Peptide Antigens and Their Uses

Abstract

The present invention provides a novel method for identifying peptide antigens associated with non-autoimmune diseases involving T cell activation, as well as novel peptides identified thereby. The isolated peptides of the present invention can be used for the diagnosis, prevention, and / or treatment of cardiovascular diseases, more specifically heart failure (HF). The present invention also provides a pharmaceutical composition comprising at least one of the isolated peptides of the present invention and a pharmaceutically acceptable carrier, vehicle, excipient, and / or diluent. The pharmaceutical composition of the present invention is suitable for oral administration as a tolerogenic vaccine.

Description

[0001] The present invention relates to a new method for identifying peptide antigens associated with diseases involving T cell activation and the new peptides thus identified. The isolated peptides of the present invention can be used for the diagnosis, prevention, and / or treatment of cardiovascular diseases, more specifically heart failure (HF).

[0002] The immune system evolved to cope with the threat of invading pathogens. Its first line of defense is the innate immunity and the innate immune system, including macrophages, neutrophils, and monocytes, which is rapid but non-specific. Innate immune cells can eliminate pathogens while they respond to and release pro-inflammatory cytokines in a positive feedback loop.

[0003] Adaptive immunity and the adaptive immune system (composed of T and B lymphocytes, called T and B cells) are used to combat persistent pathogens. It takes several days to activate. T cells and B cells have a key feature that distinguishes them from innate immune cells. They express the following antigen receptors: the T cell receptor (TCR) on T cells and the B cell receptor (BCR) on B cells. The TCR and BCR have binding sites with variable sequences that are unique in each different T cell or B cell, which is the result of the somatic recombination process that generates variability. Thus, each different T cell or B cell will have a TCR or BCR with a unique binding sequence that binds to an antigen, which is a protein fragment mainly present on invading pathogens. Therefore, a population of T cells and B cells with variable antigen specificities will be able to recognize and initiate a specific response to any possible invading pathogen. This specificity, combined with the long lifespan of lymphocytes, enables T cells and B cells to maintain a persistent memory response, a property that allows vaccines to work. In the unfortunate case where the antigen is not an invading pathogen but is expressed by the body's own cells, the adaptive response causes autoimmunity (Kallikourdis M, (2018), "T cell responses to tumors: how dominant assumptions about immune activity lead to the neglect of pathological functions and how evolutionary considerations can help identify testable hypotheses for improving immunotherapy", Cancer Immunol Immunother. 67(6):989-998). In this case, the memory capacity of T cells and B cells, combined with the persistence of self-antigens, which cannot be destroyed without damaging the body, makes the disease chronic. Therefore, these chronic processes are related to the misguided immune responses against the self that occur in autoimmunity. However, these processes are now also found to cause many other diseases with high morbidity and mortality.

[0004] To be classified as autoimmune, a disease must meet several criteria, summarized as follows:

[0005] (i) The disease must be shown to be transferable when T cells are transferred from an affected individual to a healthy individual;

[0006] (ii) The disease must be shown to be transferable when serum containing (auto)antibodies is transferred from an affected individual to a healthy individual;

[0007] (iii) The disease must be shown to be inducible when healthy individuals are immunized with autoantigens to which auto-reactive T cells and B cells respond.

[0008] The above criteria are well known (Rose, N.R. et al. (1993) "Criteria for the definition of autoimmune diseases", Immunology today: 426 - 430).

[0009] Acquired diseases such as heart failure and Alzheimer's disease typically occur with increasing age and are not caused by misguided autoreactive T cell or B cell responses, but rather by stress within the affected tissues. Thus, these diseases are not considered autoimmune. For example, in the case of heart disease, cardiac stress can be caused by many lifestyle- or environment-related risk factors such as an unhealthy diet (type 2 diabetes) or high blood pressure, which damage cardiomyocytes and initiate a pathological process (Bui, A.L. et al. (2011), "Epidemiology and risk prediction of heart failure", Nat Rev Cardiol, 8(1), 30 - 41).

[0010] Over the past few decades, scientific research has shown that adaptive immunity plays a role in regulating processes affected by many human diseases, from metabolic disorders to cancer, age-related diseases, and neurodegenerative / neurogenic diseases. Cardiovascular disease (CVD) is no exception (Ait-Oufella H. et al., 2006) "Natural regulatory T cells control the development of atherosclerosis in mice", Nat. Med., 12(2), 178 - 80). Adaptive immunity may have a feature that makes it particularly vulnerable to non-optimal function, especially in diseases of the middle-aged and elderly. It has previously been shown by Aluvihare VR et al. (2004) "Regulatory T cells mediate maternal tolerance to the fetus" Nat Immunol, 5(3), 266 - 71 that mammals require the anti-inflammatory arm of adaptive immunity, namely regulatory T cells (Tregs), in order to be able to reproduce via pregnancy through the placenta. This is because the fetus is immunologically half from the father. Without the placenta to separate it, the pro-inflammatory arm of the maternal adaptive immune system would recognize the fetus as foreign and eliminate it. T reg Actively and specifically inhibit this rejection. Importantly, T regThe full - functional form has evolved only in monotremes (i.e., egg - laying mammals) and mammals, suggesting that reproduction may be a key evolutionary driver for the development of the immunosuppressive arm of adaptive immunity. A corollary of this hypothesis is that after the age of female reproductive activity, adaptive immunity may not be under much evolutionary pressure. Thus, after the age at which fertility typically occurs, adaptive immunity may function sub - optimally for any disease with a high incidence in old age. While the same argument may apply less to innate immunity, the pregnancy - specific functions of adaptive immunity produce a cliff - edge effect in middle age, and this effect has been identified in the following diseases: autoimmune diseases (Munoz Suano A. et al. (2012), "Regulatory T cells protect from autoimmune arthritis during pregnancy", J Autoimmun, 38(2 - 3), J103 - 8), age - related inflammation (Benedusi, V, et al., (2015), "Ovariectomy shortens the lifespan of female mice", Oncotarget, 6(13), 10801 - 11), cancer (Kallikourdis M, (2018), "T - cell responses to tumors: how the dominant hypothesis of immune activity has led to the neglect of pathological functions and how evolutionary considerations can help identify testable hypotheses for improving immunotherapy", Cancer Immunol Immunother. 67(6):989 - 998), and heart failure (HF) in the last four years (Kallikourdis, M et al. (2017), "T - cell costimulation blockade alleviates pressure - overload - induced heart failure", Nat Commun, 8 14680). Most CVDs are associated with aging and inflammation, fitting this pattern. Thus, sub - optimal function of adaptive immunity may contribute to CVDs, providing effective therapeutic targets, especially considering the role of adaptive immunity in regulating the chronic nature of immune responses and all diseases associated with inflammation, such as metabolic diseases (diabetes but not type 1, metabolic syndrome), obesity, neurodegenerative diseases, and neurological diseases (amyotrophic lateral sclerosis - ALS, Alzheimer's disease, dementia, age - related dementia, mild cognitive decline, Parkinson's disease) as well as age - related diseases.

[0011] Cardiovascular diseases, neurodegenerative diseases, and cancer are major causes of morbidity and mortality. Importantly, the onset of these three types of diseases often occurs clinically simultaneously, in a situation known as multimorbidity. Multimorbidity is an increasingly prominent clinical problem, usually difficult to diagnose and treat because the division of healthcare into specialized disciplines makes interdisciplinary diagnosis almost inapplicable.

[0012] Multiple conditions can be due to tissue degeneration leading to multi-system dysregulation, or they can be iatrogenic, i.e., the effect of a drug on tissues other than the target tissue of the initial disease. In fact, as more "biological" drugs enter clinical practice, we cannot rule out that some aspects of multiple morbidity may sometimes even be iatrogenic, i.e., caused by side effects of drug treatment. This is because current clinical practice is centered around single-disease patients and there is often little knowledge of "off-target" effects. For biological and immunomodulatory drugs, "off-target" effects may indeed be legitimate effects of the drug's mechanism of action, albeit on off-target tissues. Thus, not fully accounting for these effects may lead to multiple morbidity. There is evidence that inflammation and immune responses are involved in the pathogenesis of the above three disease groups. The inherent fluidity of the immune system and its association with most chronic disease forms make it a possible contributing mechanism for multiple morbidity (a "common denominator").

[0013] For example, recent clinical observations have revealed that cancer patients receiving immunotherapy to unleash T cell anti-tumor activity sometimes develop T cell- and macrophage-mediated lethal myocarditis (Heinzerling, L. et al. (2016), "Cardiotoxicity associated with CTLA4 and PD1 blockade immunotherapy", J Immunother Cancer, 4 50.; Johnson, DB, et al. (2016), "Fulminant myocarditis with combined immune checkpoint blockade", N Engl J Med, 375(18), 1749-55). As cancer immunotherapy is increasingly used clinically, this may represent an emergent iatrogenic immune system-dependent form of multiple morbidity involving cancer and heart disease.

[0014] Heart failure (HF) is the end stage of several cardiac diseases. It can be caused by volume or pressure overload due to aortic stenosis, hypertension, or other reasons. Alternatively, it can be the result of myocardial cell damage caused by gene mutations or myocardial infarction (MI). HF is characterized by a reduced left ventricular ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), with both conditions being roughly equally prevalent in patients currently. Defects in cardiac function manifest as systolic and / or diastolic ventricular dysfunction. A small subset (<5%) of HF cases are the result of inflammatory myocarditis, a cardiac inflammation that is the result of an autoimmune response or an immune response to a virus infecting the heart.

[0015] Clinical data generated over the past 20 years have shown that pressure-overload HF and MI-induced HF are also characterized by inflammation, as stressed cardiomyocytes release pro-inflammatory cytokines such as TNFa, IL1b, and IL6 (Shioi, T, et al. (1997), "Increased expression of interleukin-1β and monocyte chemoattractant and activating factor / monocyte chemoattractant protein-1 in hypertrophied and failing hearts with pressure overload", Circ Res, 81(5), 664-71; Hofmann, U and S Frantz (2013), "How can we cure the heart in the 'flames'? A changing view of inflammation in heart failure", Basic Res Cardiol, 108(4), 356). This is consistent with the observation that during pathological hypertrophy preceding HF, a key event in the diseased heart is fibrosis, an immunologically mediated phenomenon (Wynn, TA (2003), "IL-13 effector functions", Annu Rev Immunol, 21:425-56). Cells of the innate immune system (macrophages) have been found to cause pathological cardiac inflammation (Mann, DL (2015), "Innate immunity and the failing heart: revisiting the cytokine hypothesis", Circ Res, 116(7), 1254-68; Patel, B, et al. (2018), "CCR2+ monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload", JACC Basic Transl Sci, 3(2), 230-44).

[0016] Early attempts to therapeutically block cytokine function (TNFa) in HF patients failed for a variety of reasons, possibly including redundancy of pro-inflammatory cytokine function. The expansion of pro-inflammatory cytokine research has recently led to more successful clinical trials using IL1b inhibition in the context of heart disease (Ridker, PM, et al. (2017), "Anti-inflammatory therapy with canakinumab for atherosclerotic disease", N Engl J Med, 377(12), 1119-31). However, this effect is still not effective enough to obtain FDA approval.

[0017] However, since inflammation is clearly involved in the progression of HF, a better therapeutic target that can inhibit the harmful inflammatory process still has great potential clinical benefits.

[0018] As described above, adaptive immune cells (T cells and B cells) act in an antigen-specific and chronic manner, which means that they may be key regulators of long-term responses and thus of diseases involving them, such as chronic diseases, such as HF (including pressure overload-induced HF, congestive HF, age-related HF). In fact, Nevers and colleagues (Nevers, T et al. (2015), "Pathogenesis of heart failure caused by left ventricular T cell recruitment", Circ Heart Fail, 8(4), 776-87), as well as Laroumanie and colleagues (Laroumanie, F et al. (2014), "CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload", Circulation, 129(21), 2111-24) recently demonstrated that depletion of T cells in genetically deficient mice or antibody-depleted mice has a protective effect on transverse aortic constriction (TAC)-induced HF, which is the gold standard mouse model for preclinical studies of HF (Rockman, HA, et al. (1991), "Isolation of atrial-specific and inducible expression of atrial natriuretic factor transgene in a living mouse model of myocardial hypertrophy", Proc Natl Acad Sci USA, 88(18), 8277-81). In fact, Nevers and colleagues (Nevers, T et al. (2015), "Pathogenesis of heart failure caused by left ventricular T cell recruitment", Circ Heart Fail, 8(4), 776-87), as well as Laroumanie and colleagues (Laroumanie, F et al. (2014), "CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload", Circulation, 129(21), 2111-24) recently demonstrated that depletion of T cells in genetically deficient mice or antibody-depleted mice has a protective effect on transverse aortic constriction (TAC)-induced HF, which is the gold standard mouse model for preclinical studies of HF (Rockman, HA, et al. (1991), "Isolation of atrial-specific and inducible expression of atrial natriuretic factor transgene in a living mouse model of myocardial hypertrophy", Proc Natl Acad Sci USA, 88(18), 8277-81). The effect obtained is several times that achieved by standard β-blocker therapy. The cardiotoxic effect of T cells involves the role of myocardial macrophages and affects the degree of myocardial fibrosis and the viability of cardiomyocytes. This is blocked by treatment with the T cell costimulation blocker CTLA4-Ig. The presence of T cells has been found in biopsies of patients with HFrEF and HFpEF, and T cells are also associated with age-related HF. These findings suggest that T cells are required for HF progression, even if the cause of HF is not immune-mediated.

[0019] This cardiotoxic function of T cells may be inhibited by anti-inflammatory Treg cells (Kanellakis, P, et al. (2011), "CD4+CD25+Foxp3+ regulatory T cells inhibit cardiac fibrosis in hypertensive heart", J Hypertens, 29(9), 1820-28) and the molecule CD73 (Borg, N, et al. 2017 "CD73 on T cells coordinates cardiac wound healing after myocardial infarction through purinergic metabolism reprogramming", Circulation, 136(3), 297-313). T cells are also important for the progression of heart failure after myocardial infarction (Hofmann, U, et al. (2012), "Activated CD4+ T lymphocytes improve wound healing and survival after experimental myocardial infarction in mice", Circulation, 125(13), 1652-63; Weirather, J et al. (2014), "Foxp3+CD4+ T cells improve healing after myocardial infarction by regulating monocyte / macrophage differentiation", Circ Res, 115:55-67).

[0020] Although there is increasing evidence that T cells are cardiotoxic, the antigen specificity of the naturally occurring T cell response that mediates non-autoimmune heart failure remains unclear.

[0021] To date, research on the antigen specificity of the heart failure (HF) response has mainly focused on autoimmune myocarditis, but this accounts for a small proportion (<5%) of HF cases. In this pathology, immune system defects lead to an autoimmune response that happens to target the heart (Caforio, AL et al. (1992), "Identification of α- and β-cardiac myosin heavy chain isotypes as major autoantigens in dilated cardiomyopathy", Circulation, 85(5), 1734-42; Caforio, AL et al. (2015), "Passive transfer of affinity-purified anti-heart autoantibodies (AHA) from the sera of patients with myocarditis induces experimental myocarditis in mice", Int J Cardiol, 179 166-77; Basavalingappa, RH, et al. (2016), "Identification of epitopes in adenine nucleotide translocator 1 that induce cardiac inflammation in A / J mice", Am J Pathol, 186(12), 3160-75; Krishnan, B et al. (2017), "Branched-chain α-ketoacid dehydrogenase kinase 111-130, a T cell epitope that induces autoimmune myocarditis and hepatitis in A / J mice", Immun.Inflamm.Dis, 5(4), 421-34).

[0022] US2014 / 0271694 discloses that the α isoform of myosin heavy chain enhances T cell immune responses and IgG autoantibodies in autoimmune or pathogen-induced inflammatory cardiovascular diseases, such as autoimmune diseases associated with myocardial infarction (post-infarction autoimmune syndrome, PIA) and inflammatory myocarditis.

[0023] In other studies aimed at elucidating the immune response against the heart, artificial model antigens were used, which were unrelated to the antigens that "physiologically" drive the heart failure response, the latter being naturally produced during the onset of the disease ( C, et al. (2017), "Helper T cells specific for cardiomyocyte antigens promote the progression from hypertrophy to heart failure induced by pressure overload", Sci Rep, 7(1), 15998).

[0024] Therefore, there is an urgent need to provide new and effective treatment methods to prevent the occurrence of heart failure or reduce the severity of the disease.

[0025] There is also an urgent need to provide a method for diagnosing heart failure, especially heart failure caused by non-autoimmune myocarditis.

[0026] More specifically, there is a need to provide a diagnostic method that can highly accurately determine whether an object has heart failure and / or whether the object has a tendency to develop the disease, so as to be able to provide prescriptions for lifestyle and / or drug choices to further reduce the risk of developing heart failure.

[0027] The methods, isolated peptides and their diagnostic and therapeutic uses defined in the appended claims meet these and other needs, and they form part of the specification.

[0028] As further detailed in the experimental section below, the inventors have elucidated the major role of adaptive immunity in the onset and progression of HF, even if the cause of the disease is not immune deficiency. More specifically, the inventors have found that T cell activation is not only necessary for inducing heart disease, as previously described by Kallikourdis, M, et al. (2017), "T cell costimulation blockade alleviates pressure overload-induced heart failure", Nat Commun, 8 14680, but this activation is also sufficient to induce disease progression. As Figure 1 shown, by intravenously injecting T cells extracted from heart disease mice that received transverse aortic constriction (TAC)-induced HF into healthy recipient mice, significant cardiac dysfunction was induced in the latter, thus indicating the T cell-dependence of the HF progression mechanism.

[0029] Typically, identifying the antigens recognized by T cells is a costly and technically challenging task because standard procedures require identifying the T cell receptor (TCR) sequences of T cells involved in the disease, cloning and expressing the sequences of each of the two independent TCR chains so that they fold together, and steps for scanning the TCR against a peptide library. Additionally, since TCRs only recognize peptides processed and presented by major histocompatibility (MHC) molecules, which are highly polymorphic and vary between individuals, TCR peptide screening may produce results that are limited in their effectiveness and thus applicability to smaller genetically similar populations.

[0030] To overcome the drawbacks and limitations of existing technical methods, the present invention now provides a new method for identifying peptide antigens that drive T cell responses in adaptive immunity involved in the occurrence and development of non-autoimmune diseases, particularly in the chronic stage of non-autoimmune diseases.

[0031] The method of the present invention is based on the inventors' surprising discovery that in T cell-dependent non-autoimmune diseases, the antigen specificity of IgG-switched antibodies can be used as a surrogate for the antigen specificity of the T cells required to produce these antibodies by B cells.

[0032] Antibodies specific for a particular antigen produced by B cells that interact with the antigen switch their heavy chain class (from IgM or IgD to IgG or IgA or IgE) only when the B cells interact with T cells that recognize the same particular antigen. Both T cells and B cells have different antigen receptors, and each T cell or B cell has a unique antigen receptor capable of recognizing any antigen. When B cells that produce antibodies interact with T cells that recognize the same antigen, the B cells can switch their antibody heavy chains from IgM or IgD to IgG or IgA or IgE. Thus, IgG-switched antibodies ensure that the antigen specificity of the producing B cells matches that of the activated T cells.

[0033] Accordingly, a first aspect of the present invention is a method for identifying peptide antigens associated with human or veterinary non-autoimmune diseases involving T cell activation, the method comprising the following steps:

[0034] (i) contacting a first biological fluid sample containing IgG immunoglobulins from a first non-human animal affected by a non-autoimmune disease with a microarray comprising a plurality of isolated or synthetic peptide antigens, each peptide having a predetermined position in the microarray and comprising an amino acid sequence of a protein from the non-human animal;

[0035] (ii) detecting the binding of one or more IgG immunoglobulins present in the first sample to one or more peptide antigens in the microarray to provide a first IgG-binding peptide profile;

[0036] (iii) Compare the first IgG-binding peptide profile with a second IgG-binding peptide profile generated by contacting the microarray defined in step (i) with a second biological fluid sample containing IgG immunoglobulins from a second non-human animal, wherein the second non-human animal is not affected by the non-autoimmune disease, and wherein the first and second non-human animals belong to the same species and are congenic animals;

[0037] (iv) Identify one or more IgG-binding peptides present in the first IgG-binding profile and absent in the second IgG-binding profile;

[0038] (v) Use the amino acid sequence of each IgG-binding peptide identified in step (iv) as a query to query a database of animal protein sequences in order to select one or more animal proteins that contain a peptide sequence having an amino acid sequence that is 67% to 100% identical to the amino acid sequence of the queried peptide, wherein the animal protein sequences are from animals belonging to a different non-human animal species than the first and second non-human animals of step (iii);

[0039] (vi) Identify the peptide sequences that have 67% to 100% amino acid sequence identity and are contained in animal proteins expressed in tissues affected by the non-autoimmune disease and selected in step (v) as peptide antigens associated with the non-autoimmune disease.

[0040] According to the present invention, the peptide antigens identified by the method of the present invention (hereinafter referred to as the discovery method) are associated with non-autoimmune diseases involving T cell activation, which means that the peptide antigens are sufficient to induce the non-autoimmune disease or may be involved in the progression of the non-autoimmune disease in humans or animals.

[0041] The discovery method of the present invention utilizes a microarray comprising a plurality of isolated or synthetic antigenic peptides that comprise amino acid sequences from proteins of non-human animals (e.g., mouse proteins).

[0042] For example, the amino acid sequences of the plurality of antigenic peptides can be from tissue-specific proteins of non-human animals, such as mouse heart tissue-specific proteins or mouse nerve tissue-specific proteins, or from the proteome of non-human animals, such as the mouse proteome.

[0043] In one embodiment, the microarray used in the discovery method of the present invention can be a planar microarray, wherein the isolated or synthetic antigenic peptides are immobilized at discrete individual positions on a solid support. Alternatively, the microarray can be a bead-based microarray, wherein the isolated or synthetic antigenic peptides are conjugated to color-coded or size-coded microspheres.

[0044] In the discovery method according to the present invention, a peptide microarray is analyzed using first and second biological fluid samples containing IgG immunoglobulins, the first and second biological fluid samples being from a first non-human animal affected by a non-autoimmune disease and a second non-human animal not affected by the non-autoimmune disease, respectively. After microarray analysis, different IgG-binding antigenic peptides are identified.

[0045] A key feature of the discovery method of the present invention is that the first and second non-human animals belong to the same species and are congenic, i.e., genetically identical. This key feature results in differences in the IgG antibody repertoires of these animals and the corresponding profiles of IgG-binding peptides in the microarray, which are attributed to the non-autoimmune disease affecting the first non-human animal but not the second non-human animal.

[0046] In a preferred embodiment, the first and second non-human animals are mice.

[0047] In a more preferred embodiment, the first non-human animal is a mouse model of a non-autoimmune disease, preferably a mouse model of a cardiovascular disease, more preferably a transverse aortic constriction (TAC) model.

[0048] As is known in the art, mouse TAC is a commonly used experimental model of pressure overload-induced myocardial hypertrophy and heart failure.

[0049] Other non-limiting examples of mouse disease models include gene-induced models of chronic heart failure or dilated cardiomyopathy after myocardial infarction, age-related heart failure models (aged mice), myocardial infarction models, HFpEF mouse models, hypertension models leading to HF (induced by AngII or L-NAME administration).

[0050] In the discovery method of the present invention, the amino acid sequence of each IgG-binding peptide identified as described above is used as a query sequence and compared with an animal protein sequence database, the animal being of a different species from the first and second non-human animals.

[0051] A further feature of the discovery method of the present invention is that the amino acid sequence of each IgG-binding peptide identified as described above is used to query an animal protein database. The results of the database query are selected based on whether the identified animal protein contains a peptide sequence having an amino acid sequence identity between 67% and 100% with the amino acid sequence of each peptide queried.

[0052] Preferably, the amino acid sequence identity is at least 67%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0053] As used herein, the term "percent amino acid sequence identity" with respect to a reference polypeptide sequence refers to the percentage of amino acids in a candidate sequence that are identical to the amino acids in the reference polypeptide sequence after aligning the sequences and introducing gaps (if necessary) to achieve the maximum percent sequence identity. The alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways within the capabilities of those of skill in the art, e.g., using computer software available through public databases such as BLAST, BLAST-2, or Megalign (DNASTAR) software. Those of skill in the art can determine appropriate parameters for aligning the sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, the sequence comparison computer program BLAST can be used to generate percent sequence identity values.

[0054] As another step in the discovery method of the present invention, peptide antigens associated with non-autoimmune diseases are identified as having an amino acid sequence contained in an animal protein expressed in a tissue affected by a non-autoimmune disease.

[0055] In one embodiment, the animal is a human, dog, or cat.

[0056] Any type of biological fluid sample suitable for analyzing IgG immunoglobulin content, preferably a blood sample and its derivatives such as serum and plasma, can be used to practice the discovery method of the present invention.

