CN116528882A - Peptides for use in immunotherapeutic agents - Google Patents

Abstract

The peptides according to the present application comprise at least one peptide unit, wherein the peptide unit comprises at least one B cell epitope and at least one Th epitope, and may comprise an appropriate number of accessory moieties. The peptide units are moieties designed to only uniformly induce a predetermined antibody while exhibiting at least a certain level of immunogenicity in a subject. Furthermore, the peptide units are designed to be relatively short and thus have the characteristics of easy synthesis and low production costs. Due to the nature of the peptide units described above, the peptides have properties suitable for use as immunotherapeutic agents. The design principles of the peptides and peptide units are described in detail herein.

Description

Peptides for use in immunotherapeutic agents

Technical Field

The present disclosure relates to peptides infused into a subject to generate humoral immunity, which is a technology in the area of immunotherapeutic agents.

Background

The purpose of an immunotherapeutic agent is to introduce it into a subject to induce humoral immunity against the immunotherapeutic agent itself, and thereby treat a particular disorder or disease with the resultant antibodies. In particular, the "treatment" also includes the prevention of a particular disorder or disease. Immunotherapeutic agents are similar to vaccines in that they induce antibody production by antigen-antibody reactions in a subject; however, they differ from vaccines in that the antibodies have not only binding ability to the immunotherapeutic agent itself, but also binding ability to specific targets in the body (e.g., specific tissues and cells in the body, or substances generated during metabolism, etc.), thereby making it possible to treat specific conditions or diseases and repeat administration.

Disclosure of Invention

Technical problem

The present disclosure provides peptides having the function of inducing a pre-designed antibody in a subject.

The present disclosure provides compositions for immunotherapeutic agents comprising the peptides.

The present disclosure provides nucleic acid sequences encoding the peptides.

The present disclosure provides uses of the peptides and compositions for immunotherapeutic agents comprising the peptides.

Technical proposal

According to aspects of the present disclosure, there is provided a peptide unit (peptide fragment) of length 23mer to 71mer consisting of CD4 ⁺ T cells recognize to induce humoral immunity and comprise the following:

at least one Th epitope, wherein the Th epitope is 8mer to 32mer in length; and

at least one of the epitopes of the B-cells,

wherein the B cell epitope is a fragment or mimotope (mimotope) of apolipoprotein B-100, which induces antibodies targeting apolipoprotein B-100.

In embodiments, the peptide units are in the range of 26mer to 50mer in length and the Th epitopes are in the range of 11mer to 13mer in length.

In embodiments, the peptide unit comprises one B cell epitope and one Th epitope, and the peptide unit has a length in the range of 26mer to 45 mer.

In embodiments, the peptide unit comprises one B cell epitope and two Th epitopes (referred to as a first Th epitope and a second Th epitope, respectively); the peptide units have a length in the range of 37mer to 50 mer; and the first Th epitope is linked between the B cell epitope and the second Th epitope.

In embodiments, the peptide unit comprises two B cell epitopes (referred to as a first B cell epitope and a second B cell epitope, respectively) and one Th epitope; the peptide units have a length in the range of 45mer to 50 mer; and a second B cell epitope is linked between the first B cell epitope and the Th epitope.

In embodiments, the peptide unit comprises two B cell epitopes (referred to as a first B cell epitope and a second B cell epitope, respectively) and one Th epitope; the peptide units have a length in the range of 45mer to 50 mer; and the Th epitope is linked between the first B cell epitope and the second B cell epitope.

The present disclosure provides nucleic acids encoding peptides or peptide units that do not contain non-standard amino acids in the peptide.

The present disclosure provides peptides in which more than 2 and less than 5 peptide units are linked.

The present disclosure provides a pharmaceutical composition for treating obesity, the pharmaceutical composition comprising: a peptide unit or peptide; an adjuvant.

The present disclosure provides a method of treating obesity, the method comprising: the pharmaceutical composition is administered to a subject.

The present disclosure provides the use of peptide units or peptides for the treatment of obesity.

The present disclosure provides the use of peptide units or peptides for the preparation of therapeutic agents for obesity.

Advantageous effects of the invention

When the peptide provided in the present disclosure is injected into a subject, the peptide has an effect of inducing the production of an antibody having a specific physiological function, which specifically binds to an antigenic site previously designed.

Drawings

Fig. 1 to 3 show the results of the effect confirmation experiment of the peptide according to experimental example 2, which are graphs showing the changes in body weight measured weekly according to each experimental group.

Fig. 4 shows the results of the effect confirmation experiment of the peptide according to experimental example 3, which is a graph showing the body weight measured by the ages of weeks of the test subjects of each experimental group, wherein thin represents a control group having normal body weight, obese represents an obese group induced by a high fat diet, blank represents a group to which a placebo is administered, and 3H-OTP represents group 2-1.

Fig. 5 shows the results of the effect confirmation experiment of the peptide according to experimental example 3, which is a graph showing the measured antibody titer observed in the test subjects of each experimental group, wherein obesity represents an obese group induced by a high fat diet, a blank control represents a group to which a placebo was administered, and 3H-OTP represents group 2-1.

Fig. 6 shows the results of the effect confirmation experiment of the peptide according to experimental example 3, which is a graph showing the measured lipolytic ability of the hormone-sensitive lipase in adipocytes of test subjects of each experimental group, wherein the basal represents the case of no treatment with norepinephrine, the hormone represents the case of treatment with norepinephrine, and the lean represents the control group having normal body weight, the obese group induced by a high fat diet, the blank group represents the group to which placebo was administered, and the 3H-OTP represents group 2-1. (a) Every 10 ⁵ Concentration of glycerol secreted by individual adipocytes, (b) concentration of glycerol secreted by each 1g of adipocytes.

Fig. 7 shows the results of the effect confirmation experiment of the peptide according to experimental example 3, which is an image showing the measured size of adipocytes of test subjects of each experimental group, wherein lean represents a control group with normal body weight, and obesity represents an obese group induced by a high fat diet (DAPI staining image, lipidTOX staining image, and combined image are shown, respectively).

Fig. 8 shows the results of the effect confirmation experiment of the peptide according to experimental example 3, which is an image showing the measured size of adipocytes of test subjects of each experimental group (DAPI staining image showing nuclei and lipids of adipocytes of each experimental group), wherein lean represents a control group having normal body weight, obese represents an obese group induced by a high fat diet, blank represents a group given placebo, and 3H-OTP represents group 2-1.

Fig. 9 shows the results of the effect confirmation experiment of the peptide according to experimental example 3, which is a graph showing the measured blood lipid concentrations of test subjects of each experimental group, wherein TG represents triglyceride, NEFA represents non-esterified fatty acid, CHOL represents cholesterol, HDL represents high density lipoprotein, and LDL represents low density lipoprotein.

Fig. 10 shows the results of the effect confirmation experiment of the peptide according to experimental example 4, in order to show the graph of body weight measured by the ages of weeks for the test subjects of each experimental group, wherein thin represents a control group having normal body weight, obese group represents an obese group induced by a high fat diet, blank group represents a group to which a placebo was administered, 3H-OTP 30 μg represents group 3-2, and 3H-OTP 50 μg represents group 3-1. For reference purposes, a graph relating to 3H-OTP-2W 50 μg representing group 2-1 is also shown.

FIG. 11 shows the results of the peptide effect confirmation experiment according to Experimental example 4, which is a graph showing the antibody titer measured by the ages of weeks for test subjects of each experimental group, wherein thin represents a control group having normal body weight, obese represents an obese group induced by a high fat diet, blank represents a group to which a placebo was administered, 3H-OTP 30. Mu.g represents group 3-2, and 3H-OTP 50. Mu.g represents group 3-1.

Fig. 12 shows the results of the effect confirmation experiment of the peptide according to experimental example 5, which is a graph showing the body weights measured by the ages of weeks of the test subjects of each experimental group, wherein thin represents a control group having a normal body weight, obese represents an obese group induced by a high fat diet, and 3H-OTP represents group 4-1.

FIG. 13 shows the results of the peptide effect confirmation experiment according to Experimental example 6, which is a graph showing the increase in body weight at 16 weeks of age compared to body weight at 11 weeks of age after the measurement of body weight at weeks of test subjects of each experimental group at weeks of age, wherein wild type (+/+) thin represents a control group having normal body weight, wild type (+/+) represents group 5-1, heter (+/-) represents group 5-2, and Homo (-/-) represents group 5-3.

Fig. 14 to 22 show the results of the effect confirmation experiment of the peptide according to experimental example 7, which is a graph showing the body weight measured by the ages of weeks of test subjects in each experimental group, wherein thin represents a control group having a normal body weight, obesity represents an obese group induced by a high fat diet, P1 represents group 6-1, P2 represents group 6-2, P3 represents group 6-3, P4 represents group 6-4, P5 represents group 6-5, P6 represents group 6-6, P7 represents group 6-7, P8 represents group 6-8, and P9 represents group 6-9.

Fig. 23 to 25 show the results of the effect confirmation experiment of the peptide according to experimental example 7, which is a table describing the antibody titers measured by the test subjects of each experimental group at 11 weeks of age, 16 weeks of age and 19 weeks of age, wherein thin represents a control group having normal body weight, obese represents an obese group induced by a high fat diet, P1 represents group 6-1, P2 represents group 6-2, P3 represents group 6-3, P4 represents group 6-4, P5 represents group 6-5, P7 represents group 6-7, P8 represents group 6-8, and P9 represents group 6-9. In addition, the values identified by the labels in the "No" column of each experimental group in each table represent experimental results for each individual subject in each experimental group, "ave" represents the overall average value, "sd" represents the overall standard deviation, and "se" represents the overall standard error.

Detailed Description

Hereinafter, the presently disclosed subject matter will be described in more detail according to some specific embodiments and examples with reference to the drawings. It should be noted that the figures cover some, but not all embodiments of the present disclosure. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the specific embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the disclosure will come within the mind of one skilled in the art to which the presently disclosed subject matter pertains. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

Definition of general terms.

About

As used herein, the term "about" refers to a degree of proximity to an amount, and it refers to an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by 30%, 25%, 20%, 25%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

Peptides

As used herein, the term "peptide" refers to a polymer of amino acids. The term peptide refers to a form in which a small number of amino acids are linked and is used primarily to distinguish it from proteins. There is no explicit criteria to distinguish between proteins and peptides, but as used herein, unless otherwise defined, a polymer of about 200 amino acids is referred to as a peptide, but a polymer of more than 200 amino acids is referred to as a protein. The term "peptide" may include all other meanings as recognized by a person skilled in the art.

A subject

As used herein, the term "subject" refers to an organism that is the subject of exposure to a particular substance (e.g., peptide, etc.). A subject may refer to an independent organism (e.g., a human, an animal, etc.), or may refer to a partial composition of an independent organism (e.g., a cell, a portion of a tissue, etc.). The meaning may be interpreted appropriately depending on the context. Furthermore, the term "subject" may also include all meanings recognized by those of skill in the art.

Immunotherapeutic agent

As used herein, the term "immunotherapeutic agent" is a concept that is distinguished from a general therapeutic agent or vaccine. Immunotherapeutic agents are identical to existing vaccines in that they are injected into a subject, thereby inducing a humoral immune response against the immunotherapeutic agent itself. However, immunotherapeutic agents differ from existing vaccines in that antibodies induced as a result of humoral immune responses have the ability to bind not only to the immunotherapeutic agent itself, but also to specific tissues and cells in the body (e.g. cell surface receptors) or specific substances produced during metabolic processes (e.g. peptides, lipids, proteins and/or sugars); so that they can treat a particular condition or disease and they can be administered continuously and repeatedly. Thus, immunotherapeutic agents typically comprise an antigen designed to induce antibodies having the ability to bind to specific target tissues, cells or substances in the body. Unless otherwise defined, the term "immunotherapeutic agent" is to be construed as including all antigens (e.g., peptides, proteins, lipids, saccharides, and/or complexes thereof, etc.) that may be suitably used by those skilled in the art having the functions described above. The term "immunotherapeutic agent" may be further defined as "humoral immunotherapeutic agent". Furthermore, the term "immunotherapeutic agent" may include all the meanings recognized by those skilled in the art.

Therapeutic or therapeutic agent

As used herein, the term "treating" refers generally to any direct or indirect action or measure that eliminates, reduces, inhibits or ameliorates a disease, condition, disorder, and/or symptom in a subject, or that results in the prevention of the disease, condition, disorder, and/or symptom. As used herein, the term "therapeutic agent" refers to a variety of substances (e.g., compounds or peptides) that may exhibit a "therapeutic" effect when administered to a subject in an appropriate manner. Furthermore, the term "treatment" or "therapeutic agent" may include all other meanings recognized by those skilled in the art.

Immunogenicity of

As used herein, the term "immunogenicity" collectively refers to "the property of being an antigen capable of inducing an immune response" in a dictionary. There are various methods for detecting the immunogenicity of a specific antigen, and these methods may be appropriately employed or designed according to the purpose. For example, the method may include 1) a method for confirming whether an IgG, igA, and/or IgE type antibody is produced in a subject when an antigen is administered into the subject, 2) a method for confirming the time of producing an IgG, igA, and/or IgE type antibody according to the administration cycle, 3) a method for confirming the titer of an induced antibody against the antigen, and 4) a method for measuring the effect according to the mechanism of action of an induced antibody when the mechanism of action is found, but the method is not limited thereto. The expression "increased immunogenicity" may be used interchangeably with, for example, "increased effect of inducing an immune response", "increased ability to induce antibodies" and "increased effectiveness as an immunotherapeutic agent", and it includes all expressions which can be properly interpreted by the person skilled in the art depending on the context.

mer

As used herein, the term "mer" generally refers to the number of units in a high molecular weight polymer. As used herein, when referring to the length of a peptide, the term "mer" is generally expressed together with the number as "peptide having an N mer length," which refers to a peptide in which the number of N amino acids are polymerized. The unit indicated by the expression "mer" should be interpreted appropriately in context and it includes all other meanings that can be recognized by a person skilled in the art.

Standard amino acids

As used herein, the term "standard amino acids" refers to 20 amino acids synthesized by the transcription and translation processes of genes in an organism. Specifically, standard amino acids include alanine (Ala, a), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (gin, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V). Standard amino acids have corresponding DNA codons and can be represented by conventional single or three letter representations of amino acids. The objects to which the term standard amino acid refers should be interpreted appropriately depending on the context, and they include all other meanings that a person skilled in the art can recognize.

Non-standard amino acids

As used herein, the term "non-standard amino acid" refers to amino acids other than standard amino acids. Non-standard amino acids include artificial amino acids and unnatural amino acids, and it includes those amino acids that are chemically modified in the organism by post-translational modification, and the like. Non-standard amino acids include, for example, D-alanine, L-cyclohexanoalanine, 6-aminocaproic acid, and the like. Since a non-standard amino acid does not have a corresponding DNA codon, it cannot be represented by the conventional single-letter or three-letter representation of the amino acid, but is written in other characters and interpreted by additional explanation. The term nonstandard amino acids refers to an object that should be interpreted appropriately depending on the context, and they include all other meanings that a person skilled in the art can recognize.

Description of peptide sequences

Unless otherwise indicated, when describing peptide sequences in this application, single-letter or three-letter representations of amino acids are used and written in a direction from the N-terminus to the C-terminus. For example, when expressed as RNVP, it refers to a peptide in which arginine, asparagine, valine and proline are sequentially connected in the direction from the N-terminal end to the C-terminal end. As another example, when expressed as Thr-Leu-Lys, it refers to a peptide in which threonine, leucine and lysine are sequentially linked in a direction from the N-terminus to the C-terminus. For the case of amino acids that cannot be represented by a single letter notation, other letters are used to describe these amino acids and will be explained by additional explanation.

When a peptide is represented as a structural formula, N-and-C may be used to clearly indicate the N-terminus or the C-terminus, and may be underlined to distinguish between the N-terminus and/or the C-terminus. For example, when the structural formula of the peptide is represented byN-B-T-A-CWhen written at the beginning, unless otherwise indicated "N"and writing at the endC"is a symbol used to clarify the N-terminal and C-terminal directions. This refers to peptides in which the sequences represented by B, T and a are linked in a direction from the N-terminus to the C-terminus.

Background-humoral immunity

Humoral immunity of immunoglobulin M (IgM)

In humoral immunity, igM-induced immune response is an innate immune function that is primarily active in the primary immune response, and it occurs rapidly in the early stages of infection. IgM is secreted predominantly in pentameric form and theoretically has 10 antigen binding sites, so it can bind to a large number of antigens simultaneously. Although IgM can bind to antigens of many types and forms, the affinity and avidity of binding is limited by the inherent affinity of IgM itself. Therefore, igM has significantly lower affinity and avidity for antigen than antibodies (such as IgG produced by helper T cell help).

Limitations of humoral immunity to IgM

Although IgM-induced humoral immunity plays an important role in the initial immune response, the role of IgM-dependent humoral immunity is limited because: 1) low production of IgM by B cells compared to production of other types of antibodies (e.g., igG produced by differentiated B cells, etc.), 2) low specific binding of IgM to antigen compared to specific binding of IgG to antigen, and 3) a weak secondary immune response upon re-exposure to the same antigen. Therefore, from the viewpoint of designing an antigen that induces an immune response, in the case where the antigen injected into the subject induces only humoral immunity of IgM, it is highly likely that the desired effect will not be obtained. Therefore, it is important to design antigens to induce humoral immunity to IgG.

Humoral immunity 1-overview of immunoglobulin G (IgG)

Humoral immunity to IgG occurs mainly in the germinal center of lymph nodes or spleen and proceeds through the complex action of B cells, helper T cells and Antigen Presenting Cells (APC). The whole process is as follows. 1) B cells recognize invading antigens (mainly protein or peptide antigens). 2) After an antigen (or fragment thereof) is endocytosed by an antigen presenting cell and cleaved into smaller fragments within the cell, a portion of the fragments are presented to the MHC class II surface of the antigen presenting cell. 3) Helper T cells recognize antigen fragments presented to MHC class II. 4) Helper T cells transmit differentiation signals to B cells (antigen recognizing cells). 5) B cells are activated and some B cells differentiate into plasma cells to produce IgG antibodies with a high specific binding capacity for antigen. 6) As a result of B cell activation, some cells differentiate into memory B cells and are stored in the body so that they can trigger an immune response that rapidly produces IgG antibodies upon re-invasion of the same antigen.

Humoral immune 2-antigen recognizing cell of IgG

Antigen presenting cells refer to a generic term for cells capable of endocytosing a protein fragment or peptide, cleaving it into shorter peptide fragments, placing it on MHC class II, and presenting it to the surface of an antigen presenting cell. The primary antigen presenting cells include B cells, macrophages, dendritic cells, and the like. Antigen presenting cells transport endocytic antigen fragments from the site of infection to the lymph nodes and present the antigen fragments to helper T cells via MHC class II, thereby playing a role in inducing an immune response by activating helper T cells that recognize the antigen fragments.

Humoral immunity 3-MHCII class of IgG

MHC class II is a molecule expressed on the surface of antigen presenting cells and has a heterodimeric structure consisting of alpha/beta chains. Due to its structure, MHC class II can bind to a length of peptide and present it. Antigen presenting cells allow peptide fragments derived from foreign antigens to bind to MHC class II and present them on the cell surface. HLA gene complexes (human leukocyte antigen gene complexes) are involved in expression of human MHC-II, and among them, gene complexes such as HLA-DP, DQ, DR, etc. are known to be involved in expression of MHC-II cell surface receptors on the surface of antigen presenting cells. In humans, HLA-DR genes are known to have a variety of alleles depending on the race, and about 12 HLA-DR genes are known to be the most common alleles.

Humoral immunity 4-presentation of IgG by MHC class II antigen presenting cells

Despite slight differences between the literature, peptides presented in MHC class II are known to range in length from about 17mer to about 24 mer. Thus, antigen presenting cells do not present endocytic antigen proteins or peptide fragments on MHC class II as they are, but rather undergo a cleavage process that cleaves them into smaller fragments of 17mer to 24 mer. The antigen fragment (protein or peptide fragment) endocytosed by the antigen presenting cell is presented in an endosome, and the endosome is fused with the lysosome of the antigen presenting cell. Thereafter, the antigen fragments are cleaved into shorter peptides by various degrading enzymes present in the lysosome. Examples of degrading enzymes include endopeptidases and exopeptidases. Endopeptidases cleave antigen fragments by acting on peptide bonds within the antigen fragment, whereas exopeptidases cleave antigen fragments primarily by acting on peptide bonds at both ends of the antigen fragment. When the antigen fragments are cleaved into appropriately sized peptides by the above procedure, some of them bind to MHC class II present in the lysosomal membrane. Lysosomes return to the cell surface and fuse with the cytoplasmic membrane, so MHC class II and its associated peptide fragments are exposed on the surface of antigen presenting cells. This whole process is also referred to as "antigen presenting process by antigen presenting cells".

