arg Ile Pro Gly Ile Val Pro Met Gln Ile Pro Ser Pro Glu 1010 1015 1020 Val Phe Glu Glu Leu Ile Lys Phe Ser Phe His Thr Asn Val Leu 1025 1030 1035 Glu Asp Asn Ile Gly Tyr Leu Arg Phe Asp Met Phe Gly Asp Gly 1040 1045 1050 Glu Leu Leu Thr Gln Val Ser Arg Leu Leu Val Glu His Ile Trp 1055 1060 1065 Lys Lys Ile Met His Thr Asp Ala Met Ile Ile Asp Met Arg Phe 1070 1075 1080 Asn Ile Gly Gly Pro Thr Ser Ser Ile Pro Ile Leu Cys Ser Tyr 1085 1090 1095 Phe Phe Asp Glu Gly Pro Pro Val Leu Leu Asp Lys Ile Tyr Ser 1100 1105 1110 Arg Pro Asp Asp Ser Val Ser Glu Leu Trp Thr His Ala Gln Val 1115 1120 1125 Val Gly Glu Arg Tyr Gly Ser Lys Lys Ser Met Val Ile Leu Thr 1130 1135 1140 Ser Ser Val Thr Ala Gly Thr Ala Glu Glu Phe Thr Tyr Ile Met 1145 1150 1155 Lys Arg Leu Gly Arg Ala Leu Val Ile Gly Glu Val Thr Ser Gly 1160 1165 1170 Gly Cys Gln Pro Pro Gln Thr Tyr His Val Asp Asp Thr Asn Leu 1175 1180 1185 Tyr Leu Thr Ile Pro Thr Ala Arg Ser Val Gly Ala Ser Asp Gly 1190 1195 1200 Ser Ser Trp Glu Gly Val Gly Val Thr Pro His Val Val Val Pro 1205 1210 1215 Ala Glu Glu Ala Leu Ala Arg Ala Lys Glu Met Leu Gln His Asn 1220 1225 1230 Gln Leu Arg Val Lys Arg Ser Pro Gly Leu Gln Asp His Leu 1235 1240 1245 <210> 8 <211> 1286 <212> PRT <213> Bos taurus <400> 8 Met Val Arg Lys Trp Ala Leu Leu Leu Pro Met Leu Leu Cys Gly Leu 1 5 10 15 Thr Gly Pro Ala His Leu Phe Gln Pro Ser Leu Val Leu Glu Met Ala 20 25 30 Gln Val Leu Leu Asp Asn Tyr Cys Phe Pro Glu Asn Leu Met Gly Met 35 40 45 Gln Gly Ala Ile Glu Gln Ala Ile Lys Ser Gln Glu Ile Leu Ser Ile 50 55 60 Ser Asp Pro Gln Thr Leu Ala His Val Leu Thr Ala Gly Val Gln Ser 65 70 75 80 Ser Leu Asn Asp Pro Arg Leu Val Ile Ser Tyr Glu Pro Ser Thr Leu 85 90 95 Glu Ala Pro Pro Arg Ala Pro Ala Val Thr Asn Leu Thr Leu Glu Glu 100 105 110 Ile Ile Ala Gly Leu Gln Asp Gly Leu Arg His Glu Ile Leu Glu Gly 115 120 125 Asn Val Gly Tyr Leu Arg Val Asp Asp Ile Pro Gly Gln Glu Val Met 130 135 140 Ser Lys Leu Arg Ser Phe Leu Val Ala Asn Val Trp Arg Lys Leu Val 145 150 155 160 Asn Thr Ser Ala Leu Val Leu Asp Leu Arg His Cys Thr Gly Gly His 165 170 175 Val Ser Gly Ile Pro Tyr Val Ile Ser Tyr Leu His Pro Gly Ser Thr 180 185 190 Val Ser His Val Asp Thr Val Tyr Asp Arg Pro Ser Asn Thr Thr Thr 195 200 205 Glu Ile Trp Thr Leu Pro Glu Ala Leu Gly Glu Lys Tyr Ser Ala Asp 210 215 220 Lys Asp Val Val Val Leu Thr Ser Ser Arg Thr Gly Gly Val Ala Glu 225 230 235 240 Asp Ile Ala Tyr Ile Leu Lys Gln Met Arg Arg Ala Ile Val Val Gly 245 250 255 Glu Arg Thr Val Gly Gly Ala Leu Asn Leu Gln Lys Leu Arg Val Gly 260 265 270 Gln Ser Asp Phe Phe Leu Thr Val Pro Val Ser Arg Ser Leu Gly Pro 275 280 285 Leu Gly Glu Gly Ser Gln Thr Trp Glu Gly Ser Gly Val Leu Pro Cys 290 295 300 Val Gly Thr Pro Ala Glu Gln Ala Leu Glu Lys Ala Leu Ala Val Leu 305 310 315 320 Met Leu Arg Arg Ala Leu Pro Gly Val Ile Gln Arg Leu Gln Glu Ala 325 330 335 Leu Arg Glu Tyr Tyr Thr Leu Val Asp