[0057] In a preferred embodiment, binding of one or more IgG immunoglobulins present in a first and / or second biological fluid sample to one or more antigenic peptides in a microarray is achieved through a secondary antibody. Generally, the secondary antibody is directed against an IgG immunoglobulin that is part of an immune complex formed between the IgG and the peptide and is produced in an animal species different from the first and second non-human animals providing the first and second biological fluid samples.

[0058] Preferably, the secondary antibody used in the discovery method of the present invention is an anti-IgG antibody, more preferably an anti-IgG antibody labeled with a detectable tag, which is preferably selected from radioisotopes, fluorophores, enzymes, chemiluminescent compounds, affinity tags such as avidin or biotin.

[0059] Although the present experimental study has been conducted using a heart failure mouse model, it should be understood that the discovery method of the present invention is directly applicable to the identification of peptide antigens associated with other non-autoimmune diseases, particularly chronic non-autoimmune diseases that may be mediated by T cells. Examples of non-autoimmune diseases are not limited to cardiac diseases, vascular diseases, atherosclerosis, vascular stenosis, metabolic diseases (non-Type 1 diabetes, metabolic syndrome), obesity, neurodegenerative and neurological diseases (amyotrophic lateral sclerosis, ALS, Alzheimer's disease, dementia, age-related dementia, mild cognitive decline, Parkinson's disease) or age-related diseases.

[0060] In a preferred embodiment, heart failure is hemodynamically induced heart failure, i.e., heart failure caused by hemodynamic stress on cardiomyocytes, which includes increased load after myocardial infarction, increased preload or afterload due to valvular disease or elevated arterial pressure, or an inherent genetic defect in cardiomyocytes.

[0061] In yet another embodiment, the discovery method of the present invention can be used as a tool for managing multimorbidity.

[0062] As described above, multimorbidity refers to a clinical situation in which a patient suffers from the following group of diseases simultaneously: cardiovascular, neurological, oncological, and metabolic diseases.

[0063] According to the present invention, peptide antigens associated with a wide range of non-autoimmune diseases (such as cardiovascular, neurological, oncological, and metabolic diseases) involving T cell activation can be identified, and such antigens can be used for real-time assessment of the propensity / early diagnosis of emerging adaptive immune responses against different tissues.

[0064] Due to the method of the present invention, the first subclinical signs of the pathogenesis affecting these tissues can be provided, thereby enabling interdisciplinary diagnosis and rapid referral to specialists, focusing on newly affected tissues and preventing the progression of multimorbidity.

[0065] Advantageously, the discovery method of the present invention can be repeatedly applied until no new peptides can be identified, thereby achieving saturation. In fact, in most immune responses, the target does not mutate rapidly (i.e., it is not a virus or a tumor), and only a small number of immunodominant antigens drive the response. Therefore, several runs of the discovery method of the present invention will achieve saturation of the identification of new hits, for example, the identification of most of the antigens that drive the adaptive response promoting HF.

[0066] Due to the unique and advantageous features of the discovery method of the present invention as described above, the inventors have identified new peptides that are drivers of the adaptive immune response in response to cardiac stress, particularly drivers of the T cell response mediating heart failure (HF).

[0067] As further explained in detail below, the inventors analyzed serum samples collected from syngeneic TAC-operated (hereinafter referred to as TAC) and sham-operated (hereinafter referred to as "sham") control mice on a murine microarray containing known random oligopeptides. The profiles of IgG-binding peptides generated by microarray analysis were computationally filtered in a differential analysis to identify IgG-binding peptides present in the TAC analysis but absent in the sham analysis microarray. The results of this analysis were further filtered to select peptide antigens that have a high degree of homology only with human proteins expressed in cardiovascular tissues.

[0068] To validate the results of the above method, the inventors conducted a functional study in which healthy mice were immunized with the selected peptide antigens in the presence of an adjuvant without applying any cardiovascular stress. As Figure 6A and 6B shown, immunization of the mice unexpectedly resulted in a decrease in cardiac function as measured by fractional shortening (FS) and ejection fraction (EF) of the treated animals.

[0069] Therefore, the study conducted by the present inventors has revealed for the first time that the identified new peptides are sufficient by themselves to induce heart failure in animals and are active mediators of disease progression, and thus represent ideal diagnostic and therapeutic markers. Further supporting the above experimental results, the present inventors examined the diagnostic value of the new peptides in an ELISA immunoassay by detecting the presence of IgG antibodies that recognize these peptides in human sera from heart failure (HF) patients and healthy controls. Figure 8 The ELISA test results shown in the scatter plot in

[0070] According to the above, a second aspect of the present invention is an isolated peptide consisting of an amino acid sequence selected from the group consisting of:

[0071] SEQ ID NOs. 1, 2, 3, and 4 of human 14-3-3 protein; SEQ ID NO. 5 of human small nuclear ribonucleoprotein Sm D1 (SNRPD1); SEQ ID NO. 6 of human mitochondrial precursor ATP synthase subunit O (ATP5O); SEQ ID NO. 7 of human toll-like receptor 5 precursor (TLR5); and any combination thereof;

[0072] or an isolated peptide consisting of an amino acid sequence selected from the group consisting of:

[0073] SEQ ID NOs. 1, 2, 3, and 4 of canine 14-3-3 protein; SEQ ID NO. 8 of canine monocarboxylate transporters 3 and 4 proteins (MCT3 and MCT4); SEQ ID NO. 5 of canine SNRPD1; SEQ ID NO. 9 of canine ATP5O; SEQ ID NO. 10 of canine dihydropyrimidinase (DHP) protein, and any combination thereof;

[0074] or an isolated peptide consisting of an amino acid sequence selected from the group consisting of:

[0075] SEQ ID NOs. 1, 2, 3, and 4 of feline 14-3-3 protein; SEQ ID NO. 8 of feline MCT3 and MCT4 proteins; SEQ ID NO. 11 of feline vomeronasal 1 receptor felCatV1R6 protein; SEQ ID NO. 12 of feline protein 6 containing transmembrane emp24 domain; SEQ ID NO. 5 of feline SNRPD1; SEQ ID NO. 13 of feline ATP5O; SEQ ID NO. 10 of feline DHP protein, and any combination thereof.

[0076] According to the present invention, the isolated peptide of the present invention is heart-specific because it consists of the amino acid sequences of proteins expressed in human, canine, or feline heart tissues, but does not exclude its possible expression in other tissues.

[0077] The term "14-3-3 protein" as used in this specification refers to different isoforms of human, canine, and feline 14-3-3 proteins, including human isoforms: 14-3-3 protein ε, 14-3-3 protein ε isoform X1, 14-3-3 protein ε isoform X2, 14-3-3 protein β / α, 14-3-3 protein θ, 14-3-3 protein ζ / δ, 14-3-3 protein η, 14-3 protein γ, 14-3-3 protein σ; canine isoforms: 14-3-3 protein ε isoform X1, 14-3-3 protein ε isoform X2, 14-3-3 protein ε isoform X3, 14-3-3 protein ε isoform X4, 14-3-3 protein θ-like, 14-3-3 protein θ, 14-3-3 protein ζ / δ, 14-3-3 protein β / α, 14-3-3 protein η, 14-3-3 protein γ, 14-3-3 protein σ; and feline isoforms: 14-3-3 protein ε isoform X1, 14-3-3 protein ε isoform X2, 14-3-3 protein ε isoform X3, 14-3-3 protein θ, 14-3-3 protein ζ / δ, 14-3-3 protein β / α, 14-3-3 protein η, 14-3-3 protein γ, 14-3-3 protein σ.

[0078] As used herein, the term "monocarboxylate transporter 3 (MCT3) or 4 (MCT4) protein" refers to different isoforms of human, canine, and feline MCT3 and MCT4 proteins, including feline MCT4 isoforms X2 and X21.

[0079] As used herein, the term "protein 6 containing the transmembrane emp24 domain" refers to different isoforms of protein 6 containing the human, canine, and feline transmembrane emp24 domains, including protein 6 isoforms X1 and X2 containing the feline transmembrane emp24 domain.

[0080] As used herein, the term "small nuclear ribonucleoprotein Sm D1 (SNRPD1)" refers to different isoforms of human, canine, and feline SNRPD1, including feline SNRPD1 isoforms X1 and X2.

[0081] As used herein, the term "dihydropyrimidinase protein" refers to different isoforms of human, canine, and feline dihydropyrimidinase proteins, including feline dihydropyrimidinase isoforms X1 and X2.

[0082] According to the present invention, any possible combination of the above isolated peptides is contemplated to be included in the present invention.

[0083] A preferred embodiment of the present invention is at least one peptide of human 14-3-3 protein selected from the group consisting of SEQ ID NOs. 1, 2, 3, and 4, in combination with the peptide consisting of SEQ ID NO. 5 of human small nuclear ribonucleoprotein Sm D1 (SNRPD1) and the peptide consisting of SEQ ID NO. 6 of human ATP5O protein.

[0084] Another preferred embodiment of the present invention is at least two peptides of human 14-3-3 protein selected from the group consisting of SEQ ID NOs. 1, 2, 3, and 4; in combination with the peptide consisting of SEQ ID NO. 5 of human SNRPD1 and the peptide consisting of SEQ ID NO. 6 of human ATP5O protein. The at least two peptides of human 14-3-3 protein are, for example, (a) the peptide of SEQ ID NO. 1 and the peptide of SEQ ID NO. 2, (b) the peptide of SEQ ID NO. 1 and the peptide of SEQ ID NO. 3, (c) the peptide of SEQ ID NO. 1 and the peptide of SEQ ID NO. 4, (d) the peptide of SEQ ID NO. 2 and the peptide of SEQ ID NO. 3, (e) the peptide of SEQ ID NO. 2 and the peptide of SEQ ID NO. 4, or (f) the peptide of SEQ ID NO. 3 and the peptide of SEQ ID NO. 4.

[0085] Another preferred embodiment of the present invention is at least three peptides of human 14-3-3 protein selected from the following group: SEQ ID NO.1, 2, 3, and 4; in combination with the peptide consisting of SEQ ID NO.5 of human SNRPD1 and the peptide consisting of SEQ ID NO.6 of human ATP5O protein. The at least three peptides of human 14-3-3 protein are, for example, (g) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.2, and the peptide of SEQ ID NO.3, (h) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.2, and the peptide of SEQ ID NO.4, (i) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.3, and the peptide of SEQ ID NO.4, or (j) the peptide of SEQ ID NO.2, the peptide of SEQ ID NO.3, and the peptide of SEQ ID NO.4.

[0086] Another preferred embodiment of the present invention is at least four peptides consisting of SEQ ID NO.1, 2, 3, and 4 of human 14-3-3 protein respectively; in combination with the peptide consisting of SEQ ID NO.5 of human SNRPD1 and the peptide consisting of SEQ ID NO.6 of human ATP5O protein.

[0087] Optionally, in the above embodiments according to the present invention, the combination of peptides may further comprise a peptide consisting of SEQ ID NO.7 of human TLR5 protein.

[0088] A third aspect of the present invention is an in vitro method for diagnosing heart failure (HF) in a human subject and / or predicting the risk of developing heart failure (HF) in a human subject, the method comprising the steps of: (i) contacting a biological fluid sample containing IgG immunoglobulin from a human subject affected by HF or suspected of being at risk of developing HF with one or more isolated antigenic peptides from one or more human proteins selected from the group consisting of: 14-3-3 protein epsilon (SEQ ID NO.18), 14-3-3 protein epsilon isoform X1 (SEQ ID NO.19), 14-3-3 protein epsilon isoform X2 (SEQ ID NO.20), 14-3-3 protein beta / alpha (SEQ ID NO.21), 14-3-3 protein theta (SEQ ID NO.22), 14-3-3 protein zeta / delta (SEQ ID NO.23), 14-3-3 protein eta (SEQ ID NO.24), 14-3-3 protein gamma (SEQ ID NO.25), 14-3-3 protein sigma (SEQ ID NO.26), small nuclear ribonucleoprotein Sm D1 isoform 1 (SEQ ID NO.27), mitochondrial precursor ATP synthase subunit O (SEQ ID NO.28), toll-like receptor 5 precursor (SEQ ID NO.29), and any combination thereof, wherein the one or more isolated antigenic peptides are from 6 to 50 amino acids in length;

[0089] (ii) detecting the formation of one or more immune complexes between the IgG immunoglobulin in the biological fluid sample and the one or more isolated antigenic peptides, the formation of the one or more immune complexes indicating that the human subject is affected by HF or at risk of developing HF.

[0090] In a preferred embodiment, the one or more isolated antigenic peptides consist of amino acid sequences selected from the group consisting of: SEQ ID NOs. 1, 2, 3, and 4 of human 14-3-3 protein; SEQ ID NO. 5 of human small nuclear ribonucleoprotein Sm D1 (SNRPD1); SEQ ID NO. 6 of human mitochondrial precursor ATP synthase subunit O (ATP5O); SEQ ID NO. 7 of human toll-like receptor 5 precursor (TLR5); and any combination thereof.

[0091] In a more preferred embodiment, the method of the present invention uses at least one peptide of human 14-3-3 protein selected from the group consisting of: SEQ ID NOs. 1, 2, 3, and 4; in combination with a peptide consisting of SEQ ID NO. 5 of human SNRPD1 and a peptide consisting of SEQ ID NO. 6 of human ATP5O protein.

[0092] In another preferred embodiment, the method of the present invention uses at least two peptides of human 14-3-3 protein selected from the group consisting of: SEQ ID NO.1, 2, 3, and 4; in combination with the peptide consisting of SEQ ID NO.5 of human SNRPD1 and the peptide consisting of SEQ ID NO.6 of human ATP5O. The at least two peptides of human 14-3-3 protein are, for example, (a) the peptide of SEQ ID NO.1 and the peptide of SEQ ID NO.2, (b) the peptide of SEQ ID NO.1 and the peptide of SEQ ID NO.3, (c) the peptide of SEQ ID NO.1 and the peptide of SEQ ID NO.4, (d) the peptide of SEQ ID NO.2 and the peptide of SEQ ID NO.3, (e) the peptide of SEQ ID NO.2 and the peptide of SEQ ID NO.4, or (f) the peptide of SEQ ID NO.3 and the peptide of SEQ ID NO.4.

[0093] In another preferred embodiment, the method of the present invention uses at least three peptides of human 14-3-3 protein selected from the group consisting of: SEQ ID NO.1, 2, 3, and 4; in combination with the peptide consisting of SEQ ID NO.5 of human SNRPD1 and the peptide consisting of SEQ ID NO.6 of human ATP5O protein. The at least three peptides of human 14-3-3 protein are, for example, (g) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.2, and the peptide of SEQ ID NO.3, (h) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.2, and the peptide of SEQ ID NO.4, (i) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.3, and the peptide of SEQ ID NO.4, or (j) the peptide of SEQ ID NO.2, the peptide of SEQ ID NO.3, and the peptide of SEQ ID NO.4.

[0094] In still another preferred embodiment, the method of the present invention uses at least four peptides consisting of SEQ ID NO.1, 2, 3, and 4 of human 14-3-3 protein; in combination with the peptide consisting of SEQ ID NO.5 of human SNRPD1 and the peptide consisting of SEQ ID NO.6 of human ATP5O protein.

[0095] Optionally, in the above embodiments of the method according to the present invention, the combination of peptides may further comprise a peptide consisting of SEQ ID NO.7 of human TLR5 protein.

[0096] In the case where there is an immune response against diseased cardiovascular tissue that has not yet led to clinically observable symptoms, the detection of IgG antibodies in the in vitro method of the present invention by the identified neoantigens provides a valuable indication of the tendency of the subject to develop clinically recognizable disease symptoms. If the heart disease has already presented clinically recognizable symptoms, the detection of IgG antibodies against the identified neoantigens in the method of the present invention can diagnose a specific heart disease.

[0097] The present invention is not limited to human diagnosis and can also be used in veterinary applications.

[0098] Thus, in another aspect, the method of the present invention is an in vitro method for diagnosing and / or prognosticating canine heart failure (HF), and / or predicting the risk of a dog developing HF, wherein the isolated antigenic peptides are from one or more canine proteins selected from the group consisting of: 14-3-3 protein epsilon isoform X1 (SEQ ID NO.30), 14-3-3 protein epsilon isoform X2 (SEQ ID NO.31), 14-3-3 protein epsilon isoform X3 (SEQ ID NO.32), 14-3-3 protein epsilon isoform X4 (SEQ ID NO.33), 14-3-3 protein theta-like (SEQ ID NO.34), 14-3-3 protein theta (SEQ ID NO.35), 14-3-3 protein zeta / delta (SEQ ID NO.36), 14-3-3 protein beta / alpha (SEQ ID NO.37), 14-3-3 protein eta (SEQ ID NO.38), 14-3-3 protein gamma (SEQ ID NO.39), 14-3 protein sigma (SEQ ID NO.40), monocarboxylate transporter 3 and 4 proteins (SEQ ID NOs. 41 and 42), small nuclear ribonucleoprotein Sm D1 (SEQ ID NO.43), mitochondrial precursor ATP synthase subunit O (SEQ ID NO.44), dihydropyrimidinase protein (SEQ ID NO.45) and any combination thereof, wherein one or more of the isolated antigenic peptides are 6 to 50 amino acids in length.

[0099] In a preferred embodiment, one or more of the isolated antigenic peptides consist of amino acid sequences selected from the group consisting of: SEQ ID NOs. 1, 2, 3 and 4 of canine 14-3-3 protein; SEQ ID NO.8 of canine monocarboxylate transporter 3 and 4 proteins (MCT3 and MCT4); SEQ ID NO.5 of canine SNRPD1; SEQ ID NO.9 of canine ATP5O; SEQ ID NO.10 of canine dihydropyrimidinase (DHP) protein and any combination thereof.

[0100] In a preferred embodiment, this aspect of the invention may be related to heart failure caused by dilated cardiomyopathy, which is caused by gene mutations in dog breeds including but not limited to Doberman Pinschers, Great Danes, Boxers, and Cocker Spaniels.

[0101] In another aspect, the method of the invention is an in vitro method for diagnosing and / or prognosticating feline heart failure (HF), and / or predicting the risk of a cat developing heart failure (HF), wherein the isolated antigenic peptides are derived from one or more feline proteins selected from the group consisting of: 14-3-3 protein epsilon isoform X1 (SEQ ID NO. 46), 14-3-3 protein epsilon isoform X2 (SEQ ID NO. 47), 14-3-3 protein epsilon isoform X3 (SEQ ID NO. 48), 14-3-3 protein theta (SEQ ID NO. 49), 14-3-3 protein zeta / delta (SEQ ID NO. 50), 14-3-3 protein beta / alpha (SEQ ID NO. 51), 14-3-3 protein eta (SEQ ID NO. 52), 14-3-3 protein gamma (SEQ ID NO. 53), 14-3-3 protein sigma (SEQ ID NO. 54), monocarboxylate transporter 3 (SEQ ID NO. 55), monocarboxylate transporter 4 isoform X2 (SEQ ID NO. 56) and isoform X21 (SEQ ID NO. 57), vomeronasal 1 receptor felCatV1R6 protein (SEQ ID NO. 58), protein 6 containing a transmembrane emp24 domain, isoform X1 (SEQ ID NO. 59), protein 6 containing a transmembrane emp24 domain, isoform X2 (SEQ ID NO. 60), small nuclear ribonucleoprotein Sm D1, isoform X1 (SEQ ID NO. 61), small nuclear ribonucleoprotein Sm D1, isoform X2 (SEQ ID NO. 62), mitochondrial precursor ATP synthase subunit O (SEQ ID NO. 63), dihydropyrimidinase protein isoform X1 (SEQ ID NO. 64), dihydropyrimidinase protein isoform X2 (SEQ ID NO. 65), and any combination thereof, wherein the length of one or more of the isolated antigenic peptides is from 6 to 50 amino acids.

[0102] In a preferred embodiment, one or more isolated antigenic peptides consist of the following amino acid sequences: SEQ ID NOs. 1, 2, 3, and 4 of feline 14-3-3 protein; SEQ ID NO. 8 of feline monocarboxylate transporters 3 and 4 proteins (MCT3 and MCT4); SEQ ID NO. 11 of feline vomeronasal receptor 1 felCatV1R6 protein; SEQ ID NO. 12 of feline protein 6 containing transmembrane emp24 domain; SEQ ID NO. 5 of feline SNRPD1; SEQ ID NO. 13 of feline ATP5O; SEQ ID NO. 10 of feline DHP protein and any combination thereof.

[0103] In a preferred embodiment, this aspect of the invention may be related to heart failure caused by dilated cardiomyopathy, which is caused by gene mutations in cat breeds including but not limited to Burmese, Abyssinian, and Siamese cat breeds.

[0104] In a preferred embodiment, this aspect of the invention may be related to heart failure caused by hypertrophic cardiomyopathy, which is caused by gene mutations in cat breeds including but not limited to Maine Coon, Ragdoll, British Shorthair, Sphynx, Chartreux, and Persian cat breeds.

[0105] According to the in vitro method of the present invention, one or more isolated antigenic peptides are 6 to 50 amino acids in length, preferably 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 to 50 amino acids in length.

[0106] Among the most commonly used methods for identifying and quantifying antigen-specific antibodies in biological samples, immunological methods are the preferred methods. Thus, in a preferred embodiment, the in vitro method of the present invention is an immunoassay.

[0107] In a more preferred embodiment, the in vitro method of the present invention is an enzyme-linked immunosorbent assay, called ELISA. In this assay, an immune complex is formed between one or more antigenic peptides immobilized on a solid phase (such as a microtiter plate or bead surface) and IgG antibodies present in a biological fluid sample (such as a serum or plasma sample) from a patient.

[0108] The formation of the IgG antibody / antigenic peptide complex can then be detected using any suitable method. In a preferred embodiment, a labeled anti-IgG immunoglobulin secondary antibody is used. Suitable labels for use in the present invention include, for example, fluorescent compounds, chemiluminescent compounds, radioactive compounds, enzymes and enzyme substrates, and molecules suitable for colorimetric detection.

[0109] Obviously, the use of any type of immunoassay format (the selection of which is within the technical scope of those of ordinary skill in the art) is within the scope of the present invention.

[0110] Preferably, the biological liquid sample is selected from whole blood, serum, plasma, synovial fluid, follicular fluid, and intraocular fluid. The biological liquid sample may optionally include other components such as diluents, preservatives, stabilizers, and / or buffers. If desired, dilutions of the biological liquid sample are prepared using any suitable diluent buffer known in the art.

[0111] In one embodiment of the in vitro method of the present invention, the level of cardiovascular antigen-specific IgG antibodies in a patient can be quantitatively evaluated according to the criteria of "true" healthy controls and healthy controls with matched age and sex. According to the present invention, the readings of such an evaluation provide an indication of the propensity / risk of developing cardiovascular disease with clinically recognizable symptoms in the subject. In the case where elderly "healthy" individuals have a non-zero cardiac-specific antibody titer, a non-zero signal quantified as a "true negative" in the method of the present invention still represents a propensity for a cardiotoxic immune response and thus represents cardiovascular disease.

[0112] In one embodiment, the in vitro method of the present invention is applicable to the real-time evaluation of cardiotoxicity in cancer immunotherapy.

[0113] Checkpoint blockade immunotherapy (CBI) (e.g., via anti-PD1, anti-CTLA4) is a highly successful novel treatment for advanced hematological and solid tumors and is being increasingly used clinically (Barbee, MS, et al. (2015), "Current status and future directions of immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology", Ann Pharmacother, 49(8), 907-37). Cardiotoxicity reactions are mediated by T cell-driven mechanisms. Thus, when a patient still has subclinical cardiac symptoms, the in vitro method according to the present invention can advantageously enable the prediction and / or detection and quantification of T cell responses against cardiovascular tissue. Although cardiotoxicity reactions affect a small but increasing proportion of patients, once they occur, they are rapidly fatal, and early detection can be life-saving.

[0114] In another embodiment, the in vitro method of the present invention provides a diagnosis of the potential risks associated with the introduction of new biopharmaceuticals or immunotherapeutic drugs or vaccines.

[0115] As more and more immunomodulatory drugs, monoclonal antibodies, and vaccines are introduced into clinical trials and ultimately used, the risk of inducing off-target inflammation is increasing. Advantageously, the in vitro method of the present invention is capable of real-time evaluating such responses against the heart in the clinical trial phase of new drugs under development, as well as in patients with higher-risk profiles and / or those showing a higher risk of off-target toxicity during approved clinical practice.

[0116] In another embodiment, the in vitro method of the present invention is applicable to heart transplant monitoring because the detected heart antigen-specific IgG antibodies can represent transplant heart rejection in real time.

[0117] The device suitable for implementing the in vitro method of the present invention is assembled into a kit for use.

[0118] Accordingly, another aspect of the present invention is a kit for diagnosing and / or predicting the risk of a human, canine or feline developing heart failure (HF), as defined in appended claims 9, 10 and 11.