Humoral immune 5-helper T cell of IgG

Helper T lymphocytes are also known as CD4 ⁺ Cells because they express CD4. Helper T cells express T Cell Receptors (TCRs) that have the ability to bind to MHC class II on the surface. T cell receptors typically form complexes with CD 3. Helper T when antigen (e.g., peptide fragment) delivered by antigen presenting cells to lymph nodes is presented by MHC class IIThe cells recognize the presented antigen fragments. The T cell receptor-CD 3 complex and CD4 are involved in this recognition process. When helper T cells successfully recognize antigen fragments, they are activated to secrete various cytokines or to differentiate themselves. The secreted cytokines are involved in the differentiation of B cells, which will be described later.

Humoral immune 6-B cell differentiation of IgG

Under the influence of cytokines secreted by helper T cells (e.g., interleukin-4 (IL-4), etc.), B cells undergo immunoglobulin class switching, thereby altering the isotype of antibodies produced by B cells (e.g., from IgM to IgG). In addition, some B cells differentiate into memory B cells and are stored in order to induce a rapid immune response upon re-invasion of the same antigen, while some B cells differentiate into plasma cells and actively produce IgG antibodies.

Conditions for humoral immunity of IgG 7-IgG production

For IgG to produce humoral immunity, it is crucial that 1) a specific three-dimensional structure of the antigen is recognized by B cells, and 2) some fragments of the antigen are recognized by helper T cells via MHC class II. In general, although the antigen moiety recognized by B cells and the antigen moiety recognized by helper T cells are different from each other, and they activate an immune response by different pathways from each other, it is generally known that an immune response occurs only when the B cell-recognized moiety (B cell epitope) and the helper T cell-recognized moiety (Th epitope) have at least some linkage. For example, the B cell epitope and Th epitope may be contained in one molecule, form a conjugate, or have other linkages.

Limitations of the prior art

Considerations in designing peptides useful as immunotherapeutic agents

As described above, immunotherapeutic agents are needed because they are characterized in that: 1) They are capable of stably inducing an immune response in a subject, 2) they are capable of minimizing side effects by uniformly inducing only the desired antibodies in a subject; and 3) for their commercialization, they are easy to synthesize, and their production costs are reasonable. Thus, in designing peptides that can be used as immunotherapeutic agents, the following three conditions should be considered: 1) the peptide should exhibit a certain degree of immunogenicity, 2) the peptide should trigger an immune response in the subject that uniformly induces antigen recognition specificity of a predetermined antibody, isotype controlling physiological functions of the antibody, etc., and 3) the peptide should be easily synthesized in consideration of economic feasibility.

Limitations of the prior art

Antibodies specific for artificially produced peptides having specific sequences are also known to bind to exposed sites of ApoB-100 protein in LDL molecules, and thus are useful as immunotherapeutic agents, as disclosed in previously filed patent applications US10/378,707 and PCT/KR2005/000784 and Kim et al (2016,An apolipoprotein B100 mimotope prevents obesity in mice,Clinical Science 130,105-116). Using this property, an immunotherapeutic agent containing a peptide is designed and disclosed in the above-mentioned patent application and the like. However, the prior art has focused mainly on increasing the immunogenicity of peptides, e.g., 1) preparing long, contiguous identical sequences of peptides (concatemers), 2) designing immunotherapeutic agents by linking helper T cell epitopes (long enough at the protein level) to concatemers, etc. Thus, conventionally designed immunotherapeutic agents have the following limitations: 1) Multiple types of antibodies are induced and homogeneity is reduced due to the presence of multiple epitopes (antigenic determinants), and 2) economic viability is low due to their high production costs.

Necessity of establishing peptide design method

Regarding peptides for use as immunotherapeutic agents, no principle has been established regarding: 1) Only homogeneous induction of the intended immune response and 2) design of peptides that are easy to synthesize and inexpensive to produce. Accordingly, in the present specification, technical problems to be considered in designing a peptide for use as an immunotherapeutic agent and a method of designing the peptide will be provided.

Peptides

Peptide overview

The peptides provided herein comprise at least one peptide unit (peptide fragment). The peptide unit comprises at least one B cell epitope, at least one Th epitope and a suitable number of helper moieties. In embodiments, the peptide may comprise one peptide unit. In another embodiment, the peptide may comprise more than two peptide units.

Characteristic 1 of peptide-comprising peptide units

The peptide unit is designed as follows: 1) Exhibit more than a certain level of immunogenicity, and 2) induce only a uniform, predetermined antibody. Thus, the peptide units provided herein have properties suitable for use as immunotherapeutic agents.

Characterization of the peptide the length of the 2-peptide units is relatively short

Since the peptide units are designed to have a relatively short length, they are easy to synthesize and are inexpensive to produce. Peptides are designed using peptide units as a component thereof, and in particular, in the form of one or more peptide unit linkages. When the peptide contains only a small amount of peptide units, the total peptide length is short, and thus has an advantage of easy synthesis. Even when the peptide has a relatively long sequence including a plurality of peptide units, the peptide units themselves are well designed to be easy to synthesize, and thus, the peptide can be prepared by synthesizing the peptide units in parallel and then ligating these peptide units. As a result, in addition to the characteristics of the peptide units described above, the peptides provided herein have the characteristics of ease of synthesis, which is a characteristic suitable for use of the peptides as immunotherapeutic agents.

Peptide function

When the peptide is injected into a subject, it has a function of uniformly inducing only antibodies capable of specifically binding to the B cell epitope contained in the peptide.

B cell epitopes

Definition of B cell epitopes

The peptides provided herein comprise one or more B cell epitopes. As used herein, the term B cell epitope refers to a peptide unit that is intentionally designed to induce one type of homogeneous antibody. Thus, when a peptide comprising a B cell epitope is injected into a subject, the result is that each type of B cell epitope induces predominantly one type of antibody.

Structure of B cell epitope

The B cell epitope comprises a moiety for forming a three-dimensional structure and its neighboring moieties. The moiety for forming the three-dimensional structure is a moiety that forms a peptide having a higher structure, and the moiety is designed so that B cells can recognize the peptide having a higher structure and produce an antibody capable of specifically binding to the peptide. Adjacent portions are portions that directly or indirectly affect the portions for forming a three-dimensional structure to stably form a higher-order structure. Specifically, the adjacent portion may have, for example, the following functions: 1) a function for forming a portion of a three-dimensional structure to form a specific structure, 2) a linker function not affecting a portion for forming a three-dimensional structure when a B cell epitope is linked to another portion within a peptide unit, 3) a function for protecting a portion for forming a three-dimensional structure, and the like, but their functions are not limited thereto. In embodiments, the B cell epitope may have a sequence in which a first portion for forming a three-dimensional structure and a first adjacent portion thereof are sequentially connected from an N-terminal to a C-terminal. In another embodiment, the B cell epitope may have a sequence in which a second adjacent portion, a second portion for forming a three-dimensional structure, and a third adjacent portion are sequentially connected from the N-terminus to the C-terminus. In yet another embodiment, the B cell epitope may have a sequence in which a third portion and a fourth adjacent portion for forming a three-dimensional structure are sequentially connected from the N-terminus to the C-terminus.

Design of B cell epitopes 1-design of parts for Forming three-dimensional Structure

The B cell epitope should be able to recognize its three-dimensional structure by the B cell and uniformly induce the generation of antibodies to which it specifically binds. The three-dimensional structure recognized by B cells can be expressed by appropriate peptides having higher order structures. Thus, B cell epitopes are designed to contain moieties for forming three-dimensional structures that form peptides with higher order structures. Depending on its purpose, the moiety used to form the three-dimensional structure may form the desired peptide with a higher order structure. In embodiments, the moiety used to form the three-dimensional structure may comprise an alpha-helical structure. In another embodiment, the moiety used to form the three-dimensional structure may comprise a beta structure. In yet another embodiment, the moiety used to form the three-dimensional structure may comprise an alpha-helix and/or a beta structure. In another embodiment, the moiety for forming the three-dimensional structure may comprise a peptide having a tertiary structure. In yet another embodiment, the moiety for forming the three-dimensional structure may comprise a peptide having a quaternary structure.

Design of B cell epitopes 2-adjacent part

In designing B cell epitopes, not all sequences must form peptides with higher order structures. In other words, the B cell epitope may be designed to additionally contain adjacent moieties in addition to the moiety for forming the three-dimensional structure. Adjacent portions may affect portions for forming a three-dimensional structure so as to stably form a higher-order structure. The adjacent portions may perform various other functions and their roles may overlap those of the auxiliary portions. In an embodiment, the adjacent portions may have a joint function. In another embodiment, the adjacent portions may have a protective function against portions for forming a three-dimensional structure. In yet another embodiment, adjacent portions may have one or more functions.

Length of B cell epitope

The B cell epitope should have 1) a size sufficient to be recognized by the B cell, and 2) one type or a very small number of types of antibodies that specifically bind to the B cell epitope. The length of the B cell epitope should be limited to a suitable level. When the length of the B cell epitope is too short, it is not recognized by the B cell and thus does not have antibody induction ability, whereas when the length of the B cell epitope is too long, various types of antibodies can be induced, which deviates from the intended purpose. In embodiments, the length of the B cell epitope can be about 8mer, about 9mer, about 10mer, about 11mer, about 12mer, about 13mer, about 14mer, about 15mer, about 16mer, about 17mer, about 18mer, about 20mer, about 21mer, about 22mer, about 23mer, about 24mer, about 25mer, about 26mer, about 27mer, about 28mer, about 29mer, or about 30mer.

In another embodiment, the length of the B cell epitope may have a value within the two numerical ranges selected in the previous sentence.

Embodiment of B cell epitope

In embodiments, the B cell epitope may be an epitope that induces antibodies that target apolipoprotein B-100. In another embodiment, the B cell epitope may be a fragment of apolipoprotein B-100 and/or a mimotope of apolipoprotein B-100. In yet another embodiment, the B cell epitope is characterized in that it induces antibodies targeting a site selected from the group consisting of:

An external exposure site of apolipoprotein B-100 contained in Low Density Lipoprotein (LDL); and an external exposure site of apolipoprotein B-100 contained in Very Low Density Lipoprotein (VLDL).

Embodiments of B cell epitope sequences

In an embodiment, the B cell epitope is a peptide comprising a sequence selected from the group consisting of: RNVPPIFNDVYWIAF (SEQ ID NO: 6),

In another embodiment, the B cell epitope may be a peptide comprising an epitope comprised in a sequence selected from the group consisting of SEQ ID NOs: 6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222, and a peptide of the group consisting of 222.

Sequences similar to exemplary sequences of B cell epitopes

In this document, sequences similar to the exemplary sequences of B cell epitopes are disclosed. In embodiments, the B cell epitope may have a sequence selected from the group consisting of SEQ ID NOs: 6-SEQ ID NO:34 and SEQ ID NO:221-SEQ ID NO:222 have sequences 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In another embodiment, the B cell epitope may be a sequence matching a value selected from the group consisting of SEQ ID NOs: 6-SEQ ID NO: 34. SEQ ID NO:221-SEQ ID NO: 222. For example, a B cell epitope may have a sequence identical to SEQ ID NO:6 having more than 90% identity.

Th epitopes

Definition of Th epitopes

The Th epitope contained in the peptide provided herein refers to a portion designed such that, after the peptide is endocytosed by an antigen presenting cell, the portion binds to MHC class II, is presented on the surface of the antigen presenting cell, and functions to be recognized by helper T cells (Th, helper T lymphocytes) in the process of being presented on the surface of the antigen presenting cell by MHC class II. The process by which antigen presenting cells treat endocytosed peptides and bind to MHC class II presenting antigens has been described hereinbefore. In other words, a Th epitope is a portion that functions to be recognized by T helper cells when a peptide is injected into a subject; thus, it plays a direct role in inducing antibodies of the IgG type against peptides.

Design of Th epitopes 1-anchoring residues

Th epitopes are designed to have anchor residues capable of binding MHC class II in their sequence. Whether or not an anchor residue is included in the sequence is an important factor affecting Th epitope function. In embodiments, a Th epitope may comprise one or more amino acids selected from the group consisting of: tyrosine (Y), phenylalanine (F), tryptophan (W), arginine (R), leucine (L), valine (V), isoleucine (I) and methionine (M).

Design of Th epitopes 2-species specific Th epitopes

As the Th epitope, a Th epitope having the ability to bind to MHC class II of a specific species may be selected according to its purpose. In embodiments, the Th epitope may be a Th epitope having the ability to bind human MHC class II. In another embodiment, the Th epitope may be a Th epitope having the ability to bind to MHC class II belonging to a species of mammal. In particular, the Th epitope may be a Th epitope having the ability to bind mouse MHC class II.

Design of Th epitopes 3-Gene-specific Th epitopes

The structure of MHC class II can vary from race to race and from individual to individual due to the diverse nature of HLA gene complexes. Thus, th epitopes can be designed that have the ability to bind HLA-DP, HLA-DQ and/or HLA-DR (which are MHC class II of a particular genetic trait). In embodiments, the Th epitope may be a peptide sequence with high binding capacity to MHC class II expressed by one or more HLA-DR genes selected from the group consisting of 2w2b, 2w2a, 3, 4w4, 4w14, 5, 7, 52a, 52b, 52c and 53 (which are HLA-DR1 alleles).

In embodiments, th epitopes may be peptide sequences with high binding capacity to MHC class II expressed by one or more genes selected from the group consisting of HLA-DQ5, HLA-DR1 to HLA-DR8, HLA-DR11, HLA-DR13, HLA-DR14, HLA-DRw52, HLA-DR2w15, HLA-DPw4, HLA-DRB1, each subtype (e.g., 0301, 01, 03, 04, 07, 08, 09, 11, 12, 13, 15 and 0301) and HLA-DRB 5.

In another embodiment, the Th epitope may be the sequence disclosed in Cara C.Wilson et al (2001,Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-advanced Helper T-Lymphocyte Epitopes, journal of Virology,75 (9) 4195-4207) under the name HA 307-312.

In yet another embodiment, the Th epitope may be one of the HLA class II restriction epitopes disclosed in Table 2 of Christopher P Desmond et al (2008,Asystematic review of T-cell epitopes in hepatitis B virus: identification, genotypic variation and relevance to antiviral therapeutics, antiviral Therapy: 161-175).

Design of Th epitopes 4-Gene non-specific Th epitopes

Th epitopes having binding ability to various MHC class II are known regardless of the traits of HLA gene complexes, and Th epitopes capable of binding to various MHC class II irrespective of genetic traits can be designed. In embodiments, the Th epitope may be a sequence known as a "pan DR-binding peptide" as disclosed in U.S. patent application No.305,871.

Design 5 of Th epitopes-possibility of exclusion as B cell epitopes

Th epitopes are designed to be presented by MHC class II of antigen presenting cells and recognized by helper T cells. Thus, th epitopes generally have a very high binding capacity to MHC class II, and thus the likelihood that Th epitopes can act as B cell epitopes is very low. In other words, th epitopes are designed to be antibodies that do not induce specific binding to the Th epitope's own three-dimensional structure.

Design of Th epitope Length

The Th epitope should be designed to be of a suitable length so that it can bind to one unit of MHC class II. It is well known that one unit that can directly bind to the Th epitope of MHC class II is in a length of about 30mer (Abbas, A.K., lichtman, A.H. and Piclai, S.Cellular and molecular immunology (pp 124-126), 7 Th edition, (2012) Philadelphia PA, elsevier Saunderser, et al). Furthermore, 1) when the length of the Th epitope becomes too short, there is a risk that the Th epitope loses its ability to bind to MHC class II, and 2) when the length of the Th epitope is too long, the Th epitope has a space to independently function as a B cell epitope, thereby deviating from the intended purpose. Therefore, it is necessary to design Th epitopes with an appropriate length.

Length range of Th epitope

In embodiments, the Th epitope can be 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33mer in length. In another embodiment, the length of the Th epitope may have a value within the two value ranges selected in the previous sentence. For example, the length of Th epitopes can range from 8mer to 32 mer. For another example, the length of the Th epitope may be in the range of 11mer to 13 mer.

Design of Th epitope embodiment-PADRE

In embodiments, the Th epitope may be a peptide known as a "pan DR binding peptide" disclosed in U.S. patent application No. 305871. In another embodiment, the Th epitope may be one of the peptides disclosed in table VIII a and table IX of U.S. patent No.6,413,935B1. In yet another embodiment, the Th epitope may have a peptide sequence satisfying structural formula I below:

[ I ]

N-Lys-X ₁ -X ₂ -Ala-Ala-X ₃ -Thr-X ₄ -X ₅ -Ala-Ala-C

Wherein X is ₁ Can be tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine, but X ₁ Not limited thereto.

X ₂ May be a hydrophobic amino acid, or may be leucine (Leu) or isoleucine (Ile), but X ₂ Not limited thereto.

X ₃ Can be an aromatic amino acid or a cyclic amino acid, or can be phenylalanine (Phe), tyrosine (Tyr) or histidine (His), but X ₃ Not limited thereto.

X ₄ Can be aliphatic long chain amino acids, or can be isoleucine (Ile) or valine (Val), but X ₄ Not limited thereto.

X ₅ May be a charged amino acid, or may be arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln) or glycine (Gly), but X ₅ Not limited thereto.

In embodiments, the Th epitope may have a peptide sequence satisfying structural formula II below:

[ II ]

N-X ₁ -X ₂ -Val-X ₃ -Ala-X ₄ -Thr-Leu-Lys-Ala-Ala-C

Wherein X is ₁ Is lysine (Lys) or arginine (Arg),

X ₂ tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine,

X ₃ lysine as lysine(Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala) or methionine (Met), and

X ₄ is asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys) or alanine (Ala).

Embodiments of Th epitope sequences

In embodiments, the Th epitope may be selected from the group consisting of:

/>

in this case, "a" means D-alanine, "Z" means 6-aminocaproic acid, and "(Cha)" means L-cyclohexylalanine.

Sequences similar to the exemplary sequence of the Th epitope

In this document, sequences similar to the exemplary sequences of Th epitopes are disclosed. In embodiments, the Th epitope may have a sequence that hybridizes to SEQ ID NO:1-SEQ ID NO: 5. SEQ ID NO:162-SEQ ID NO: 192. SEQ ID NO:195-SEQ ID NO:196 and SEQ ID NO:223-SEQ ID NO: 247. the sequence satisfying the above [ formula I ] or the sequence satisfying the above [ formula II ] has 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity. In another embodiment, the Th epitope may have a sequence matching the value selected in the preceding sentence or higher of the following sequence: SEQ ID NO:1-SEQ ID NO: 5. SEQ ID NO:162-SEQ ID NO: 192. SEQ ID NO:195-SEQ ID NO:196 and SEQ ID NO:223-SEQ ID NO: 247. a sequence satisfying the above [ formula I ] or a sequence satisfying the above [ formula II ]. For example, a Th epitope may have a sequence identical to SEQ ID NO:1, and a sequence having an identity of 90% or more.

Auxiliary part

Definition of auxiliary part

The peptides disclosed herein may comprise one or more auxiliary moieties. The accessory moiety is collectively referred to as an additional moiety that can directly or indirectly affect the peptide to elicit a desired immune response in the subject. The auxiliary moiety may have one or more functions, and the composition of the peptide sequence and/or the position of the sequence may be appropriately designed according to the purpose.

Function 1 of auxiliary part-functioning as a linker

The helper portion may function as a linker linking the B cell epitope and the Th epitope. The B cell epitope and Th epitope may be directly linked or they may be linked through a helper moiety that acts as a linker. Furthermore, the auxiliary moiety may be designed to have a linker function for linking a plurality of units contained in the peptide. In embodiments, the sequence of the helper portion may be located between the B cell epitope sequence and the Th epitope sequence. Specifically, the helper portion has a linker function that links the B cell epitope and the Th epitope. In another embodiment, the sequence of the auxiliary moiety may be located between the sequence of the first peptide unit and the sequence of the second peptide unit in the peptide. Specifically, the auxiliary moiety has a linker function for linking the first peptide unit and the second peptide unit.

Function 2-protection function of auxiliary part

In the case of the peptide units provided herein, they are characterized by having a relatively short sequence length. Thus, when a peptide comprising a peptide unit is injected into a subject, the Th epitope sequence may be degraded before being recognized by the helper T cell, and thus, an intended immune response may not occur. In embodiments, the protective unit may protect the Th epitope from cleavage by enzymes in the subject. For example, the enzyme in the subject may be a peptidase. In particular, the peptidase may be an exopeptidase and/or an endopeptidase, but the peptidase is not limited thereto. In another embodiment, the helper moiety may be linked to the N-terminus and/or the C-terminus of the Th epitope. Specifically, the helper portion has a function of protecting the Th epitope. In yet another embodiment, the auxiliary moiety may comprise at least one non-standard amino acid.

Function of auxiliary part 3-function of forming a ring form

The auxiliary moiety may be designed to be attached to both ends of the peptide unit, thereby having a function of allowing the peptide to form a loop. In embodiments, the peptide may comprise a first auxiliary moiety at the N-terminus and a second auxiliary moiety at the C-terminus. In particular, the first auxiliary moiety and the second auxiliary moiety may each comprise one or more cysteines (S). In another embodiment, the peptide may exist in a cyclic form. In particular, the N-terminus and the C-terminus of the peptide may be linked by a helper moiety.