Arg Val Pro Ala Leu Leu Ser 340 345 350 His Leu Ala Ala Met Asp Leu Ser Ser Val Val Ser Glu Asp Asp Leu 355 360 365 Val Thr Lys Leu Asn Ala Gly Leu Gln Ala Val Ser Glu Asp Pro Arg 370 375 380 Leu Gln Val Gln Val Val Arg Pro Lys Glu Ala Ser Ser Gly Pro Glu 385 390 395 400 Glu Glu Ala Glu Glu Pro Pro Glu Ala Val Pro Glu Val Pro Glu Asp 405 410 415 Glu Ala Val Arg Arg Ala Leu Val Asp Ser Val Phe Gln Val Ser Val 420 425 430 Leu Pro Gly Asn Val Gly Tyr Leu Arg Phe Asp Ser Phe Ala Asp Ala 435 440 445 Ser Val Leu Glu Val Leu Gly Pro Tyr Ile Leu His Gln Val Trp Glu 450 455 460 Pro Leu Gln Asp Thr Glu His Leu Ile Met Asp Leu Arg Gln Asn Pro 465 470 475 480 Gly Gly Pro Ser Ser Ala Val Pro Leu Leu Leu Ser Tyr Phe Gln Ser 485 490 495 Pro Asp Ala Ser Pro Val Arg Leu Phe Ser Thr Tyr Asp Arg Arg Thr 500 505 510 Asn Ile Thr Arg Glu His Phe Ser Gln Thr Glu Leu Leu Gly Arg Pro 515 520 525 Tyr Gly Thr Gln Arg Gly Val Tyr Leu Leu Thr Ser His Arg Thr Ala 530 535 540 Thr Ala Ala Glu Glu Leu Ala Phe Leu Met Gln Ser Leu Gly Trp Ala 545 550 555 560 Thr Leu Val Gly Glu Ile Thr Ala Gly Ser Leu Leu His Thr His Thr 565 570 575 Val Ser Leu Leu Glu Thr Pro Glu Gly Gly Leu Ala Leu Thr Val Pro 580 585 590 Val Leu Thr Phe Ile Asp Asn His Gly Glu Cys Trp Leu Gly Gly Gly 595 600 605 Val Val Pro Asp Ala Ile Val Leu Ala Glu Glu Ala Leu Asp Arg Ala 610 615 620 Gln Glu Val Leu Glu Phe His Arg Ser Leu Gly Glu Leu Val Glu Gly 625 630 635 640 Thr Gly Arg Leu Leu Glu Ala His Tyr Ala Arg Pro Glu Val Val Gly 645 650 655 Gln Met Gly Ala Leu Leu Arg Ala Lys Leu Ala Gln Gly Ala Tyr Arg 660 665 670 Thr Ala Val Asp Leu Glu Ser Leu Ala Ser Gln Leu Thr Ala Asp Leu 675 680 685 Gln Glu Met Ser Gly Asp His Arg Leu Leu Val Phe His Ser Pro Gly 690 695 700 Glu Met Val Ala Glu Glu Ala Pro Pro Pro Pro Pro Val Val Pro Ser 705 710 715 720 Pro Glu Glu Leu Ser Tyr Leu Ile Glu Ala Leu Phe Lys Thr Glu Val 725 730 735 Leu Pro Gly Gln Leu Gly Tyr Leu Arg Phe Asp Ala Met Ala Glu Leu 740 745 750 Glu Thr Val Lys Ala Val Gly Pro Gln Leu Val Gln Leu Val Trp Gln 755 760 765 Lys Leu Val Asp Thr Ala Ala Leu Val Val Asp Leu Arg Tyr Asn Pro 770 775 780 Gly Ser Tyr Ser Thr Ala Val Pro Leu Leu Cys Ser Tyr Phe Phe Glu 785 790 795 800 Ala Glu Pro Arg Arg His Leu Tyr Ser Val Phe Asp Arg Ala Thr Ser 805 810 815 Arg Val Thr Glu Val Trp Thr Leu Pro His Val Thr Gly Gln Arg Tyr 820 825 830 Gly Ser His Lys Asp Leu Tyr Val Leu Val Ser His Thr Ser Gly Ser 835 840 845 Ala Ala Glu Ala Phe Ala His Thr Met Gln Asp Leu Gln Arg Ala Thr 850 855 860 Ile Ile Gly Glu Pro Thr Ala Gly Gly Ala Leu Ser Val Gly Ile Tyr 865 870 875 880 Gln Val Gly Ser Ser Ala Leu Tyr Ala Ser Met Pro Thr Gln Met Ala 885 890 895 Met Ser Ala Ser Thr Gly Glu Ala Trp Asp Leu Ala Gly Val Glu Pro 900 905 910 Asp Ile Thr Val Pro Met Ser Val Ala Leu Ser Thr Ala Arg Asp Ile 915 920 925 Val Thr Leu Arg Ala Lys Val Pro Thr Val Leu Gln Thr Ala Gly Lys 930 935 940 