[0119] In a preferred embodiment, one or more isolated antigenic peptides in the kit of the present invention consist of amino acid sequences selected from the group consisting of SEQ ID NOs. 1, 2, 3 and 4 of human 14-3-3 protein; SEQ ID NO. 5 of human small nuclear ribonucleoprotein Sm D1 (SNRPD1); SEQ ID NO. 6 of human mitochondrial precursor ATP synthase subunit O (ATP5O); SEQ ID NO. 7 of human toll-like receptor 5 precursor (TLR5) and any combination thereof.

[0120] In a more preferred embodiment, one or more isolated antigenic peptides in the kit of the present invention consist of at least one peptide of human 14-3-3 protein selected from the group consisting of SEQ ID NOs. 1, 2, 3 and 4; in combination with a peptide consisting of SEQ ID NO. 5 of human SNRPD1 and a peptide consisting of SEQ ID NO. 6 of human ATP5O protein.

[0121] In another preferred embodiment, one or more isolated antigenic peptides in the kit of the present invention consist of at least two peptides of human 14-3-3 protein selected from the group consisting of SEQ ID NOs. 1, 2, 3 and 4; in combination with a peptide consisting of SEQ ID NO. 5 of human SNRPD1 and a peptide consisting of SEQ ID NO. 6 of human ATP5O protein. The at least two peptides of human 14-3-3 protein are, for example, (a) the peptide of SEQ ID NO. 1 and the peptide of SEQ ID NO. 2, (b) the peptide of SEQ ID NO. 1 and the peptide of SEQ ID NO. 3, (c) the peptide of SEQ ID NO. 1 and the peptide of SEQ ID NO. 4, (d) the peptide of SEQ ID NO. 2 and the peptide of SEQ ID NO. 3, (e) the peptide of SEQ ID NO. 2 and the peptide of SEQ ID NO. 4, or (f) the peptide of SEQ ID NO. 3 and the peptide of SEQ ID NO. 4.

[0122] In another preferred embodiment, one or more isolated antigenic peptides in the kit of the present invention consist of at least three peptides of human 14-3-3 protein selected from the group consisting of SEQ ID NO.1, 2, 3, and 4; in combination with the peptide consisting of SEQ ID NO.5 of human SNRPD1 and the peptide consisting of SEQ ID NO.6 of human ATP5O protein. At least three peptides of human 14-3-3 protein are, for example, (g) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.2, and the peptide of SEQ ID NO.3, (h) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.2, and the peptide of SEQ ID NO.4, (i) the peptide of SEQ ID NO.1, the peptide of SEQ ID NO.3, and the peptide of SEQ ID NO.4, or (j) the peptide of SEQ ID NO.2, the peptide of SEQ ID NO.3, and the peptide of SEQ ID NO.4.

[0123] In yet another preferred embodiment, one or more isolated antigenic peptides in the kit of the present invention consist of at least four peptides of human 14-3-3 protein selected from the group consisting of SEQ ID NO.1, 2, 3, and 4; in combination with the peptide consisting of SEQ ID NO.5 of human SNRPD1 and the peptide consisting of SEQ ID NO.6 of human ATP5O protein.

[0124] Optionally, in the above embodiments according to the present invention, the combination of peptides may further comprise the peptide consisting of SEQ ID NO.7 of human TLR5 protein.

[0125] In another preferred embodiment, one or more isolated antigenic peptides in the kit of the present invention consist of amino acid sequences selected from the group consisting of SEQ ID NO.1, 2, 3, and 4 of canine 14-3-3 protein; SEQ ID NO.8 of canine monocarboxylate transporter 3 and 4 proteins (MCT3 and MCT4); SEQ ID NO.5 of canine SNRPD1; SEQ ID NO.9 of canine ATP5O; SEQ ID NO.10 of canine dihydropyrimidinase (DHP) protein, and any combination thereof.

[0126] In yet another preferred embodiment, one or more isolated antigenic peptides in the kit of the present invention are composed of amino acid sequences selected from the group consisting of SEQ ID NO.1, 2, 3, and 4 of feline 14-3-3 protein; SEQ ID NO.8 of feline MCT3 and MCT4 proteins; SEQ ID NO.11 of feline vomeronasal receptor felCatV1R6 protein; SEQ ID NO.12 of feline protein 6 containing transmembrane emp24 domain; SEQ ID NO.5 of feline SNRPD1; SEQ ID NO.13 of feline ATP5O; SEQ ID NO.10 of feline DHP protein, and any combination thereof.

[0127] In the kit of the present invention, one or more antigenic peptides are immobilized on a solid support. Non-limiting examples of suitable solid supports include the wells of microtiter plates, the surfaces of microparticles (such as latex, polystyrene, silica, chelating agarose, or magnetic beads), membranes, strips, or chips.

[0128] In addition, the kit of the present invention comprises the detection means related to the in vitro diagnostic method as described above.

[0129] Further experimental studies conducted by the inventors of the present invention (see the experimental section below for details) showed that healthy mice fed with the peptide antigens of the present invention experienced less heart disease when subjected to transverse aortic constriction (TAC) compared to control animals treated only with phosphate-buffered saline. Surprisingly, these findings indicate that the peptide antigens of the present invention are capable of inducing oral tolerance when administered to animals, which results in prophylactic protection against severe heart failure.

[0130] Therefore, the isolated peptides of the present invention, alone or in combination with each other, are particularly suitable for oral administration for the treatment and / or prevention of heart disease.

[0131] Therefore, another aspect of the present invention is an isolated peptide for treating heart failure and / or preventing heart failure in a subject in need thereof as defined above, said treatment comprising orally administering the peptide to the subject to induce oral tolerance to the peptide.

[0132] In the context of the present specification, the term "oral tolerance" refers to an active process in which the immune system does not mount an inflammatory response to an antigen administered orally. More specifically, the human body is able to tolerate antigens in the gastrointestinal tract, which is likely a necessary condition for maintaining the gut microbiota and digesting food.

[0133] The oral tolerance process is thought to be induced by the generation of immunosuppressive Treg (iTreg) cells, which may respond to these antigens (Larché, M (2014), “Mechanisms of peptide immunotherapy in allergic airway disease”, Ann Am Thorac Soc, 11 Suppl 5S292-6; Chen, X, et al (2017), “Oral administration of visceral adipose tissue antigens improves metabolic disorders in mice and enhances visceral adipose tissue-resident CD4(+)CD25(+)Foxp3(+) regulatory T cells”, Vaccine).

[0134] Without wishing to be bound by any theory, the inventors believe that oral tolerance induction to the inventive peptide antigens that drive the adaptive responses mediating heart failure disease may lead to the generation of antigen-specific immunosuppressive Treg and iTreg cells. When the harmful response begins, these cells act by suppressing any adaptive immune responses leading to heart failure mediated by pro-inflammatory T cells and B cells.

[0135] The method of the present invention can prevent the occurrence of the disease or reduce its severity. In terms of prevention, the method can delay or prevent the occurrence of one or more heart failure symptoms. In terms of treatment, the method can delay or prevent the progression of one or more heart failure symptoms.

[0136] Subjects in need of treatment with the peptides of the present invention can be human patients or non-human patients. In certain embodiments, the non-human patient can be a non-human mammal, such as a dog or a cat. Several domestic dog and cat breeds suffer from congenital heart defects leading to early-onset cardiac insufficiency.

[0137] Another aspect of the present invention is a pharmaceutical composition comprising at least one isolated peptide antigen of the present invention, or any combination thereof as defined above in connection with the preferred embodiments of the present invention, and a pharmaceutically acceptable carrier, vehicle or diluent. The selection of the carrier, vehicle or diluent and any other excipients required to prepare the desired pharmaceutical dosage form is within the capabilities of those skilled in the art.

[0138] The above pharmaceutical composition is preferably a tolerance vaccine suitable for administration by the oral route. As is known in the art, tolerance vaccines are capable of inducing antigen-specific immune tolerance in a subject.

[0139] Preferably, the tolerance vaccine does not contain any adjuvants, i.e., any substances capable of specifically eliciting antigenicity and inflammation.

[0140] Oral formulations generally include an inert diluent or an edible carrier. It can be encapsulated in a gel capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges or capsules.

[0141] Another aspect of the present invention is a food, feed or beverage product comprising at least one of the isolated peptides defined above or any combination thereof defined in connection with the preferred embodiments of the present invention. The food, feed or beverage product of the present invention may be classified as a medical food, a food supplement or other categories, and may be any food or beverage whose preparation does not alter the integrity of the peptide composition.

[0142] The following experimental section is provided purely for illustration and is not intended to limit the scope of the present invention as defined in the appended claims.

[0143] Example 1: Transfer of T cells is sufficient to transfer heart failure (HF) from diseased mice to healthy mice

[0144] To evaluate whether T cells are necessary and sufficient to induce heart failure (HF), the inventors employed the Figure 1 experimental method shown in A. This method involves transferring T cells from mice that have undergone transverse aortic constriction (TAC) surgery to induce HF (or sham surgery control) into healthy recipient mice and examining whether such transfer is sufficient to transfer the disease. Briefly, 4 weeks after TAC or sham surgery, T cells isolated from the cardiac draining lymph nodes (LN) of 8-week-old male C57BL6 / J mice were transferred into healthy mouse recipients. Recipient C57BL6 / J 8-week-old male mice received 1*10 6 cells by intravenous injection.

[0145] Cells isolated from the cardiac draining lymph nodes were stained by FACS analysis to detect the T cell population isolated from the cardiac draining lymph nodes and injected into healthy recipients. As Figure 1 shown in B, T cells isolated from the lymph nodes include cytotoxic CD8+, CD4+ conventional naive T cells and CD4+ conventional effector T cells as well as regulatory T cells.

[0146] At baseline examination (before receiving T cells), and 9 and 12 weeks after cell transplantation, the cardiac function of recipient mice was evaluated by echocardiography. The fractional shortening (%FS) measured by echocardiography is an indication of left ventricular function and represents the percentage of shortening of the left ventricular diameter between end-diastolic and end-systolic. The cardiac function of mice receiving cells from mice that had undergone TAC surgery was significantly reduced (%FS) compared to mice receiving T cells from control (sham surgery) mice, indicating reduced cardiac function ( Figure 1 C). Data are plotted as mean ± SEM; solid lines represent mice receiving cells from mice that had undergone TAC surgery, dashed lines represent mice receiving cells from mice that had undergone sham surgery, (n = 6-7) two-way ANOVA analysis, Bonferroni post hoc test. *p < 0.05.

[0147] Example 2: Antigen development strategy

[0148] Four weeks after sham surgery or TAC surgery, serum samples were collected from 5 sham-operated mice or 5 TAC-operated mice. The sera were pooled into two samples (1 TAC and 1 sham). The pooled serum samples were analyzed on a commercially available murine autoantigen and random antigen discovery array ( Figure 2 ). Bound antibodies were then detected with anti-IgG reagent. The IgG antibody signals for each hit were quantified, and each identified peptide sequence (i.e., the oligopeptide sequence randomly found on the array) and the corresponding signal intensity were reported for further analysis. By detecting only IgG antibodies, the inventors narrowed the analysis to IgG-switched antibodies that had received T cell help. Importantly, all mice used in the experiments were congenic, i.e., genetically identical.

[0149] Example 3: Bioinformatics analysis strategy for antigen discovery process for array readout differential analysis

[0150] To identify the peptide antigens driving T cells relevant to HF pathology, the inventors established a discovery strategy as Figure 3 shown.

[0151] For differential analysis of the array readout, when testing with the TAC pooled serum, the inventors ranked each random oligopeptide based on its differential ability to produce a hit (TAC-IgG binding signal - positive ("up" signal)), and no hit when testing with the sham pooled serum (sham IgG binding signal - negative "down" signal).

[0152] Specifically, epitopes recognized by antibodies with a user-defined threshold of x > 10 (x = mean and corrected fluorescence intensity change between sham mouse serum and TAC mouse serum) were selected. The identified oligopeptides (i.e., epitopes) were used to predict possible antigen proteins using the National Center for Biotechnology Information's PSI-BLAST (Position-Specific Iterative Basic Local Alignment Search Tool, a protein sequence similarity search program) and the RefSeq non-redundant protein database (organism Mus musculus (taxid: 10090)). The PSI-BLAST parameters were set to default values. Candidate proteins corresponding to each identified epitope were selected based on an E-value < 0.01.

[0153] To ensure that the identified proteins are relevant to human diseases, the hits were screened to select only proteins highly homologous to human proteins. The sequence identity (at the protein level) of the list of proteins or protein domains with "up" and "down" hits was tested against human sequences. PSI-BLAST was used to evaluate homology to humans based on the RefSeq non-redundant protein database (organism: human (taxid: 9606)). Proteins with a percent identity higher than 67% were selected. Then, the Human Protein Atlas database (https: / / www.proteinatlas.org / ) was used to evaluate the enrichment of each protein in the heart.

[0154] Figure 4 The peptides identified as the final result of the above process are listed in the table. The table contains the following information: the name of the mouse gene encoding the entire protein, the amino acid FASTA of the sequence of the original entire protein (sequences not fully visible in the figure), the start and end amino acid numbers of the identified peptides in each source protein, the amino acid sequence of the identified peptides, the peptide length, the number of source peptides found on the array that gave rise to each peptide hit, and the percent homology of the peptide to the homologous human protein.

[0155] The three peptides that make up Group 3 are derived from the mouse β-1 adrenergic receptor protein (SEQ ID NO. 66) and are composed of the amino acid sequences designated SEQ ID NO. 15 (SAPLSQQWTAGMGLLLALIVLL), SEQ ID NO. 16 (KALKTLGIIMGVFTLCWL), and SEQ ID NO. 17 (HRDLVPDRLFVFFNWL), respectively. The β-1 adrenergic receptor is known to be an autoantigen-driven response in autoimmune myocarditis (Caforio, AL et al. (2002), "Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathological and clinical implications", Eur J Heart Fail, 4 411-17; Basavalingappa, RH, et al. (2017), "The β1-adrenergic receptor contains multiple IAk and IEk binding epitopes that induce T cell responses in A / J mice with varying degrees of autoimmune myocarditis", Front Immunol, 8 1567). It is well known that peptides from this protein can cause autoimmune responses against the heart. In the discovery method of the present invention, Group 3 serves as an internal positive control to verify the functionality of the process.

[0156] As Figure 4As shown, Group 4 includes the peptide consisting of the amino acid sequence SEQ ID NO.1, which is derived from the mouse 14-3-3 protein (SEQ ID NO.70), the peptide consisting of the amino acid sequence SEQ ID NO.5, which is derived from the mouse Snrpd1 protein (SEQ ID NO.79), and the peptide consisting of the amino acid sequence SEQ ID NO.14, which is derived from the mouse Atp5O protein (SEQ ID NO.80).

[0157] Example 4: Immunization protocol for evaluating peptide cardiac-specific immunogenicity

[0158] To verify the functional relevance of the identified antigens driving T cell recognition of HF, the inventors conducted the experiments described below, as Figure 5 shown.

[0159] Briefly, 8-week-old male C57BL6 / J mice were screened for cardiac function at baseline by echocardiography and randomly divided into three experimental groups. Mice in the negative control group (CTR-, only CFA) were subcutaneously injected (vaccinated) with 100 μl of complete Freund's adjuvant (CFA) on day 0 and boosted with 100 μl of incomplete Freund's adjuvant (IFA) on day 21, without any antigen. Mice belonging to Group 3 (CTR+) were subcutaneously injected (vaccinated) with 100 μg of each of the three peptides derived from the β-adrenergic receptor emulsified in complete Freund's adjuvant (CFA) on day 0 and injected with 100 μg of the three peptides emulsified in incomplete Freund's adjuvant (IFA) on day 21. Mice belonging to Group 4 (Group 4) were subcutaneously injected (vaccinated) with 100 μg of each of the three peptides SEQ ID NO.1, 5, and 14 from mouse 14-3-3, Snrpd1, and Atp5o proteins emulsified in complete Freund's adjuvant on day 0 and boosted with 100 μg of each of the three peptides emulsified in complete Freund's adjuvant (CFA) on day 21. On days 0 and 2, all mice were intraperitoneally injected with 200 ng of pertussis toxin (PTX) according to the standard immunization protocol. At 2, 5, and 9 weeks after the first subcutaneous injection, the cardiac function of all mice was analyzed by echocardiography.

[0160] Immunization experiments in healthy mice with peptides from the β-adrenergic receptor and 14-3-3, Snrpd1, and Atp5o resulted in cardiac dysfunction. As shown in the bar graphs of Figure 6A and 6B at 2, 5, and 9 weeks after the first subcutaneous injection, as analyzed by echocardiography, mice immunized with peptides from the β-adrenergic receptor (CTR+) and 14-3-3, Snrpd1, and Atp5o proteins (Group 4) showed a significant decrease in cardiac function. Left ventricular function was expressed as %FS(Figure 6A ) and ejection fraction (%EF) ( Figure 6B ), which measure the volume of blood pumped by the left ventricle. Data are plotted as mean ± SEM (n = 4 - 6). Two-way ANOVA and Tukey's multiple comparison test. *P < 0.05, **P < 0.01.

[0161] Example 5: Immunization of healthy mice with single peptides from 14-3-3, Snrpd1, and Atp5o can induce cardiac dysfunction. Figure 7

[0162] Cardiac function was screened in 8-week-old male C57BL6 / J mice at baseline by echocardiography and they were randomly divided into 5 experimental groups. Control group (CTR-, only CFA) mice were subcutaneously injected (vaccinated, but without using antigen: negative control) with 100 μl of complete Freund's adjuvant (CFA) on day 0 and boosted with 100 μl of incomplete Freund's adjuvant (IFA) on day 21. Mice belonging to group 3 (CTR+) were subcutaneously injected (vaccinated with known antigen: positive control) with 100 μg of each of the three peptides (SEQ ID NOs. 15 - 17) derived from β-adrenergic receptor and emulsified in complete Freund's adjuvant (CFA) on day 0 and injected with 100 μg of these three peptides emulsified in incomplete Freund's adjuvant (IFA) on day 21. Mice in group 4_A (peptide 4_A) were subcutaneously injected (vaccinated) with the peptide of SEQ ID NO. 1 derived from 14 - 3 - 3 protein emulsified in 100 μg of complete Freund's adjuvant (CFA) on day 0 and injected with 100 μg of these three peptides emulsified in incomplete Freund's adjuvant (IFA) on day 21. Mice in group 4_B (peptide 4_B) were subcutaneously injected (vaccinated) with the peptide of SEQ ID NO. 5 derived from Snrpd1 protein emulsified in 100 μg of complete Freund's adjuvant (CFA) on day 0 and injected with 100 μg of each of these three peptides emulsified in incomplete Freund's adjuvant (IFA) on day 21. Mice in group 4_C (peptide 4_C) were subcutaneously injected (vaccinated) with the peptide of SEQ ID NO. 14 derived from Atp5o protein emulsified in 100 μg of complete Freund's adjuvant (CFA) on day 0 and injected with 100 μg of each of these three peptides emulsified in incomplete Freund's adjuvant (IFA) on day 21. On days 0 and 2, all mice were intraperitoneally injected with 200 ng of pertussis toxin. Cardiac function of all mice was analyzed by echocardiography at 2, 5, and 9 weeks after the first subcutaneous injection. Example 6: Validation of the functional relevance of identified antigens recognized by T cells driving HFShows the results of echocardiographic analysis of cardiac function parameters %FS and %EF in C57BL6 / J mice inoculated with SEQ ID NO.1 peptide (14-3-3 protein), SEQ ID NO.5 peptide (Snrpd1 protein), or SEQ ID NO.14 peptide (Atp5o protein). Mice immunized with peptides from β-adrenergic receptors and 14-3-3, Snrpd1, and Atp5o proteins showed significantly reduced %FS and %EF. Data are plotted as mean ± SEM (n = 4 - 6). Two-way ANOVA and Tukey's multiple comparison test with matched subjects. *p < 0.05, **p < 0.01, ***p < 0.001.

[0163] Figure 8

[0164] The present inventors conducted elaborate experiments to evaluate whether human heart failure patients produce IgG responses to newly identified antigens, and thus to assess whether the T cell-dependent antibody response to the antigens can be used to distinguish HF patients.

[0165] ELISA analysis using peptides of SEQ ID NO.1 (peptide 4_A), SEQ ID NO.5 (peptide 4_B), and SEQ ID NO.14 (peptide 4_C) alone or in combination as capture molecules. A total of 100 ng of peptide 4_A, peptide 4_B, or peptide 4_C or a combination of these peptides was coated overnight on a 96-well plate and non-specific binding was blocked. Then, human serum samples from healthy or heart failure patients were added and incubated for 1 hour. Anti-human IgG-HRP was used to detect the bound IgG antibodies present in the serum. Adding TMB (3,3',5,5'-tetramethylbenzidine) to the wells produced a colorimetric reaction that was proportional to the presence of the bound antibody. The intensity of the colorimetric reaction was measured and the absorbance of each sample was plotted after subtracting the blank ( Example 7: Application of antigens recognized by T cells driving HF identified in preventive treatment experiments ). Data are plotted as mean ± SEM (n = 2); unpaired t-test. *p < 0.05.

[0166] The results of the above ELISA analysis indicate that the peptides according to the present invention alone or in combination are capable of detecting significant differences between HF patients and healthy controls.

[0167] Figure 9

[0168] To evaluate the protective potential of oral tolerance with newly identified peptides to prevent the occurrence of heart failure, the inventors employed an oral tolerance protocol to induce heart-specific tolerance to these peptides and then actively induced heart failure by TAC. Figure 10 Shows a schematic diagram of the protocol employed by the inventors.

[0169] Briefly, 8-week-old male C57BL6 / J mice were screened by echocardiography at baseline. Each mouse was orally administered 0.8 mg of each peptide from Group 4: the peptide of SEQ ID NO.1 (14-3-3 protein), the peptide of SEQ ID NO.5 (Snrpd1 protein), and the peptide of SEQ ID NO.14 (Atp5o protein) (i.e., 0.8 mg of each peptide per day, so a total of 2.4 mg / day) diluted in 600 μl of phosphate buffered saline (PBS) or PBS only (as a control) by oral gavage for 4 consecutive days. Three days after the end of this procedure, i.e., on day 7, the mice underwent TAC surgery to experimentally induce heart failure. At 2, 4, and 8 weeks after TAC surgery, echocardiography was performed on both groups of mice to monitor their cardiac function. As Figure 11 shown, oral administration of the peptides prevented cardiac dysfunction in mice subjected to TAC surgery. Mice orally receiving the identified peptides (peptides of SEQ ID NO.1, 5, and 14) using the above tolerance induction protocol showed significantly better cardiac function (measured by %FS and %EF, solid lines) at 8 weeks postoperatively compared to mice treated with PBS alone (dashed line). Data are plotted as mean ± SEM (n = 8 - 11). Two-way ANOVA and Tukey's multiple comparison test with matched subjects. **p < 0.01, ***p < 0.001.