Function 3 of auxiliary part-other functions

The auxiliary portion may have another function in addition to the above-described functions. In embodiments, the auxiliary moiety may comprise a hydrophilic amino acid, and may have the function of increasing the solubility of the peptide. In another embodiment, the auxiliary moiety may consist of a sequence that is not biologically active in the subject. Specifically, the auxiliary moiety has no effect on the functions of B cell epitopes and Th epitopes, and may have a dummy (dummy) function of extending the peptide length. In particular, the peptide may be a His tag, but is not limited thereto.

Can perform multiple functions

The auxiliary portion may have one or more functions. In an embodiment, the auxiliary portion may have a joint function, a protection function, a function of forming a ring form, a dummy function, and/or a solubility increasing function.

Can contain non-standard amino acids

The auxiliary moiety may comprise one or more non-standard amino acids. Artificial amino acids may be necessary for the auxiliary moiety to exhibit linker functions, protective functions, and/or other functions. In embodiments, the auxiliary moiety may comprise at least one non-standard amino acid. Specifically, the non-standard amino acid may be one or more non-standard amino acids selected from the group consisting of L-cyclohexylalanine, D-alanine and 6-aminocaproic acid, but the non-standard amino acid is not limited thereto.

Auxiliary part length

The auxiliary portion may be designed to have an appropriate length according to its function. When the auxiliary portion has a plurality of functions, it may be designed to have an appropriate length to exhibit all of the plurality of functions. In embodiments, the auxiliary moiety may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31mer or longer in length. In another embodiment, the length of the auxiliary portion may have a value within two numerical ranges of the previous sentence. For example, the length of the auxiliary moiety may be in the range of 1mer to 8 mer. For another example, the length of the auxiliary moiety may be in the range of 15mer to 26 mer.

The nature of the helper portion-little effect on the function of the B cell epitope

The accessory moiety does not significantly affect the peptide units and/or the peptide-induced function of the antibodies disclosed herein that specifically bind to a B cell epitope in the subject.

Implementation of the auxiliary partial sequence

In an embodiment, the auxiliary moiety may be a peptide selected from the group consisting of: a. z, aZ, za, RN, AF, CR, LS, KT, KH, RF, DP, SV, GL, ZRNV (SEQ ID NO: 36), aZRN (SEQ ID NO: 37), IAFZ (SEQ ID NO: 38), AFza (SEQ ID NO: 39), RNVP (SEQ ID NO: 40), WIAF (SEQ ID NO: 41), ZCRF (SEQ ID NO: 42), aZCR (SEQ ID NO: 43), YLSZ (SEQ ID NO: 44), LSza (SEQ ID NO: 45), CRFR (SEQ ID NO: 46), VYLS (SEQ ID NO: 47), ZKTT (SEQ ID NO: 48), aZKT (SEQ ID NO: 49), NKHZ (SEQ ID NO: 50), KHZa (SEQ ID NO: 51), GSHHHHHHGSDDDDK (SEQ ID NO: 52), HHHHHHHHHHHHHHHHHHHS (SEQ ID NO: 53), MRGSHHHHHHGSDDDDKIVIVD (SEQ ID NO: 54), GGGGSGGGGGGGSS (SEQ ID NO: 55), RRRRRR (SEQ ID NO: 159), GSHHHHHHHHHHDDDDDDKaZ (SEQ ID NO: 193) and ZDDDHHHHGSHHHHHHGSK (SEQ ID NO: 194). Specifically, "a" represents D-alanine, and "Z" represents 6-aminocaproic acid.

Design of peptide units-population

Methods for designing possible peptide units and their forms will be described below. Each unit may comprise at least one B cell epitope and at least one Th epitope, and may comprise an appropriate number of helper moieties. The order of attachment of the B cell epitope, th epitope and helper portion is exemplified for each type. Unless otherwise indicated, the design of the individual parts comprised in the peptide unit substantially follows the design principles described above.

Design unit A

Structure 1-overview of cell A

As provided herein, a peptide unit is designated "unit a" and may comprise 1) one B cell epitope and one Th epitope, and 2) one or more accessory moieties. The function of the helper portion is not particularly limited as long as it does not impair the functions of the B cell epitope and Th epitope, and is appropriately designed as needed.

In embodiments, unit a may be a unit in which a first B cell epitope and a first Th epitope are sequentially connected in a direction from the N-terminal end to the C-terminal end.

Furthermore, unit a may further comprise a first auxiliary portion. When unit a comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located on the N-terminal side relative to the sequence of the first B cell epitope within the sequence of unit a. Specifically, the first auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the first auxiliary portion is not limited thereto.

Furthermore, unit a may further comprise a second auxiliary portion. When unit a comprises a second helper portion, the sequence of the second helper portion is located between the first B cell epitope sequence and the first Th epitope sequence within the unit a sequence. Specifically, the second auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the second auxiliary portion is not limited thereto.

Furthermore, unit a may further comprise a third auxiliary portion. When unit a comprises a third helper portion, the sequence of the third helper portion is located on the C-terminal side relative to the sequence of the first Th epitope within the sequence of unit a. Specifically, the third auxiliary portion may have a dummy function, a solubility improving function, a joint function, a protecting function, and/or a function of forming a loop form, but the function of the third auxiliary portion is not limited thereto.

In another embodiment, the unit a may be a unit in which the second Th epitope and the second B cell epitope are sequentially connected in a direction from the N-terminal to the C-terminal.

Furthermore, unit a may further comprise a fourth auxiliary portion. When unit a comprises a fourth helper portion, the sequence of the fourth helper portion is located on the N-terminal side relative to the sequence of the second Th epitope within the sequence of unit a. Specifically, the fourth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fourth auxiliary portion is not limited thereto.

Furthermore, unit a may further comprise a fifth auxiliary portion. When unit a comprises a fifth helper portion, the sequence of the fifth helper portion is located between the sequence of the second B cell epitope and the sequence of the second Th epitope within the sequence of unit a. Specifically, the fifth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fifth auxiliary portion is not limited thereto.

Furthermore, unit a may further comprise a sixth auxiliary portion. When unit a comprises a sixth helper portion, the sequence of the sixth helper portion is located on the C-terminal side relative to the sequence of the second B cell epitope within the sequence of unit a. Specifically, the sixth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the sixth auxiliary portion is not limited thereto.

Unit AStructure 2-Structure

In an embodiment, unit a is a peptide represented by the following [ formula a ] or [ formula a' ].

[ A ]

N-A ₁ -B ₁ -A ₂ -T ₁ -A ₃ -C

[ A' ]

N-A ₄ -T ₂ -A ₅ -B ₂ -A ₆ -C

B ₁ And B ₂ Are B cell epitopes and they follow the design principles described above.

T ₁ And T ₂ Are Th epitopes and they follow the design principles described above.

A ₁ To A ₆ Are auxiliary parts, and they may be omitted.

Specifically, A ₁ To A ₆ May have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but A ₁ To A ₆ Not limited thereto.

Length of unit A

In embodiments, the length of unit A can be about 16mer, about 17mer, about 18mer, about 19mer, about 20mer, about 21mer, about 22mer, about 23mer, about 24mer, about 25mer, about 26mer, about 27mer, about 28mer, about 29mer, about 30mer, about 31mer, about 32mer, about 33mer, about 34mer, about 35mer, about 36mer, about 37mer, about 38mer, about 39mer, about 40mer, about 41mer, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99 or about 100. In another embodiment, the length of cell a may have a value within the two value ranges selected in the previous sentence. For example, the length of unit a may range from about 16mer to about 30 mer. For another example, the length of unit a can be in the range of about 23mer to about 60 mer.

Embodiment of cell a-exemplary design

In embodiments, unit a may have a sequence in which the first B cell epitope, the first helper portion, and the first Th epitope are sequentially linked. In particular, the first auxiliary moiety has a linker function and it comprises one or more artificial amino acids.

In another embodiment, unit a may have a sequence in which the second helper portion, the second B cell epitope, the third helper portion, and the second Th epitope are sequentially linked. In particular, the second auxiliary moiety is a His-tag and the third auxiliary moiety has a linker function and it comprises one or more artificial amino acids.

In yet another embodiment, unit a may have a sequence in which a third B cell epitope, a fourth helper portion, a third Th epitope, and a fifth helper portion are sequentially linked. Specifically, the fourth auxiliary portion has a joint function and a protection function, and the fifth auxiliary portion has a protection function. The fourth auxiliary moiety and the fifth auxiliary moiety each comprise one or more artificial amino acids.

In yet another embodiment, unit a may have a sequence in which a sixth helper portion, a fourth B cell epitope, a seventh helper portion, a fourth Th epitope, and an eighth helper portion are sequentially linked. Specifically, the sixth auxiliary portion is a His tag, the seventh auxiliary portion has a linker function and a protecting function, and the eighth auxiliary portion has a protecting function. The seventh and eighth auxiliary parts comprise one or more artificial amino acids.

Embodiment of the sequence of units A

In an embodiment, unit a is a unit peptide selected from the group consisting of:

/>

in this case, "a" means D-alanine, "Z" means 6-aminocaproic acid, "(Cha)" means L-cyclohexylalanine, and "X" means any standard amino acid.

Design unit B

Structure 1-overview of cell B

As peptide units provided herein, a peptide unit 1) comprising two B cell epitopes and one Th epitope, 2) wherein the sequence of one of the two B cell epitopes is located between the sequence of the other B cell epitope and the sequence of the Th epitope, and 3) may comprise one or more helper moieties is designated as "unit B". The function of the helper portion is not particularly limited as long as it does not impair the functions of the B cell epitope and Th epitope, and is appropriately designed as needed.

In embodiments, unit B may be a unit in which a first B cell epitope, a second B cell epitope, and a first Th epitope are sequentially connected in a direction from the N-terminus to the C-terminus.

Furthermore, unit B may further comprise a first auxiliary portion. When unit B comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located on the N-terminal side relative to the sequence of the first B cell epitope within the sequence of unit B. Specifically, the first auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the first auxiliary portion is not limited thereto.

Furthermore, unit B may further comprise a second auxiliary portion. When unit B comprises a second helper portion, the sequence of the second helper portion is located between the sequence of the first B cell epitope and the sequence of the second B cell epitope within the unit B sequence. Specifically, the second auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the second auxiliary portion is not limited thereto.

Furthermore, unit B may further comprise a third auxiliary portion. When unit B comprises a third helper portion, the sequence of the third helper portion is located between the sequence of the second B cell epitope and the sequence of the first Th epitope within the sequence of unit B. Specifically, the third auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the third auxiliary portion is not limited thereto.

In addition, unit B may further include a fourth auxiliary portion. When unit B comprises a fourth helper portion, the sequence of the fourth helper portion is located on the C-terminal side relative to the sequence of the first Th epitope within the sequence of unit B. Specifically, the fourth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fourth auxiliary portion is not limited thereto.

In another embodiment, the unit B may be a unit in which a second Th epitope, a third B cell epitope, and a fourth B cell epitope are sequentially connected in a direction from the N-terminus to the C-terminus.

In addition, unit B may further include a fifth auxiliary portion. When unit B comprises a fifth helper portion, the sequence of the fifth helper portion is located on the N-terminal side relative to the sequence of the second Th epitope within the sequence of unit B. Specifically, the fifth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fifth auxiliary portion is not limited thereto.

In addition, the unit B may further include a sixth auxiliary portion. When unit B comprises a sixth helper portion, the sequence of the sixth helper portion is located between the sequence of the second Th epitope and the sequence of the third B cell epitope within the sequence of unit B. Specifically, the sixth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the sixth auxiliary portion is not limited thereto.

In addition, the unit B may further include a seventh auxiliary portion. When unit B comprises a seventh auxiliary moiety, the sequence of the seventh auxiliary moiety is located between the sequence of the third B cell epitope and the sequence of the fourth B cell epitope within the unit B sequence. Specifically, the seventh auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the seventh auxiliary portion is not limited thereto.

Furthermore, unit B may further comprise an eighth auxiliary portion. When unit B comprises an eighth helper portion, the sequence of the eighth helper portion is located on the C-terminal side relative to the sequence of the fourth B cell epitope within the sequence of unit B. Specifically, the eighth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the eighth auxiliary portion is not limited thereto.

Structure 2-Structure of Unit B

In an embodiment, unit B is a peptide represented by the following [ formula B ] or [ formula B' ].

[ B ]

N-A ₁ -B ₁ -A ₂ -B ₂ -A ₃ -T ₁ -A ₄ -C

[ B' ]

N-A ₅ -T ₂ -A ₆ -B ₃ -A ₇ -B ₄ -A ₈ -C

B ₁ To B ₄ Are B cell epitopes and they follow the design principles described above.

T ₁ And T ₂ Are Th epitopes and they follow the design principles described above.

A ₁ To A ₈ Are auxiliary parts, and they may be omitted.

Specifically, A ₁ To A ₈ May have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but A ₁ To A ₈ Not limited thereto.

Length of unit B

In embodiments, the length of unit B can be about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 80, about 82, about 84, about 98, about 91, about 98, about 91, about 82, about 91, about 82, about 98. In another embodiment, the length of cell B may have a value within the two value ranges selected in the previous sentence. For example, the length of unit B may range from about 24mer to about 45 mer. For another example, the length of unit B can be in the range of about 40mer to about 80 mer.

Embodiment of cell B-exemplary design

In embodiments, unit B may have a sequence in which the first helper portion, the first B cell epitope, the second helper portion, and the first Th epitope are sequentially linked. In particular, the first auxiliary moiety is a His-tag, the second auxiliary moiety has a linker function and it comprises one or more artificial amino acids.

In another embodiment, unit B may have a sequence in which a third B cell epitope, a fourth B cell epitope, a third helper portion, and a second Th epitope are sequentially linked. In particular, the third auxiliary moiety has a linker function and it comprises one or more artificial amino acids.

In another embodiment, unit B may have a sequence in which a fourth helper portion, a fifth B cell epitope, a sixth B cell epitope, a fifth helper portion, a third Th epitope, and a sixth helper portion are sequentially linked. Specifically, the fourth auxiliary moiety is a His tag, the fifth auxiliary moiety has a linker function and a protecting function and comprises one or more artificial amino acids, and the sixth auxiliary moiety has a protecting function and comprises one or more artificial amino acids.

In yet another embodiment, unit B may have a sequence in which a seventh B cell epitope, an eighth B cell epitope, a seventh helper portion, a fourth Th epitope, and an eighth helper portion are sequentially linked. Specifically, the seventh auxiliary moiety has a linker function, a protective function, and comprises one or more artificial amino acids, and the eighth auxiliary moiety has a protective function, and comprises one or more artificial amino acids.

In yet another embodiment, unit B may have a sequence in which an eighth helper portion, a ninth B cell epitope, a ninth helper portion, a tenth B cell epitope, a tenth helper portion, and a fifth Th epitope are sequentially linked. Specifically, the eighth auxiliary moiety is a His tag, the ninth auxiliary moiety has a linker function, and the tenth auxiliary moiety has a linker function and comprises one or more artificial amino acids.

In yet another embodiment, unit B may have a sequence in which an eleventh B cell epitope, an eleventh helper portion, a twelfth B cell epitope, a twelfth helper portion, and a sixth Th epitope are sequentially linked. Specifically, the eleventh auxiliary moiety has a linker function and the twelfth auxiliary moiety has a linker function and comprises one or more artificial amino acids.

In yet another embodiment, unit B may have a sequence in which the thirteenth B cell epitope, thirteenth helper portion, fourteenth B cell epitope, fourteenth helper portion, seventh Th epitope, and fifteenth helper portion are sequentially linked. Specifically, the thirteenth auxiliary portion has a linker function, the fourteenth auxiliary portion has a linker function and a protecting function and comprises one or more artificial amino acids, and the fifteenth auxiliary portion has a protecting function and comprises one or more artificial amino acids.

Embodiment of the sequence of unit B

In an embodiment, unit B is a peptide unit selected from the group consisting of:

/>

in this case, "a" means D-alanine, "Z" means 6-aminocaproic acid, "(Cha)" means L-cyclohexylalanine, and "X" means any standard amino acid.

Design unit C

Structure 1-overview of cell C

As peptide units provided herein, the peptide unit 1) comprises two B cell epitopes and one Th epitope, 2) wherein the sequence of the Th epitope is located between the sequence of one B cell epitope and the sequence of the other B cell epitope of the two B cell epitopes, and 3) may comprise one or more helper moieties is designated as "unit C". The function of the helper portion is not particularly limited as long as it does not impair the functions of the B cell epitope and Th epitope, and is appropriately designed as needed.

In embodiments, unit C may be a unit in which a first B cell epitope, a first Th epitope, and a second B cell epitope are sequentially connected in a direction from the N-terminus to the C-terminus.

Furthermore, the unit C may further include a first auxiliary portion. When unit C comprises a first helper portion, the sequence of the first helper portion is on the N-terminal side relative to the sequence of the first B cell epitope within the sequence of unit C. Specifically, the first auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the first auxiliary portion is not limited thereto.

Furthermore, the unit C may further include a second auxiliary portion. When unit C comprises a second helper portion, the sequence of the second helper portion is located between the sequence of the first B cell epitope and the sequence of the first Th epitope within the sequence of unit C. Specifically, the second auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the second auxiliary portion is not limited thereto.

Furthermore, the unit C may further include a third auxiliary portion. When unit C comprises a third helper portion, the sequence of the third helper portion is located between the sequence of the first Th epitope and the sequence of the second B cell epitope within the sequence of unit C. Specifically, the third auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the third auxiliary portion is not limited thereto.

Furthermore, the unit C may further include a fourth auxiliary portion. When unit C comprises a fourth auxiliary moiety, the sequence of the fourth auxiliary moiety is located on the C-terminal side relative to the sequence of the second B cell epitope within the sequence of unit C. Specifically, the fourth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fourth auxiliary portion is not limited thereto.

Structure 2-Structure of Unit C

In an embodiment, unit C is a peptide represented by the following [ formula C ].

[ C ]

N-A ₁ -B ₁ -A ₂ -T ₁ -A ₃ -B ₂ -A ₄ -C

B ₁ And B ₂ Are B cell epitopes and they follow the design principles described above.

T ₁ Is a Th epitope and it follows the design principles described above.

A ₁ 、A ₂ 、A ₃ And A ₄ Are auxiliary parts, and they may be omitted.

Specifically, A ₁ 、A ₂ 、A ₃ And A ₄ May have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but A ₁ 、A ₂ ，A ₃ And A ₄ Not limited thereto.

Length of unit C

In embodiments, the length of the unit C can be about 24mer, about 25mer, about 26mer, about 27mer, about 28mer, about 29mer, about 30mer, about 31mer, about 32mer, about 33mer, about 34mer, about 35mer, about 36mer, about 37mer, about 38mer, about 39mer, about 40mer, about 41mer, about 42mer, about 43mer, about 44mer, about 45mer, about 46mer, about 47mer, about 48mer, about 49mer, about 50mer, about 51mer, about 52mer, about 53mer, about 54mer, about 55mer, about 56mer, about 57mer, about 58mer, about 59mer, about 60mer, about 61mer, about 62mer, about 63mer, about 64mer, about 65mer, about 66mer, about 67mer, about 68mer, about 69mer, about 70mer, about 71, about 72mer, about 73mer, about 74, about 75, about 76mer, about 77mer, about 78, about 79mer, about 80mer, about 81mer, about 82mer, about 83mer, about 84mer, about 85mer, about 86mer, about 87mer, about 88mer, about 89mer, about 90mer, about 91mer, about 92mer, about 93mer, about 94mer, about 95mer, about 96mer, about 97mer, about 98mer, about 99mer, about 100mer. In another embodiment, the length of cell C may have a value within the two value ranges selected in the previous sentence. For example, the length of unit C may range from about 24mer to about 45 mer. For another example, the length of unit C can be in the range of about 40mer to about 80 mer.

Embodiment of cell C-exemplary design

In embodiments, unit C may have a sequence in which a first B cell epitope, a first helper portion, a first Th epitope, a second helper portion, and a second B cell epitope are sequentially linked. Specifically, the first auxiliary portion and the second auxiliary portion each have a joint function and a protection function. The first auxiliary moiety and the second auxiliary moiety each comprise one or more artificial amino acids.

In another embodiment, unit C may have a sequence in which a third helper portion, a third B cell epitope, a fourth helper portion, a second Th epitope, a fifth helper portion, and a fourth B cell epitope are sequentially linked. Specifically, the third auxiliary moiety is a His tag, and the fourth auxiliary moiety and the fifth auxiliary moiety each have a linker function and a protecting function. The fourth auxiliary moiety and the fifth auxiliary moiety each comprise one or more artificial amino acids.

Embodiment of the sequence of units C

In an embodiment, unit C is a peptide unit selected from the group consisting of:

/>

in this case, "a" means D-alanine, "Z" means 6-aminocaproic acid, "(Cha)" means L-cyclohexylalanine, and "X" means any standard amino acid.

Design unit D

Structure 1-overview of cell D

As peptide units provided herein, the peptide unit 1) comprises one B cell epitope and two Th epitopes, 2) wherein the sequence of one of the two Th epitopes is located between the sequence of the other Th epitope and the sequence of the B cell epitope, and 3) may comprise one or more helper moieties is designated as "unit C". The function of the helper portion is not particularly limited as long as it does not impair the functions of the B cell epitope and Th epitope, and is appropriately designed as needed.