Leu Val Ala Asp Asn Tyr Ala Ser Pro Glu Leu Gly Val Lys Met Ala 945 950 955 960 Ala Glu Leu Ser Gly Leu Gln Ser Arg Tyr Ala Arg Val Thr Ser Glu 965 970 975 Ala Ala Leu Ala Glu Leu Leu Gln Ala Asp Leu Gln Val Leu Ser Gly 980 985 990 Asp Pro His Leu Lys Thr Ala His Ile Pro Glu Asp Ala Lys Asp Arg 995 1000 1005 Ile Pro Gly Ile Val Pro Met Gln Ile Pro Ser Pro Glu Val Phe 1010 1015 1020 Glu Asp Leu Ile Lys Phe Ser Phe His Thr Asn Val Leu Glu Gly 1025 1030 1035 Asn Val Gly Tyr Leu Arg Phe Asp Met Phe Gly Asp Cys Glu Leu 1040 1045 1050 Leu Thr Gln Val Ser Glu Leu Leu Val Glu His Val Trp Lys Lys 1055 1060 1065 Ile Val His Thr Asp Ala Leu Ile Val Asp Met Arg Phe Asn Ile 1070 1075 1080 Gly Gly Pro Thr Ser Ser Ile Ser Ala Leu Cys Ser Tyr Phe Phe 1085 1090 1095 Asp Glu Gly Pro Pro Ile Leu Leu Asp Lys Ile Tyr Asn Arg Pro 1100 1105 1110 Asn Asn Ser Val Ser Glu Leu Trp Thr Leu Ser Gln Leu Glu Gly 1115 1120 1125 Glu Arg Tyr Gly Ser Lys Lys Ser Met Val Ile Leu Thr Ser Thr 1130 1135 1140 Leu Thr Ala Gly Ala Ala Glu Glu Phe Thr Tyr Ile Met Lys Arg 1145 1150 1155 Leu Gly Arg Ala Leu Val Ile Gly Glu Val Thr Ser Gly Gly Cys 1160 1165 1170 Gln Pro Pro Gln Thr Tyr His Val Asp Asp Thr Asp Leu Tyr Leu 1175 1180 1185 Thr Ile Pro Thr Ala Arg Ser Val Gly Ala Ala Asp Gly Ser Ser 1190 1195 1200 Trp Glu Gly Val Gly Val Val Pro Asp Val Ala Val Pro Ala Glu 1205 1210 1215 Ala Ala Leu Thr Arg Ala Gln Glu Met Leu Gln His Thr Pro Leu 1220 1225 1230 Arg Ala Arg Arg Ser Pro Arg Leu His Gly Arg Arg Lys Gly His 1235 1240 1245 His Arg Gln Ser Gln Gly Arg Ala Gly Ser Leu Gly Arg Asn Gln 1250 1255 1260 Gly Val Val Arg Pro Glu Val Leu Thr Glu Ala Pro Ser Gly Gln 1265 1270 1275 Lys Arg Gly Leu Leu Gln Cys Gly 1280 1285 <210> 9 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 9 Ala Asp Gly Ser Ser Trp Glu Gly Val Gly Val Val Pro Asp Val 1 5 10 15

Claims

1. 1. A composition comprising a myelin basic protein peptide for use in treating or preventing uveitis in a subject: MBP 30-44 consisting of SEQ ID NO:1; MBP 83-99 consisting of SEQ ID NO:2; MBP 131-145 consisting of SEQ ID NO:3; and MBP 140-154 consisting of SEQ ID NO: 4 wherein the peptide is formulated in the composition as a neutral or salt form.

2. 2. The composition for use according to claim 1, wherein the uveitis is posterior uveitis, anterior uveitis or intermediate uveitis.

3. 1. A kit for use in treating or preventing uveitis in a subject comprising the following myelin basic protein peptides: MBP 30-44 consisting of SEQ ID NO:1; MBP 83-99 consisting of SEQ ID NO:2; MBP 131-145 consisting of SEQ ID NO:3; and MBP 140-154 consisting of SEQ ID NO: 4 wherein the peptide is formulated in the composition as a neutral or salt form.

4. The kit for use according to claim 3, wherein the MBP peptides are for simultaneous, separate or sequential administration.

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