[0170] In addition, the inventors found that oral administration of the peptides induced oral tolerance to the fed peptides through the production of retinoic acid, which is known to promote the generation of induced immunosuppressive regulatory T cells. Briefly, 8 weeks after oral tolerance induction in mice subjected to TAC surgery, mesenteric lymph nodes (MLN) were collected and dendritic cells (DC) were isolated for FACS analysis. Retinoic acid produced by dendritic cells through aldehyde dehydrogenase (ALDH) was measured using Aldefluor fluorescent dye. FACS analysis of DC isolated from the MLN of mice administered the peptides of SEQ ID NO.1, 5, and 14 showed a significant increase in ALDH activity ( Figure 11 ), which represents retinoic acid production. Retinoic acid produced by tolerogenic DCs contributes to the generation of regulatory T cells (Tregs), which is crucial for tolerance induction. ​ The bar graph in shows that the percentage of ALDH-positive DCs and the mean fluorescence intensity (MFI) (induced by the fluorescent dye) were significantly increased in mice orally administered the peptides compared to mice fed only PBS. Data are plotted as mean ± SEM (n = 7 - 8). Unpaired t-test. *p < 0.05. Sequence Listing <110> HUMANITAS MIRASOLE S.P.A.; HUMANITAS UNIVERSITY <120> Peptide Antigens and Their Uses <130> E0127644 <160> 80 <170> BiSSAP 1.3.6 <210> 1 <211> 15 <212> PRT <213> Homo sapiens <400> 1 Leu Gly Leu Ala Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile Leu 1 5 10 15 <210> 2 <211> 14 <212> PRT <213> Homo sapiens <400> 2 Leu Gly Leu Ala Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile 1 5 10 <210> 3 <211> 14 <212> PRT <213> Homo sapiens <400> 3 Leu Gly Leu Ala Leu Asn Tyr Ser Val Phe Tyr Tyr Glu Ile 1 5 10 <210> 4 <211> 14 <212> PRT <213> Homo sapiens <400> 4 Leu Gly Leu Ala Leu Asn Phe Ser Val Phe His Tyr Glu Ile 1 5 10 <210> 5 <211> 25 <212> PRT <213> Homo sapiens <400> 5 Glu Pro Val Gln Leu Glu Thr Leu Ser Ile Arg Gly Asn Asn Ile Arg 1 5 10 15 Tyr Phe Ile Leu Pro Asp Ser Leu Pro 20 25 <210> 6 <211> 15 <212> PRT <213> Homo sapiens <400> 6 Leu Thr Thr Asn Leu Ile Asn Leu Leu Ala Glu Asn Gly Arg Leu 1 5 10 15 <210> 7 <211> 13 <212> PRT <213> Homo sapiens <400> 7 Leu Thr Ala Asn Leu Ile His Leu Ser Glu Asn Arg Leu 1 5 10 <210> 8 <211> 7 <212> PRT <213> Canis lupus familiaris <400> 8 Leu Gly Leu Ala Leu Asn Phe 1 5 <210> 9 <211> 14 <212> PRT <213> Canis lupus familiaris <400> 9 Thr Ser Asn Leu Ile Asn Leu Leu Ala Glu Asn Gly Arg Leu 1 5 10 <210> 10 <211> 8 <212> PRT <213> Canis lupus familiaris <400> 10 Leu Met Asn Leu Leu Ala Asn Gly 1 5 <210> 11 <211> 9 <212> PRT <213> Felis catus <400> 11 Leu Gly Asn Phe Ser Val Phe Tyr Tyr 1 5 <210> 12 <211> 7 <212> PRT <213> Felis catus <400> 12 Leu Asn Phe Gly Val Phe Tyr 1 5 <210> 13 <211> 15 <212> PRT <213> Felis catus <400> 13 Leu Thr Cys Asn Leu Ile Asn Leu Leu Ala Glu Asn Gly Arg Leu 1 5 10 15 <210> 14 <211> 15 <212> PRT <213> Mus musculus <400> 14 Leu Thr Ala Asn Leu Met Asn Leu Leu Ala Glu Asn Gly Arg Leu 1 5 10 15 <210> 15 <211> 22 <212> PRT <213> Mouse (Mus musculus) <400> 15 Ser Ala Pro Leu Ser Gln Gln Trp Thr Ala Gly Met Gly Leu Leu Leu 1 5 10 15 Ala Leu Ile Val Leu Leu 20 <210> 16 <211> 18 <212> PRT <213> Mouse (Mus musculus) <400> 16 Lys Ala Leu Lys Thr Leu Gly Ile Ile Met Gly Val Phe Thr Leu Cys 1 5 10 15 Trp Leu <210> 17 <211> 16 <212> PRT <213> Mouse (Mus musculus) <400> 17 His Arg Asp Leu Val Pro Asp Arg Leu Phe Val Phe Phe Asn Trp Leu 1 5 10 15 <210> 18 <211> 255 <212> PRT <213> Human (Homo sapiens) <400> 18 Met Asp Asp Arg Glu Asp Leu Val Tyr Gln Ala Lys Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20 25 30 Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 50 55 60 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65 70 75 80 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85 90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 100 105 110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 115 120 125 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130 135 140 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150 155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 180 185 190 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195 200 205 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Gly Glu 225 230 235 240 Glu Gln Asn Lys Glu Ala Leu Gln Asp Val Glu Asp Glu Asn Gln 245 250 255 <210> 19 <211> 240 <212> PRT <213> Homo sapiens <400> 19 Met Asp Asp Arg Glu Asp Leu Val Tyr Gln Ala Lys Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20 25 30 Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 50 55 60 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65 70 75 80 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85 90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 100 105 110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 115 120 125 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130 135 140 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150 155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 180 185 190 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195 200 205 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Asp Ser 225 230 235 240 <210> 20 <211> 218 <212> PRT <213> Homo sapiens <400> 20 Met Val Glu Ser Met Lys Lys Val Ala Gly Met Asp Val Glu Leu Thr 1 5 10 15 Val Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr Lys Asn Val Ile Gly 20 25 30 Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser Ser Ile Glu Gln Lys Glu 35 40 45 Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys Met Ile Arg Glu Tyr Arg 50 55 60 Gln Met Val Glu Thr Glu Leu Lys Leu Ile Cys Cys Asp Ile Leu Asp 65 70 75 80 Val Leu Asp Lys His Leu Ile Pro Ala Ala Asn Thr Gly Glu Ser Lys 85 90 95 Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr His Arg Tyr Leu Ala Glu 100 105 110 Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala Ala Glu Asn Ser Leu Val 115 120 125 Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met Thr Glu Leu Pro Pro Thr 130 135 140 His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val Phe Tyr Tyr 145 150 155 160 Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys Arg Leu Ala Lys Ala Ala 165 170 175 Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu Glu Ser Tyr 180 185 190 Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn Leu Thr Leu 195 200 205 Trp Thr Ser Asp Met Gln Gly Asp Asp Ser 210 215 <210> 21 <211> 244 <212> PRT <213> Homo sapiens <400> 21 Met Thr Met Asp Lys Ser Glu Leu Val Gln Lys Ala Lys Leu Ala Glu 1 5 10 15 Gln Ala Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Ala Val Thr 20 25 30 Glu Gln Gly His Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val 35 40 45 Ala Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile 50 55 60 Ser Ser Ile Glu Gln Lys Thr Glu Arg Asn Glu Lys Lys Gln Gln Met 65 70 75 80 Gly Lys Glu Tyr Arg Glu Lys Ile Glu Ala Glu Leu Gln Asp Ile Cys 85 90 95 Asn Asp Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Pro Asn Ala Thr 100 105 110 Gln Pro Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe 115 120 125 Arg Tyr Leu Ser Glu Val Ala Ser Gly Asp Asn Lys Gln Thr Thr Val 130 135 140 Ser Asn Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys 145 150 155 160 Glu Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe 165 170 175 Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser 180 185 190 Leu Ala Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu 195 200 205 Asn Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg 210 215 220 Asp Asn Leu Thr Leu Trp Thr Ser Glu Asn Gln Gly Asp Glu Gly Asp 225 230 235 240 Ala Gly Glu Gly <210> 22 <211> 245 <212> PRT <213> Homo sapiens <400> 22 Met Glu Lys Thr Glu Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Thr Cys Met Lys Ala Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Arg Arg Ser Ala Trp Arg Val Ile Ser Ser 50 55 60 Ile Glu Gln Lys Thr Asp Thr Ser Asp Lys Lys Leu Gln Leu Ile Lys 65 70 75 80 Asp Tyr Arg Glu Lys Val Glu Ser Glu Leu Arg Ser Ile Cys Thr Thr 85 90 95 Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Ala Asn Ala Thr Asn Pro 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe Arg Tyr 115 120 125 Leu Ala Glu Val Ala Cys Gly Asp Asp Arg Lys Gln Thr Ile Asp Asn 130 135 140 Ser Gln Gly Ala Tyr Gln Glu Ala Phe Asp Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Asn Pro Glu Leu Ala Cys Thr Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu 195 200 205 Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Ser Ala Gly Glu Glu Cys Asp Ala Ala 225 230 235 240 Glu Gly Ala Glu Asn 245 <210> 23 <211> 253 <212> PRT <213> Homo sapiens <400> 23 Met Asp Lys Asn Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Ala Cys Met Lys Ser Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Val Ser Ser 50 55 60 Ile Glu Gln Lys Thr Glu Gly Ala Glu Lys Lys Gln Gln Met Ala Arg 65 70 75 80 Glu Tyr Arg Glu Lys Ile Glu Thr Glu Leu Arg Asp Ile Cys Asn Asp 85 90 95 Val Leu Ser Leu Leu Glu Lys Phe Leu Ile Pro Asn Ala Ser Gln Ala 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr Arg Tyr 115 120 125 Leu Ala Glu Val Ala Ala Gly Asp Asp Lys Lys Gly Ile Val Asp Gln 130 135 140 Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu 195 200 205 Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Thr Gln Gly Asp Glu Ala Glu Ala Gly 225 230 235 240 Glu Gly Gly Glu Asn Ser Asp Met Gln Gly Asp Asp Ser 245 250 <210> 24 <211> 246 <212> PRT <213> Homo sapiens <400> 24 Met Gly Asp Arg Glu Gln Leu Leu Gln Arg Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ser Ala Met Lys Ala Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Asp Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Met Ala Asp Gly Asn Glu Lys Lys Leu Glu 65 70 75 80 Lys Val Lys Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Thr Val 85 90 95 Cys Asn Asp Val Leu Ser Leu Leu Asp Lys Phe Leu Ile Lys Asn Cys 100 105 110 Asn Asp Phe Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Ser Gly Glu Lys Lys Asn 130 135 140 Ser Val Val Glu Ala Ser Glu Ala Ala Tyr Lys Glu Ala Phe Glu Ile 145 150 155 160 Ser Lys Glu Gln Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys Leu Leu Ala Lys Gln Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Glu 225 230 235 240 Glu Ala Gly Glu Gly Asn 245 <210> 25 <211> 247 <212> PRT <213> Homo sapiens <400> 25 Met Val Asp Arg Glu Gln Leu Val Gln Lys Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Asn Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Ser Ala Asp Gly Asn Glu Lys Lys Ile Glu 65 70 75 80 Met Val Arg Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Ala Val 85 90 95 Cys Gln Asp Val Leu Ser Leu Leu Asp Asn Tyr Leu Ile Lys Asn Cys 100 105 110 Ser Glu Thr Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Thr Gly Glu Lys Arg Ala 130 135 140 Thr Val Val Glu Ser Ser Glu Lys Ala Tyr Ser Glu Ala His Glu Ile 145 150 155 160 Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Tyr Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys His Leu Ala Lys Thr Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Asp 225 230 235 240 Asp Gly Gly Glu Gly Asn Asn 245 <210> 26 <211> 248 <212> PRT <213> Homo sapiens <400> 26 Met Glu Arg Ala Ser Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Glu Asp Met Ala Ala Phe Met Lys Gly Ala Val Glu Lys 20 25 30 Gly Glu Glu Leu Ser Cys Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Gln Arg Ala Ala Trp Arg Val Leu Ser Ser 50 55 60 Ile Glu Gln Lys Ser Asn Glu Glu Gly Ser Glu Glu Lys Gly Pro Glu 65 70 75 80 Val Arg Glu Tyr Arg Glu Lys Val Glu Thr Glu Leu Gln Gly Val Cys 85 90 95 Asp Thr Val Leu Gly Leu Leu Asp Ser His Leu Ile Lys Glu Ala Gly 100 105 110 Asp Ala Glu Ser Arg Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr 115 120 125 Arg Tyr Leu Ala Glu Val Ala Thr Gly Asp Asp Lys Lys Arg Ile Ile 130 135 140 Asp Ser Ala Arg Ser Ala Tyr Gln Glu Ala Met Asp Ile Ser Lys Lys 145 150 155 160 Glu Met Pro Pro Thr Asn Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe 165 170 175 Ser Val Phe His Tyr Glu Ile Ala Asn Ser Pro Glu Glu Ala Ile Ser 180 185 190 Leu Ala Lys Thr Thr Phe Asp Glu Ala Met Ala Asp Leu His Thr Leu 195 200 205 Ser Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg 210 215 220 Asp Asn Leu Thr Leu Trp Thr Ala Asp Asn Ala Gly Glu Glu Gly Gly 225 230 235 240 Glu Ala Pro Gln Glu Pro Gln Ser 245 <210> 27 <211> 119 <212> PRT <213> Homo sapiens <400> 27 Met Lys Leu Val Arg Phe Leu Met Lys Leu Ser His Glu Thr Val Thr 1 5 10 15 Ile Glu Leu Lys Asn Gly Thr Gln Val His Gly Thr Ile Thr Gly Val 20 25 30 Asp Val Ser Met Asn Thr His Leu Lys Ala Val Lys Met Thr Leu Lys 35 40 45 Asn Arg Glu Pro Val Gln Leu Glu Thr Leu Ser Ile Arg Gly Asn Asn 50 55 60 Ile Arg Tyr Phe Ile Leu Pro Asp Ser Leu Pro Leu Asp Thr Leu Leu 65 70 75 80 Val Asp Val Glu Pro Lys Val Lys Ser Lys Lys Arg Glu Ala Val Ala 85 90 95 Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg 100 105 110 Gly Arg Gly Gly Pro Arg Arg 115 <210> 28 <211> 213 <212> PRT <213> Homo sapiens <400> 28 Met Ala Ala Pro Ala Val Ser Gly Leu Ser Arg Gln Val Arg Cys Phe 1 5 10 15 Ser Thr Ser Val Val Arg Pro Phe Ala Lys Leu Val Arg Pro Pro Val 20 25 30 Gln Val Tyr Gly Ile Glu Gly Arg Tyr Ala Thr Ala Leu Tyr Ser Ala 35 40 45 Ala Ser Lys Gln Asn Lys Leu Glu Gln Val Glu Lys Glu Leu Leu Arg 50 55 60 Val Ala Gln Ile Leu Lys Glu Pro Lys Val Ala Ala Ser Val Leu Asn 65 70 75 80 Pro Tyr Val Lys Arg Ser Ile Lys Val Lys Ser Leu Asn Asp Ile Thr 85 90 95 Ala Lys Glu Arg Phe Ser Pro Leu Thr Thr Asn Leu Ile Asn Leu Leu 100 105 110 Ala Glu Asn Gly Arg Leu Ser Asn Thr Gln Gly Val Val Ser Ala Phe 115 120 125 Ser Thr Met Met Ser Val His Arg Gly Glu Val Pro Cys Thr Val Thr 130 135 140 Ser Ala Ser Pro Leu Glu Glu Ala Thr Leu Ser Glu Leu Lys Thr Val 145 150 155 160 Leu Lys Ser Phe Leu Ser Gln Gly Gln Val Leu Lys Leu Glu Ala Lys 165 170 175 Thr Asp Pro Ser Ile Leu Gly Gly Met Ile Val Arg Ile Gly Glu Lys 180 185 190 Tyr Val Asp Met Ser Val Lys Thr Lys Ile Gln Lys Leu Gly Arg Ala 195 200 205 Met Arg Glu Ile Val 210 <210> 29 <211> 858 <212> PRT <213> Homo sapiens <400> 29 Met Gly Asp His Leu Asp Leu Leu Leu Gly Val Val Leu Met Ala Gly 1 5 10 15 Pro Val Phe Gly Ile Pro Ser Cys Ser Phe Asp Gly Arg Ile Ala Phe 20 25 30 Tyr Arg Phe Cys Asn Leu Thr Gln Val Pro Gln Val Leu Asn Thr Thr 35 40 45 Glu Arg Leu Leu Leu Ser Phe Asn Tyr Ile Arg Thr Val Thr Ala Ser 50 55 60 Ser Phe Pro Phe Leu Glu Gln Leu Gln Leu Leu Glu Leu Gly Ser Gln 65 70 75 80 Tyr Thr Pro Leu Thr Ile Asp Lys Glu Ala Phe Arg Asn Leu Pro Asn 85 90 95 Leu Arg Ile Leu Asp Leu Gly Ser Ser Lys Ile Tyr Phe Leu His Pro 100 105 110 Asp Ala Phe Gln Gly Leu Phe His Leu Phe Glu Leu Arg Leu Tyr Phe 115 120 125 Cys Gly Leu Ser Asp Ala Val Leu Lys Asp Gly Tyr Phe Arg Asn Leu 130 135 140 Lys Ala Leu Thr Arg Leu Asp Leu Ser Lys Asn Gln Ile Arg Ser Leu 145 150 155 160 Tyr Leu His Pro Ser Phe Gly Lys Leu Asn Ser Leu Lys Ser Ile Asp 165 170 175 Phe Ser Ser Asn Gln Ile Phe Leu Val Cys Glu His Glu Leu Glu Pro 180 185 190 Leu Gln Gly Lys Thr Leu Ser Phe Phe Ser Leu Ala Ala Asn Ser Leu 195 200 205 Tyr Ser Arg Val Ser Val Asp Trp Gly Lys Cys Met Asn Pro Phe Arg 210 215 220 Asn Met Val Leu Glu Ile Leu Asp Val Ser Gly Asn Gly Trp Thr Val 225 230 235 240 Asp Ile Thr Gly Asn Phe Ser Asn Ala Ile Ser Lys Ser Gln Ala Phe 245 250 255 Ser Leu Ile Leu Ala His His Ile Met Gly Ala Gly Phe Gly Phe His 260 265 270 Asn Ile Lys Asp Pro Asp Gln Asn Thr Phe Ala Gly Leu Ala Arg Ser 275 280 285 Ser Val Arg His Leu Asp Leu Ser His Gly Phe Val Phe Ser Leu Asn 290 295 300 Ser Arg Val Phe Glu Thr Leu Lys Asp Leu Lys Val Leu Asn Leu Ala 305 310 315 320 Tyr Asn Lys Ile Asn Lys Ile Ala Asp Glu Ala Phe Tyr Gly Leu Asp 325 330 335 Asn Leu Gln Val Leu Asn Leu Ser Tyr Asn Leu Leu Gly Glu Leu Tyr 340 345 350 Ser Ser Asn Phe Tyr Gly Leu Pro Lys Val Ala Tyr Ile Asp Leu Gln 355 360 365 Lys Asn His Ile Ala Ile Ile Gln Asp Gln Thr Phe Lys Phe Leu Glu 370 375 380 Lys Leu Gln Thr Leu Asp Leu Arg Asp Asn Ala Leu Thr Thr Ile His 385 390 395 400 Phe Ile Pro Ser Ile Pro Asp Ile Phe Leu Ser Gly Asn Lys Leu Val 405 410 415 Thr Leu Pro Lys Ile Asn Leu Thr Ala Asn Leu Ile His Leu Ser Glu 420 425 430 Asn Arg Leu Glu Asn Leu Asp Ile Leu Tyr Phe Leu Leu Arg Val Pro 435 440 445 His Leu Gln Ile Leu Ile Leu Asn Gln Asn Arg Phe Ser Ser Cys Ser 450 455 460 Gly Asp Gln Thr Pro Ser Glu Asn Pro Ser Leu Glu Gln Leu Phe Leu 465 470 475 480 Gly Glu Asn Met Leu Gln Leu Ala Trp Glu Thr Glu Leu Cys Trp Asp 485 490 495 Val Phe Glu Gly Leu Ser His Leu Gln Val Leu Tyr Leu Asn His Asn 500 505 510 Tyr Leu Asn Ser Leu Pro Pro Gly Val Phe Ser His Leu Thr Ala Leu 515 520 525 Arg Gly Leu Ser Leu Asn Ser Asn Arg Leu Thr Val Leu Ser His Asn 530 535 540 Asp Leu Pro Ala Asn Leu Glu Ile Leu Asp Ile Ser Arg Asn Gln Leu 545 550 555 560 Leu Ala Pro Asn Pro Asp Val Phe Val Ser Leu Ser Val Leu Asp Ile 565 570 575 Thr His Asn Lys Phe Ile Cys Glu Cys Glu Leu Ser Thr Phe Ile Asn 580 585 590 Trp Leu Asn His Thr Asn Val Thr Ile Ala Gly Pro Pro Ala Asp Ile 595 600 605 Tyr Cys Val Tyr Pro Asp Ser Phe Ser Gly Val Ser Leu Phe Ser Leu 610 615 620 Ser Thr Glu Gly Cys Asp Glu Glu Glu Val Leu Lys Ser Leu Lys Phe 625 630 635 640 Ser Leu Phe Ile Val Cys Thr Val Thr Leu Thr Leu Phe Leu Met Thr 645 650 655 Ile Leu Thr Val Thr Lys Phe Arg Gly Phe Cys Phe Ile Cys Tyr Lys 660 665 670 Thr Ala Gln Arg Leu Val Phe Lys Asp His Pro Gln Gly Thr Glu Pro 675 680 685 Asp Met Tyr Lys Tyr Asp Ala Tyr Leu Cys Phe Ser Ser Lys Asp Phe 690 695 700 Thr Trp Val Gln Asn Ala Leu Leu Lys His Leu Asp Thr Gln Tyr Ser 705 710 715 720 Asp Gln Asn Arg Phe Asn Leu Cys Phe Glu Glu Arg Asp Phe Val Pro 725 730 735 Gly Glu Asn Arg Ile Ala Asn Ile Gln Asp Ala Ile Trp Asn Ser Arg 740 745 750 Lys Ile Val Cys Leu Val Ser Arg His Phe Leu Arg Asp Gly Trp Cys 755 760 765 Leu Glu Ala Phe Ser Tyr Ala Gln Gly Arg Cys Leu Ser Asp Leu Asn 770 775 780 Ser Ala Leu Ile Met Val Val Val Gly Ser Leu Ser Gln Tyr Gln Leu 785 790 795 800 Met Lys His Gln Ser Ile Arg Gly Phe Val Gln Lys Gln Gln Tyr Leu 805 810 815 Arg Trp Pro Glu Asp Phe Gln Asp Val Gly Trp Phe Leu His Lys Leu 820 825 830 Ser Gln Gln Ile Leu Lys Lys Glu Lys Glu Lys Lys Lys Asp Asn Asn 835 840 845 Ile Pro Leu Gln Thr Val Ala Thr Ile Ser 850 855 <210> 30 <211> 262 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 30 Methionine, Aspartic Acid, Aspartic Acid, Arginine, Glutamic Acid, Aspartic Acid, Leucine, Valine, Tyrosine, Glutamine, Alanine, Lysine, Leucine, Alanine, Glutamic Acid, Glutamine 1, 5, 10, 15 Alanine, Glutamic Acid, Arginine, Tyrosine, Aspartic Acid, Valine, Glutamine, Methionine, Alanine, Phenylalanine, Cysteine, Aspartic Acid, Glutamic Acid, Methionine, Valine, Glutamic Acid 20, 25, 30 Serine, Methionine, Lysine, Lysine, Valine, Alanine, Glycine, Methionine, Aspartic Acid, Valine, Glutamic Acid, Leucine, Threonine, Valine, Glutamic Acid, Glutamic Acid 35, 40, 45 Arginine, Asparagine, Leucine, Leucine, Serine, Valine, Alanine, Tyrosine, Lysine, Asparagine, Valine, Isoleucine, Glycine, Alanine, Arginine, Arginine 50, 55, 60 Alanine, Serine, Tryptophan, Arginine, Isoleucine, Isoleucine, Serine, Serine, Isoleucine, Glutamic Acid, Glutamine, Lysine, Glutamic Acid, Glutamic Acid, Asparagine, Lysine 65, 70, 75, 80 Glycine, Glycine, Glutamic Acid, Aspartic Acid, Lysine, Leucine, Lysine, Methionine, Isoleucine, Arginine, Glutamic Acid, Tyrosine, Arginine, Glutamine, Methionine, Valine 85, 90, 95 Glutamic Acid, Threonine, Glutamic Acid, Leucine, Lysine, Leucine, Isoleucine, Cysteine, Cysteine, Aspartic Acid, Isoleucine, Leucine, Aspartic Acid, Valine, Leucine, Aspartic Acid 100, 105, 110 Lysine, Histidine, Leucine, Isoleucine, Proline, Alanine, Alanine, Asparagine, Threonine, Glycine, Glutamic Acid, Serine, Lysine, Valine, Phenylalanine, Tyrosine 115, 120, 125 Tyrosine, Lysine, Methionine, Lysine, Glycine, Aspartic Acid, Tyrosine, Histidine, Arginine, Tyrosine, Leucine, Alanine, Glutamic Acid, Phenylalanine, Alanine, Threonine 130, 135, 140 Glycine, Asparagine, Aspartic Acid, Arginine, Lysine, Glutamic Acid, Alanine, Alanine, Glutamic Acid, Asparagine, Serine, Leucine, Valine, Alanine, Tyrosine, Lysine 145, 150, 155, 160 Ala Ala Ser Asp Ile Ala Met Thr Glu Leu Pro Pro Thr His Pro Ile 165 170 175 Arg Leu Gly Leu Ala Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile Leu 180 185 190 Asn Ser Pro Asp Arg Ala Cys Arg Leu Ala Lys Ala Ala Phe Asp Asp 195 200 205 Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu Glu Ser Tyr Lys Asp Ser 210 215 220 Thr Leu Ile Met Gln Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser 225 230 235 240 Asp Met Gln Gly Asp Gly Glu Glu Gln Asn Lys Glu Ala Leu Gln Asp 245 250 255 Val Glu Asp Glu Asn Gln 260 <210> 31 <211> 255 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 31 Met Asp Asp Arg Glu Asp Leu Val Tyr Gln Ala Lys Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20 25 30 <401> 31Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 50 55 60 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65 70 75 80 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85 90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 100 105 110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 115 120 125 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130 135 140 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150 155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 180 185 190 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195 200 205 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Gly Glu 225 230 235 240 Glu Gln Asn Lys Glu Ala Leu Gln Asp Val Glu Asp Glu Asn Gln 245 250 255 <210> 32 <211> 224 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 32 Met Ala Phe Cys Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 1 5 10 15 Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 20 25 30 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 35 40 45 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 50 55 60 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 65 70 75 80 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 85 90 95 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 100 105 110 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 115 120 125 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 130 135 140 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 145 150 155 160 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 165 170 175 