In embodiments, unit D may be a unit in which a first B cell epitope, a first Th epitope, and a second Th epitope are sequentially connected in a direction from the N-terminus to the C-terminus.

Furthermore, the unit D may further include a first auxiliary portion. When unit D comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located on the N-terminal side relative to the sequence of the first B cell epitope within the sequence of unit D. Specifically, the first auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the first auxiliary portion is not limited thereto.

Furthermore, the unit D may further include a second auxiliary portion. When unit D comprises a second helper portion, the sequence of the second helper portion is located between the sequence of the first B cell epitope and the sequence of the first Th epitope within the sequence of unit D. Specifically, the second auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the second auxiliary portion is not limited thereto.

Furthermore, the unit D may further include a third auxiliary portion. When the unit D comprises a third helper portion, the sequence of the third helper portion is located between the sequence of the first Th epitope and the sequence of the second Th epitope within the sequence of the unit D. Specifically, the third auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the third auxiliary portion is not limited thereto.

Furthermore, the unit D may further include a fourth auxiliary portion. When unit D comprises a fourth helper portion, the sequence of the fourth helper portion is located on the C-terminal side relative to the sequence of the second Th epitope within the sequence of unit D. Specifically, the fourth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fourth auxiliary portion is not limited thereto.

In another embodiment, the unit D may be a unit in which a third Th epitope, a fourth Th epitope, and a second B cell epitope are sequentially linked in a direction from the N-terminus to the C-terminus.

Furthermore, the unit D may further include a fifth auxiliary portion. When unit D contains a fifth helper portion, the sequence of the fifth helper portion is located on the N-terminal side relative to the sequence of the third Th epitope within the sequence of unit D. Specifically, the fifth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fifth auxiliary portion is not limited thereto.

In addition, the unit D may further include a sixth auxiliary portion. When unit D comprises a sixth helper portion, the sequence of the sixth helper portion is located between the sequence of the third Th epitope and the sequence of the fourth Th epitope within the sequence of unit D. Specifically, the sixth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the sixth auxiliary portion is not limited thereto.

Furthermore, the unit D may further include a seventh auxiliary portion. When unit D comprises a seventh helper portion, the sequence of the seventh helper portion is located between the sequence of the fourth Th epitope and the sequence of the second B cell epitope within the sequence of unit D. Specifically, the seventh auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the seventh auxiliary portion is not limited thereto.

Furthermore, the unit D may further include an eighth auxiliary portion. When unit D comprises an eighth helper portion, the sequence of the eighth helper portion is located on the C-terminal side relative to the sequence of the second B cell epitope within the sequence of unit D. Specifically, the eighth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the eighth auxiliary portion is not limited thereto.

Structure-Structure of cell D2

In an embodiment, unit B is a peptide represented by the following [ formula D ] or [ formula D' ].

[ D ]

N-A ₁ -B ₁ -A ₂ -T ₁ -A ₃ -T ₂ -A ₄ -C

[ D' ]

N-A ₅ -T ₃ -A ₆ -T ₄ -A ₇ -B ₂ -A ₈ -C

B ₁ And B ₂ Are B cell epitopes and they follow the design principles described above.

T ₁ -T ₄ Are Th epitopes and they follow the design principles described above.

A ₁ -A ₈ Are auxiliary parts, and they may be omitted.

Specifically, A ₁ -A ₈ May have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but A ₁ -A ₈ Not limited thereto.

Length of unit D

In the present embodiment of the present invention, the length of unit D can be about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61 about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99 or about 100. In another embodiment, the length of cell B may have a value within the two value ranges selected in the previous sentence. For example, the length of unit D may range from about 24mer to about 45 mer. For another example, the length of unit D can be in the range of about 40mer to about 80 mer.

Embodiment of cell D-exemplary design

In embodiments, unit D may have a sequence in which the first helper portion, the first B cell epitope, the second helper portion, the first Th epitope, the third helper portion, and the second Th epitope are sequentially linked. Specifically, the first auxiliary moiety is a His tag, and the second auxiliary moiety and the third auxiliary moiety each have a linker function. The second auxiliary moiety and the third auxiliary moiety each comprise one or more artificial amino acids.

In another embodiment, the unit D may have a sequence in which a fourth helper portion, a second B cell epitope, a fifth helper portion, a third Th epitope, a sixth helper portion, a fourth Th epitope, and a seventh helper portion are sequentially linked. Specifically, the fourth auxiliary portion is a His tag, the fifth auxiliary portion and the sixth auxiliary portion each have a linker function, and the seventh auxiliary portion has a protective function. The fifth auxiliary moiety, the sixth auxiliary moiety and the seventh auxiliary moiety each comprise one or more artificial amino acids.

In yet another embodiment, unit D comprises a third B cell epitope, an eighth helper portion, a fifth Th epitope, a ninth helper portion, and a sixth Th epitope. Specifically, the eighth auxiliary portion and the ninth auxiliary portion each have a joint function. The eighth auxiliary portion and the ninth auxiliary portion each have a protective function and each comprise one or more artificial amino acids.

In yet another embodiment, unit D comprises a fourth B cell epitope, a tenth helper portion, a seventh Th epitope, an eleventh helper portion, an eighth Th epitope, and a twelfth helper portion. Specifically, the tenth auxiliary portion and the eleventh auxiliary portion each have a joint function. The twelfth auxiliary part has a protective function. The tenth auxiliary portion, the eleventh auxiliary portion and the twelfth auxiliary portion each comprise one or more artificial amino acids.

Implementation of the sequence of units D

In an embodiment, unit D is a peptide unit selected from the group consisting of:

in this case, "a" means D-alanine, "Z" means 6-aminocaproic acid, "(Cha)" means L-cyclohexylalanine, and "X" means any standard amino acid.

Design unit E

Structure 1-overview of cell E

As peptide units provided herein, the peptide unit 1) comprises two B cell epitopes and two Th epitopes, 2) wherein each sequence of the two Th epitopes is located between the sequence of one B cell epitope and the sequence of the other B cell epitope of the two B cell epitopes, and 3) may comprise one or more auxiliary moieties is designated as "unit E". The function of the helper portion is not particularly limited as long as it does not impair the functions of the B cell epitope and Th epitope, and is appropriately designed as needed.

In embodiments, the unit E may be a unit in which a first B cell epitope, a first Th epitope, a second Th epitope, and a second B cell epitope are sequentially connected in a direction from the N-terminus to the C-terminus.

Furthermore, the unit E may further comprise a first auxiliary portion. When unit E comprises a first helper portion, the sequence of the first helper portion is located on the N-terminal side relative to the sequence of the first B cell epitope within the sequence of unit E. Specifically, the first auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the first auxiliary portion is not limited thereto.

Furthermore, the unit E may further comprise a second auxiliary portion. When unit E comprises a second helper portion, the sequence of the second helper portion is located between the sequence of the first B cell epitope and the sequence of the first Th epitope within the sequence of unit E. Specifically, the second auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the second auxiliary portion is not limited thereto.

Furthermore, unit E may further comprise a third auxiliary portion. When the unit E comprises a third helper portion, the sequence of the third helper portion is located between the sequence of the first Th epitope and the sequence of the second Th epitope within the sequence of the unit E. Specifically, the third auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the third auxiliary portion is not limited thereto.

Furthermore, the unit E may further comprise a fourth auxiliary portion. When unit E comprises a fourth helper portion, the sequence of the fourth helper portion is located between the sequence of the second B cell epitope and the sequence of the second B cell epitope within the sequence of unit E. Specifically, the fourth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a protecting function, but the function of the fourth auxiliary portion is not limited thereto.

Furthermore, unit E may further comprise a fifth auxiliary portion. When unit E comprises a fifth auxiliary moiety, the sequence of the fifth auxiliary moiety is located on the C-terminal side relative to the sequence of the second B cell epitope within the sequence of unit E. Specifically, the fifth auxiliary portion may have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but the function of the fifth auxiliary portion is not limited thereto.

Structure 2-Structure of Unit E

In an embodiment, unit E is a peptide represented by the following [ formula E ].

[ E ]

N-A ₁ -B ₁ -A ₂ -T ₁ -A ₃ -T ₂ -A ₄ -B ₂ -A ₅ -C

B ₁ And B ₂ Are B cell epitopes and they follow the design principles described above.

T ₁ And T ₂ Are Th epitopes and they follow the design principles described above.

A ₁ 、A ₂ 、A ₃ 、A ₄ And A ₅ Are auxiliary parts, and they may be omitted.

Specifically, A ₁ 、A ₂ 、A ₃ 、A ₄ And A ₅ May have a dummy function, a solubility-improving function, a joint function, and/or a function of forming a ring form, but A ₁ 、A ₂ 、A ₃ 、A ₄ And A ₅ Not limited thereto.

Length of unit E

In embodiments, the length of the unit E can be about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 88, about 92, about 91, about 94, about 98, about 94 or about 93. In another embodiment, the length of unit E may have a value within the two value ranges selected in the previous sentence. For example, the length of unit E may range from about 32mer to about 60 mer. For another example, the length of the unit E may be in the range of about 50mer to about 100mer.

Embodiment of cell E-exemplary design

In embodiments, unit E may have a sequence in which a first helper moiety, a first B cell epitope, a second helper moiety, a first Th epitope, a third helper moiety, a second Th epitope, a fourth helper moiety, and a second B cell epitope are sequentially linked. In particular, the first auxiliary moiety is a His tag. The second auxiliary portion and the fourth auxiliary portion each have a joint function and a protection function. The third auxiliary portion has a joint function. The second auxiliary moiety, the third auxiliary moiety and the fourth auxiliary moiety comprise one or more artificial amino acids.

In another embodiment, unit E may have a sequence in which a third B cell epitope, a fifth helper portion, a third Th epitope, a sixth helper portion, a fourth Th epitope, a seventh helper portion, and a fourth B cell epitope are sequentially linked. Specifically, the fifth auxiliary portion and the seventh auxiliary portion each have a joint function and a protection function. The sixth auxiliary portion has a joint function. The fifth auxiliary portion, the sixth auxiliary portion and the seventh auxiliary portion comprise one or more artificial amino acids.

Embodiment of the sequence of units E

In an embodiment, unit E is a peptide unit selected from the group consisting of:

In this case, "a" represents D-alanine, "Z" represents 6-aminocaproic acid, and "(Cha)" represents L-cyclohexylalanine.

Design peptides

Design of peptides-overview

The peptides provided herein can be designed using one or more of the peptide units described above. These peptides comprise one or more peptide units and may comprise one or more types of peptide units. For example, the peptide may be designed by: 1) comprising only one peptide unit, 2) designing a concatemer by ligating one type of a plurality of peptide units having the same sequence, 3) designing a peptide in the form of a bead by ligating one or more types of peptide units having different sequences, 4) designing a peptide in the form of a ring by mixing the above-mentioned designing methods 1) to 3), and 5) designing a peptide in the form of a ring by ligating both ends of the peptide designed in the above-mentioned methods, but the designing method is not limited thereto. Hereinafter, each design method will be described in detail.

Single cell design

The peptide may be designed to comprise only one of the peptide units described above. In embodiments, the peptide may comprise one peptide unit selected from the group consisting of unit a, unit B, unit C, unit D, and unit E. Specifically, the peptide unit has the constitution described above.

Series body design 1-overview

Peptides can be designed in concatamer form, in which multiple peptide units having the same sequence are linked. Peptides designed in tandem form are composed of 1) one type of peptide unit and 2) a plurality of peptide units having the same or equivalent sequence.

Specifically, two peptide units having "equivalent sequences" refer to the following cases: 1) When the auxiliary moiety is present at the N-terminus and/or the C-terminus of each of the two peptides, and 2) when the auxiliary moiety is present, the sequences are identical even though the two are different. For example, when a first peptide has a sequence in which a first auxiliary moiety and a first unit A are linked in a direction from N-terminus to C-terminus, a second peptide has a sequence in which a first unit A and a first auxiliary moiety are linked in a direction from N-terminus to C-terminus, a third peptide has a sequence in which a second auxiliary moiety, a first unit A and a third auxiliary moiety are linked in a direction from N-terminus to C-terminus, and a fourth peptide has a first unit A sequence, the first to fourth peptides are said to have equivalent sequences.

In embodiments, the peptide may include a peptide in which a first peptide unit and a second peptide unit are sequentially linked. Specifically, the first peptide unit is a peptide unit selected from the group consisting of unit a, unit B, unit C, unit D, and unit E; and the second peptide unit has the same or an equivalent sequence as the first peptide unit.

In another embodiment, the peptide may include a peptide in which a third peptide unit, a fourth peptide unit, and a fifth peptide unit are sequentially connected. Specifically, the third peptide unit is a peptide unit selected from the group consisting of unit a, unit B, unit C, unit D, and unit E; and the fourth peptide unit and the fifth peptide unit each have the same or equivalent sequence as the third peptide unit.

In yet another embodiment, the peptide may include a peptide in which a sixth peptide unit, a seventh peptide unit, an eighth peptide unit, and a ninth peptide unit are sequentially connected. Specifically, the third peptide unit is a peptide unit selected from the group consisting of unit a, unit B, unit C, unit D, and unit E; and the seventh peptide unit, the eighth peptide unit and the ninth peptide unit each have the same or equivalent sequence as the sixth peptide unit.

Design 2-Structure of a Concatenation

In an embodiment, the peptide may be a peptide represented by the following [ formula 1 ].

[ 1]

N-U ₁ -U ₂ -…-U _n -C

Wherein U is ₁ To U (U) _n Each of which is a peptide unit selected from the group consisting of unit a, unit B, unit C, unit D and unit E, and which have the constitution of the peptide unit described above.

U ₁ To U (U) _n Having identical or equivalent sequences.

N is an integer of 2 or more.

Design of concatemers 3-exemplary sequences

In an embodiment, the peptide is a peptide selected from the group consisting of:

in this case, "a" means D-alanine, "Z"Represents 6-aminocaproic acid, "(Cha)" represents L-cyclohexylalanine.

Bead design 1-overview

The peptide may be designed in the form of a bead in which a plurality of peptide units having different sequences are linked. Peptides designed in the form of beads consist of 1) at least one type of peptide unit and 2) a plurality of peptide units having different sequences.

In embodiments, the peptide may include a peptide in which a first peptide unit and a second peptide unit are sequentially linked. Specifically, the first peptide unit and the second peptide unit are each peptide units selected from the group consisting of unit a, unit B, unit C, unit D, and unit E; and the first peptide unit and the second peptide unit have sequences different from each other.

In another embodiment, the peptide may include a peptide in which a third peptide unit, a fourth peptide unit, and a fifth peptide unit are sequentially connected. Specifically, the third peptide unit, the fourth peptide unit, and the fifth peptide are each peptide units selected from the group consisting of unit a, unit B, unit C, unit D, and unit E; and the third peptide unit, the fourth peptide unit and the fifth peptide unit have sequences different from each other.

In yet another embodiment, the peptide may include a peptide in which a sixth peptide unit, a seventh peptide unit, an eighth peptide unit, and a ninth peptide unit are sequentially connected. Specifically, each of the sixth peptide unit, the seventh peptide unit, the eighth peptide unit, and the ninth peptide unit is a peptide unit selected from the group consisting of unit a, unit B, unit C, unit D, and unit E; and the sixth peptide unit, the seventh peptide unit, the eighth peptide unit and the ninth peptide unit have sequences different from each other.

2-structural type bead design

In an embodiment, the peptide may be a peptide represented by the following [ formula 2 ]:

[ 2]

N-U ₁ -U ₂ -…-U _n -C

Wherein U is ₁ -U _n Each is selected from the group consisting of unit A, unit B, and unitC. The peptide units in the group consisting of unit D and unit E, and they have the constitution of the peptide units described above.

U ₁ -U _n With different sequences.

n is an integer of 2 or more.

Bead design 3-exemplary sequence

In embodiments, the peptide may be a peptide of RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 156), wherein "a" represents D-alanine, Z represents 6-aminocaproic acid, and (Cha) represents L-cyclohexylalanine.

Hybrid design 1-overview

Peptides can be designed by appropriate mixing of 1) the single unit design, 2) the concatemer design, and 3) the beading design described above. In an embodiment, a peptide may be designed by first designing a single peptide according to the design methods described above, and then ligating multiple single peptides.

In embodiments, the peptide may be a peptide in which a first unit peptide and a second unit peptide are sequentially linked. Specifically, the first unit peptide and the second unit peptide each have a constitution of a peptide according to any one of a single unit design, a concatemer design, and a bead design, and the sequence of the first unit peptide and the sequence of the second unit peptide are different from each other.

In another embodiment, the peptide may be a peptide in which a third unit peptide, a fourth unit peptide, and a fifth unit peptide are sequentially linked. Specifically, the third unit peptide, the fourth unit peptide, and the fifth unit peptide each have a composition of a peptide according to any one of a single unit design, a concatemer design, and a bead design, and the sequences of the third unit peptide, the fourth unit peptide, and the fifth unit peptide are different from each other.

In yet another embodiment, the peptide may be a peptide in which a sixth unit peptide, a seventh unit peptide, an eighth unit peptide, and a ninth unit peptide are sequentially connected. Specifically, the sixth unit peptide, the seventh unit peptide, the eighth unit peptide, and the ninth unit peptide each have a constitution of a peptide according to any one of a single unit design, a concatemer design, and a bead design, and the sequences of the sixth unit peptide, the seventh unit peptide, the eighth unit peptide, and the ninth unit peptide are different from each other.

Hybrid design 2-Structure

In an embodiment, the peptide may be a peptide represented by the following [ formula 3 ]:

[ 3]

N-P ₁ -P ₂ -…-P _n -C

Wherein P is ₁ To P _n Each of which is a unit peptide designed by a method selected from the group consisting of a single unit design, a concatemer design and a bead design, and which have the designs and constitutions of the peptides described above.

n is an integer of 2 or more.

Hybrid design 3-exemplary sequence

In an embodiment, the peptide is a peptide selected from the group consisting of:

in this case, "a" means D-alanine, "Z" means 6-aminocaproic acid, and "(Cha)" means L-cyclohexylalanine.

Design of annular form

Peptides can be designed to form a cyclic form. When the peptide is in cyclic form, stability in the subject is increased; thus, when a peptide having a cyclic form is used as an immunotherapeutic agent, an improved effect can be expected. In an embodiment, for a peptide designed by a design method selected from the group consisting of a single unit design, a concatemer design, a bead design, and a mixed design method, the peptide may be designed to further have an auxiliary moiety having a function of forming a loop form at the N-terminal and the C-terminal. In another embodiment, for peptides designed by a design method selected from the group consisting of a single unit design, a concatemer design, a bead design, and a mixed design method, the peptides may be designed to further comprise an auxiliary moiety, and form a circular form by the auxiliary moiety.

Other designs

In addition to the above-described design methods, the peptide may be designed by other methods as necessary. In embodiments, for peptides designed by a design method selected from the group consisting of a single unit design, a concatemer design, a bead design, and a mixed design method, the peptide may further comprise one or more helper moieties, one or more B cell epitopes, and/or one or more Th epitopes.

Sequences similar to the disclosed peptide units and/or peptides

In this document, peptide units and/or peptides having sequences similar to those disclosed in the paragraphs of "unit a design", "unit B design", "unit C design", "unit D design", "unit E design" and "peptide design" described above are disclosed.

In embodiments, a peptide unit may have a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of the sequences disclosed in the paragraphs of "unit a design", "unit B design", "unit C design", "unit D design" and "unit E design". In another embodiment, the peptide unit may have a sequence that matches any of the sequences disclosed in the paragraphs of "unit a design", "unit B design", "unit C design", "unit D design" and "unit E design" by at least the values selected in the previous sentence. In yet another embodiment, the peptide unit may have a sequence that hybridizes to a sequence selected from the group consisting of SEQ ID NOs: 56-SEQ ID NO: 150. SEQ ID NO:160-SEQ ID NO:161 and SEQ ID NO:198-SEQ ID NO:220 has 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity. In yet another embodiment, the peptide unit may have a sequence that hybridizes to a sequence selected from the group consisting of SEQ ID NOs: 56-SEQ ID NO: 150. SEQ ID NO:160-SEQ ID NO:161 and SEQ ID NO:198-SEQ ID NO:220 matches with at least the value selected in the previous sentence. For example, the peptide unit may have a sequence identical to SEQ ID NO:56 has a sequence with more than 90% identity.

In yet another embodiment, a peptide may have a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of the sequences disclosed in the paragraph of "peptide design". In yet another embodiment, the peptide may have a sequence that matches any of the sequences disclosed in the paragraph of "peptide design" by at least the value selected in the preceding sentence. In yet another embodiment, the peptide may have a sequence that hybridizes to a sequence selected from the group consisting of SEQ ID NOs: 151-SEQ ID NO:158 has 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity. In yet another embodiment, the peptide may have a sequence that hybridizes to SEQ ID NO:151-SEQ ID NO:158 match with at least the value selected in the previous sentence. For example, the peptide may have a sequence identical to SEQ ID NO:151 has a sequence having identity of 90% or more.

Use of peptides

Use of peptides-overview

The peptides provided herein are suitable as immunotherapeutic agents because they have the following characteristics when introduced into a subject: 1) They induce the production of antibodies that specifically bind to the intentionally designed B cell epitope, and 2) they induce the production of homogeneous antibodies. Thus, the peptides are useful as immunotherapeutic agents. In embodiments, the peptides provided herein are useful as immunotherapeutic agents for obesity. In another embodiment, the peptide units provided herein and/or peptides comprising the peptide units are useful for treating obesity.

Use of peptides for the treatment of obesity

The peptides provided herein comprise B cell epitopes. In embodiments, the B cell epitope may be a polypeptide comprised in SEQ ID NO:41-SEQ ID NO: 75. In particular, B cell epitopes are known to induce antibodies with the ability to bind to ApoB-100 (U.S. patent application Ser. No.10/378,707, PCT/KR2005/000784, and Kim et al, 2016,An apolipoprotein B100 mimotope prevents obesity in mice,Clinical Science 130,105-116). From the above prior document, it is known that an antibody having the ability to bind to ApoB-100 has an immunotherapeutic effect on obesity when induced by a B cell epitope in a subject. Thus, in this document, the use of peptides for the treatment of obesity and methods thereof are disclosed. To describe the immunotherapeutic effect of peptides on obesity, U.S. patent application Ser. No.10/378,707, PCT/KR2005/000784, and Kim et al, 2016,An apolipoprotein B100 mimotope prevents obesity in mice,Clinical Science 130,105-116 are incorporated herein by reference. In the event of a conflict between a reference portion and a description of the present application, it is to be understood that the description in the present application takes precedence over the reference portion.

Pharmaceutical compositions comprising peptides

Disclosed herein are pharmaceutical compositions comprising the peptides described above. The peptide is useful as an immunotherapeutic agent, and has in common with vaccines that it induces humoral immunity when injected into the body. Thus, the person skilled in the art may include suitable ingredients in the pharmaceutical composition comprising the peptide, which ingredients may be added for administration of the vaccine in general and/or to enhance the effect of inducing an immune response. For example, the pharmaceutical composition may comprise a formulated peptide, a pharmaceutically acceptable carrier, a supplement, and/or an adjuvant, but is not limited thereto. In particular, the pharmaceutical composition may compriseWater, saline, dextrose, ethanol, glycerol, sodium chloride, dextrose, mannitol, sorbitol, lactose, gelatin, albumin, aluminum hydroxide, freund's incomplete and complete adjuvants (Pifco Laboratories, detroit, mich.), merck antigen adjuvant 65 (Merck and Company, inc., rahway, NJ.), alhydragel (Al (OH) ₃ ) Aluminum hydroxide gel (Alum) or aluminum salts (e.g., aluminum phosphate), AS04 series, MF, squalene, MF59, QS21, insoluble suspensions of calcium, iron or zinc salts, acylated fructose, cationically or anionically derivatized polysaccharides, polyphosphazenes, biodegradable microspheres, quil A, toll-like receptor (TLR) agonists, PHAD [ Avanti polar lipid, monophosphoryl lipid A (synthetic) ]Mono-phosphoryl lipid a (MPL, mono-phosphoryl lipid a), synthetic lipid a, lipid a mimics or analogues, aluminium salts, cytokines, saponins, prolactin, growth hormone deoxycholic acid, beta-glucan, polyribonucleotides, muramyl Dipeptide (MDP) derivatives, cpG oligonucleotides, gram negative bacterial Lipopolysaccharide (LPS), polyphosphazenes, emulsions, virosomes, cochleates, poly (lactide-co-glycolide) (PLG) microparticles, poloxamer particles, microparticles, liposomes or suitable combinations thereof.

Method for producing peptide

The peptides provided herein may be prepared by known methods that can be employed by those skilled in the art, and the preparation method is not particularly limited. In embodiments, the peptides may be prepared by recombinant protein preparation methods. In another embodiment, the peptide may be chemically synthesized. Specifically, the peptide may be synthesized by a liquid phase peptide synthesis method, a solid phase peptide synthesis method, or a small peptide fragment aggregation (convergent) method, but the method is not limited thereto.

Nucleic acids encoding peptide units and/or peptides

Nucleic acid-overview encoding peptide units and/or peptides

In this document, nucleic acids encoding the peptide units and/or peptides disclosed above (hereinafter "encoding nucleic acids") are disclosed. Although the peptide units and peptides disclosed herein may comprise non-standard amino acids, codons corresponding to non-standard amino acids are not present in nature. Thus, non-standard amino acids cannot be encoded in a general way. It is therefore necessary to replace these nonstandard amino acids with the appropriate standard amino acids in order to encode them in the form of nucleic acids. When the peptide unit and/or peptide does not contain non-standard amino acids, the nucleic acid codons corresponding to each standard amino acid can be used to design the encoding nucleic acid.

For ease of description, in this application peptide units and/or peptides include substitutions of non-standard amino acids with appropriate standard amino acids; and peptide units and/or peptides comprising only standard amino acids are referred to as target peptides to be encoded, and DNA and/or RNA encoding target peptides to be encoded are referred to as encoding nucleic acids. In particular, when the peptide unit and/or peptide does not comprise a non-standard amino acid, the peptide unit and/or peptide has the same amino acid sequence as the target peptide to be encoded.

As used herein, the term "target peptide to be encoded" is a conceptual term introduced to easily describe the resulting encoding nucleic acid, and is independent of the method or procedure by which the encoding nucleic acid is prepared.

Design of target peptides to be encoded

When the peptide units and peptides disclosed herein comprise non-standard amino acids, the target peptide to be encoded is designed by substituting the non-standard amino acid with an appropriate standard amino acid. When the peptide units and peptides disclosed herein do not comprise non-standard amino acids, the corresponding target peptide to be encoded has the same sequence as the peptide units and peptides. In embodiments, the target peptide to be encoded may be a peptide in which a non-standard amino acid is substituted with any standard amino acid. In another embodiment, the target peptide to be encoded may be a peptide in which a non-standard amino acid is substituted with a standard amino acid having the same or equivalent function as the non-standard amino acid. In yet another embodiment, the target peptide to be encoded may have the same sequence as the peptide unit and/or peptide. In particular, the peptide units and/or peptides are characterized by the absence of non-standard amino acids.

Design of the embodiment of the target peptide to be encoded-case comprising PADRE

The peptide units and peptides disclosed herein comprise one or more Th epitopes. In particular, when the Th epitope is the sequence disclosed in U.S. patent application No.305,871 under the name PADRE, it may comprise the nonstandard amino acid L-cyclohexylalanine. According to the literature, L-cyclohexylalanine can have both the function of protecting PADRE from peptide degrading enzymes and the function of being able to bind to anchoring residues of MHC class II. Thus, the target peptide to be encoded is designed by substituting L-cyclohexylalanine with an appropriate standard amino acid having the same or equivalent function. In embodiments, the L-cyclohexylalanine can be substituted with any standard amino acid. In another embodiment, L-cyclohexylalanine can be replaced with phenylalanine or tyrosine. In yet another embodiment, the sequence of the target peptide corresponding to PADRE to be encoded may be KFVAAWTLKAA (SEQ ID NO: 195), KYVAAWTLKAA (SEQ ID NO: 196) or KXVAAWTLKAA (SEQ ID NO: 197), wherein X represents any standard amino acid.

Embodiments of the sequences of the target peptides to be encoded

In an embodiment, the sequence of the target peptide to be encoded is selected from

In this case, "X" represents any standard amino acid.

Design of coding nucleic acids 1-nucleic acid codon based

The coding nucleic acids disclosed herein refer to the codons of the nucleic acid encoding the target peptide to be encoded. Since the sequences of the target peptides to be encoded are all standard amino acids, the encoding nucleic acids are designed based on nucleic acid codons corresponding to the respective amino acids of the target peptides to be encoded. In particular, since one or more nucleic acid codons may correspond to one standard amino acid, eventually more than two encoding nucleic acids encoding one target peptide to be encoded may be designed. In embodiments, the encoding nucleic acid may be DNA and/or RNA codons encoding the target peptide to be encoded. In another embodiment, the encoding nucleic acid may have a DNA and/or RNA sequence capable of complementarily binding to DNA and/or RNA codons encoding the target peptide to be encoded.

The sequence of the encoding nucleic acid may be codon optimized, as will be described in more detail below.

Design of coding nucleic acids 2-codon optimisation

As described above, if a coding nucleic acid is designed by simply ligating nucleic acid codons corresponding to respective amino acids of a target peptide to be coded, a plurality of coding nucleic acids can be designed for one target nucleic acid to be coded. Since an average of 1 to 6 nucleic acid codons per standard amino acid increases the number of possible nucleic acid codon combinations exponentially with increasing amino acid sequence length. However, not all of these combinations are equally important. In general, there are combinations of nucleic acid codons that are capable of better expressing the target peptide to be encoded in the cell, which may differ depending on the higher order structure of the sequence itself, the type of target cell into which the encoding nucleic acid is to be injected, and the like. The discovery of such combinations of nucleic acid codons and assigning the discovered combinations to sequences encoding nucleic acids is referred to as codon optimization. For a target peptide to be encoded, there need not be only one codon optimized sequence, but there may be more than two codon optimized sequences.

In embodiments, the encoding nucleic acid may have a codon optimized DNA and/or RNA sequence. In another embodiment, the encoding nucleic acid may have a non-codon optimized DNA and/or RNA sequence.

Codon optimization of coding nucleic acids 1-consideration of the higher order structure of the coding nucleic acids

Codon optimisation of the encoding nucleic acid may be performed taking into account the high order structure of the nucleic acid sequence itself. In embodiments, the coding nucleic acid may be codon optimized taking into account the GC content of the sequence. In another embodiment, the sequence of the encoding nucleic acid may have a GC content within the following range: about less than 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%. In yet another embodiment, the sequence of the encoding nucleic acid may have a GC content within the numerical range selected in the previous sentence. For example, the sequence of the encoding nucleic acid may have a GC content in the range of about 20% to about 50%. In yet another embodiment, the sequence of the encoding nucleic acid may have a GC content less than the value selected in the previous sentence. For example, the sequence encoding the nucleic acid may have a GC content of less than about 25%.

Codon optimization of coding nucleic acids 2-consideration of target cells to be expressed

Codon optimization of the encoding nucleic acid may be achieved in view of the cell into which the encoding nucleic acid is to be injected and expressed. In embodiments, codon optimization of the encoding nucleic acid may be accomplished by considering the use of codons in prokaryotic or eukaryotic cells. In another embodiment, codon usage of the animal cell may be considered to achieve codon optimization of the encoding nucleic acid. In yet another embodiment, codon optimization of the encoding nucleic acid may be achieved in view of mammalian codon usage. In yet another embodiment, codon optimization of the encoding nucleic acid may be achieved in view of the use of human codons. In yet another embodiment, the encoding nucleic acid may be a codon optimized nucleic acid for E.coli. In yet another embodiment, the encoding nucleic acid may be a mammalian codon optimized nucleic acid. In yet another embodiment, the encoding nucleic acid may be a human codon optimized nucleic acid.

Embodiments of the coding nucleic acid sequences

In embodiments, the coding nucleic acid may be represented by a sequence selected from the group consisting of:

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in embodiments, the coding nucleic acid may consist of a sequence selected from the group consisting of SEQ ID NOs: 248-SEQ ID NO:278, and a sequence equivalent RNA sequence.

In another embodiment, the encoding nucleic acid may be a nucleic acid selected from the group consisting of SEQ ID NOs: 248-SEQ ID NO:278 by a codon encoding the same amino acid. For example, the coding nucleic acid may be SEQ ID NO:248 (first to third nucleic acids at the 5' end, i.e., CGT) is replaced by CGC, CGG, CGA, AGA or AGG.

In yet another embodiment, the coding nucleic acid may consist of a sequence selected from the group consisting of SEQ ID NOs: 248-SEQ ID NO:278, wherein one or more codons are replaced by codons encoding the same amino acid.

Pharmaceutical composition comprising a nucleic acid encoding a peptide unit and/or a peptide

Pharmaceutical composition-overview comprising coding nucleic acid

The present application provides pharmaceutical compositions comprising nucleic acids encoding peptide units and/or peptides (i.e., encoding nucleic acids). In order to deliver the coding nucleic acid to a subject to exhibit the desired effect of inducing an immune response, the coding nucleic acid needs to be formulated by an appropriate method. The encoding nucleic acid may be formulated by known methods, for example, as disclosed in the following: K.KIM (2019,mRNA vaccine-new era in vaccinology, BRIC View 2019-R11), zhang et al (2019,Advances in mRNA Vaccines for Infectious Diseases,Frontiers in Immunology,Vol.10, article 594), reichuth et al (2016,mRNA vaccine delivery using lipid nanoparticles,Therapeutic Delivery,7 (5), 319-334), miao et al (2021,mRNA vaccine for cancer immunotherapy,Molecular Cancer,20:41), boen et al (2021,Identification of T Cell Ligands in a Library of Peptides Covalently Attached to HLA-DR4, the Journal of Immunology,165: 2040-2047), pardi et al (2018,mRNA vaccines-a new era in vaccinology, nature Reviews, vol.17, 261-279) and Korean patent application No.10-2017-0054429, but the method is not limited thereto.

In addition to the formulated encoding nucleic acid, the pharmaceutical composition comprising the encoding nucleic acid may further comprise adjuvants and/or additional ingredients. In an embodiment, a pharmaceutical composition comprising a coding nucleic acid comprises the following: a formulated encoding nucleic acid; optionally an adjuvant; and optionally additional ingredients.

Formulated encoding nucleic acids

The formulated encoding nucleic acids can be formulated by one skilled in the art by selecting appropriate delivery means (vectors) for the encoding nucleic acids. The encoding nucleic acid may be formulated using viral vectors and/or non-viral vectors. In embodiments, the formulated encoding nucleic acid may comprise a viral vector. In another embodiment, the formulated encoding nucleic acid may comprise a non-viral vector. In particular, the non-viral vector may include, but is not limited to, lipids, polymers, and inorganic nanoparticles.

In yet another embodiment, the formulated encoding nucleic acid may comprise one or more selected from the group consisting of:

a naked nucleic acid; cationic peptide-complex nucleic acids (protamine); positively charged oil-water cationic nanoemulsions (cationic nanoemulsions); nucleic acids (modified dendrimer nanoparticles) bound to chemically modified dendrimers (dendrimers) and complexed with polyethylene glycol and PEG-lipids; nucleic acids complexed with protamine in PEG-lipid nanoparticles (protamine liposomes); nucleic acids (cationic polymers) complexed with cationic polymers (e.g., polyethylenimine (PEI)); nucleic acids complexed with cationic polymers (e.g., PEI and lipid components) (cationic polymer liposomes); nucleic acids (polysaccharide particles) complexed with polysaccharide polymers (e.g., chitosan); nucleic acids complexed with cationic lipid nanoparticle polymers (cationic lipid nanoparticles); nucleic acids complexed with cationic lipids and cholesterol (cationic lipid cholesterol nanoparticles); and nucleic acids complexed with cationic lipids, cholesterol, and PEG-lipids (cationic lipid-cholesterol-PEG nanoparticles).

In yet another embodiment, the formulated encoding nucleic acid may comprise Lipid Nanoparticles (LNPs). In the specific embodiments described above, the lipid nanoparticle may be an ionizable cationic lipid, a phospholipid, cholesterol, and/or a lipid-anchored polyethylene glycol. In particular, the ionizable cationic lipid may be one or more selected from the group consisting of: DLin-DMA; DLin-KC2-DMA; DLin-MC3-DMA; c12-200; cKK-E12; DLin-MC3-DMA derivative L319 (Alnylam and AlCana Technologies); c12-200 and cKK-E12 derivatives (Anderson Group); the COVID-19 vaccine lipids ALC-0315 and SM-102; TT3 and biodegradable derivatives FTT5 (Dong subject group); vitamin-derived lipids ssPalmE and VcLNP; a9 (Acuitas); l5 (Moderna); a18 lipid; ATX lipid [ ]A composition; arctus); and LP01 (Intellia Therapeutics). Specifically, the phospholipid may be one or more selected from the group consisting of: 1, 2-dioleoyl-sn-glycero-3-phosphorylethanolamine (DOPE); and 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC).

In particular embodiments, the formulated encoding nucleic acid may comprise a polymer-based delivery system. In particular embodiments, the polymer-based delivery system may include one or more selected from the group consisting of: polyethyleneimine (PEI), polyamide-amine (PAMAM), polypropyleneimine, and polymer-based dendrimers.

In yet another embodiment, the formulated encoding nucleic acid may comprise a peptide-based delivery system. In particular embodiments, the peptide-based delivery system may comprise protamine. In particular, the formulated encoding nucleic acid may be a protamine-mRNA complex.

In yet another embodiment, the formulated encoding nucleic acid may comprise liposomes of cationic lipid composition, lipid complexes (lipoplex), and/or cationic emulsions (CNE). In particular embodiments, the cationic lipid may be 1, 2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and/or 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP).

Adjuvant

In embodiments, a pharmaceutical composition comprising a coding nucleic acid may comprise Lipid Nanoparticles (LNP), aluminum salts, 1, 2-dioleoyl-3-trimethylammonium-propane chloride, MF59 (Novartis) adjuvant, CD70, CD40 ligand (CD 40L), triMix, protamine acting through TLR7 signaling, and/or bacterial-derived monophosphoryl lipid a as adjuvants.

Composition of the components

In embodiments, the pharmaceutical composition comprising the encoding nucleic acid may optionally comprise a variety of additional ingredients. In another embodiment, the additional ingredient may be one or more selected from the group consisting of:

A lipid; salts for balancing body acidity; sucrose to maintain stability during repeated freeze thawing; vaccine stability enhancing substances.

In particular, the lipid may be SM-102, PEG2000-DMG, DPSC, cholesterol, and/or ALC-0315, but is not limited thereto. Specifically, the salt may be sodium acetate, potassium chloride, potassium dihydrogen phosphate, sodium chloride and/or disodium hydrogen phosphate dehydrate, but is not limited thereto. In particular, the vaccine stability enhancing substance may be acetic acid, an acid stabilizer (tromethamine) and/or ethanol, but is not limited thereto.

Peptide-overview

The peptides provided herein comprise at least one peptide unit, and the peptide unit comprises at least one B cell epitope and at least one Th epitope, and may comprise an appropriate number of accessory moieties. Peptide units are moieties designed to induce only the desired antibodies uniformly while exhibiting a certain level of immunogenicity in a subject. Furthermore, since the peptide unit is designed to have a relatively short length, it has features of easy synthesis and low production cost. Due to the nature of the peptide units described above, the peptides have properties suitable for use as immunotherapeutic agents. In this document, the design principles of peptides and peptide units are disclosed in detail.

For ease of explanation, the names of the various portions (e.g., auxiliary portions) of the peptides disclosed herein are given. Thus, the scope and designation of the individual parts may vary from view to view. For example, the auxiliary portion may be referred to as a protection portion, a dummy portion, and/or a tab, but is not limited thereto. For another example, B cell epitopes may be referred to as, but are not limited to, th epitope protective epitopes.

Examples

Possible embodiments of the invention

Hereinafter, possible embodiments of the invention provided in this application document are listed. The following examples provided in this paragraph correspond only to embodiments of the present invention. Accordingly, the invention provided in this application should not be construed as being limited to the following examples.

Symbols used in the various embodiments

Hereinafter, symbols for brief description of the embodiments will be described in addition to numerals for distinguishing the embodiments.

"B" means a B cell epitope. "T" means a Th epitope. "a" represents an auxiliary portion (auxiliary portion). "U" means a peptide unit.

When each component is linked by a "-" the components are meant to be linked directly to the component on either side of the "-" or through any other component. For example, when described as B-T, it comprises all peptides in which B cell epitopes and Th epitopes are directly linked, as well as peptides in which B cell epitopes and Th epitopes are linked by any other sequence.

If desired, each component may be marked with a subscript number indicating that the two components are different. For example, when expressed as B ₁ -B ₂ At the time of T, B ₁ And B ₂ Representing different B cell epitopes.

The above symbols are merely symbols for schematically describing the embodiments, and they should not be interpreted by restricting the embodiments with these symbols.

Peptide unit 1

Example 1 humoral immunity-inducible peptide units

Can pass through the quilt CD4 ⁺ A peptide unit recognized by T cells to induce humoral immunity, said peptide unit comprising the following: at least one Th epitope, and at least one B cell epitope, wherein the peptide unit is characterized by a Th epitope length of 8mer, 9mer, 10mer, 11mer, 12mer, 13mer, 14mer, 15mer, 16mer, 17mer, 18mer, 19mer, 20mer, 21mer, 22mer, 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, or 30mer; the length of the B cell epitope is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32mer; and the peptide units are 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 mers.