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 180 185 190 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 195 200 205 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Asp Ser 210 215 220 <210> 33 <211> 267 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 33 Met Ile Lys Tyr Leu Phe Ala Glu Ala Gly Lys Ile Leu Gln Asp Val 1 5 10 15 Phe Ser Leu Pro Ser Cys Cys Ser Leu Leu Val Gln Met Ala Phe Cys 20 25 30 Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly Met Asp Val Glu 35 40 45 Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr Lys Asn Val 50 55 60 Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser Ser Ile Glu Gln 65 70 75 80 Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys Met Ile Arg Glu 85 90 95 Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile Cys Cys Asp Ile 100 105 110 Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala Asn Thr Gly Glu 115 120 125 Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr His Arg Tyr Leu 130 135 140 Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala Ala Glu Asn Ser 145 150 155 160 Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met Thr Glu Leu Pro 165 170 175 Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val Phe 180 185 190 Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys Arg Leu Ala Lys 195 200 205 Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu Glu 210 215 220 Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn Leu 225 230 235 240 Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Gly Glu Glu Gln Asn Lys 245 250 255 Glu Ala Leu Gln Asp Val Glu Asp Glu Asn Gln 260 265 <210> 34 <211> 247 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 34 Met Glu Lys Thr Glu Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Gln Ala Glu Arg Tyr Asp Asp Arg Ala Thr Cys Val Met Ala Gly 20 25 30 Pro Glu Gln Gly Ala Glu Leu Ser Asn Glu Glu Arg Ser Leu Leu Ser 35 40 45 Val Ala Tyr Lys Asn Val Val Gly Gly Arg Arg Ser Ala Trp Arg Val 50 55 60 Ser Ser Ser Ile Glu Gln Lys Thr Asp Thr Ser Asp Lys Lys Leu Gln 65 70 75 80 Leu Ile Lys Asp Cys Arg Glu Lys Val Glu Ser Glu Leu Arg Ser Ile 85 90 95 Cys Thr Thr Thr Leu Glu Leu Leu Asp Lys Tyr Leu Thr Ala Asn Ala 100 105 110 Thr Asn Pro Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr 115 120 125 Phe Arg Tyr Leu Ala Glu Val Ala Arg Gly Asp Asp Arg Lys Gln Thr 130 135 140 Ile Asp Asn Ser Gln Gly Ala Tyr Gln Glu Ala Phe Asp Ile Ser Lys 145 150 155 160 Lys Glu Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Asn Pro Glu Leu Val Cys 180 185 190 Thr Leu Ala Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Gly Thr 195 200 205 Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Arg Thr Ser Asp Ser Ala Gly Glu Glu Cys Asp 225 230 235 240 Ala Ala Glu Gly Ala Glu Asn 245 <210> 35 <211> 245 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 35 Met Glu Lys Thr Glu Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Thr Cys Met Lys Ala Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Arg Arg Ser Ala Trp Arg Val Ile Ser Ser 50 55 60 Ile Glu Gln Lys Thr Asp Thr Ser Asp Lys Lys Leu Gln Leu Ile Lys 65 70 75 80 Asp Tyr Arg Glu Lys Val Glu Ser Glu Leu Arg Ser Ile Cys Thr Thr 85 90 95 Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Ala Asn Ala Thr Asn Pro 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe Arg Tyr 115 120 125 Leu Ala Glu Val Ala Cys Gly Asp Asp Arg Lys Gln Thr Ile Asp Asn 130 135 140 Ser Gln Gly Ala Tyr Gln Glu Ala Phe Asp Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Asn Pro Glu Leu Ala Cys Thr Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu 195 200 205 Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Ser Ala Gly Glu Glu Cys Asp Ala Ala 225 230 235 240 Glu Gly Ala Glu Asn 245 <210> 36 <211> 245 <212> PRT <213> Canis lupus familiaris <400> 36 Met Asp Lys Asn Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Ala Cys Met Lys Ser Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Val Ser Ser 50 55 60 Ile Glu Gln Lys Thr Glu Gly Ala Glu Lys Lys Gln Gln Met Ala Arg 65 70 75 80 Glu Tyr Arg Glu Lys Ile Glu Thr Glu Leu Arg Asp Ile Cys Asn Asp 85 90 95 Val Leu Ser Leu Leu Glu Lys Phe Leu Ile Pro Asn Ala Ser Gln Ala 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr Arg Tyr 115 120 125 Leu Ala Glu Val Ala Ala Gly Asp Asp Lys Lys Gly Ile Val Asp Gln 130 135 140 Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu 195 200 205 Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Thr Gln Gly Asp Glu Ala Glu Ala Gly 225 230 235 240 Glu Gly Gly Glu Asn 245 <210> 37 <211> 244 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 37 Met Asp Lys Ser Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Ala Val Thr Glu Gln 20 25 30 Gly His Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser Ser 50 55 60 Ile Glu Gln Lys Thr Glu Arg Asn Glu Lys Lys Gln Gln Met Gly Lys 65 70 75 80 Glu Tyr Arg Glu Lys Ile Glu Ala Glu Leu Gln Asp Ile Cys Asn Asp 85 90 95 Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Pro Asn Ala Thr Gln Pro 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe Arg Tyr 115 120 125 Leu Ser Glu Val Ala Ser Gly Asp Asn Lys Gln Thr Thr Val Ser Asn 130 135 140 Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu 195 200 205 Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Glu Asn Gln Gly Asp Glu Gly Asp Ala Gly 225 230 235 240 Glu Gly Glu Asn <210> 38 <211> 246 <212> PRT <213> Canis lupus familiaris <400> 38 Met Gly Asp Arg Glu Gln Leu Leu Gln Arg Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ser Ala Met Lys Ala Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Asp Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Met Ala Asp Gly Asn Glu Lys Lys Leu Glu 65 70 75 80 Lys Val Lys Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Thr Val 85 90 95 Cys Asn Asp Val Leu Ala Leu Leu Asp Lys Phe Leu Ile Lys Asn Cys 100 105 110 Asn Asp Phe Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Ser Gly Glu Lys Lys Asn 130 135 140 Ser Val Val Glu Ala Ser Glu Ala Ala Tyr Lys Glu Ala Phe Glu Ile 145 150 155 160 Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys Leu Leu Ala Lys Gln Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Glu 225 230 235 240 Glu Ala Gly Glu Gly Asn 245 <210> 39 <211> 232 <212> PRT <213> Canis lupus familiaris <400> 39 Met Ser Phe Cys Leu Ile Ser Ser Ser Gln Pro Glu Asn Lys Val Thr 1 5 10 15 Glu Leu Asn Glu Pro Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val 20 25 30 Ala Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile 35 40 45 Ser Ser Ile Glu Gln Lys Thr Ser Ala Asp Gly Asn Glu Lys Lys Ile 50 55 60 Glu Met Val Arg Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Ala 65 70 75 80 Val Cys Gln Asp Val Leu Ser Leu Leu Asp Asn Tyr Leu Ile Lys Asn 85 90 95 Cys Ser Glu Thr Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys 100 105 110 Gly Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Thr Gly Glu Lys Arg 115 120 125 Ala Thr Val Val Glu Ser Ser Glu Lys Ala Tyr Ser Glu Ala His Glu 130 135 140 Ile Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu 145 150 155 160 Ala Leu Asn Tyr Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu 165 170 175 Gln Ala Cys His Leu Ala Lys Thr Ala Phe Asp Asp Ala Ile Ala Glu 180 185 190 Leu Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met 195 200 205 Gln Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp 210 215 220 Asp Asp Gly Gly Glu Gly Asn Asn 225 230 <210> 40 <211> 248 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 40 Met Glu Arg Ala Ser Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Glu Asp Met Ala Ala Phe Met Lys Ser Ala Val Glu Lys 20 25 30 Gly Glu Glu Leu Ser Cys Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Gln Arg Ala Ala Trp Arg Val Leu Ser Ser 50 55 60 Ile Glu Gln Lys Gly Asn Glu Glu Ser Ser Glu Glu Lys Gly Pro Glu 65 70 75 80 Val Arg Glu Tyr Arg Glu Lys Val Glu Thr Glu Leu Arg Gly Val Cys 85 90 95 Asp Thr Val Leu Gly Leu Leu Asp Ser His Leu Ile Lys Glu Ala Gly 100 105 110 Asp Ala Glu Ser Arg Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr 115 120 125 Arg Tyr Leu Ala Glu Val Ala Thr Gly Asp Asp Lys Lys Arg Ile Ile 130 135 140 Asp Ser Ala Arg Ser Ala Tyr Gln Glu Ala Met Asp Ile Ser Lys Lys 145 150 155 160 Glu Met Pro Pro Thr Asn Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe 165 170 175 Ser Val Phe His Tyr Glu Ile Ala Asn Ser Pro Glu Glu Ala Ile Ser 180 185 190 Leu Ala Lys Thr Thr Phe Asp Glu Ala Met Ala Asp Leu His Thr Leu 195 200 205 Ser Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg 210 215 220 Asp Asn Leu Thr Leu Trp Thr Ala Asp Asn Ala Gly Glu Glu Gly Gly 225 230 235 240 Glu Ala Pro Glu Glu Pro Gln Ser 245 <210> 41 <211> 507 <212> PRT <213> Canis lupus familiaris <400> 41 Met Gly Ala Gly Gly Pro Arg Arg Gly Glu Gly Pro Pro Asp Gly Gly 1 5 10 15 Trp Gly Trp Ala Val Leu Gly Ala Cys Phe Val Val Thr Gly Phe Ala 20 25 30 Tyr Gly Phe Pro Lys Ala Val Ser Val Phe Phe Arg Ala Leu Met Arg 35 40 45 Asp Phe Gly Ala Gly Tyr Ser Asp Thr Ala Trp Val Ser Ser Ile Met 50 55 60 Leu Ala Met Leu Tyr Gly Thr Gly Pro Val Ser Ser Ile Leu Val Thr 65 70 75 80 Arg Phe Gly Cys Arg Pro Val Met Leu Val Gly Gly Leu Leu Ala Ser 85 90 95 Ala Gly Met Val Leu Ala Ser Phe Ala Thr Arg Leu Leu Glu Leu Tyr 100 105 110 Leu Thr Ala Gly Val Leu Thr Gly Leu Gly Leu Ala Leu Asn Phe Gln 115 120 125 Pro Ser Leu Ile Met Leu Gly Leu Tyr Phe Glu Arg Arg Arg Pro Leu 130 135 140 Ala Asn Gly Leu Ala Ala Ala Gly Ser Pro Val Phe Leu Ser Thr Leu 145 150 155 160 Ser Pro Leu Gly Gln Gln Leu Leu Glu His Phe Gly Trp Arg Gly Gly 165 170 175 Phe Leu Leu Leu Gly Gly Leu Leu Leu His Cys Cys Ala Cys Gly Ala 180 185 190 Val Met Arg Pro Pro Pro Gly Pro Gly Pro Arg Pro Arg Arg Asp Ser 195 200 205 Ala Asp Asp Pro Pro Ala Asp Ala Asp Ala Glu Ala Gly Ala Gly Ala 210 215 220 Asp Ala Glu Arg Pro Gly Leu Arg Leu Arg Glu Ala Pro Pro Gly Gly 225 230 235 240 Arg Pro Arg Arg Arg Leu Leu Asp Val Ala Val Cys Ala Asp Arg Ala 245 250 255 Phe Ala Val Tyr Thr Val Thr Asn Phe Leu Met Ala Leu Gly Leu Phe 260 265 270 Val Pro Ala Ile Leu Leu Val Trp Ala Lys Asp Ala Gly Val Pro Asp 275 280 285 Ala Asp Ala Ala Phe Leu Leu Ser Val Val Gly Phe Val Asp Ile Val 290 295 300 Ala Arg Pro Ala Cys Gly Ala Leu Ala Gly Leu Ala Arg Leu Arg Pro 305 310 315 320 His Val Ala Tyr Leu Phe Ser Leu Ala Leu Val Ala Asn Gly Leu Thr 325 330 335 Asp Leu Ser Ser Ala Arg Ala Arg Ser Tyr Gly Ala Leu Val Ala Phe 340 345 350 Cys Val Ala Phe Gly Leu Ser Tyr Gly Met Val Gly Ala Leu Gln Phe 355 360 365 Glu Val Leu Met Ala Ala Val Gly Ser Leu Arg Phe Pro Ser Ala Leu 370 375 380 Gly Leu Val Leu Leu Val Glu Ala Val Ala Val Leu Ile Gly Pro Pro 385 390 395 400 Ser Ala Gly Arg Leu Val Asp Ala Leu Lys Asn Tyr Glu Ile Ile Phe 405 410 415 Tyr Leu Ala Gly Ser Glu Val Ala Leu Ala Gly Ile Phe Met Ala Val 420 425 430 Ala Thr Lys Cys Cys Leu Arg Arg Ser Arg Asp Thr Pro Pro Gly Gln 435 440 445 Val Ala Glu Gly Gly Ala Ser Asp Thr Glu Asp Ala Glu Ala Glu Val 450 455 460 Asp Ser Glu Ala Leu Pro Thr Gly Ala Glu Glu Pro Gly Ser Arg Glu 465 470 475 480 Pro Leu Glu Val Pro Ser Pro Gly Ala Arg Pro Ala Glu Ala Glu Val 485 490 495 Glu Ala Gly Pro Gly Arg Asp Thr Lys Ser Val 500 505 <210> 42 <211> 498 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 42 Met Pro Pro Ala Val Gly Gly Pro Val Gly Tyr Thr Pro Pro Asp Gly 1 5 10 15 Gly Trp Gly Trp Ala Val Val Val Gly Ala Phe Ile Ser Ile Gly Phe 20 25 30 Ser Tyr Ala Phe Pro Lys Ser Ile Thr Val Phe Phe Lys Glu Ile Glu 35 40 45 Ser Ile Phe Ser Ala Thr Thr Ser Glu Val Ser Trp Ile Ser Ser Ile 50 55 60 Met Leu Ala Val Met Tyr Gly Gly Gly Pro Ile Ser Ser Ile Leu Val 65 70 75 80 Asn Lys Tyr Gly Ser Arg Pro Ile Met Ile Val Gly Gly Cys Leu Ser 85 90 95 Gly Cys Gly Leu Ile Ala Ala Ser Phe Cys Asn Thr Val Gln Glu Leu 100 105 110 Tyr Leu Cys Ile Gly Val Ile Gly Gly Leu Gly Leu Ala Phe Asn Leu 115 120 125 Asn Pro Ala Leu Thr Met Ile Gly Lys Tyr Phe Tyr Lys Arg Arg Pro 130 135 140 Leu Ala Asn Gly Leu Ala Met Ala Gly Ser Pro Val Phe Leu Ser Thr 145 150 155 160 Leu Ala Pro Leu Asn Gln Ala Phe Phe Gly Ile Phe Gly Trp Arg Gly 165 170 175 Ser Phe Leu Ile Leu Gly Gly Leu Leu Leu Asn Cys Cys Val Ala Gly 180 185 190 Ala Leu Met Arg Pro Ile Gly Pro Pro Pro Thr Ser Ala Gly Lys Asp 195 200 205 Arg Ser Lys Glu Ser Leu Gln Glu Ala Glu Lys Ser Asp Glu Lys Lys 210 215 220 Gly Gly Asp Ala Asn Thr Asp Leu Ile Gly Gly Asn Arg Lys Glu Glu 225 230 235 240 Lys Gly Ser Val Phe Gln Thr Ile Asn Lys Phe Leu Asp Leu Ser Leu 245 250 255 Phe Thr His Arg Gly Phe Leu Leu Tyr Leu Ser Gly Asn Val Leu Met 260 265 270 Phe Phe Gly Leu Phe Thr Pro Leu Val Phe Leu Ser Asn Tyr Gly Lys 275 280 285 Ser Gln His Tyr Ser Ser Glu Lys Ser Ala Phe Leu Leu Ser Ile Leu 290 295 300 Ala Phe Val Asp Met Val Ala Arg Pro Ser Met Gly Leu Val Ala Asn 305 310 315 320 Thr Lys Trp Ile Arg Pro Arg Val Gln Tyr Phe Phe Ala Ala Ser Ile 325 330 335 Val Ala Asn Gly Val Cys His Leu Leu Ala Pro Leu Ser Ser Ser Tyr 340 345 350 Ile Gly Phe Cys Val Tyr Ala Gly Phe Phe Gly Phe Ala Phe Gly Trp 355 360 365 Leu Ser Ser Val Leu Phe Glu Thr Leu Met Asp Leu Val Gly Pro Gln 370 375 380 Arg Phe Ser Ser Ala Val Gly Leu Val Thr Ile Val Glu Cys Cys Pro 385 390 395 400 Val Leu Leu Gly Pro Pro Leu Leu Gly Arg Leu Asn Asp Ile Tyr Gly 405 410 415 Asp Tyr Lys Tyr Thr Tyr Trp Ala Cys Gly Val Ile Leu Ile Ile Ala 420 425 430 Gly Ile Tyr Leu Phe Ile Gly Met Gly Ile Asn Tyr Gln Leu Val Ala 435 440 445 Lys Glu Gln Lys Ala Glu Lys Gln Gln Lys Lys Glu Ser Lys Glu Glu 450 455 460 Glu Thr Ser Val Asp Ala Ala Glu Lys Pro Lys Glu Tyr Ala Ser Glu 465 470 475 480 Ser Ala Glu Gln Lys Asp Thr Glu Gly Ser Pro Lys Glu Glu Glu Ser 485 490 495 Pro Val <210> 43 <211> 119 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 43 Met Lys Leu Val Arg Phe Leu Met Lys Leu Ser His Glu Thr Val Thr 1 5 10 15 Ile Glu Leu Lys Asn Gly Thr Gln Val His Gly Thr Ile Thr Gly Val 20 25 30 Asp Val Ser Met Asn Thr His Leu Lys Ala Val Lys Met Thr Leu Lys 35 40 45 Asn Arg Glu Pro Val Gln Leu Glu Thr Leu Ser Ile Arg Gly Asn Asn 50 55 60 Ile Arg Tyr Phe Ile Leu Pro Asp Ser Leu Pro Leu Asp Thr Leu Leu 65 70 75 80 Val Asp Val Glu Pro Lys Val Lys Ser Lys Lys Arg Glu Ala Val Ala 85 90 95 Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg 100 105 110 Gly Arg Gly Gly Pro Arg Arg 115 <210> 44 <211> 213 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 44 Met Ala Ala Pro Ala Val Ser Gly Leu Ser Arg Gln Val Arg Cys Phe 1 5 10 15 Ser Thr Ser Val Val Arg Pro Phe Ser Lys Leu Val Arg Pro Pro Val 20 25 30 Gln Ile Tyr Gly Ile Glu Gly Arg Tyr Ala Thr Ala Leu Tyr Ser Ala 35 40 45 Ala Ser Lys Gln Asn Lys Leu Glu Gln Val Glu Lys Glu Leu Leu Arg 50 55 60 Val Ala Gln Ile Leu Lys Glu Pro Lys Met Ala Ala Ser Ile Met Asn 65 70 75 80 Pro Tyr Ile Lys Arg Ser Val Lys Val Lys Ser Leu Asn Asp Met Thr 85 90 95 Ala Lys Glu Arg Phe Ser Pro Ile Thr Ser Asn Leu Ile Asn Leu Leu 100 105 110 Ala Glu Asn Gly Arg Leu Asn Asn Thr Pro Gly Val Ile Ser Ala Phe 115 120 125 Ser Thr Met Met Ser Val His Arg Gly Glu Val Pro Cys Thr Val Thr 130 135 140 Thr Ala Ser Pro Leu Asp Glu Ala Thr Leu Thr Glu Leu Lys Thr Val 145 150 155 160 Leu Lys Ser Phe Leu Ser Lys Gly Gln Val Leu Lys Leu Glu Val Lys 165 170 175 Val Asp Pro Ser Ile Met Gly Gly Met Ile Val Arg Ile Gly Glu Lys 180 185 190 Tyr Ala Asp Met Ser Ala Arg Thr Lys Ile Gln Lys Leu Ser Arg Ala 195 200 205 Met Arg Glu Val Phe 210 <210> 45 <211> 518 <212> PRT <213> Domestic dog (Canis lupus familiaris) <400> 45 Met Ala Ala Pro Ser Arg Leu Leu Ile Arg Gly Gly Arg Val Val Asn 1 5 10 15 Ala Asp Leu Ser Gln Ala Ala Asp Val Leu Val Glu Asp Gly Pro Met 20 25 30 Arg Ala Leu Gly Arg His Leu Leu Pro Pro Gly Gly Ala Ala Gly Leu 35 40 45 Arg Val Leu Asp Ala Ser Gly Lys Leu Val Leu Pro Gly Gly Ile Asp 50 55 60 Thr His Thr His Met Gln Phe Pro Phe Met Gly Ser Arg Ser Val Asp 65 70 75 80 Asp Phe Leu Gln Gly Thr Gln Ala Ala Leu Ala Gly Gly Thr Thr Met 85 90 95 Ile Ile Asp Phe Ala Ile Pro Gln Lys Gly Gly Ser Leu Ile Gln Ala 100 105 110 Phe Glu Thr Trp Arg Ser Trp Ala Asp Pro Lys Val Cys Cys Asp Tyr 115 120 125 Ser Leu His Val Ala Val Thr Trp Trp Ser Asp Gln Val Lys Glu Glu 130 135 140 Met Lys Ile Leu Thr Gln Asp Lys Gly Val Asn Ser Phe Lys Met Phe 145 150 155 160 Met Ala Tyr Lys Asp Leu Tyr Met Val Arg Asp Glu Glu Leu Tyr Ala 165 170 175 Ala Phe Ser Gln Cys Lys Glu Ile Gly Ala Ile Ala Leu Val His Ala 180 185 190 Glu Asn Gly Asp Leu Ile Ala Glu Gly Ala Lys Lys Met Leu Ala Leu 195 200 205 Gly Ile Thr Gly Pro Glu Gly His Glu Leu Cys Arg Pro Glu Ala Val 210 215 220 Glu Ala Glu Ala Thr Leu Arg Ala Ile Thr Ile Ala Ser Ala Val Asn 225 230 235 240 Cys Pro Leu Tyr Val Val His Val Met Ser Lys Ser Ala Ala Lys Val 245 250 255 Ile Ala Asp Ala Arg Arg Asp Gly Lys Val Val Tyr Gly Glu Pro Ile 260 265 270 Ala Ala Ser Leu Gly Thr Asp Gly Thr His Tyr Trp His Lys Glu Trp 275 280 285 His His Ala Ala His His Val Met Gly Pro Pro Leu Arg Pro Asp Pro 290 295 300 Ser Thr Pro Asp Phe Leu Met Asn Leu Leu Ala Asn Gly Asp Leu Thr 305 310 315 320 Thr Thr Gly Thr Asp His Cys Thr Phe Asn Thr Cys Gln Lys Ala Leu 325 330 335 Gly Lys Asp Asp Phe Thr Lys Ile Pro Asn Gly Val Asn Gly Val Glu 340 345 350 Asp Arg Met Ser Val Ile Trp Glu Lys Gly Val His Ser Gly Lys Met 355 360 365 Asp Glu Asn Arg Phe Val Ala Val Thr Ser Thr Asn Ala Ala Lys Val 370 375 380 Phe Asn Leu Tyr Pro Arg Lys Gly Arg Ile Ala Val Gly Ser Asp Ala 385 390 395 400 Asp Ile Val Ile Trp Asp Pro Lys Ala Thr Arg Thr Ile Ser Ala Lys 405 410 415 Thr His His Gln Ala Val Asn Phe Asn Ile Phe Glu Gly Met Val Cys 420 425 430 His Gly Val Pro Val Val Thr Ile Ser Arg Gly Lys Val Val Tyr Glu 435 440 445 Ala Gly Val Phe Asn Val Thr Ala Gly Asp Gly Lys Phe Ile Pro Arg 450 455 460 Lys Pro Phe Ala Glu Tyr Ile Tyr Lys Arg Ile Lys Gln Arg Asp Gln 465 470 475 480 Thr Cys Thr Pro Ile Pro Val Glu Arg Lys Pro Tyr Lys Gly Glu Val 485 490 495 Val Thr Val Lys Ser Arg Glu Thr Glu Glu Asp Ser Ala Ala Gly Met 500 505 510 Arg Lys Gln Ala Gly Pro 515 <210> 46 <211> 255 <212> PRT <213> Cat (Felis catus) <400> 46 Met Asp Asp Arg Glu Asp Leu Val Tyr Gln Ala Lys Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20 25 30 Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 50 55 60 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65 70 75 80 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85 90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 100 105 110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 115 120 125 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130 135 140 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150 155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 180 185 190 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195 200 205 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Gly Glu 225 230 235 240 Glu Gln Asn Lys Glu Ala Leu Gln Asp Val Glu Asp Glu Asn Gln 245 250 255 <210> 47 <211> 255 <212> PRT <213> Cat (Felis catus) <400> 47 Met Leu Gln Asp Val Leu Phe Ser Ser Cys Cys Ser Leu Leu Val Gln 1 5 10 15 Val Ala Phe His Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20 25 30 Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 50 55 60 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65 70 75 80 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85 90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 100 105 110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 115 120 125 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130 135 140 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150 155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 180 185 190 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195 200 205 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Gly Glu 225 230 235 240 Glu Gln Asn Lys Glu Ala Leu Gln Asp Val Glu Asp Glu Asn Gln 245 250 255 <210> 48 <211> 240 <212> PRT <213> Cat (Felis catus) <400> 48 Met Asp Asp Arg Glu Asp Leu Val Tyr Gln Ala Lys Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20 25 30 Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 50 55 60 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65 70 75 80 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85 90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 100 105 110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 115 120 125 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130 135 140 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150 155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 180 185 190 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195 200 205 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Asp Ser 225 230 235 240 <210> 49 <211> 245 <212> PRT <213> Cat (Felis catus) <400> 49 Met Glu Lys Thr Glu Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Thr Cys Met Lys Ala Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Arg Arg Ser Ala Trp Arg Val Ile Ser Ser 50 55 60 Ile Glu Gln Lys Thr Asp Thr Ser Asp Lys Lys Leu Gln Leu Ile Lys 65 70 75 80 Asp Tyr Arg Glu Lys Val Glu Ser Glu Leu Arg Ser Ile Cys Thr Thr 85 90 95 Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Ala Asn Ala Thr Asn Pro 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe Arg Tyr 115 120 125 Leu Ala Glu Val Ala Cys Gly Asp Asp Arg Lys Gln Thr Ile Asp Asn 130 135 140 Ser Gln Gly Ala Tyr Gln Glu Ala Phe Asp Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Asn Pro Glu Leu Ala Cys Thr Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu 195 200 205 Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Ser Ala Gly Glu Glu Cys Asp Ala Ala 225 230 235 240 Glu Gly Ala Glu Asn 245 <210> 50 <211> 245 <212> PRT <213> Cat (Felis catus) <400> 50 Met Asp Lys Asn Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Ala Cys Met Lys Ser Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Val Ser Ser 50 55 60 Ile Glu Gln Lys Thr Glu Gly Ala Glu Lys Lys Gln Gln Met Ala Arg 65 70 75 80 Glu Tyr Arg Glu Lys Ile Glu Thr Glu Leu Arg Asp Ile Cys Asn Asp 85 90 95 Val Leu Ser Leu Leu Glu Lys Phe Leu Ile Pro Asn Ala Ser Gln Ala 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr Arg Tyr 115 120 125 Leu Ala Glu Val Ala Ala Gly Asp Asp Lys Lys Gly Ile Val Asp Gln 130 135 140 Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu 195 200 205 Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Thr Gln Gly Asp Glu Ala Glu Ala Gly 225 230 235 240 Glu Gly Gly Glu Asn 245 <210> 51 <211> 244 <212> PRT <213> Cat (Felis catus) <400> 51 Met Asp Lys Ser Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Ala