Example 2 Induction of peptide units of antibodies targeting apolipoprotein B-100

Can pass through the quilt CD4 ⁺ A peptide unit recognized by T cells to induce humoral immunity, said peptide unit comprising the following: at least one Th epitope; and at least one B cell epitope, wherein the peptide unit is characterized by a Th epitope length of 8mer, 9mer, 10mer, 11mer, 12mer, 13mer, 14mer, 15mer, 16mer, 17mer, 18mer, 19mer, 20mer, 21mer, 22mer, 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, or 30mer; the B cell surface can induce antibodies targeting apolipoprotein B-100; and the peptide units have a length of 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 91, 94, 99, 100 or 100.

Example 3 Induction of peptide units of antibodies targeting apolipoprotein B-100 contained in LDL and/or VLDL

The peptide unit of example 2, wherein the B cell epitope is characterized in that it induces antibodies targeting a site selected from the group consisting of: an external exposure site of apolipoprotein B-100 contained in Low Density Lipoprotein (LDL); and an externally exposed site of apolipoprotein B-100 contained in Very Low Density Lipoprotein (VLDL).

Example 4 definition of type B

The peptide unit of embodiment 2, wherein the peptide unit is characterized in that the B cell epitope is a fragment of apolipoprotein B-100 and/or a mimotope of apolipoprotein B-100.

Example 5 definition of the sequence of B

The peptide unit of embodiment 4, wherein the peptide unit is characterized in that the B cell epitope is a sequence selected from the group consisting of: RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), RFRGLISLSQVYLDF (SEQ ID NO: 221) and SVCGCPVGHHDVVGL (SEQ ID NO: 222); or from SEQ ID NO:6-SEQ ID NO:8 and SEQ ID NO:221-SEQ ID NO:222, and an epitope comprised in the sequence selected in 222.

Example 6 definition of the full Length sequence of peptide units

The peptide unit of any one of embodiments 1-5, wherein the peptide unit is characterized by a length of the peptide unit of 23mer to 71mer or 26mer to 50mer.

Peptide unit 2-Unit A

Example 7, B-T and T-B

The peptide unit of any one of embodiments 1-4, wherein the peptide unit is characterized in that the peptide unit comprises one B cell epitope and one Th epitope.

Example 8 definition of sequence of B, definition of length of T and definition of length of U

The peptide unit of embodiment 7, wherein the peptide unit is characterized by a length of 26mer to 45mer; the B cell epitope is selected from RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), RFRGLISLSLSQYLDP (SEQ ID NO: 221) and SVCGCPVGHHDVVGL (SEQ ID NO: 222); and the Th epitope is 11mer to 13mer in length.

Example 9 definition of the sequence of T

The peptide unit of any one of embodiments 7 and 8, wherein the Th epitope is characterized in that it is selected from the group consisting of: k (Cha) VAAWTLKAA (SEQ ID NO: 1),

Wherein (Cha) represents L-cyclohexylalanine.

Example 10 BAT and TAB

The peptide unit of any one of embodiments 7 and 8, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the B cell epitope and the Th epitope.

Example 11 definition of A comprising non-standard amino acids

The peptide unit of embodiment 10, wherein the peptide unit is characterized in that the auxiliary moiety comprises one or more non-standard amino acids.

Example 12 definition of sequence of A comprising nonstandard amino acids

The peptide unit of example 11, wherein the peptide unit is characterized in that the auxiliary moiety is selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHTGSDDK (SEQ ID NO: 194).

Implementation of the embodimentsExample 13 definition of sequence of A not containing nonstandard amino acids

The peptide unit of embodiment 10, wherein the peptide unit is characterized in that the auxiliary moiety is selected from the group consisting of CR, HHHHH H (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

Peptide unit 3-unit D

_{1 2 2 1} Example 14, B-T-T and T-T-B

The peptide unit according to any one of embodiments 1 to 4, wherein the peptide unit is characterized in that it comprises one B cell epitope and two Th epitopes, said Th epitopes being referred to as a first Th epitope and a second Th epitope, respectively, and said first Th epitope being linked between the B cell epitope and the second Th epitope.

Example 15 definition of sequence of B, definition of length of T and definition of length of U

The peptide unit of embodiment 14, wherein the peptide unit is characterized by a length of from 37mer to 50mer; the B cell epitope is selected from RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), RFRGLISLSQVYLDP (SEQ ID NO: 221) and SVCGCPVGHHDVVGL (SEQ ID NO: 222); and the first Th epitope and the second Th epitope are each 11mer to 13mer in length.

Example 16 restriction of the sequence of T

The peptide unit of any one of embodiments 14 and 15, wherein the Th epitope is characterized in that it is selected from the group consisting of: k (Cha) VAAWTLKAA (SEQ ID NO: 1),

Wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, and Z represents 6-aminocaproic acid.

_{1 2 2 1} EXAMPLE 17 BAT-T and T-TAB

The peptide unit of any one of embodiments 14 and 15, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the B cell epitope and the first Th epitope.

_{1 2 2 1} Example 18, B-TAT and TAT-B

The peptide unit of any one of embodiments 14 and 15, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the first Th epitope and the second Th epitope.

Example 19 definition of A comprising non-standard amino acids

The peptide unit of any one of embodiments 17 and 18, wherein the peptide unit is characterized in that the auxiliary moiety comprises one or more non-standard amino acids.

Example 20 definition of sequence of A comprising nonstandard amino acids

The peptide unit of embodiment 19, wherein said peptide unit is characterized in that said auxiliary moiety is selected from the group consisting of a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHHTDDDDK (SEQ ID NO: 194).

Example 21 definition of sequence of A not containing nonstandard amino acids

The peptide unit of any one of embodiments 17 and 18, wherein the peptide unit is characterized in that the auxiliary moiety is selected from the group consisting of CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

_{1 2 2 1} Example 22 BATAT and TATAB

The peptide unit of any one of embodiments 14 and 15, wherein the peptide unit is characterized in that it further comprises a first helper moiety and a second helper moiety, and the first helper moiety is linked between the B cell epitope and the Th epitope and the second helper moiety is linked between the first Th epitope and the second Th epitope.

Example 23 definition of A comprising non-standard amino acids

The peptide unit of embodiment 22, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety comprises one or more non-standard amino acids.

Example 24 definition of sequence of A comprising nonstandard amino acids

The peptide unit of example 23, wherein the peptide unit is characterized in that the auxiliary moiety comprising one or more non-standard amino acids is independently selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and azGSHHHHHHHGDDDK (SEQ ID NO: 194).

Example 25 definition of sequence of A not containing nonstandard amino acids

The peptide unit of embodiment 22, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety is independently selected from the group consisting of CR, HHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

Peptide unit 4-unit B

_{1 2 2 1} Example 26, B-B-T and T-B

The peptide unit according to any one of embodiments 1 to 4, wherein the peptide unit is characterized in that it comprises two B cell epitopes and one Th epitope, respectively referred to as a first B cell epitope and a second B cell epitope, and the second B cell epitope is linked between the first B cell epitope and the Th epitope.

Example 27 definition of sequence of B, definition of length of T and definition of length of U

The peptide unit of embodiment 26, wherein the peptide unit is characterized by a length of 45mer to 50mer; the first B cell epitope and the second B cell epitope are independently selected from: RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), RFRGLISLSQVYLDP (SEQ ID NO: 221) and SVCGCPVGHHDVVGL (SEQ ID NO: 222); and the Th epitope is 11mer to 13mer in length.

Example 28 definition of the sequence of T

The peptide unit of any one of embodiments 26 and 27, wherein the Th epitope is characterized in that it is selected from the group consisting of: k (Cha) VAAWTLKAA (SEQ ID NO: 1),

Wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, and Z represents 6-aminocaproic acid.

_{1 2 2 1} Example 29B-BAT and TAB-B

The peptide unit of any one of embodiments 26 and 27, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the second B cell epitope and the Th epitope.

_{1 2 2 1} EXAMPLE 30 BAB-T and T-BAB

The peptide unit of any one of embodiments 26 and 27, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the first B cell epitope and the second B cell epitope.

Example 31 definition of A comprising non-standard amino acids

The peptide unit of any one of embodiments 29 and 30, wherein the peptide unit is characterized in that the auxiliary moiety comprises one or more non-standard amino acids.

Example 32 definition of sequence of A comprising nonstandard amino acids

The peptide unit of embodiment 31, wherein said peptide unit is characterized in that said auxiliary moiety is selected from the group consisting of a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHHTDDDDK (SEQ ID NO: 194).

Example 33 definition of sequence of A not containing nonstandard amino acids

The peptide unit of any one of embodiments 29 and 30, wherein the peptide unit is characterized in that the auxiliary moiety is selected from the group consisting of CR, HHHHH H (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

_{1 1 2 2 2 2 1 1} Example 34 BABAT and TABAB

The peptide unit of any one of embodiments 26 and 27, wherein the peptide unit is characterized in that it further comprises a first helper moiety and a second helper moiety, and the first helper moiety is linked between a first B cell epitope and a second B cell epitope, and the second helper moiety is linked between the second B cell epitope and a Th epitope.

Example 35 definition of A comprising non-standard amino acids

The peptide unit of embodiment 34, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety comprises one or more non-standard amino acids.

Example 36 definition of sequence of A comprising nonstandard amino acids

The peptide unit of embodiment 35, wherein the peptide unit is characterized in that the auxiliary moiety comprising one or more non-standard amino acids is each independently selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHHTDDDK (SEQ ID NO: 194).

Implementation of the embodimentsExample 37 definition of sequence of A not containing nonstandard amino acids

The peptide unit of embodiment 34, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety are each independently selected from the group consisting of CR, HHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

Peptide unit 5-unit C

_{1 2} EXAMPLE 38B-T-B

The peptide unit of any one of embodiments 1-4, wherein the peptide unit is characterized in that the peptide unit comprises two B cell epitopes and one Th epitope, the two B epitopes being referred to as a first B cell epitope and a second B cell epitope, and the Th epitope being linked between the first B cell epitope and the second B cell epitope.

Example 39 definition of sequence of B, definition of length of T and definition of length of U

The peptide unit of embodiment 38, wherein the peptide unit is characterized by a length of 45mer to 50mer; the first B cell epitope and the second B cell epitope are each independently selected from RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), RFRGLISLSQVYLDP (SEQ ID NO: 221) and SVCGCPVGHHDVVGL (SEQ ID NO: 222); and the Th epitope is 11mer to 13mer in length.

Example 40 restriction of the sequence of T

The peptide unit of any one of embodiments 38 and 39, wherein the Th epitope is characterized in that it is selected from the group consisting of: k (CHa) VAAWTLKAA (SEQ ID NO: 1),

Wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, and Z represents 6-aminocaproic acid.

_{1 2 2 1} EXAMPLE 41 BAT-B and B-TAB

The peptide unit of any one of embodiments 38 and 39, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the first B cell epitope and the Th epitope.

Example 42 definition of A comprising non-standard amino acids

The peptide unit of embodiment 41, wherein the peptide unit is characterized in that the auxiliary moiety comprises one or more non-standard amino acids.

Example 43 definition of sequence of A comprising nonstandard amino acids

The peptide unit of embodiment 42, wherein the peptide unit is characterized in that the auxiliary moiety is selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHTGSDDK (SEQ ID NO: 194).

Example 44 definition of the sequence of A which does not contain nonstandard amino acids

The peptide unit of embodiment 41, wherein said peptide unit is characterized in that said auxiliary moiety is selected from the group consisting of CR, HHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

_{1 1 2 2} Example 45 BATAB

The peptide unit of any one of embodiments 38 and 39, wherein the peptide unit is characterized in that it further comprises a first auxiliary moiety and a second auxiliary moiety; the first helper moiety is linked between the first B cell epitope and the Th epitope; and a second helper moiety is linked between the second B cell epitope and the Th epitope.

Example 46, definition of A, comprising non-standard amino acids

The peptide unit of embodiment 45, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety comprises one or more non-standard amino acids.

Example 47 definition of the sequence of A comprising nonstandard amino acids

The peptide unit of example 46, wherein the peptide unit is characterized in that the auxiliary moiety comprising one or more non-standard amino acids is each independently selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHHTDDDK (SEQ ID NO: 194).

Example 48 definition of sequence of A not containing nonstandard amino acids

The peptide unit of embodiment 45, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety are each independently selected from the group consisting of CR, HHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

Peptide unit 6-unit E

_{1 1 2 2} Example 49, B-T-T-B

The peptide unit according to any one of embodiments 1 to 4, wherein the peptide unit is characterized in that it comprises two B cell epitopes, referred to as a first B cell epitope and a second B cell epitope, respectively, and two Th epitopes, referred to as a first Th epitope and a second Th epitope, respectively; the first B cell epitope, the first Th epitope, the second Th epitope, and the second B cell epitope are sequentially linked in a direction from the N-terminus to the C-terminus.

Example 50 definition of sequence of B, definition of length of T and definition of length of U

The peptide unit of embodiment 49, wherein the peptide unit is characterized by a length of 52mer to 90mer; the first B cell epitope and the second B cell epitope are each independently selected from RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), RFRGLISLSQVYLDP (SEQ ID NO: 221) and SVCGCPVGHHDVVGL (SEQ ID NO: 222); and the first Th epitope and the second Th epitope are each 11mer to 13mer in length.

Example 51 restriction of the sequence of T

The peptide unit of embodiment 50, wherein the first Th epitope and the second Th epitope are each independently selected from the group consisting of:

wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, and Z represents 6-aminocaproic acid.

_{1 1 2 2 2 2 1 1} EXAMPLE 52 BAT-T-B and B-T-TAB

The peptide unit of any one of embodiments 49 and 50, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the first B cell epitope and the first Th epitope.

_{1 1 2 2} Example 53, B-TAT-B

The peptide unit of any one of embodiments 49 and 50, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the first Th epitope and the second Th epitope.

_{1 1 2 2 2 2 1 1} Example 54, B-T-TAB and BAT-T-B

The peptide unit of any one of embodiments 49 and 50, wherein the peptide unit is characterized in that it further comprises a helper moiety, and the helper moiety is linked between the second Th epitope and the second B cell epitope.

Example 55 definition of A comprising non-standard amino acids

The peptide unit of any one of embodiments 52-54, wherein the peptide unit is characterized in that the auxiliary moiety comprises one or more non-standard amino acids.

Example 56 definition of sequence of A comprising nonstandard amino acids

The peptide unit of any one of embodiments 52-54, wherein the peptide unit is characterized in that the auxiliary moiety is selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and azgshhhhhhhgsdddk (SEQ ID NO: 194).

Example 57 definition of sequence of A not containing nonstandard amino acids

The peptide unit of any one of embodiments 52-54, wherein the peptide unit is characterized in that the auxiliary moiety is selected from the group consisting of CR, HHHHH H (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

_{1 1 1 2 2 2 2 2 2 1 1 1} Example 58 BATAT-B and B-TATAB

The peptide unit of any one of embodiments 49 and 50, wherein the peptide unit is characterized in that it further comprises a first helper moiety and a second helper moiety, and the first helper moiety is linked between the first B cell epitope and the first Th epitope and the second helper moiety is linked between the first Th epitope and the second Th epitope.

_{1 1 1 2 2 2} EXAMPLE 59 BAT-TAB

The peptide unit of any one of embodiments 49 and 50, wherein the peptide unit is characterized in that it further comprises a first helper moiety and a second helper moiety, and the first helper moiety is linked between the first B cell epitope and the first Th epitope and the second helper moiety is linked between the second Th epitope and the second B cell epitope.

_{1 1 1 2 2 2 2 2 2 1 1 1} Example 60, B-TATAB and B-TATAB

The peptide unit of any one of embodiments 49 and 50, wherein the peptide unit is characterized in that it further comprises a first helper moiety and a second helper moiety, and the first helper moiety is linked between a first Th epitope and a second Th epitope, and the second helper moiety is linked between the second Th epitope and a second B cell epitope.

Example 61 definition of A comprising non-standard amino acids

The peptide unit of any one of embodiments 58-60, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety comprises one or more non-standard amino acids.

Example 62 definition of sequence of A comprising nonstandard amino acids

The peptide unit of any one of embodiments 58-60, wherein the peptide unit is characterized in that the auxiliary moiety comprising one or more nonstandard amino acids is each independently selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and azgshhhhhgsdddk (SEQ ID NO: 194).

Example 63 definition of the sequence of A which does not contain nonstandard amino acids

The peptide unit of any one of embodiments 58-60, wherein the peptide unit is characterized in that the first auxiliary moiety and/or the second auxiliary moiety are each independently selected from CR, hhhhhhhh (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

_{1 1 1 2 2 3 2} Example 64 BATATAB

The peptide unit of any one of embodiments 49 and 50, wherein the peptide unit is characterized in that it further comprises a first auxiliary moiety, a second auxiliary moiety, and a third auxiliary moiety; the first helper portion is linked between the first B cell epitope and the first Th epitope; the second helper portion is linked between the first Th epitope and the second Th epitope; and the third helper portion is linked between the second Th epitope and the second B cell epitope.

Example 65 definition of A comprising non-standard amino acids

The peptide unit of embodiment 64, wherein the peptide unit is characterized in that the first auxiliary moiety, the second auxiliary moiety and/or the third auxiliary moiety comprises one or more non-standard amino acids.

Example 66 definition of the sequence of A comprising nonstandard amino acids

The peptide unit of embodiment 65, wherein the peptide unit is characterized in that the auxiliary moiety comprising one or more non-standard amino acids is each independently selected from a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHHTDDDK (SEQ ID NO: 194).

Example 67 definition of sequence of A not containing nonstandard amino acids

The peptide unit of embodiment 64, wherein the peptide unit is characterized in that the first auxiliary moiety, the second auxiliary moiety and/or the third auxiliary moiety are each independently selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

Peptide unit 7-unit and additional auxiliary moiety

Example 68 AU and UA

A peptide unit comprising the following: the peptide unit of any one of embodiments 1-67; and an additional auxiliary portion.

Example 69 definition of A comprising non-Standard amino acids

The peptide unit of embodiment 67, wherein the peptide unit is characterized in that the additional auxiliary moiety comprises one or more non-standard amino acids.

Example 70 for the sequence of A comprising nonstandard amino acidsColumn definition

The peptide unit of embodiment 69, wherein the peptide unit is characterized in that the additional auxiliary moiety is selected from the group consisting of a, Z, aZ, za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHHTGSDDDK (SEQ ID NO: 194).

Example 71 definition of the sequence of A which does not contain nonstandard amino acids

The peptide unit of embodiment 68, wherein the peptide unit is characterized in that the additional auxiliary moiety is selected from the group consisting of CR, HHHHH H (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

Example 72 AUA

A peptide unit comprising the following: the peptide unit of any one of embodiments 1-67; and a first additional auxiliary portion and a second additional auxiliary portion. In particular, the peptide unit is linked between the first additional auxiliary moiety and the second additional auxiliary moiety.

Example 73 definition of A, comprising non-standard amino acids

The peptide unit of embodiment 72, wherein the peptide unit is characterized in that the first additional auxiliary moiety and/or the second additional auxiliary moiety comprises one or more non-standard amino acids.

Example 74 definition of sequence of A comprising nonstandard amino acids

The peptide unit of example 73, wherein the peptide unit is characterized in that the additional auxiliary moiety comprising one or more non-standard amino acids is each independently selected from a, Z, aZ, za, HSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

Example 75 definition of sequence of A not containing nonstandard amino acids

The peptide unit of embodiment 72, wherein the peptide unit is characterized in that the first additional auxiliary moiety and/or the second additional auxiliary moiety are each independently selected from the group consisting of CR, HHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

Peptide unit 8-definition of the sequence of the units

Example 76 definition of the sequence of Unit A

The peptide unit of any one of embodiments 1-8 and embodiments 68-75, wherein the peptide unit is selected from the group consisting of:

/>

wherein a represents D-alanine, Z represents 6-aminocaproic acid, (Cha) represents L-cyclohexylalanine, and X represents any standard amino acid.

Example 77 definition of the sequence of cell D

The peptide unit of any one of embodiments 1-6, 14-15 and 68-75, wherein the peptide unit is selected from the group consisting of:

Wherein a represents D-alanine, Z represents 6-aminocaproic acid, and (Cha) represents L-cyclohexylalanine.

Example 78 definition of the sequence of Unit B

The peptide unit of any one of embodiments 1-6, 26-27 and 68-75, wherein the peptide unit is selected from the group consisting of:

/>

wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, Z represents 6-aminocaproic acid, and X represents any standard amino acid.

Example 79 definition of the sequence of Unit C

The peptide unit of any one of embodiments 1-6, 38-39 and 68-75, wherein the peptide unit is selected from the group consisting of:

/>

wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, Z represents 6-aminocaproic acid, and X represents any standard amino acid.

Example 80 definition of the sequence of Unit E

The peptide unit of any one of embodiments 1-6, 49-50 and 68-75, wherein the peptide unit is selected from the group consisting of:

/>

wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, and Z represents 6-aminocaproic acid.