Val Thr Glu Gln 20 25 30 Gly His Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser Ser 50 55 60 Ile Glu Gln Lys Thr Glu Arg Asn Glu Lys Lys Gln Gln Met Gly Lys 65 70 75 80 Glu Tyr Arg Glu Lys Ile Glu Ala Glu Leu Gln Asp Ile Cys Asn Asp 85 90 95 Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Pro Asn Ala Thr Gln Pro 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe Arg Tyr 115 120 125 Leu Ser Glu Val Ala Ser Gly Asp Asn Lys Gln Thr Thr Val Ser Asn 130 135 140 Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu 195 200 205 Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Glu Asn Gln Gly Asp Glu Gly Asp Ala Gly 225 230 235 240 Glu Gly Glu Asn <210> 52 <211> 246 <212> PRT <213> Cat (Felis catus) <400> 52 Met Gly Asp Arg Glu Gln Leu Leu Gln Arg Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ser Ala Met Lys Ala Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Asp Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Met Ala Asp Gly Asn Glu Lys Lys Leu Glu 65 70 75 80 Lys Val Lys Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Thr Val 85 90 95 Cys Asn Asp Val Leu Ala Leu Leu Asp Lys Phe Leu Ile Lys Asn Cys 100 105 110 Asn Asp Phe Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Ser Gly Glu Lys Lys Asn 130 135 140 Ser Val Val Glu Ala Ser Glu Ala Ala Tyr Lys Glu Ala Phe Glu Ile 145 150 155 160 Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys Leu Leu Ala Lys Gln Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Glu 225 230 235 240 Glu Ala Gly Glu Gly Asn 245 <210> 53 <211> 247 <212> PRT <213> Cat (Felis catus) <400> 53 Met Val Asp Arg Glu Gln Leu Val Gln Lys Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Asn Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Ser Ala Asp Gly Asn Glu Lys Lys Ile Glu 65 70 75 80 Met Val Arg Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Ala Val 85 90 95 Cys Gln Asp Val Leu Ser Leu Leu Asp Asn Tyr Leu Ile Lys Asn Cys 100 105 110 Ser Glu Thr Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Thr Gly Glu Lys Arg Ala 130 135 140 Thr Val Val Glu Ser Ser Glu Lys Ala Tyr Ser Glu Ala His Glu Ile 145 150 155 160 Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Tyr Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys His Leu Ala Lys Thr Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Asp 225 230 235 240 Asp Gly Gly Glu Gly Asn Asn 245 <210> 54 <211> 248 <212> PRT <213> Cat (Felis catus) <400> 54 Met Glu Arg Ala Ser Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Glu Asp Met Ala Ala Phe Met Lys Ser Ala Val Glu Lys 20 25 30 Gly Glu Glu Leu Ser Cys Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Gln Arg Ala Ala Trp Arg Val Leu Ser Ser 50 55 60 Ile Glu Gln Lys Gly Asn Glu Glu Ser Ser Glu Glu Lys Gly Pro Glu 65 70 75 80 Val Arg Glu Tyr Arg Glu Lys Val Glu Thr Glu Leu Arg Gly Val Cys 85 90 95 Asp Thr Val Leu Gly Leu Leu Asp Thr His Leu Ile Lys Glu Ala Gly 100 105 110 Asp Ala Glu Ser Arg Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr 115 120 125 Arg Tyr Leu Ala Glu Val Ala Thr Gly Asp Asp Lys Lys Arg Ile Ile 130 135 140 Asp Ser Ala Arg Ser Ala Tyr Gln Glu Ala Met Asp Ile Ser Lys Lys 145 150 155 160 Glu Met Pro Pro Thr Asn Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe 165 170 175 Ser Val Phe His Tyr Glu Ile Ala Asn Ser Pro Glu Glu Ala Ile Ser 180 185 190 Leu Ala Lys Thr Thr Phe Asp Glu Ala Met Ala Asp Leu His Thr Leu 195 200 205 Ser Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg 210 215 220 Asp Asn Leu Thr Leu Trp Thr Ala Asp Asn Ala Gly Glu Glu Gly Gly 225 230 235 240 Glu Ala Pro Glu Glu Pro Gln Ser 245 <210> 55 <211> 500 <212> PRT <213> Cat (Felis catus) <400> 55 Met Gly Ala Gly Gly Pro Arg Arg Gly Ala Gly Pro Pro Asp Gly Gly 1 5 10 15 Trp Gly Trp Ala Val Leu Gly Ala Cys Phe Val Ile Thr Gly Phe Ala 20 25 30 Tyr Gly Phe Pro Lys Ala Val Ser Val Phe Phe Arg Ala Leu Met Arg 35 40 45 Asp Phe Gly Ala Gly Tyr Ser Asp Thr Ala Trp Val Ser Ser Ile Met 50 55 60 Leu Ala Met Leu Tyr Gly Thr Gly Pro Val Ser Ser Ile Leu Val Thr 65 70 75 80 Arg Phe Gly Cys Arg Pro Val Met Leu Val Gly Gly Leu Leu Ala Ser 85 90 95 Ala Gly Met Val Leu Ala Ser Phe Ala Thr Arg Leu Leu Glu Leu Tyr 100 105 110 Leu Thr Ala Gly Val Leu Thr Gly Leu Gly Leu Ala Leu Asn Phe Gln 115 120 125 Pro Ser Leu Ile Met Leu Gly Leu Tyr Phe Glu Arg Arg Arg Pro Leu 130 135 140 Ala Asn Gly Leu Ala Ala Ala Gly Ser Pro Val Phe Leu Ser Ala Leu 145 150 155 160 Ser Pro Leu Gly Gln Gln Leu Leu Glu His Phe Gly Trp Arg Gly Gly 165 170 175 Phe Leu Leu Leu Gly Gly Leu Leu Leu His Cys Cys Ala Cys Gly Ala 180 185 190 Val Met Arg Pro Pro Pro Gly Pro Gly Pro Arg Pro Arg Gly Asp Ser 195 200 205 Ala Glu Asp Ala Pro Gly Glu Ala Glu Ala Asp Arg Ala Gly Leu Arg 210 215 220 Leu Arg Glu Ala Pro Pro Gly Gly Arg Thr Arg Arg Arg Leu Leu Asp 225 230 235 240 Val Ala Val Cys Ala Asp Arg Ala Phe Gly Val Tyr Ala Ile Thr Lys 245 250 255 Phe Leu Met Ala Leu Gly Leu Phe Val Pro Ala Ile Leu Leu Val Asn 260 265 270 Tyr Ala Lys Asp Ala Gly Val Pro Asp Ala Asp Ala Ala Phe Leu Leu 275 280 285 Ser Ile Val Gly Phe Val Asp Ile Val Ala Arg Pro Ala Cys Gly Ala 290 295 300 Leu Ala Gly Leu Ala Arg Leu Arg Pro His Val Ala Tyr Leu Phe Ser 305 310 315 320 Leu Ala Leu Met Ala Asn Gly Leu Thr Asp Leu Ser Ser Ala Arg Ala 325 330 335 Arg Ser Tyr Gly Ala Leu Val Ala Phe Cys Val Ala Phe Gly Leu Ser 340 345 350 Tyr Gly Met Val Gly Ala Leu Gln Phe Glu Val Leu Met Ala Ala Val 355 360 365 Gly Ser His Arg Phe Pro Ser Ala Leu Gly Leu Val Leu Leu Val Glu 370 375 380 Ala Val Ala Val Leu Ile Gly Pro Pro Ser Ala Gly Arg Leu Val Asp 385 390 395 400 Ala Leu Lys Asn Tyr Glu Ile Ile Phe Tyr Leu Ala Gly Ser Glu Val 405 410 415 Ala Leu Ala Gly Ile Phe Met Ala Val Ala Thr Lys Cys Cys Leu Arg 420 425 430 Arg Ser Lys Asp Thr Pro Pro Ser Gln Gly Ala Gln Gly Gly Ala Ser 435 440 445 Asp Thr Glu Asp Ala Glu Ala Gln Glu Asp Ala Glu Ala Leu Pro Ala 450 455 460 Gly Ala Glu Glu Pro Gly Ser Leu Gln Ala Leu Glu Ala Pro Ser Pro 465 470 475 480 Gly Ala Gly Pro Gly Glu Pro Lys Ala Glu Ala Glu Ala Gly Val Asp 485 490 495 Pro Glu Ser Val 500 <210> 56 <211> 460 <212> PRT <213> Cat (Felis catus) <400> 56 Met Gly Gly Ala Val Val Asp Glu Gly Pro Thr Gly Ile Lys Ala Pro 1 5 10 15 Asp Gly Gly Trp Gly Trp Ala Val Leu Phe Gly Cys Phe Val Ile Thr 20 25 30 Gly Phe Ser Tyr Ala Phe Pro Lys Ala Val Ser Val Phe Phe Lys Glu 35 40 45 Leu Met Arg Glu Phe Gly Ile Gly Tyr Ser Asp Thr Ala Trp Ile Ser 50 55 60 Ser Ile Leu Leu Ala Met Leu Tyr Gly Thr Gly Pro Leu Cys Ser Val 65 70 75 80 Cys Val Asn Arg Phe Gly Cys Arg Pro Val Met Leu Ala Gly Gly Leu 85 90 95 Leu Ala Ser Leu Gly Met Val Ala Ala Ser Phe Cys Gly Ser Ile Ile 100 105 110 Gln Leu Tyr Leu Thr Thr Gly Val Ile Thr Gly Leu Gly Leu Ala Leu 115 120 125 Asn Phe Gln Pro Ser Leu Ile Met Leu Asn Arg Tyr Phe Asn Lys Arg 130 135 140 Arg Pro Met Ala Asn Gly Leu Ala Ala Ala Gly Ser Pro Val Phe Leu 145 150 155 160 Cys Ala Leu Ser Pro Leu Gly Gln Leu Leu Gln Asp His Tyr Gly Trp 165 170 175 Arg Gly Gly Phe Leu Ile Leu Gly Gly Leu Leu Leu Asn Cys Cys Val 180 185 190 Cys Ala Ala Leu Met Arg Pro Leu Glu Ala Ser Arg Pro Gly Ser Gly 195 200 205 Pro Gly Pro Gln Arg Pro Ala Arg Arg Leu Leu Asp Leu Ser Val Phe 210 215 220 Arg Asp Arg Gly Phe Val Ile Tyr Ala Ala Ala Ala Ser Ile Met Val 225 230 235 240 Leu Gly Leu Phe Val Pro Pro Val Phe Val Val Ser Tyr Ala Lys Asp 245 250 255 Leu Gly Val Pro Asp Thr Gln Ala Ala Phe Leu Leu Thr Val Leu Gly 260 265 270 Phe Ile Asp Ile Phe Ala Arg Pro Ala Ala Gly Phe Ile Thr Gly Leu 275 280 285 Lys Lys Val Arg Pro Tyr Ser Val Tyr Leu Phe Ser Phe Ser Met Phe 290 295 300 Phe Asn Gly Phe Thr Asp Leu Thr Gly Ser Thr Ala Ser Asp Tyr Gly 305 310 315 320 Gly Leu Val Val Phe Cys Ile Phe Phe Gly Ile Ser Tyr Gly Met Val 325 330 335 Gly Ala Leu Gln Phe Glu Val Leu Met Ala Ile Val Gly Thr Gln Lys 340 345 350 Phe Ser Ser Ala Ile Gly Leu Val Leu Leu Leu Glu Ala Ile Ala Val 355 360 365 Leu Ile Gly Pro Pro Ser Gly Gly Lys Leu Leu Asp Ala Thr His Val 370 375 380 Tyr Gln Tyr Val Phe Leu Leu Ala Gly Ala Glu Val Val Ala Ser Ser 385 390 395 400 Leu Val Leu Val Leu Gly Asn Phe Phe Cys Ile Lys Lys Arg Pro Glu 405 410 415 Ala Ala Val Glu Glu Gly Glu Arg His Lys Pro Pro Ala Asp Val Arg 420 425 430 Val Asp Ser Arg Glu Val Glu His Phe Leu Lys Ala Glu Pro Glu Lys 435 440 445 Asn Gly Glu Val Val His Thr Pro Glu Thr Ser Val 450 455 460 <210> 57 <211> 480 <212> PRT <213> Cat (Felis catus) <400> 57 Met Gly Gly Ala Val Val Asp Glu Gly Pro Thr Gly Ile Lys Ala Pro 1 5 10 15 Asp Gly Gly Trp Gly Trp Ala Val Leu Phe Gly Cys Phe Val Ile Thr 20 25 30 Gly Phe Ser Tyr Ala Phe Pro Lys Ala Val Ser Val Phe Phe Lys Glu 35 40 45 Leu Met Arg Glu Phe Gly Ile Gly Tyr Ser Asp Thr Ala Trp Ile Ser 50 55 60 Ser Ile Leu Leu Ala Met Leu Tyr Gly Thr Gly Pro Leu Cys Ser Val 65 70 75 80 Cys Val Asn Arg Phe Gly Cys Arg Pro Val Met Leu Ala Gly Gly Leu 85 90 95 Leu Ala Ser Leu Gly Met Val Ala Ala Ser Phe Cys Gly Ser Ile Ile 100 105 110 Gln Leu Tyr Leu Thr Thr Gly Val Ile Thr Gly Glu Trp Gly Pro Ala 115 120 125 Gly Ser Gly Ala Gly His Gly Thr Leu Thr Pro Gln Trp Pro Gly Leu 130 135 140 Gly Leu Ala Leu Asn Phe Gln Pro Ser Leu Ile Met Leu Asn Arg Tyr 145 150 155 160 Phe Asn Lys Arg Arg Pro Met Ala Asn Gly Leu Ala Ala Ala Gly Ser 165 170 175 Pro Val Phe Leu Cys Ala Leu Ser Pro Leu Gly Gln Leu Leu Gln Asp 180 185 190 His Tyr Gly Trp Arg Gly Gly Phe Leu Ile Leu Gly Gly Leu Leu Leu 195 200 205 Asn Cys Cys Val Cys Ala Ala Leu Met Arg Pro Leu Glu Ala Ser Arg 210 215 220 Pro Gly Ser Gly Pro Gly Pro Gln Arg Pro Ala Arg Arg Leu Leu Asp 225 230 235 240 Leu Ser Val Phe Arg Asp Arg Gly Phe Val Ile Tyr Ala Ala Ala Ala 245 250 255 Ser Ile Met Val Leu Gly Leu Phe Val Pro Pro Val Phe Val Val Ser 260 265 270 Tyr Ala Lys Asp Leu Gly Val Pro Asp Thr Gln Ala Ala Phe Leu Leu 275 280 285 Thr Val Leu Gly Phe Ile Asp Ile Phe Ala Arg Pro Ala Ala Gly Phe 290 295 300 Ile Thr Gly Leu Lys Lys Val Arg Pro Tyr Ser Val Tyr Leu Phe Ser 305 310 315 320 Phe Ser Met Phe Phe Asn Gly Phe Thr Asp Leu Thr Gly Ser Thr Ala 325 330 335 Ser Asp Tyr Gly Gly Leu Val Val Phe Cys Ile Phe Phe Gly Ile Ser 340 345 350 Tyr Gly Met Val Gly Ala Leu Gln Phe Glu Val Leu Met Ala Ile Val 355 360 365 Gly Thr Gln Lys Phe Ser Ser Ala Ile Gly Leu Val Leu Leu Leu Glu 370 375 380 Ala Ile Ala Val Leu Ile Gly Pro Pro Ser Gly Gly Lys Leu Leu Asp 385 390 395 400 Ala Thr His Val Tyr Gln Tyr Val Phe Leu Leu Ala Gly Ala Glu Val 405 410 415 Val Ala Ser Ser Leu Val Leu Val Leu Gly Asn Phe Phe Cys Ile Lys 420 425 430 Lys Arg Pro Glu Ala Ala Val Glu Glu Gly Glu Arg His Lys Pro Pro 435 440 445 Ala Asp Val Arg Val Asp Ser Arg Glu Val Glu His Phe Leu Lys Ala 450 455 460 Glu Pro Glu Lys Asn Gly Glu Val Val His Thr Pro Glu Thr Ser Val 465 470 475 480 <210> 58 <211> 327 <212> PRT <213> Cat (Felis catus) <400> 58 Met Gln Glu Pro Gly Ser Glu Glu Glu Phe His Ser Leu Gly Phe Tyr 1 5 10 15 Arg Met Thr Thr Arg Asp Leu Thr Met Ala Met Ile Phe Phe Leu Gln 20 25 30 Thr Thr Val Gly Ile Leu Gly Asn Phe Ser Val Phe Tyr Tyr Tyr Leu 35 40 45 Phe Leu Tyr Leu Thr Gly Tyr Lys Leu Arg Cys Thr Asp Leu Ile Val 50 55 60 Lys Tyr Leu Thr Val Ala Asn Leu Leu Val Ile Phe Ser Lys Gly Ile 65 70 75 80 Pro Gln Thr Met Ala Ser Phe Gly Leu Pro His Phe Leu Asp Asp Phe 85 90 95 Gly Cys Lys Leu Val Phe Phe Val His Arg Val Gly Arg Asp Val Ala 100 105 110 Ile Gly Thr Thr Cys Leu Leu Thr Val Phe Gln Val Ile Met Ile Ser 115 120 125 Pro Gly Asp Ser Arg Trp Ala Gln Leu Lys Ile Lys Ala Pro Lys Tyr 130 135 140 Met Gly Thr Ser Asn Ile Phe Cys Trp Val Leu Asn Ile Val Arg Ser 145 150 155 160 Ile Val Val Pro Phe His Leu Thr Asp Lys Arg Asn Asn Ile Asn Val 165 170 175 Thr Lys Lys Ile Asp Gln Asp Tyr Cys Tyr Ala Ile Ser Ser Asp Lys 180 185 190 Ile Ala Gln Ser Phe Tyr Val Pro Leu Leu Leu Ser His Asp Gly Phe 195 200 205 Cys Leu Gly Leu Met Leu Trp Ala Ser Gly Ser Met Val Phe Ile Leu 210 215 220 His Ser His Lys Gln Arg Val Gln Tyr Ile Arg Arg Asn Asn Leu Ser 225 230 235 240 Pro Arg Ser Ser Pro Glu Ser Arg Ala Thr Arg Ser Ile Leu Val Leu 245 250 255 Ala Phe Phe Phe Leu Ser Leu Trp Met Leu Ser Ser Ile Phe His Met 260 265 270 Cys Phe Ser Val Phe Asn Asn Pro Ser Leu Trp Leu Arg Asn Thr Ser 275 280 285 Thr Ile Leu Thr Met Cys Phe Pro Thr Leu Ser Pro Tyr Ile Leu Met 290 295 300 Arg His Asp Pro Arg Val Ser Thr Leu Tyr Ser Ala Trp Ile Arg Lys 305 310 315 320 Gln Asn Arg Leu Asn Leu Ser 325 <210> 59 <211> 241 <212> PRT <213> Cat (Felis catus) <400> 59 Met Phe Pro Leu Leu Ser Gly Ala Gly Leu Val Val Leu Asn Leu Val 1 5 10 15 Thr Ser Ala Arg Ser Leu Lys Thr Glu Pro Phe Ile Gly Ser Gly Asp 20 25 30 Gln Pro Leu Phe His Gly Ala Asp Arg Ser Asp Phe Ala Val Met Ile 35 40 45 Pro Pro Gly Gly Thr Glu Cys Phe Trp Gln Phe Ala Tyr Gln Asn Gly 50 55 60 Tyr Phe Tyr Phe Ser Tyr Glu Val Gln Arg Thr Leu Gly Met Ser His 65 70 75 80 Asp Arg His Val Ala Ala Thr Ala His Thr Pro Gln Gly Phe Leu Ile 85 90 95 Asp Ser Ser Gln Asp Val Arg Gly Gln Ile Asn Phe Ser Ile Lys Glu 100 105 110 Thr Gly Phe Tyr Gln Leu Cys Leu Asn Asn Gln Gln Asn His Phe Gly 115 120 125 Ser Val Gln Val Tyr Leu Asn Phe Gly Val Phe Tyr Glu Gly Pro Glu 130 135 140 Met Asp His Lys Gln Lys Asn Glu Arg Lys Gln Leu Asn Asp Thr Leu 145 150 155 160 Asp Ala Ile Glu Glu Ser Thr Gln Lys Met Gln Asn Asn Ile Phe His 165 170 175 Met Trp Arg Tyr Tyr Asn Phe Ala Arg Met Arg Lys Met Ala Asp Phe 180 185 190 Phe Leu Leu Gln Ser Asn Tyr Asn Tyr Val Asn Trp Trp Ser Thr Ala 195 200 205 Gln Ser Phe Val Ile Val Leu Ser Gly Ile Leu Gln Leu Tyr Phe Leu 210 215 220 Lys Arg Leu Phe Asn Val Pro Lys Val Thr Asp Thr Lys Lys Pro Arg 225 230 235 240 Cys <210> 60 <211> 239 <212> PRT <213> Cat (Felis catus) <400> 60 Met Phe Pro Leu Leu Ser Gly Ala Gly Leu Val Val Leu Asn Leu Val 1 5 10 15 Thr Ser Ala Arg Ser Leu Lys Thr Glu Pro Phe Ile Gly Ser Gly Asp 20 25 30 Gln Pro Leu Phe His Gly Ala Asp Arg Ser Asp Phe Ala Val Met Ile 35 40 45 Pro Pro Gly Gly Thr Glu Cys Phe Trp Gln Phe Ala Tyr Gln Asn Gly 50 55 60 Tyr Phe Tyr Phe Ser Tyr Glu Arg Thr Leu Gly Met Ser His Asp Arg 65 70 75 80 His Val Ala Ala Thr Ala His Thr Pro Gln Gly Phe Leu Ile Asp Ser 85 90 95 Ser Gln Asp Val Arg Gly Gln Ile Asn Phe Ser Ile Lys Glu Thr Gly 100 105 110 Phe Tyr Gln Leu Cys Leu Asn Asn Gln Gln Asn His Phe Gly Ser Val 115 120 125 Gln Val Tyr Leu Asn Phe Gly Val Phe Tyr Glu Gly Pro Glu Met Asp 130 135 140 His Lys Gln Lys Asn Glu Arg Lys Gln Leu Asn Asp Thr Leu Asp Ala 145 150 155 160 Ile Glu Glu Ser Thr Gln Lys Met Gln Asn Asn Ile Phe His Met Trp 165 170 175 Arg Tyr Tyr Asn Phe Ala Arg Met Arg Lys Met Ala Asp Phe Phe Leu 180 185 190 Leu Gln Ser Asn Tyr Asn Tyr Val Asn Trp Trp Ser Thr Ala Gln Ser 195 200 205 Phe Val Ile Val Leu Ser Gly Ile Leu Gln Leu Tyr Phe Leu Lys Arg 210 215 220 Leu Phe Asn Val Pro Lys Val Thr Asp Thr Lys Lys Pro Arg Cys 225 230 235 <210> 61 <211> 119 <212> PRT <213> Cat (Felis catus) <400> 61 Met Lys Leu Val Arg Phe Leu Met Lys Leu Ser His Glu Thr Val Thr 1 5 10 15 Ile Glu Leu Lys Asn Gly Thr Gln Val His Gly Thr Ile Thr Gly Val 20 25 30 Asp Val Ser Met Asn Thr His Leu Lys Ala Val Lys Met Thr Leu Lys 35 40 45 Asn Arg Glu Pro Val Gln Leu Glu Thr Leu Ser Ile Arg Gly Asn Asn 50 55 60 Ile Arg Tyr Phe Ile Leu Pro Asp Ser Leu Pro Leu Asp Thr Leu Leu 65 70 75 80 Val Asp Val Glu Pro Lys Val Lys Ser Lys Lys Arg Glu Ala Val Ala 85 90 95 Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg 100 105 110 Gly Arg Gly Gly Pro Arg Arg 115 <210> 62 <211> 112 <212> PRT <213> Cat (Felis catus) <400> 62 Met Lys Leu Ser His Glu Thr Val Thr Ile Glu Leu Lys Asn Gly Thr 1 5 10 15 Gln Val His Gly Thr Ile Thr Gly Val Asp Val Ser Met Asn Thr His 20 25 30 Leu Lys Ala Val Lys Met Thr Leu Lys Asn Arg Glu Pro Val Gln Leu 35 40 45 Glu Thr Leu Ser Ile Arg Gly Asn Asn Ile Arg Tyr Phe Ile Leu Pro 50 55 60 Asp Ser Leu Pro Leu Asp Thr Leu Leu Val Asp Val Glu Pro Lys Val 65 70 75 80 Lys Ser Lys Lys Arg Glu Ala Val Ala Gly Arg Gly Arg Gly Arg Gly 85 90 95 Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Gly Pro Arg Arg 100 105 110 <210> 63 <211> 213 <212> PRT <213> Cat (Felis catus) <400> 63 Met Ala Ser Ser Ala Val Ser Gly Leu Ser Arg Gln Val Arg Cys Phe 1 5 10 15 Ser Thr Ser Val Val Arg Pro Phe Ala Lys Leu Val Arg Pro Pro Val 20 25 30 Gln Ile Tyr Gly Ile Glu Gly Arg Tyr Ala Thr Ala Leu Tyr Ser Ala 35 40 45 Ala Ser Lys Gln Asn Lys Leu Glu Gln Val Glu Lys Glu Leu Leu Arg 50 55 60 Val Ala Gln Ile Leu Lys Glu Pro Lys Met Ala Ala Ser Ile Met Asn 65 70 75 80 Pro Tyr Val Lys Arg Ser Val Lys Val Lys Ser Leu Asn Asp Met Thr 85 90 95 Ala Lys Glu Arg Phe Ser Pro Leu Thr Cys Asn Leu Ile Asn Leu Leu 100 105 110 Ala Glu Asn Gly Arg Leu Asn Asn Thr Pro Gly Val Val Ser Ala Phe 115 120 125 Ser Thr Met Met Ser Val His Arg Gly Glu Val Pro Cys Thr Val Thr 130 135 140 Thr Ala Ser Pro Leu Asp Glu Pro Thr Leu Ala Glu Leu Arg Thr Val 145 150 155 160 Leu Lys Ser Phe Leu Ser Lys Gly Gln Val Leu Lys Leu Glu Val Lys 165 170 175 Ile Asp Pro Ser Ile Met Gly Gly Met Ile Val Arg Ile Gly Glu Lys 180 185 190 Tyr Ala Asp Met Ser Ala Lys Thr Lys Ile Gln Lys Leu Ser Arg Ala 195 200 205 Met Arg Glu Ile Phe 210 <210> 64 <211> 519 <212> PRT <213> Cat (Felis catus) <400> 64 Met Ala Ala Pro Ser Arg Leu Leu Ile Arg Gly Gly Arg Val Val Asn 1 5 10 15 Asp Asp Leu Ser Gln Val Ala Asp Val Leu Val Glu Asp Gly Val Val 20 25 30 Arg Ala Leu Gly Arg Asp Leu Leu Pro Pro Gly Gly Ala Pro Ala Gly 35 40 45 Leu Arg Val Leu Asp Ala Ala Gly Lys Leu Val Leu Pro Gly Gly Ile 50 55 60 Asp Thr His Thr His Met Gln Phe Pro Phe Met Gly Ala Arg Ser Val 65 70 75 80 Asp Asp Phe His Gln Gly Thr Lys Ala Ala Leu Ala Gly Gly Thr Thr 85 90 95 Met Ile Ile Asp Phe Ala Ile Pro Gln Lys Gly Gly Ser Leu Ile Lys 100 105 110 Ala Phe Glu Thr Trp Arg Ser Trp Ala Asp Pro Lys Val Cys Cys Asp 115 120 125 Tyr Ser Leu His Val Ala Val Thr Trp Trp Ser Asp Gln Val Lys Glu 130 135 140 Glu Met Lys Ile Leu Thr Gln Asp Lys Gly Val Asn Ser Phe Lys Met 145 150 155 160 Phe Met Ala Tyr Lys Asp Leu Tyr Met Val Arg Asp Glu Glu Leu Tyr 165 170 175 Ala Ala Phe Ser Gln Cys Lys Glu Ile Gly Ala Ile Ala Gln Val His 180 185 190 Ala Glu Asn Gly Asp Leu Ile Ala Glu Gly Ala Lys Lys Met Leu Ala 195 200 205 Leu Gly Ile Thr Gly Pro Glu Gly His Glu Leu Cys Arg Pro Glu Ala 210 215 220 Val Glu Ala Glu Ala Thr Leu Arg Ala Ile Thr Ile Ala Ser Ala Val 225 230 235 240 Asn Cys Pro Leu Tyr Ile Val His Val Met Ser Lys Ser Ala Ala Lys 245 250 255 Val Ile Ala Asp Ala Arg Arg Asp Gly Lys Val Val Tyr Gly Glu Pro 260 265 270 Ile Ala Ala Ser Leu Gly Thr Asp Gly Thr His Tyr Trp His Lys Asp 275 280 285 Trp His His Ala Ala His His Val Met Gly Pro Pro Leu Arg Pro Asp 290 295 300 Pro Ser Thr Pro Asp Phe Leu Met Asn Leu Leu Ala Asn Gly Asp Leu 305 310 315 320 Thr Thr Thr Gly Thr Asp His Cys Thr Phe Asn Thr Cys Gln Lys Ala 325 330 335 Leu Gly Lys Asp Asp Phe Thr Lys Ile Pro Asn Gly Val Asn Gly Val 340 345 350 Glu Asp Arg Met Ser Val Ile Trp Glu Lys Gly Val His Ser Gly Lys 355 360 365 Met Asp Glu Asn Arg Phe Val Ala Val Thr Ser Thr Asn Ala Ala Lys 370 375 380 Val Phe Asn Leu Tyr Pro Arg Lys Gly Arg Ile Ala Val Gly Ser Asp 385 390 395 400 Ala Asp Ile Val Ile Trp Asp Pro Lys Ala Thr Arg Thr Ile Ser Ala 405 410 415 Arg Thr His His Gln Ala Val Asn Phe Asn Ile Phe Glu Gly Met Val 420 425 430 Cys His Gly Val Pro Leu Val Thr Ile Ser Arg Gly Lys Val Val Tyr 435 440 445 Glu Ala Gly Val Leu Ser Val Thr Ala Gly Asp Gly Lys Phe Ile Pro 450 455 460 Arg Lys Pro Phe Ala Glu Tyr Ile Tyr Lys Arg Ile Lys Gln Arg Asp 465 470 475 480 Gln Thr Cys Thr Pro Thr Pro Val Glu Arg Glu Pro Tyr Lys Gly Glu 485 490 495 Val Val Thr Leu Lys Thr Arg Glu Thr Lys Glu Asp Ala Ala Ala Gly 500 505 510 Thr Arg Lys Gln Ala His Pro 515 <210> 65 <211> 513 <212> PRT <213> Cat (Felis catus) <400> 65 Met Ala Ala Pro Ser Arg Leu Leu Ile Arg Gly Gly Arg Val Val Asn 1 5 10 15 Asp Asp Leu Ser Gln Val Ala Asp Val Leu Val Glu Asp Gly Val Val 20 25 30 Arg Ala Leu Gly Arg Asp Leu Leu Pro Pro Gly Gly Ala Pro Ala Gly 35 40 45 Leu Arg Val Leu Asp Ala Ala Gly Lys Leu Val Leu Pro Gly Gly Ile 50 55 60 Asp Thr His Thr His Met Gln Phe Pro Phe Met Gly Ala Arg Ser Val 65 70 75 80 Asp Asp Phe His Gln Gly Thr Lys Ala Ala Leu Ala Gly Gly Thr Thr 85 90 95 Met Ile Ile Asp Phe Ala Ile Pro Gln Lys Gly Gly Ser Leu Ile Lys 100 105 110 Ala Phe Glu Thr Trp Arg Ser Trp Ala Asp Pro Lys Val Cys Cys Asp 115 120 125 Tyr Ser Leu His Val Ala Val Thr Trp Trp Ser Asp Gln Val Lys Glu 130 135 140 Glu Met Lys Ile Leu Thr Gln Asp Lys Gly Val Asn Ser Phe Lys Met 145 150 155 160 Phe Met Ala Tyr Lys Asp Leu Tyr Met Val Arg Asp Glu Glu Leu Tyr 165 170 175 Ala Ala Phe Ser Gln Cys Lys Glu Ile Gly Ala Ile Ala Gln Val His 180 185 190 Ala Glu Asn Gly Asp Leu Ile Ala Glu Gly Ala Lys Lys Met Leu Ala 195 200 205 Leu Gly Ile Thr Gly Pro Glu Gly His Glu Leu Cys Arg Pro Glu Ala 210 215 220 Val Glu Ala Glu Ala Thr Leu Arg Ala Ile Thr Ile Ala Ser Ala Val 225 230 235 240 Asn Cys Pro Leu Tyr Ile Val His Val Met Ser Lys Ser Ala Ala Lys 245 250 255 Val Ile Ala Asp Ala Arg Arg Asp Gly Lys Val Val Tyr Gly Glu Pro 260 265 270 Ile Ala Ala Ser Leu Gly Thr Asp Gly Thr His Tyr Trp His Lys Asp 275 280 285 Trp His His Ala Ala His His Val Met Gly Pro Pro Leu Arg Pro Asp 290 295 300 Pro Ser Thr Pro Asp Phe Leu Met Asn Leu Leu Ala Asn Gly Asp Leu 305 310 315 320 Thr Thr Thr Gly Thr Asp His Cys Thr Phe Asn Thr Cys Gln Lys Ala 325 330 335 Leu Gly Lys Asp Asp Phe Thr Lys Ile Pro Asn Gly Val Asn Gly Val 340 345 350 Glu Asp Arg Met Ser Val Ile Trp Glu Lys Gly Val His Ser Gly Lys 355 360 365 Met Asp Glu Asn Arg Phe Val Ala Val Thr Ser Thr Asn Ala Ala Lys 370 375 380 Val Phe Asn Leu Tyr Pro Arg Lys Gly Arg Ile Ala Val Gly Ser Asp 385 390 395 400 Ala Asp Ile Val Ile Trp Asp Pro Lys Ala Thr Arg Thr Ile Ser Ala 405 410 415 Arg Thr His His Gln Ala Val Asn Phe Asn Ile Phe Glu Gly Met Val 420 425 430 Cys His Gly Val Pro Leu Val Thr Ile Ser Arg Gly Lys Val Val Tyr 435 440 445 Glu Ala Gly Val Leu Ser Val Thr Ala Gly Asp Gly Lys Phe Ile Pro 450 455 460 Arg Lys Pro Phe Ala Glu Tyr Ile Tyr Lys Arg Ile Lys Gln Arg Asp 465 470 475 480 Gln Val Lys Ser Glu Lys Arg Ile Leu Leu Phe Pro Ser Leu Leu Ser 485 490 495 Val Val Ser Pro Trp Arg Asn Arg Pro His Phe Asn Ser Pro Arg Cys 500 505 510 Phe <210> 66 <211> 466 <212> PRT <213> Mouse (Mus musculus) <400> 66 Met Gly Ala Gly Ala Leu Ala Leu Gly Ala Ser Glu Pro Cys Asn Leu 1 5 10 15 Ser Ser Ala Ala Pro Leu Pro Asp Gly Ala Ala Thr Ala Ala Arg Leu 20 25 30 Leu Val Leu Ala Ser Pro Pro Ala Ser Leu Leu Pro Pro Ala Ser Glu 35 40 45 Gly Ser Ala Pro Leu Ser Gln Gln Trp Thr Ala Gly Met Gly Leu Leu 50 55 60 Leu Ala Leu Ile Val Leu Leu Ile Val Val Gly Asn Val Leu Val Ile 65 70 75 80 Val Ala Ile Ala Lys Thr Pro Arg Leu Gln Thr Leu Thr Asn Leu Phe 85 90 95 Ile Met Ser Leu Ala Ser Ala Asp Leu Val Met Gly Leu Leu Val Val 100 105 110 Pro Phe Gly Ala Thr Ile Val Val Trp Gly Arg Trp Glu Tyr Gly Ser 115 120 125 Phe Phe Cys Glu Leu Trp Thr Ser Val Asp Val Leu Cys Val Thr Ala 130 135 140 Ser Ile Glu Thr Leu Cys Val Ile Ala Leu Asp Arg Tyr Leu Ala Ile 145 150 155 160 Thr Ser Pro Phe Arg Tyr Gln Ser Leu Leu Thr Arg Ala Arg Ala Arg 165 170 175 Ala Leu Val Cys Thr Val Trp Ala Ile Ser Ala Leu Val Ser Phe Leu 180 185 190 Pro Ile Leu Met His Trp Trp Arg Ala Glu Ser Asp Glu Ala Arg Arg 195 200 205 Cys Tyr Asn Asp Pro Lys Cys Cys Asp Phe Val Thr Asn Arg Ala Tyr 210 215 220 Ala Ile Ala Ser Ser Val Val Ser Phe Tyr Val Pro Leu Cys Ile Met 225 230 235 240 Ala Phe Val Tyr Leu Arg Val Phe Arg Glu Ala Gln Lys Gln Val Lys 245 250 255 Lys Ile Asp Ser Cys Glu Arg Arg Phe Leu Gly Gly Pro Ala Arg Pro 260 265 270 Pro Ser Pro Glu Pro Ser Pro Ser Pro Gly Pro Pro Arg Pro Ala Asp 275 280 285 Ser Leu Ala Asn Gly Arg Ser Ser Lys Arg Arg Pro Ser Arg Leu Val 290 295 300 Ala Leu Arg Glu Gln Lys Ala Leu Lys Thr Leu Gly Ile Ile Met Gly 305 310 315 320 Val Phe Thr Leu Cys Trp Leu Pro Phe Phe Leu Ala Asn Val Val Lys 325 330 335 Ala Phe His Arg Asp Leu Val Pro Asp Arg Leu Phe Val Phe Phe Asn 340 345 350 Trp Leu Gly Tyr Ala Asn Ser Ala Phe Asn Pro Ile Ile Tyr Cys Arg 355 360 365 Ser Pro Asp Phe Arg Lys Ala Phe Gln Arg Leu Leu Cys Cys Ala Arg 370 375 380 Arg Ala Ala Cys Arg Arg Arg Ala Ala His Gly Asp Arg Pro Arg Ala 385 390 395 400 Ser Gly Cys Leu Ala Arg Ala Gly Pro Pro Pro Ser Pro Gly Ala Pro 405 410 415 Ser Asp Asp Asp Asp Asp Asp Ala Gly Thr Thr Pro Pro Ala Arg Leu 420 425 430 Leu Glu Pro Trp Thr Gly Cys Asn Gly Gly Thr Thr Thr Val Asp Ser 435 440 445 Asp Ser Ser Leu Asp Glu Pro Gly Arg Gln Gly Phe Ser Ser Glu Ser 450 455 460 Lys Val 465 <210> 67 <211> 477 <212> PRT <213> Homo sapiens <400> 67 Met Gly Ala Gly Val Leu Val Leu Gly Ala Ser Glu Pro Gly Asn Leu 1 5 10 15 Ser Ser Ala Ala Pro Leu Pro Asp Gly Ala Ala Thr Ala Ala Arg Leu 20 25 30 Leu Val Pro Ala Ser Pro Pro Ala Ser Leu Leu Pro Pro Ala Ser Glu 35 40 45 Ser Pro Glu Pro Leu Ser Gln Gln Trp Thr Ala Gly Met Gly Leu Leu 50 55 60 Met Ala Leu Ile Val Leu Leu Ile Val Ala Gly Asn Val Leu Val Ile 65 70 75 80 Val Ala Ile Ala Lys Thr Pro Arg Leu Gln Thr Leu Thr Asn Leu Phe 85 90 95 Ile Met Ser Leu Ala Ser Ala Asp Leu Val Met Gly Leu Leu Val Val 100 105 110 Pro Phe Gly Ala Thr Ile Val Val Trp Gly Arg Trp Glu Tyr Gly Ser 115 120 125 Phe Phe Cys Glu Leu Trp Thr Ser Val Asp Val Leu Cys Val Thr Ala 130 135 140 Ser Ile Glu Thr Leu Cys Val Ile Ala Leu Asp Arg Tyr Leu Ala Ile 145 150 155 160 Thr Ser Pro Phe Arg Tyr Gln Ser Leu Leu Thr Arg Ala Arg Ala Arg 165 170 175 Gly Leu Val Cys Thr Val Trp Ala Ile Ser Ala Leu Val Ser Phe Leu 180 185 190 Pro Ile Leu Met His Trp Trp Arg Ala Glu Ser Asp Glu Ala Arg Arg 195 200 205 Cys Tyr Asn Asp Pro Lys Cys Cys Asp Phe Val Thr Asn Arg Ala Tyr 210 215 220 Ala Ile Ala Ser Ser Val Val Ser Phe Tyr Val Pro Leu Cys Ile Met 225 230 235 240 Ala Phe Val Tyr Leu Arg Val Phe Arg Glu Ala Gln Lys Gln Val Lys 245 250 255 Lys Ile Asp Ser Cys Glu Arg Arg Phe Leu Gly Gly Pro Ala Arg Pro 260 265 270 Pro Ser Pro Ser Pro Ser Pro Val Pro Ala Pro Ala Pro Pro Pro Gly 275 280 285 Pro Pro Arg Pro Ala Ala Ala Ala Ala Thr Ala Pro Leu Ala Asn Gly 290 295 300 Arg Ala Gly Lys Arg Arg Pro Ser Arg Leu Val Ala Leu Arg Glu Gln 305 310 315 320 Lys Ala Leu Lys Thr Leu Gly Ile Ile Met Gly Val Phe Thr Leu Cys 325 330 335 Trp Leu Pro Phe Phe Leu Ala Asn Val Val Lys Ala Phe His Arg Glu 340 345 350 Leu Val Pro Asp Arg Leu Phe Val Phe Phe Asn Trp Leu Gly Tyr Ala 355 360 365 Asn Ser Ala Phe Asn Pro Ile Ile Tyr Cys Arg Ser Pro Asp Phe Arg 370 375 380 Lys Ala Phe Gln Arg Leu Leu Cys Cys Ala Arg Arg Ala Ala Arg Arg 385 390 395 400 Arg His Ala Thr His Gly Asp Arg Pro Arg Ala Ser Gly Cys Leu Ala 405 410 415 Arg Pro Gly Pro Pro Pro Ser Pro Gly Ala Ala Ser Asp Asp Asp Asp 420 425 430 Asp Asp Val Val Gly Ala Thr Pro Pro Ala Arg Leu Leu Glu Pro Trp 435 440 445 Ala Gly Cys Asn Gly Gly Ala Ala Ala Asp Ser Asp Ser Ser Leu Asp 450 455 460 Glu Pro Cys Arg Pro Gly Phe Ala Ser Glu Ser Lys Val 465 470 475 <210> 68 <211> 473 <212> PRT <213> Canis lupus familiaris <400> 68 Met Gly Ala Gly Ala Leu Ala Leu Gly Ala Ser Glu Pro Cys Asn Leu 1 5 10 15 Ser Ser Ala Ala Pro Leu Pro Asp Gly Ala Ala Thr Ala Ala Arg Leu 20 25 30 Leu Val Pro Ala Ser Pro Ser Ala Ser Pro Leu Ala Pro Thr Ser Glu 35 40 45 Gly Pro Ala Pro Leu Ser Gln Gln Trp Thr Ala Gly Ile Gly Leu Leu 50 55 60 Met Ala Leu Ile Val Leu Leu Ile Val Ala Gly Asn Val Leu Val Ile 65 70 75 80 Ala Ala Ile Ala Lys Thr Pro Arg Leu Gln Thr Leu Thr Asn Leu Phe 85 90 95 Ile Met Ser Leu Ala Ser Ala Asp Leu Val Met Gly Leu Leu Val Val 100 105 110 Pro Phe Gly Ala Thr Ile Val Met Arg Gly Arg Trp Glu Tyr Gly Ser 115 120 125 Phe Leu Cys Glu Leu Trp Thr Ser Val Asp Val Leu Cys Val Thr Ala 130 135 140 Ser Ile Glu Thr Leu Cys Val Ile Ala Leu Asp Arg Tyr Leu Ala Ile 145 150 155 160 Thr Ala Pro Phe Arg Tyr Gln Ser Leu Leu Thr Arg Ala Arg Ala Arg 165 170 175 Ala Leu Val Cys Thr Val Trp Ala Ile Ser Ala Leu Val Ser Phe Leu 180 185 190 Pro Ile Leu Met His Trp Trp Arg Ala Gly Gly Asp Glu Ala Arg Arg 195 200 205 Cys Tyr Asn Asp Pro Lys Cys Cys Asp Phe Val Thr Asn Arg Ala Tyr 210 215 220 Ala Ile Ala Ser Ser Val Val Ser Phe Tyr Val Pro Leu Cys Ile Met 225 230 235 240 Ala Phe Val Tyr Leu Arg Val Phe Arg Glu Ala Gln Lys Gln Val Lys 245 250 255 Lys Ile Asp Ser Cys Glu Arg Arg Phe Leu Gly Gly Pro Ala Arg Pro 260 265 270 Pro Ala Pro Pro Pro Ala Pro Ala Pro Ala Pro Pro Pro Ala Pro Gly 275 280 285 Ser Pro Arg Pro Ala Ala Ala Ala Pro Leu Ala Asn Gly Arg Val Gly 290 295 300 Arg Arg Arg Pro Ser Arg Leu Val Ala Leu Arg Glu Gln Lys Ala Leu 305 310 315 320 Lys Thr Leu Gly Ile Ile Met Gly Val Phe Thr Leu Cys Trp Leu Pro 325 330 335 Phe Phe Leu Ala Asn Val Val Lys Ala Phe His Arg Asp Leu Val Pro 340 345 350 Asp Arg Leu Phe Val Phe Phe Asn Trp Leu Gly Tyr Ala Asn Ser Ala 355 360 365 Phe Asn Pro Ile Ile Tyr Cys Arg Ser Pro Asp Phe Arg Arg Ala Phe 370 375 380 Gln Arg Leu Leu Cys Cys Ala Arg Arg Ala Ala Arg Gly Ser His Gly 385 390 395 400 Ala Ala Gly Asp Pro Pro Arg Ala Arg Pro Pro Pro Ser Pro Gly Ala 405 410 415 Ala Ser Asp Asp Asp Asp Asp Asp Glu Asp Asp Ala Gly Ala Gly Ala 420 425 430 Gly Ala Ala Pro Pro Ala Arg Leu Leu Glu Pro Trp Ala Gly Cys Asn 435 440 445 Gly Gly Ala Ala Ala Asp Ser Asp Ser Ser Leu Asp Gly Ala Gly Ser 450 455 460 Pro Ala Gly Ala Ser Glu Ser Arg Val 465 470 <210> 69 <211> 474 <212> PRT <213> Cat (Felis catus) <400> 69 Met Gly Ala Gly Ala Leu Ala Leu Gly Ala Ser Glu Pro Cys Asn Leu 1 5 10 15 Ser Ser Ala Ala Pro Leu Pro Asp Gly Ala Ala Thr Ala Ala Arg Leu 20 25 30 Leu Val Pro Ala Ser Pro Ser Ala Ser Pro Leu Thr Pro Thr Ser Glu 35 40 45 Gly Pro Ala Pro Leu Ser Gln Gln Trp Thr Ala Gly Ile Gly Leu Leu 50 55 60 Met Ala Leu Ile Val Leu Leu Ile Val Ala Gly Asn Val Leu Val Ile 65 70 75 80 Val Ala Ile Ala Lys Thr Pro Arg Leu Gln Thr Leu Thr Asn Leu Phe 85 90 95 Ile Met Ser Leu Ala Ser Ala Asp Leu Val Met Gly Leu Leu Val Val 100 105 110 Pro Phe Gly Ala Thr Ile Val Met Arg Gly Arg Trp Glu Tyr Gly Ser 115 120 125 Phe Phe Cys Glu Leu Trp Thr Ser Val Asp Val Leu Cys Val Thr Ala 130 135 140 Ser Ile Glu Thr Leu Cys Val Ile Ala Leu Asp Arg Tyr Leu Ala Ile 145 150 155 160 Thr Ser Pro Phe Arg Tyr Gln Ser Leu Leu Thr Arg Ala Arg Ala Arg 165 170 175 Ala Leu Val Cys Thr Val Trp Ala Ile Ser Ala Leu Val Ser Phe Leu 180 185 190 Pro Ile Leu Met His Trp Trp Arg Ala Glu Gly Asp Glu Ala Arg Arg 195 200 205 Cys Tyr Asn Asp Pro Lys Cys Cys Asp Phe Val Thr Asn Arg Ala Tyr 210 215 220 Ala Ile Ala Ser Ser Val Val Ser Phe Tyr Val Pro Leu Cys Ile Met 225 230 235 240 Ala Phe Val Tyr Leu Arg Val Phe Arg Glu Ala Gln Lys Gln Val Lys 245 250 255 Lys Ile Asp Ser Cys Glu Arg Arg Phe Leu Ser Gly Pro Ala Arg Pro 260 265 270 Pro Ser Pro Ala Pro Ala Pro Gly Ser Pro Arg Pro Ala Ala Thr Ala 275 280 285 Ala Ala Ala Ala Ala Ala Ala Pro Leu Ala Asn Gly Arg Ile Ser Lys 290 295 300 Arg Arg Pro Ser Arg Leu Val Ala Leu Arg Glu Gln Lys Ala Leu Lys 305 310 315 320 Thr Leu Gly Ile Ile Met Gly Val Phe Thr Leu Cys Trp Leu Pro Phe 325 330 335 Phe Leu Ala Asn Val Val Lys Ala Phe His Arg Asp Leu Val Pro Asp 340 345 350 Arg Leu Phe Val Phe Phe Asn Trp Leu Gly Tyr Ala Asn Ser Ala Phe 355 360 365 Asn Pro Ile Ile Tyr Cys Arg Ser Pro Asp Phe Arg Lys Ala Phe Gln 370 375 380 Arg Leu Leu Cys Phe Ala Arg Arg Ala Ala Arg Gly Gly His Ala Ala 385 390 395 400 Ala Gly Asp Arg Pro Arg Ala Ser Gly Cys Leu Pro Gly Thr Arg Pro 405 410 415 Pro Pro Ser Pro Gly Ala Ala Ser Asp Glu Asp Asp Asp Asp Asp Val 420 425 430 Gly Ala Ala Pro Pro Ala Arg Leu Leu Glu Pro Trp Ala Gly Cys Asn 435 440 445 Gly Gly Ala Ala Ala Ala Asp Ser Asp Ser Ser Leu Asp Glu Pro Gly 450 455 460 Arg Pro Ala Gly Ala Ser Glu Ser Lys Val 465 470 <210> 70 <211> 255 <212> PRT <213> Mouse (Mus musculus) <400> 70 Met Asp Asp Arg Glu Asp Leu Val Tyr Gln Ala Lys Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20 25 30 Met Asp Val Glu Leu Thr Val Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile Ile Ser 50 55 60 Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65 70 75 80 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85 90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala 100 105 110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 115 120 125 His Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130 135 140 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150 155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn 165 170 175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 180 185 190 Arg Leu Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195 200 205 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215 220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Gly Glu 225 230 235 240 Glu Gln Asn Lys Glu Ala Leu Gln Asp Val Glu Asp Glu Asn Gln 245 250 255 <210> 71 <211> 246 <212> PRT <213> Mouse (Mus musculus) <400> 71 Met Thr Met Asp Lys Ser Glu Leu Val Gln Lys Ala Lys Leu Ala Glu 1 5 10 15 Gln Ala Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Ala Val Thr 20 25 30 Glu Gln Gly His Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val 35 40 45 Ala Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile 50 55 60 Ser Ser Ile Glu Gln Lys Thr Glu Arg Asn Glu Lys Lys Gln Gln Met 65 70 75 80 Gly Lys Glu Tyr Arg Glu Lys Ile Glu Ala Glu Leu Gln Asp Ile Cys 85 90 95 Asn Asp Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Leu Asn Ala Thr 100 105 110 Gln Ala Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe 115 120 125 Arg Tyr Leu Ser Glu Val Ala Ser Gly Glu Asn Lys Gln Thr Thr Val 130 135 140 Ser Asn Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys 145 150 155 160 Glu Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe 165 170 175 Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser 180 185 190 Leu Ala Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu 195 200 205 Asn Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg 210 215 220 Asp Asn Leu Thr Leu Trp Thr Ser Glu Asn Gln Gly Asp Glu Gly Asp 225 230 235 240 Ala Gly Glu Gly Glu Asn 245 <210> 72 <211> 245 <212> PRT <213> Mouse (Mus musculus) <400> 72 Met Asp Lys Asn Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Ala Cys Met Lys Ser Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Val Ser Ser 50 55 60 Ile Glu Gln Lys Thr Glu Gly Ala Glu Lys Lys Gln Gln Met Ala Arg 65 70 75 80 Glu Tyr Arg Glu Lys Ile Glu Thr Glu Leu Arg Asp Ile Cys Asn Asp 85 90 95 Val Leu Ser Leu Leu Glu Lys Phe Leu Ile Pro Asn Ala Ser Gln Pro 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr Arg Tyr 115 120 125 Leu Ala Glu Val Ala Ala Gly Asp Asp Lys Lys Gly Ile Val Asp Gln 130 135 140 Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu 195 200 205 Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Thr Gln Gly Asp Glu Ala Glu Ala Gly 225 230 235 240 Glu Gly Gly Glu Asn 245 <210> 73 <211> 245 <212> PRT <213> Mouse (Mus musculus) <400> 73 Met Glu Lys Thr Glu Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Thr Cys Met Lys Ala Val Thr Glu Gln 20 25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Arg Arg Ser Ala Trp Arg Val Ile Ser Ser 50 55 60 Ile Glu Gln Lys Thr Asp Thr Ser Asp Lys Lys Leu Gln Leu Ile Lys 65 70 75 80 Asp Tyr Arg Glu Lys Val Glu Ser Glu Leu Arg Ser Ile Cys Thr Thr 85 90 95 Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Ala Asn Ala Thr Asn Pro 100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe Arg Tyr 115 120 125 Leu Ala Glu Val Ala Cys Gly Asp Asp Arg Lys Gln Thr Ile Glu Asn 130 135 140 Ser Gln Gly Ala Tyr Gln Glu Ala Phe Asp Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Asn Pro Glu Leu Ala Cys Thr Leu Ala 180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu 195 200 205 Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215 220 Leu Thr Leu Trp Thr Ser Asp Ser Ala Gly Glu Glu Cys Asp Ala Ala 225 230 235 240 Glu Gly Ala Glu Asn 245 <210> 74 <211> 246 <212> PRT <213> Mouse (Mus musculus) <400> 74 Met Gly Asp Arg Glu Gln Leu Leu Gln Arg Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ser Ala Met Lys Ala Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Asp Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Met Ala Asp Gly Asn Glu Lys Lys Leu Glu 65 70 75 80 Lys Val Lys Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Thr Val 85 90 95 Cys Asn Asp Val Leu Ala Leu Leu Asp Lys Phe Leu Ile Lys Asn Cys 100 105 110 Asn Asp Phe Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Ser Gly Glu Lys Lys Asn 130 135 140 Ser Val Val Glu Ala Ser Glu Ala Ala Tyr Lys Glu Ala Phe Glu Ile 145 150 155 160 Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys Leu Leu Ala Lys Gln Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Glu 225 230 235 240 Glu Ala Gly Glu Gly Asn 245 <210> 75 <211> 247 <212> PRT <213> Mouse (Mus musculus) <400> 75 Met Val Asp Arg Glu Gln Leu Val Gln Lys Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Asn Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Ser Ala Asp Gly Asn Glu Lys Lys Ile Glu 65 70 75 80 Met Val Arg Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Ala Val 85 90 95 Cys Gln Asp Val Leu Ser Leu Leu Asp Asn Tyr Leu Ile Lys Asn Cys 100 105 110 Ser Glu Thr Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Thr Gly Glu Lys Arg Ala 130 135 140 Thr Val Val Glu Ser Ser Glu Lys Ala Tyr Ser Glu Ala His Glu Ile 145 150 155 160 Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Tyr Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys His Leu Ala Lys Thr Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Asp 225 230 235 240 Asp Gly Gly Glu Gly Asn Asn 245 <210> 76 <211> 248 <212> PRT <213> Mouse (Mus musculus) <400> 76 Met Glu Arg Ala Ser Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Glu Asp Met Ala Ala Phe Met Lys Ser Ala Val Glu Lys 20 25 30 Gly Glu Glu Leu Ser Cys Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Gln Arg Ala Ala Trp Arg Val Leu Ser Ser 50 55 60 Ile Glu Gln Lys Ser Asn Glu Glu Gly Ser Glu Glu Lys Gly Pro Glu 65 70 75 80 Val Lys Glu Tyr Arg Glu Lys Val Glu Thr Glu Leu Arg Gly Val Cys 85 90 95 Asp Thr Val Leu Gly Leu Leu Asp Ser His Leu Ile Lys Gly Ala Gly 100 105 110 Asp Ala Glu Ser Arg Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr 115 120 125 Arg Tyr Leu Ala Glu Val Ala Thr Gly Asp Asp Lys Lys Arg Ile Ile 130 135 140 Asp Ser Ala Arg Ser Ala Tyr Gln Glu Ala Met Asp Ile Ser Lys Lys 145 150 155 160 Glu Met Pro Pro Thr Asn Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe 165 170 175 Ser Val Phe His Tyr Glu Ile Ala Asn Ser Pro Glu Glu Ala Ile Ser 180 185 190 Leu Ala Lys Thr Thr Phe Asp Glu Ala Met Ala Asp Leu His Thr Leu 195 200 205 Ser Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg 210 215 220 Asp Asn Leu Thr Leu Trp Thr Ala Asp Ser Ala Gly Glu Glu Gly Gly 225 230 235 240 Glu Ala Pro Glu Glu Pro Gln Ser 245 <210> 77 <211> 492 <212> PRT <213> Mouse (Mus musculus) <400> 77 Met Gly Ala Gly Gly Pro Arg Arg Gly Ala Gly Pro Pro Asp Gly Gly 1 5 10 15 Trp Gly Trp Val Val Leu Gly Ala Cys Phe Val Val Thr Gly Phe Ala 20 25 30 Tyr Gly Phe Pro Lys Ala Val Ser Val Phe Phe Arg Glu Leu Lys Arg 35 40 45 Asp Phe Gly Ala Gly Tyr Ser Asp Thr Ala Trp Val Ser Ser Ile Met 50 55 60 Leu Ala Met Leu Tyr Gly Thr Gly Pro Leu Ser Ser Ile Leu Val Thr 65 70 75 80 Arg Phe Gly Cys Arg Pro Val Met Leu Ala Gly Gly Leu Leu Ala Ser 85 90 95 Ala Gly Met Ile Leu Ala Ser Phe Ala Ser Arg Leu Val Glu Leu Tyr 100 105 110 Leu Thr Ala Gly Val Leu Thr Gly Leu Gly Leu Ala Leu Asn Phe Gln 115 120 125 Pro Ser Leu Ile Met Leu Gly Leu Tyr Phe Glu Arg Arg Arg Pro Leu 130 135 140 Ala Asn Gly Leu Ala Ala Ala Gly Ser Pro Val Phe Leu Ser Met Leu 145 150 155 160 Ser Pro Leu Gly Gln Leu Leu Gly Glu Arg Phe Gly Trp Arg Gly Gly 165 170 175 Phe Leu Leu Phe Gly Gly Leu Leu Leu His Cys Cys Ala Cys Gly Ala 180 185 190 Val Met Arg Pro Pro Pro Gly Pro Pro Pro Arg Arg Asp Pro Ser Pro 195 200 205 His Gly Gly Pro Ala Arg Arg Arg Arg Leu Leu Asp Val Ala Val Cys 210 215 220 Thr Asp Arg Ala Phe Val Val Tyr Val Val Thr Lys Phe Leu Met Ala 225 230 235 240 Leu Gly Leu Phe Val Pro Ala Ile Leu Leu Val Asn Tyr Ala Lys Asp 245 250 255 Ala Gly Val Pro Asp Ala Glu Ala Ala Phe Leu Leu Ser Ile Val Gly 260 265 270 Phe Val Asp Ile Val Ala Arg Pro Ala Cys Gly Ala Leu Ala Gly Leu 275 280 285 Gly Arg Leu Arg Pro His Val Pro Tyr Leu Phe Ser Leu Ala Leu Leu 290 295 300 Ala Asn Gly Leu Thr Asp Leu Ile Ser Ala Arg Ala Arg Ser Tyr Gly 305 310 315 320 Thr Leu Val Ala Phe Cys Ile Ala Phe Gly Leu Ser Tyr Gly Met Val 325 330 335 Gly Ala Leu Gln Phe Glu Val Leu Met Ala Thr Val Gly Ala Pro Arg 340 345 350 Phe Pro Ser Ala Leu Gly Leu Val Leu Leu Val Glu Ala Val Ala Val 355 360 365 Leu Ile Gly Pro Pro Ser Ala Gly Arg Leu Val Asp Ala Leu Lys Asn 370 375 380 Tyr Glu Ile Ile Phe Tyr Leu Ala Gly Ser Glu Val Ala Leu Ala Gly 385 390 395 400 Val Phe Met Ala Val Thr Thr Tyr Cys Cys Leu Arg Cys Ser Lys Asn 405 410 415 Ile Ser Ser Gly Arg Ser Ala Glu Gly Gly Ala Ser Asp Pro Glu Asp 420 425 430 Val Glu Ala Glu Arg Asp Ser Glu Pro Met Pro Ala Ser Thr Glu Glu 435 440 445 Pro Gly Ser Leu Glu Ala Leu Glu Val Leu Ser Pro Arg Ala Gly Ser 450 455 460 Pro Glu Gln Glu Pro Glu Glu Glu Ala Val Pro Glu Leu Asp His Glu 465 470 475 480 Ser Ile Gly Gly His Glu Ala Arg Gly Gln Lys Ala 485 490 <210> 78 <211> 470 <212> PRT <213> Mouse (Mus musculus) <400> 78 Met Gly Gly Ala Val Val Asp Glu Gly Pro Thr Gly Ile Lys Ala Pro 1 5 10 15 Asp Gly Gly Trp Gly Trp Ala Val Leu Phe Gly Cys Phe Ile Ile Thr 20 25 30 Gly Phe Ser Tyr Ala Phe Pro Lys Ala Val Ser Val Phe Phe Lys Glu 35 40 45 Leu Met His Glu Phe Gly Ile Gly Tyr Ser Asp Thr Ala Trp Ile Ser 50 55 60 Ser Ile Leu Leu Ala Met Leu Tyr Gly Thr Gly Pro Leu Cys Ser Val 65 70 75 80 Cys Val Asn Arg Phe Gly Cys Arg Pro Val Met Leu Val Gly Gly Leu 85 90 95 Phe Ala Ser Leu Gly Met Val Ala Ala Ser Phe Cys Arg Ser Ile Ile 100 105 110 Gln Ile Tyr Leu Thr Thr Gly Val Ile Thr Gly Leu Gly Leu Ala Leu 115 120 125 Asn Phe Gln Pro Ser Leu Ile Met Leu Asn Arg Tyr Phe Asn Lys Arg 130 135 140 Arg Pro Ile Ala Asn Gly Leu Ala Ala Ala Gly Ser Pro Val Phe Leu 145 150 155 160 Cys Ala Leu Ser Pro Leu Gly Gln Leu Leu Gln Asp His Tyr Gly Trp 165 170 175 Arg Gly Gly Phe Leu Ile Leu Gly Gly Leu Leu Leu Asn Cys Cys Val 180 185 190 Cys Ala Ala Leu Met Arg Pro Leu Val Ala Pro Gln Val Gly Gly Gly 195 200 205 Thr Glu Pro Arg Gly Pro Gln Arg Pro Pro Gln Arg Leu Leu Asp Leu 210 215 220 Ser Val Phe Arg Asp Arg Gly Phe Leu Ile Tyr Ala Val Ala Ala Ser 225 230 235 240 Ile Met Val Leu Gly Leu Phe Val Pro Pro Val Phe Val Val Ser Tyr 245 250 255 Ala Lys Asp Met Gly Val Pro Asp Thr Lys Ala Ala Phe Leu Leu Thr 260 265 270 Ile Leu Gly Phe Ile Asp Ile Phe Ala Arg Pro Thr Ala Gly Phe Ile 275 280 285 Thr Gly Leu Lys Lys Val Arg Pro Tyr Ser Val Tyr Leu Phe Ser Phe 290 295 300 Ala Met Phe Phe Asn Gly Phe Thr Asp Leu Thr Gly Ser Thr Ala Thr 305 310 315 320 Asp Tyr Gly Gly Leu Val Val Phe Cys Ile Phe Phe Gly Ile Ser Tyr 325 330 335 Gly Met Val Gly Ala Leu Gln Phe Glu Val Leu Met Ala Ile Val Gly 340 345 350 Thr Gln Lys Phe Ser Ser Ala Ile Gly Leu Val Leu Leu Leu Glu Ala 355 360 365 Val Ala Val Leu Ile Gly Pro Pro Ser Gly Gly Lys Leu Leu Asp Ala 370 375 380 Thr Lys Val Tyr Lys Tyr Val Phe Ile Leu Ala Gly Ala Glu Val Leu 385 390 395 400 Thr Ser Ser Leu Val Leu Leu Leu Gly Asn Phe Phe Cys Ile Gly Lys 405 410 415 Arg Lys Arg Pro Glu Val Thr Glu Pro Glu Glu Val Ala Ser Glu Glu 420 425 430 Lys Leu His Lys Pro Pro Val Asp Val Gly Val Asp Ser Arg Glu Val 435 440 445 Glu His Phe Leu Lys Ala Glu Pro Glu Lys Asn Gly Glu Val Val His 450 455 460 Thr Pro Glu Thr Ser Val 465 470 <210> 79 <211> 119 <212> PRT <213> Mouse (Mus musculus) <400> 79 Met Lys Leu Val Arg Phe Leu Met Lys Leu Ser His Glu Thr Val Thr 1 5 10 15 Ile Glu Leu Lys Asn Gly Thr Gln Val His Gly Thr Ile Thr Gly Val 20 25 30 Asp Val Ser Met Asn Thr His Leu Lys Ala Val Lys Met Thr Leu Lys 35 40 45 Asn Arg Glu Pro Val Gln Leu Glu Thr Leu Ser Ile Arg Gly Asn Asn 50 55 60 Ile Arg Tyr Phe Ile Leu Pro Asp Ser Leu Pro Leu Asp Thr Leu Leu 65 70 75 80 Val Asp Val Glu Pro Lys Val Lys Ser Lys Lys Arg Glu Ala Val Ala 85 90 95 Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg 100 105 110 Gly Arg Gly Gly Pro Arg Arg 115 <210> 80 <211> 213 <212> PRT <213> Mouse (Mus musculus) <400> 80 Met Ala Ala Pro Ala Ala Ser Gly Leu Ser Arg Gln Val Arg Ser Phe 1 5 10 15 Ser Thr Ser Val Val Arg Pro Phe Ala Lys Leu Val Arg Pro Pro Val 20 25 30 Gln Val Tyr Gly Ile Glu Gly Arg Tyr Ala Thr Ala Leu Tyr Ser Ala 35 40 45 Ala Ser Lys Glu Lys Lys Leu Asp Gln Val Glu Lys Glu Leu Leu Arg 50 55 60 Val Gly Gln Leu Leu Lys Asp Pro Lys Val Ser Leu Ala Val Leu Asn 65 70 75 80 Pro Tyr Ile Lys Arg Thr Val Lys Val Lys Ser Leu Asn Asp Ile Thr 85 90 95 Lys Arg Glu Lys Phe Ser Pro Leu Thr Ala Asn Leu Met Asn Leu Leu 100 105 110 Ala Glu Asn Gly Arg Leu Gly Asn Thr Gln Gly Ile Ile Ser Ala Phe 115 120 125 Ser Thr Ile Met Ser Val His Arg Gly Glu Val Pro Cys Thr Val Thr 130 135 140 Thr Ala Ser Pro Leu Asp Asp Ala Val Leu Ser Glu Leu Lys Thr Val 145 150 155 160 Leu Lys Ser Phe Leu Ser Pro Asn Gln Ile Leu Lys Leu Glu Ile Lys 165 170 175 Thr Asp Pro Ser Ile Met Gly Gly Met Ile Val Arg Ile Gly Glu Lys 180 185 190 Tyr Val Asp Met Ser Ala Lys Ser Lys Ile Gln Lys Leu Ser Lys Ala 195 200 205 Met Arg Glu Met Leu 210