Peptide unit 9-Structure

Example 81 higher conception of structural formula of Unit A

The peptide unit of any one of embodiments 1-2, wherein the peptide unit is represented by the following [ formula a ] or [ formula a' ]:

[ A ]]A ₁ -B-A ₂ -T-A ₃

[ A ]']A ₁ -T-A ₂ -B-A ₃

Wherein the peptide unit is capable of being purified by CD4 ⁺ T cell recognizes a peptide unit that induces humoral immunity and is 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71mer in length;

wherein A is ₁ Is the first auxiliary portion or is absent; wherein the first auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₂ is a second auxiliary portion or is absent; wherein the second auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₃ is a third auxiliary portion or is absent; wherein the third auxiliary part is provided with a joint Head function, protection function, function to form a loop form, dummy function, and/or solubility increasing function, and may optionally have non-standard amino acids;

b is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100;

t is Th epitope, which can be replaced by CD4 ⁺ T cell recognition and length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32mer.

Example 82 combination of Unit A sequences

In the case of the embodiment (81),

A ₁ 、A ₂ and A ₃ Each independently selected from the group consisting of: a. z, aZ, za, RN, AF, CR, LS, KT, KH, RF, DP, SV, GL, ZRNV (SEQ ID NO: 36), aZRN (SEQ ID NO: 37), IAFZ (SEQ ID NO: 38), AFza (SEQ ID NO: 39), RNVP (SEQ ID NO: 40), WIAF (SEQ ID NO: 41), ZCRF (SEQ ID NO: 42), aZCR (SEQ ID NO: 43), YLSZ (SEQ ID NO: 44), LSza (SEQ ID NO: 45), CRFR (SEQ ID NO: 46), VYLS (SEQ ID NO: 47), ZKTT (SEQ ID NO: 48), aZKT (SEQ ID NO: 49), NKHZ (SEQ ID NO: 50), KHza (SEQ ID NO: 51), GSHHHHHHGSDDDK (SEQ ID NO: 52), HHHHHHHHHHHHHHHHHHS (SEQ ID NO: 53), MRGSHHHHHHGSDDDDKIVD (SEQ ID NO: 54), GGGGSGGGGGGSS (SEQ ID NO: 55), RRRRRR (SEQ ID NO: 159), GSHHHHHHHHHHHHHDDZHHHHHHHGSHHHHHHHHHHHHHHGSDK (SEQ ID NO: 194) and the presence of amino acid type of the amino acid-caproic acid is expressed, and the amino acid is not expressed in the form of DK, SEQ ID, 6;

B has:

one selected from the group consisting of:

an epitope comprised in SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222, or any one of the above; or alternatively

And SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222 matches 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more of the sequence;

wherein a represents D-alanine and Z represents 6-aminocaproic acid;

t is selected from the group consisting of:

one selected from the group consisting of:

a sequence represented by the following [ formula I ] or [ formula II ];

[ I ]]N-Lys-X ₁ -X ₂ -Ala-Ala-X ₃ -Thr-X ₄ -X ₅ -Ala-Ala-C

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ is a hydrophobic amino acid, or leucine (Leu) or isoleucine (Ile);

X ₃ is an aromatic amino acid or a cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr) or histidine (His);

X ₄ is aliphatic long chain amino acid, or isoleucine (Ile) or Valine (Val); and is also provided with

X ₅ Is a charged amino acid, or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly);

[ II ]]N-Lys-X ₁ -Val-X ₂ -Ala-X ₃ -Thr-Leu-Lys-Ala-Ala-C

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); and is also provided with

X ₃ Asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys) or alanine (Ala); and

and the sequence represented by SEQ ID NO:1-SEQ ID NO: 5. SEQ ID NO:162-SEQ ID NO: 192. SEQ ID NO:195-SEQ ID NO: 196. SEQ ID NO: 223-SEQ ID NO:247 and any one of the sequences represented by the formula I or the formula II match 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more;

wherein (Cha) represents L-cyclohexylalanine and X represents any standard amino acid.

Example 83 higher conception of structural formula of Unit B

The peptide unit according to any one of embodiments 1 and 2, wherein the peptide unit is represented by the following [ formula B ] or [ formula B' ]:

[ B ]]A ₁ -B ₁ -A ₂ -B ₂ -A ₃ -T-A ₄

[ B ]']A ₁ -T-A ₂ -B ₁ -A ₃ -B ₂ -A ₄

Wherein the peptide unit is characterized in that it can be produced by a peptide unit comprising a peptide represented by CD4 ⁺ T cell recognition to induce humoral immunity and is 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71 in length;

wherein A is ₁ Is the first auxiliary portion or is absent; wherein the first auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₂ is a second auxiliary portion or is absent; wherein the second auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₃ Is a third auxiliary portion or is absent; wherein the third auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₄ is a fourth auxiliary portion or is absent; wherein the fourth auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

B ₁ is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100;

B ₂ is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100; and

t is Th epitope, which can be replaced by CD4 ⁺ T cell recognition and length of 8mer, 9mer, 10mer, 11mer, 12mer, 13mer, 14mer, 15mer, 16mer, 17mer, 18mer, 19mer, 20mer, 21mer, 22mer, 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, or 32mer.

Example 84 combination of sequences of Unit B

In the case of the embodiment 83 of the present invention,

A ₁ 、A ₂ And A ₃ Each independently selected from the group consisting of: a. z, aZ, za, RN, AF, CR, LS, KT, KH, RF, DP, SV, GL, ZRNV (SEQ ID NO: 36), aZRN (SEQ ID NO: 37), IAFZ (SEQ ID NO: 38), AFza (SEQ ID NO: 39), RNVP (SEQ ID NO: 40), WIAF (SEQ ID NO: 41), ZCRF (SEQ ID NO: 42), aZCR (SEQ ID NO: 43), YLSZ (SEQ ID NO: 44), LSza (SEQ ID NO: 45), CRFR (SEQ ID NO: 46), VYLS (SEQ ID NO: 47), ZKTT (SEQ ID NO: 48), aZKT (SEQ ID NO: 49), NKHZ (SEQ ID NO: 50), KHza (SEQ ID NO: 51), GSHHHHHHGSDDDDK (SEQ ID NO: 52), HHHHHHHHHHHHHHHHHHHD (SEQ ID NO: 53), MRGSHHHHHHGSDDDDKIVD (SEQ ID NO: 54), GGGGSGGGGGGSS (SEQ ID NO: 55), RRRRRR (SEQ ID NO: 159), GSHHHHHHHHHHHDDDDZHHHHHHHHHHHHGSHHHHHHHHDK (SEQ ID NO: 194) or not present. Wherein a represents D-alanine and Z represents 6-aminocaproic acid;

B ₁ and B ₂ Each of which is independent of the other,

selected from the group consisting of:

an epitope comprised in SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222, in any one of claims; or alternatively

Has a sequence identical to SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222 matches 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more of the sequence;

Wherein a represents D-alanine and Z represents 6-aminocaproic acid;

t is selected from the group consisting of:

one selected from the group consisting of:

a sequence represented by the following [ formula I ] or [ formula II ]:

[ I ]]N-Lys-X ₁ -X ₂ -Ala-Ala-X ₃ -Thr-X ₄ -X ₅ -Ala-Ala-C

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ is a hydrophobic amino acid, or leucine (Leu) or isoleucine (Ile);

X ₃ is an aromatic amino acid or a cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr) or histidine (His);

X ₄ is aliphatic long chain amino acid, or isoleucine (Ile) or valine (Val); x is as follows ₅ Is a charged amino acid, or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly);

[ II ]]N-Lys-X ₁ -Val-X ₂ -Ala-X ₃ -Thr-Leu-Lys-Ala-Ala-C

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); and is also provided with

X ₃ Asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys) or alanine (Ala); and

and the sequence represented by SEQ ID NO:1-SEQ ID NO: 5. SEQ ID NO:162-SEQ ID NO: 192. SEQ ID NO:195-SEQ ID NO: 196. SEQ ID NO: 223-SEQ ID NO:247 and any one of the sequences represented by the formula I or the formula II match 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more;

Wherein (Cha) represents L-cyclohexylalanine and X represents any standard amino acid.

Embodiment 85 higher conception of structural formula of Unit C

The peptide unit of any one of embodiments 1 and 2, wherein the peptide unit is represented by the following [ formula C ]:

[ C]A ₁ -B ₁ -A ₂ -T-A ₃ -B ₂ -A ₄

Wherein the peptide unit is characterized in that it can be produced by a peptide unit comprising a peptide represented by CD4 ⁺ T cell recognition to induce humoral immunity and is 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71 in length;

wherein A is ₁ Is the first auxiliary portion or is absent; wherein the first auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₂ is a second auxiliary portion or is absent; wherein the second auxiliary part has a joint function, a protection function, a function of forming a ring form, a dummy function, and/or a solubility increasing function, and And may optionally have non-standard amino acids;

A ₃ is a third auxiliary portion or is absent; wherein the third auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₄ is a fourth auxiliary portion or is absent; wherein the fourth auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

B ₁ is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100;

B ₂ is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100; and

t is Th epitope, which can be replaced by CD4 ⁺ T cell recognition and length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32mer.

Example 86 combination of sequences of Unit C

In the case of the embodiment of the present invention in which the sample is a solid,

A ₁ 、A ₂ 、A ₃ and A ₄ Each independently selected from the group consisting of: a. z, aZ, za, RN, AF, CR, LS, KT, KH, RF, DP, SV, GL, ZRNV (SEQ ID NO: 36), aZRN (SEQ ID NO: 37), IAFZ (SEQ ID NO: 38), AFZa (SEQ ID NO: 39), RNVP (SEQ ID NO: 40), WIAF (SEQ ID NO: 41), ZCRF (SEQ ID NO: 42), aZCR (SEQ ID NO: 43), YLSZ (SEQ ID NO: 44), LSZa (SEQ ID NO: 45), CRFR (SEQ ID NO: 46), vYLS (SEQ ID NO: 47), ZKTT (SEQ ID NO: 48), aZKT (SEQ ID NO: 49), NKHZ (SEQ ID NO: 50), KHZa (SEQ ID NO: 51), GSHHHHHHGSDDDDK (SEQ ID NO: 52), HHHHHHHHHHH (SEQ ID NO: 45)NO:53 MRGSHHHHHHGSDDDDKIVD (SEQ ID NO:54 GGGGSGGGGGGGSS (SEQ ID NO:55 Rrrrrrrr (SEQ ID NO:159 GSHHHHHHHGSDDDDKZa (SEQ ID NO:193 aZGSHHHHHHGSDDDDK (SEQ ID NO:194 Or is absent; wherein a represents D-alanine and Z represents 6-aminocaproic acid;

B ₁ and B ₂ Each independently having one selected from the group consisting of:

one selected from the group consisting of:

an epitope comprised in SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222, or any one of the above; or alternatively

And the sequence represented by SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222, or a fragment thereof, matches 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more of the sequence;

wherein "a" represents D-alanine and "Z" represents 6-aminocaproic acid; t is selected from the group consisting of:

one selected from the group consisting of:

a sequence represented by the following [ formula I ] or [ formula II ]:

[ I ]]N-Lys-X ₁ -X ₂ -Ala-Ala-X ₃ -Thr-X ₄ -X ₅ -Ala-Ala-C

Wherein X is ₁ Is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine；

X ₂ Is a hydrophobic amino acid, or leucine (Leu) or isoleucine (Ile);

X ₃ is an aromatic amino acid or a cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr) or histidine (His);

X ₄ is aliphatic long chain amino acid, or isoleucine (Ile) or valine (Val); x is as follows ₅ Is a charged amino acid, or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly);

[ II ]]N-Lys-X ₁ -Val-X ₂ -Ala-X ₃ -Thr-Leu-Lys-Ala-Ala-C

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); and is also provided with

X ₃ Asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys) or alanine (Ala); and

and the sequence represented by SEQ ID NO:1-SEQ ID NO: 5. SEQ ID NO:162-SEQ ID NO: 192. SEQ ID NO:195-SEQ ID NO: 196. SEQ ID NO: 223-SEQ ID NO:247 and any one of the sequences represented by the formula I or the formula II match 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more;

wherein (Cha) represents L-cyclohexylalanine and X represents any standard amino acid.

Example 87 higher conception of structural formula of Unit D

The peptide unit according to any one of embodiments 1 and 2, wherein the peptide unit is represented by the following [ formula D ] or [ formula D' ]:

[ D]A ₁ -B-A ₂ -T ₁ -A ₃ -T ₂ -A ₄

[ D ]']A ₁ -T ₁ -A ₂ -T ₂ -A ₃ -B-A ₄

Wherein the peptide unit is characterized in that it can be produced by a peptide unit comprising a peptide represented by CD4 ⁺ T cell recognition to induce humoral immunity and is 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71 in length;

wherein A is ₁ Is the first auxiliary portion or is absent; wherein the first auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₂ is a second auxiliary portion or is absent; wherein the second auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally may have a non-standard amino acid;

A ₃ is a third auxiliary portion or is absent; wherein the third auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₄ Is a fourth auxiliary portion or is absent; wherein the fourth auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

b is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100;

T ₁ is Th epitope, can be CD4 ⁺ T cell recognition and length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32mer; and is also provided with

T ₂ Is Th epitope, can be CD4 ⁺ T cell recognition and length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32mer.

Example 88 combination of sequences of units D

In the case of the embodiment 87 of the present invention,

A ₁ 、A ₂ 、A ₃ and A ₄ Each independently selected from the group consisting of: a. z, aZ, za, RN, AF, CR, LS, KT, KH, RF, DP, SV, GL, ZRNV (SEQ ID NO: 36), aZRN (SEQ ID NO: 37), IAFZ (SEQ ID NO: 38), AFza (SEQ ID NO: 39), RNVP (SEQ ID NO: 40), WIAF (SEQ ID NO: 41), ZCRF (SEQ ID NO: 42), aZCR (SEQ ID NO: 43), YLSZ (SEQ ID NO: 44), LSza (SEQ ID NO: 45), CRFR (SEQ ID NO: 46), VYLS (SEQ ID NO: 47), ZKTT (SEQ ID NO: 48), aZKT (SEQ ID NO: 49), NKHZ (SEQ ID NO: 50), KHza (SEQ ID NO: 51), GSHHHHHHGSDDDDK (SEQ ID NO: 52), HHHHHHHHHHHHHHHHH (SEQ ID NO: 53), MRGSHHHHHHGSDDDDKIVD (SEQ ID NO: 54), GGGGSGGGGGGSS (SEQ ID NO: 55), RRRRRR (SEQ ID NO: 159), GSHHHHHHHHHHDDKZKZKZa (SEQ ID NO: 193) and aZGSHHHHHHHHHGSK (194) or not present. Wherein a represents D-alanine and Z represents 6-aminocaproic acid;

B has:

one selected from the group consisting of:

an epitope comprised in SEQ ID NO:6-SEQ ID NO:35 and SEQ id no:221-SEQ ID NO:222, or any one of the above; or alternatively

And the sequence represented by SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222, or a fragment thereof, matches 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more of the sequence;

wherein a represents D-alanine and Z represents 6-aminocaproic acid;

T ₁ and T ₂ Each independently selected from the group consisting of:

one selected from the group consisting of:

/>

a sequence represented by the following [ formula I ] or [ formula II ]:

[ I ]]N-Lys-X ₁ -X ₂ -Ala-Ala-X ₃ -Thr-X ₄ -X ₅ -Ala-Ala-C

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ is a hydrophobic amino acid, or leucine (Leu) or isoleucine (Ile);

X ₃ is an aromatic amino acid or a cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr) or histidine (His);

X ₄ Is aliphatic long chain amino acid, or isoleucine (Ile) or valine (Val); and is also provided with

X ₅ Is charged ammoniaA base acid, or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (gin), or glycine (Gly);

[ II ]]N-Lys-X ₁ -Val-X ₂ -Ala-X ₃ -Thr-Leu-Lys-Ala-Ala-C：

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met);

X ₃ asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys) or alanine (Ala); and

and the sequence represented by SEQ ID NO:1-SEQ ID NO: 5. SEQ ID NO:162-SEQ ID NO: 192. SEQ ID NO:195-SEQ ID NO: 196. SEQ ID NO:223-SEQ ID NO:247 and any one of the sequences represented by the formula I or the formula II match 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more;

wherein (Cha) represents L-cyclohexylalanine and X represents any standard amino acid.

Example 89 higher concept of Unit E Structure

The peptide unit of any one of embodiments 1 and 2, wherein the peptide unit is represented by the following [ formula E ]:

[ E]A ₁ -B ₁ -A ₂ -T ₁ -A ₃ -T ₂ -A ₄ -B ₂ -A ₅

Wherein the peptide unit is capable of being purified by CD4 ⁺ T cells recognize peptide units that induce humoral immunity and are 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 mers in length40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71 mers;

wherein A is ₁ Is the first auxiliary portion or is absent; wherein the first auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₂ is a second auxiliary portion or is absent; wherein the second auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally may have a non-standard amino acid;

A ₃ Is a third auxiliary portion or is absent; wherein the third auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

A ₄ is a fourth auxiliary portion or is absent; wherein the fourth auxiliary moiety has a linker function, a protecting function, a function of forming a loop form, a dummy function, and/or a solubility increasing function, and optionally has a non-standard amino acid;

B ₁ is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100;

B ₂ is a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100, and can induce antibodies targeting apolipoprotein B-100;

T ₁ is a Th epitope, characterized in that it can be encoded by CD4 ⁺ T cell recognition and length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 merA mer; and

T ₂ is a Th epitope, characterized in that it can be encoded by CD4 ⁺ T cell recognition and length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32mer.

Example 90 combination of Unit E sequences

In the case of the embodiment 89 of the present invention,

A ₁ 、A ₂ 、A ₃ and A ₄ Each independently selected from the group consisting of: a. z, aZ, za, RN, AF, CR, LS, KT, KH, RF, DP, SV, GL, ZRNV (SEQ ID NO: 36), aZRN (SEQ ID NO: 37), IAFZ (SEQ ID NO: 38), AFza (SEQ ID NO: 39), RNVP (SEQ ID NO: 40), WIAF (SEQ ID NO: 41), ZCRF (SEQ ID NO: 42), aZCR (SEQ ID NO: 43), YLSZ (SEQ ID NO: 44), LSza (SEQ ID NO: 45), CRFR (SEQ ID NO: 46), VYLS (SEQ ID NO: 47), ZKTT (SEQ ID NO: 48), aZKT (SEQ ID NO: 49), NKHZ (SEQ ID NO: 50), KHza (SEQ ID NO: 51), GSHHHHHHGSDDDDK (SEQ ID NO: 52), HHHHHHHHHHHHHHHHH (SEQ ID NO: 53), MRGSHHHHHHGSDDDDKIVD (SEQ ID NO: 54), GGGGSGGGGGGSS (SEQ ID NO: 55), RRRRRRR (SEQ ID NO: 159), GSHHHHHHHHHDDKZKZa (SEQ ID NO: 193) and aZHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHg194 (DK 194) are absent or not present. Wherein a represents D-alanine and Z represents 6-aminocaproic acid;

B ₁ And B ₂ Each independently having one selected from the group consisting of:

one selected from the group consisting of:

an epitope comprised in SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222, or any one of the above; or alternatively

And the sequence represented by SEQ ID NO:6-SEQ ID NO:35 and SEQ ID NO:221-SEQ ID NO:222 matches 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more of the sequence;

wherein a represents D-alanine and Z represents 6-aminocaproic acid;

T ₁ and T ₂ Each independently selected from the group consisting of:

one selected from the group consisting of:

/>

a sequence represented by the following [ formula I ] or [ formula II ]:

[ I ]]N-Lys-X ₁ -X ₂ -Ala-Ala-X ₃ -Thr-X ₄ -X ₅ -Ala-Ala-C

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ is a hydrophobic amino acid, or leucine (Leu) or isoleucine (Ile);

X ₃ is an aromatic amino acid or a cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr) or histidine (His);

X ₄ Is aliphatic long chain amino acid, or isoleucine (Ile) or valine (Val); x is as follows ₅ Is a charged amino acid, or arginine (Arg), leucine (Leu), aspartic acid (Asp)) Glutamine (Gln) or glycine (Gly);

[ II ]]N-Lys-X ₁ -Val-X ₂ -Ala-X ₃ -Thr-Leu-Lys-Ala-Ala-C：

Wherein X is ₁ Tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

X ₂ lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); and is also provided with

X ₃ Asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys) or alanine (Ala); and

and the sequence represented by SEQ ID NO:1-SEQ ID NO: 5. SEQ ID NO:162-SEQ ID NO: 192. SEQ ID NO:195-SEQ ID NO: 196. SEQ ID NO: 223-SEQ ID NO:247 and any one of the sequences represented by the formula I or the formula II match 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more;

Wherein (Cha) represents L-cyclohexylalanine and X represents any standard amino acid.

Peptides comprising peptide units

Example 91 peptides comprising more than 2 peptide units

A peptide in which more than 2 peptide units of any one of examples 1-90 are linked.

Example 92 peptide comprising 2 to 8 peptide units

A peptide in which 2, 3, 4, 5, 6, 7 or 8 peptide units of any one of examples 1-90 are linked.

Example 93 concatemer sequence

The peptide of embodiment 91, wherein each peptide unit has the same or equivalent sequence.

Example 94 beading

The peptide of embodiment 91, wherein each peptide unit has a different sequence.