Claims

1. An isolated peptide, consisting of SEQ ID NO.

1.

2. A combination of a peptide consisting of the amino acid sequence of SEQ ID NO:1 and at least one peptide selected from a peptide consisting of the amino acid sequence of SEQ ID NO:5, a peptide consisting of the amino acid sequence of SEQ ID NO:6, and a peptide consisting of the amino acid sequence of SEQ ID NO:

14.

3. A combination of peptides, which is a peptide consisting of the amino acid sequence of SEQ ID NO:1, a peptide consisting of the amino acid sequence of SEQ ID NO:5, and a peptide consisting of the amino acid sequence of SEQ ID NO:

6.

4. A combination of peptides, which is a peptide consisting of the amino acid sequence of SEQ ID NO:1, a peptide consisting of the amino acid sequence of SEQ ID NO:5, and a peptide consisting of the amino acid sequence of SEQ ID NO:

14.

5. Use of the isolated peptide according to claim 1 or the combination according to any one of claims 2-4 for preparing a kit for diagnosing heart failure (HF) in a human subject and / or predicting the risk of developing HF in a human subject, said diagnosis comprising the following steps: (i) contacting a biological fluid sample containing IgG immunoglobulin from a human subject affected by HF or suspected of being at risk of developing HF with the antigenic peptide of the isolated peptide according to claim 1 or the combination according to any one of claims 2-4; (ii) detecting the formation of one or more immune complexes between the IgG immunoglobulin in the biological fluid sample and one or more isolated antigenic peptides, the formation of one or more immune complexes indicating that the human subject is affected by HF or at risk of developing HF.

6. The use according to claim 5, wherein the kit further comprises SEQ ID NOs. 2, 3, and 4 of human 14-3-3 protein.

7. The use according to claim 5, wherein the kit further comprises SEQ ID NO.7 of human toll-like receptor 5 precursor (TLR5).

8. The use according to claim 5, wherein the biological fluid sample is selected from whole blood, plasma, serum, synovial fluid, follicular fluid, and intraocular fluid.

9. A kit for diagnosing heart failure (HF) in a human subject and / or predicting the risk of developing HF in a human subject, said kit comprising the isolated peptide according to claim 1 or the combination according to any one of claims 2-4, and - a device suitable for detecting the formation of one or more immune complexes between the one or more isolated antigenic peptides and IgG immunoglobulin in a biological fluid sample of a human subject affected by HF or suspected of being at risk of developing HF.

10. The kit according to claim 9, wherein the kit further comprises SEQ ID NOs. 2, 3, and 4 of human 14-3-3 protein.

11. The kit according to claim 9, wherein the kit further comprises SEQ ID NO.7 of human toll-like receptor 5 precursor (TLR5).

12. Use of the peptide according to claim 1 or the combination according to claims 2 - 4 for the preparation of a medicament for treating heart failure in a subject in need thereof and / or preventing heart failure in a subject in need thereof, said treatment comprising orally administering the peptide to the subject so as to induce oral tolerance to the peptide.

13. A pharmaceutical composition comprising at least one isolated peptide according to claim 1 or the combination according to claims 2 - 4, and a pharmaceutically acceptable carrier, excipient and / or diluent.

14. The pharmaceutical composition according to claim 13, which comprises a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 13, which is a tolerance vaccine.

16. The pharmaceutical composition according to claim 13, which is a tolerance vaccine formulated for oral administration.

17. The pharmaceutical composition according to claim 15, wherein the tolerance vaccine does not contain any adjuvant.

Images