Example 95, ring form

The peptide of embodiment 91, wherein the peptide is characterized in that it further comprises an auxiliary moiety having a function of forming a cyclic form at the N-terminal and the C-terminal, and the peptide is formed into a cyclic form by the auxiliary moiety.

Nucleic acids encoding peptide units and/or peptides

Example 96 coding nucleic acid comprising no nonstandard amino acids

Nucleic acid encoding the peptide unit of any one of embodiments 1-6 and/or the peptide of any one of embodiments 91-95, wherein the peptide unit and the peptide do not comprise non-standard amino acids.

Example 97 nucleic acids encoding the respective Unit Structure containing no nonstandard amino acids

A nucleic acid encoding a peptide unit of any one of examples 7-10, 14-18, 22, 26-30, 34, 38-41, 45, 49-54, 58-60, 64, 68 and 72, wherein the peptide unit is characterized in that it does not comprise a non-standard amino acid.

Example 98 definition of the sequence of the Unit peptide

The nucleic acid of any one of embodiments 96 and 97, wherein the nucleic acid encodes a peptide unit selected from the group consisting of:

wherein X represents any standard amino acid.

Example 99 restriction of the sequence of the DNA encoding the Unit

The nucleic acid of embodiment 98, a DNA represented by a sequence selected from the group consisting of:

/>

/>

example 100 definition of the sequence of RNA of coding Unit

The nucleic acid of embodiment 98, an RNA represented by a sequence selected from the group consisting of:

/>

/>

example 101, support

A vector comprising any one of the nucleic acids described in examples 96-100.

Example 102 definition of Carrier

The vector of embodiment 101, wherein the vector is selected from the group consisting of a plasmid, retrovirus, lentivirus, adenovirus, adeno-associated virus, vaccinia virus, poxvirus, and herpes simplex virus.

Example 103 mammalian codon optimized nucleic acids

The nucleic acid of any one of embodiments 96-98, wherein the nucleic acid is codon optimized for a species selected from the group consisting of mammals.

Example 104 human codon optimized nucleic acids

The nucleic acid of any one of embodiments 96-98, wherein the nucleic acid is human codon optimized.

Example 105 prokaryotic codon optimized nucleic acids

The nucleic acid of any one of embodiments 96-98, wherein the nucleic acid is codon optimized for a species selected from the group consisting of prokaryotes.

Example 106 E.coli codon optimized nucleic acids

The nucleic acid of any one of embodiments 96-98, wherein the nucleic acid is codon optimized for e.

Pharmaceutical compositions comprising peptides

Example 107 pharmaceutical compositions for immunotherapy

A pharmaceutical composition for immunotherapy, the pharmaceutical composition comprising:

the peptide unit of any one of embodiments 1-90 and/or the peptide of any one of embodiments 91-95; and

an adjuvant.

Example 108 pharmaceutical composition for treatment of obesity

A pharmaceutical composition for the treatment of obesity, the pharmaceutical composition comprising:

the peptide unit of any one of embodiments 1-90 and/or the peptide of any one of embodiments 91-95; and

An adjuvant.

Example 109 definition of adjuvant

In any of embodiments 107-108, the adjuvant is water, saline, dextrose, ethanol, glycerol, sodium chloride, dextrose, mannitol, sorbitol, lactose, gelatin, albumin, aluminum hydroxide, freund's incomplete adjuvant, and complete adjuvant (Pifco Laboratories, detroit, mich.), merck antigen adjuvant 65 (Merck and Company, inc., rahway, NJ.), alhydrogel (Al (OH) ₃ ) Aluminum hydroxide gel (alum) or aluminum salts (e.g., aluminum phosphate), AS04 series, MF, squalene, MF59, QS21, insoluble suspensions of calcium, iron or zinc salts, acylated fructose, cationically or anionically derivatized polysaccharides, polyphosphazenes, biodegradable microspheres, quil A, toll-like receptor (TLR) agonists, PHAD [ Avanti polar lipid, monophosphoryl lipid A (synthetic)]Mono-phosphoryl lipid a (MPL, mono-phosphoryl lipid a), synthetic lipid a, lipid a mimics or analogues, aluminium salts, cytokines, saponins, prolactin, growth hormone deoxycholic acid, beta-glucan, polyribonucleotides, muramyl Dipeptide (MDP) derivatives, cpG oligonucleotides, gram negative bacterial Lipopolysaccharide (LPS), polyphosphazenes, emulsions, virosomes, cochleates, poly (lactide-co-glycolide) (PLG) microparticles, poloxamer particles, microparticles, liposomes or suitable combinations thereof.

Pharmaceutical compositions comprising coding nucleic acids

Example 110 formulated encoding nucleic acids

Formulated encoding nucleic acid, characterized in that the nucleic acid of any one of examples 96-106 is formulated using viral vectors and/or non-viral vectors.

Example 111 definition of viral vectors

In example 110, the encoding nucleic acid is characterized in that the viral vector is selected from the group consisting of:

retroviruses, lentiviruses, adenoviruses, adeno-associated viruses, vaccinia viruses, poxviruses, and herpes simplex viruses.

Example 112 definition of the form of formulated nucleic acids

In example 110, the encoding nucleic acid is characterized in that the formulated nucleic acid is selected from the group consisting of:

a naked nucleic acid; cationic peptide-complex nucleic acids (protamine); positively charged oil-water cationic nanoemulsions (cationic nanoemulsions) comprising nucleic acids; nucleic acids coupled to chemically modified dendrimers and complexed with polyethylene glycol and PEG-lipids (modified dendrimer nanoparticles); nucleic acids complexed with protamine in PEG-lipid nanoparticles (protamine liposomes); nucleic acids (cationic polymers) complexed with cationic polymers (such as polyethylenimine and PEI); nucleic acids complexed with cationic polymers (e.g., PEI and lipid components) (cationic polymer liposomes); nucleic acids (polysaccharide particles) complexed with polysaccharide polymers (e.g., chitosan); nucleic acids complexed with cationic lipid nanoparticle polymers (cationic lipid nanoparticles); nucleic acids complexed with cationic lipids and cholesterol (cationic lipid cholesterol nanoparticles); and nucleic acids complexed with cationic lipids, cholesterol, and PEG-lipids (cationic lipid-cholesterol-PEG nanoparticles).

Example 113 pharmaceutical composition for immunotherapy comprising formulated nucleic acids

A pharmaceutical composition for immunotherapy, said pharmaceutical composition comprising the following:

the formulated nucleic acid of any one of embodiments 100-112; and

an adjuvant.

Example 114 pharmaceutical composition for treatment of obesity comprising formulated nucleic acids

A pharmaceutical composition for the treatment of obesity, said pharmaceutical composition comprising the following:

the formulated nucleic acid of any one of embodiments 100-112; and

an adjuvant.

Example 115, paraadjuvantIs defined by (a)

The pharmaceutical composition of any one of embodiments 113 and 114, wherein the adjuvant is one or more selected from the group consisting of:

lipid Nanoparticles (LNP), aluminum salts, 1, 2-dioleoyl-3-trimethylammonium-propane chloride, MF59 (Novartis) adjuvant, CD70, CD40 ligand (CD 40L), triMix, protamine acting through TLR7 signaling, and/or monophosphoryl lipid a of bacterial origin.

Example 116, comprising other ingredients

The pharmaceutical composition of any one of embodiments 113-114, wherein the pharmaceutical composition comprises one or more additional ingredients selected from the group consisting of:

lipids, salts that balance body acidity, sucrose to maintain stability during repeated freeze thawing, and vaccine stability enhancing substances.

Example 117 definition of additional Components

The pharmaceutical composition of embodiment 116,

wherein the pharmaceutical composition is characterized in that the lipid is one or more selected from SM-102, PEG2000-DMG, DPSC, cholesterol and ALC-0315;

the salt is one or more selected from sodium acetate, potassium chloride, potassium dihydrogen phosphate, sodium chloride and disodium hydrogen phosphate dehydrate; and is also provided with

The vaccine stability enhancing substance is one or more selected from acetic acid, acid stabilizer (tromethamine) and ethanol.

Use of peptides

Example 118 use for immunotherapy (first medical use)

Use of the peptide unit of any one of embodiments 1-90, the peptide of any one of embodiments 91-95, the nucleic acid of any one of embodiments 96-106 and/or the pharmaceutical composition of any one of embodiments 107-109 and embodiments 113-117 for immunotherapy.

Example 119 use for obesity treatment (first medical use)

Use of the peptide unit of any one of embodiments 1-90, the peptide of any one of embodiments 91-95, the nucleic acid of any one of embodiments 96-106, and/or the pharmaceutical composition of any one of embodiments 107-109 and embodiments 113-117 for the treatment of obesity.

Example 120 use for the preparation of an immunotherapeutic agent (second medical use)

Use of the peptide unit of any one of embodiments 1-90, the peptide of any one of embodiments 91-95, the nucleic acid of any one of embodiments 96-106 and/or the pharmaceutical composition of any one of embodiments 107-109 and embodiments 113-117 for the preparation of an immunotherapeutic agent.

Example 121 use for the preparation of a medicament for the treatment of obesity (second medical use)

Use of the peptide unit of any one of embodiments 1-90, the peptide of any one of embodiments 91-95, the nucleic acid of any one of embodiments 96-106, and/or the pharmaceutical composition of any one of embodiments 107-109 and embodiments 113-117 for the preparation of a therapeutic agent for the treatment of obesity.

Methods of treatment using peptides

Example 122 immunotherapy Using peptides

An immunotherapy comprising the following:

administering the peptide unit of any one of embodiments 1-90, the peptide of any one of embodiments 91-95, the nucleic acid of any one of embodiments 96-106, and/or the pharmaceutical composition of any one of embodiments 107-109 and 113-117 in vivo to a subject.

Example 123 methods for treatment of obesity Using peptides

The following methods for obesity treatment were used:

administering the peptide unit of any one of embodiments 1-90, the peptide of any one of embodiments 91-95, the nucleic acid of any one of embodiments 96-106, and/or the pharmaceutical composition of any one of embodiments 107-109 and 113-117 in vivo to a subject.

Sequences similar to peptide units and/or peptides

Example 124 sequence similar to peptide Unit

A peptide unit having a sequence that matches any of the peptide units described in examples 1-90 by 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more.

Example 125 sequence similar to peptide

A peptide having a sequence matching any of the peptide units described in examples 91-95 by 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% or more.

Experimental example

Hereinafter, the invention provided in the present application document will be described in more detail through experimental examples and examples. These examples are merely illustrative of the disclosure of the present application and it will be apparent to those skilled in the art that the scope of the disclosure of the present application should not be construed as being limited by these examples.

Experimental example 1, experimental method

Experimental example 1.1 preparation of peptides

The peptide was obtained by applying to peptide synthesis company (Anygen, korea, calif.). The peptide of the present invention can be synthesized using conventionally known techniques (e.g., liquid phase peptide synthesis, solid phase peptide synthesis, pooling of small peptide fragments, etc.), and the synthesis method is not limited. For example, the OTP3 peptide of the present invention can be synthesized using a convergent method of small peptide fragments, in which a site of a long chain peptide, which can be easily coupled, is virtually cleaved, and various moieties are prepared based thereon, and then combined with each other, thereby finally synthesizing a desired peptide. The above pooling method is limited in that a specific amino acid must exist within a peptide sequence, and thus, peptides can also be efficiently synthesized by a combinatorial peptide synthesis method, in which a solution phase synthesis method and a solid phase peptide synthesis method are appropriately combined.

Experimental example 1.2, confirmation of the prepared peptide 1-purity analysis

The purity of the peptides prepared in experimental example 1.1 was measured by HPLC analysis (Shimadzu HPLC LabSolutions) using a C-18 reverse phase column (SHIMADZU C18 analytical column). Regarding the analysis conditions, the samples were separated at 60 ℃ and developed in an aqueous solution of 0.05% trifluoroacetic acid (TFA) and 0.05% TFA acetonitrile solution, and then purity was confirmed by measuring peak absorbance at a wavelength of 230 nm.

Experimental example 1.3 confirmation of the prepared peptide 2-molecular weight analysis

The molecular weight of the peptide prepared in Experimental example 1.1 was analyzed by a mass spectrometer (AXIMA Asspirance, MALDI-TOF, shimadzu).

Experimental example 1.4, confirmation of the prepared peptide 3-quantitative analysis

The peptides prepared in experimental example 1.1 were quantified by measuring the UV extinction coefficient (Ultrospec 3000Pro UV/VIS spectrophotometer, pharmacia). Specifically, quantification was performed using an extinction coefficient at 280 nm.

Experimental example 1.5 preparation of compositions for in vivo administration

By mixing the peptide prepared in Experimental example 1.1, alhydrogel (Al (OH) ₃ The compositions for in vivo administration were prepared by mixing InvivoGe, inc. and PHAD (manufactured by Avanti). The specific flow is as follows.

(1) The peptide powder prepared was dissolved in 100% dimethyl sulfoxide (DMSO) to obtain a concentration of 100 mg/L.

(2) PBS was added to the peptide-DMSO solution of (1) and mixed to prepare the peptide at a concentration of 50 mg/mL.

(3) PHAD was dissolved in 100% DMSO to a concentration of 10mg/mL, and then diluted with distilled water to a concentration of 1 mg/mL.

(4) Alhydrogel adjuvant (Invivogen, USA) and PHAD solution were added to the mixture of (2). The concentration of the mixed composition was 50. Mu.g of peptide, 10. Mu.g of PHAD and 10% (v/v) of Alhydrogel adjuvant per 100. Mu.L, which is a dose.

(5) After thoroughly mixing the mixture of (4), the resultant was reacted overnight with stirring in a low temperature chamber (4 ℃) with a rotator.

(6) For washing of DSMO, the reaction of (5) was centrifuged at 1400rpm for 15 minutes, and the supernatant, except for about 1mL above the pellet, was removed. Thereafter, 10mL of PBS was added thereto and mixed.

(7) The washing process of (6) was repeated 3 times.

(8) After the final wash process, PBS was added thereto to adjust the final concentration of the composition. Specifically, the peptide concentration was 50. Mu.g/100. Mu.L (particularly, 30. Mu.g/100. Mu.L in example 4), the PHAD concentration was 10. Mu.g/100. Mu.L, and the Alhydrogel adjuvant concentration was 10% (v/v).

(9) The amount of peptide adsorbed to the aluminium gel was measured according to the method described in experimental example 2.3. As a result, the adsorption rate was confirmed to be 95% or more, and the peptide was used for experiments.

Experimental example 1.6 preparation of test subjects

To test the effect of the composition for in vivo administration prepared in experimental example 1.5, C57BL/6, balbc and/or ICR species were used as experimental mice (purchased from Central Lab Animal inc.). Despite some differences between species, the purchased mice were averaged 7 weeks of age and allowed to adapt for one week and were used for the experiment at their 8 weeks of age. The experimental mice were kept in a constant temperature and humidity environment at a temperature of 23.+ -. 1 ℃ and a relative humidity of 50.+ -. 5% and an environment controlled to be a 12-hour light room/12-hour dark room. Drinking water and food were provided ad libitum. In the case of a normal diet (purchased from Central Lab Animal inc.) it consists of 20% protein, 70% carbohydrate and 10% fat according to total calories, whereas in the case of an obesity induced diet (purchased from Research diets) it consists of a high fat diet comprising 20% protein, 20% carbohydrate and 60% fat according to total calories. The experimental mice were divided into groups to have different dietary conditions and composition administration conditions, and experiments were performed with the number of individuals statistically treatable for each experimental group. The detailed conditions are as disclosed in each specific experimental example.

Experimental example 1.7 administration of a composition comprising a peptide to a test subject

For the test subjects prepared in experimental example 1.6, different compositions were administered to each experimental group. All compositions were administered by intramuscular injection and 50 μl of each was injected after the muscles of both thighs of each mouse were disinfected with alcohol swabs, with a total of 100 μl.

Experimental example 1.8 Effect confirmation of composition for in vivo administration 1-weight measurement

To confirm the weight loss effect of the composition administered in vivo according to experimental example 1.7 on the test subjects, the body weight and organ weight of the mice of each experimental group were measured. For mice in each experimental group, from the time of entry to the end of the experiment, the average was calculated after three measurements per week to obtain an average body weight value per week. After the completion of the experiment, each mouse was anesthetized, organs were dissected, and weights were measured, and the average value of each experimental group was obtained.

Experimental example 1.9 confirmation of Effect of compositions for in vivo administration confirmation of 2-antibody titres

To determine whether the composition for in vivo administration administered in experimental example 1.7 induced antibodies against B cell epitopes, the method of confirming antibody titer using the target antigen was as follows. Specifically, the target antigen is RNVPPIFNDVYWIAF (SEQ ID NO: 6) or ApoB100. The time to confirm antibody titer can vary as desired, and the time of each experimental example is specifically described.

1. Antigen coating reaction process

1-1) for each injection of a composition for in vivo administration to a test subject, about 200 μl of blood was collected from the tail vein of the test subject one week after injection.

1-2) after the collected blood was left at 4℃for 1 hour, centrifugation of the blood sample was performed at 14,000rpm for 10 minutes to separate serum (i.e., supernatant).

1-3) the target antigen was diluted to a concentration of 50. Mu.g/100. Mu.L in coating buffer (0.05M, bicarbonate, pH 9.6), and the antigen was added to a 96-well plate in an amount of 50. Mu.g per well and allowed to react overnight at 4℃to coat the peptide on the well wall.

1-4) plates coated with target antigen were washed three times per well using 300. Mu.L of Phosphate Buffered Saline (PBS) -T (containing 0.05% Tween-20).

2. Closed reaction process

2-1) 300. Mu.L of 0.5% casein blocking solution was added to each well in the well plate and allowed to react overnight at 4 ℃.

2-2) washing the well plate three times with 300. Mu.L of PBS-T per well.

3. Reaction-resistant process

3-1) as primary antibody, the isolated serum was diluted to an appropriate concentration, added in an amount of 100. Mu.L per well, and allowed to react at 37℃for 1 hour. Specifically, serum was serially diluted by diluting serum to 1/20 to 1/1000 in the experiment after the primary injection, and diluting serum to 1/500 to 1/10000 according to subjects during the experiment after the second to third injections. As positive control, the purification was followed by the use of the nucleic acid sequence directed against SEQ ID NO: 41.

3-2) after the reaction of 3-1, the well plate was washed three times with 300. Mu.L of PBS-T per well.

4. Process of secondary antibody reaction

4-1) as a secondary antibody, 100. Mu.L of horseradish peroxidase (HRP) conjugated to an anti-mouse IgG antibody recognizing a mouse antibody was added to each well, and allowed to react at 37℃for 1 hour.

4-2) after the reaction of 4-1), the well plate was washed three times with 300. Mu.L of PBS-T per well.

5. Process for confirming color development and absorbance

5-1) 100. Mu.L of o-phenylenediamine dihydrochloride (OPD) solution was added per well and allowed to react at 37℃for 10 minutes, and the absorbance at OD 450nm was measured (Synergy HT microplate reader, bioTek).

5-2) antibody titer in serum was obtained by converting extinction coefficient, which was measured based on 1mg/mL concentration of monoclonal antibody against the target antibody as positive control.

Experimental example 1.10 confirmation of the Effect of compositions for in vivo administration 3-blood lipid concentration

The experimental procedure for confirming the effect of the composition for in vivo administration administered in experimental example 1.7 on the blood lipid concentration of the test subjects was as follows:

(1) One week after administration of each composition, about 200 μl of blood was collected from the tail vein of the subject.

(2) Blood Triglyceride (TG) concentration measurement: triglyzyme V (Shinyak Chemical Co., ltd.) was used. i) After mixing 4. Mu.L of blood sample and 300. Mu.L of chromogenic reagent, the mixture was allowed to react at 37℃for 5 minutes. ii) for the red quinone produced, the absorbance at 505nm was measured and the concentration calculated by comparison with the absorbance of the reference solution.

(3) Measurement of total cholesterol concentration in blood: cholestezyme-V (Shinyak Chemical Co., ltd.) was used. i) After mixing 4. Mu.L of blood sample and 300. Mu.L of chromogenic reagent, the mixture was allowed to react at 37℃for 5 minutes. ii) for the red quinone produced, the absorbance at 505nm was measured and the concentration calculated by comparison with the absorbance of the reference solution.

(4) Measurement of High Density Lipoprotein (HDL) concentration in blood: HDL-C555 (Shinyak Chemical Co., ltd.) was used. i) After mixing 10 μl of blood sample and 10 μl of precipitation reagent, the mixture was allowed to react at room temperature for at least 10 minutes. ii) centrifuging the reaction at 300rpm or more and separating the supernatant. iii) After mixing 4. Mu.L of the supernatant and 300. Mu.L of the chromogenic reagent, the mixture was reacted at 37℃for 5 minutes. iv) for the above reaction, the absorbance at 555nm was measured and the concentration was calculated by comparison with the absorbance of the reference solution.

(5) Measurement of Low Density Lipoprotein (LDL) concentration in blood. i) The reaction was performed using a direct LDL cholesterol assay kit (Randox). ii) after the reaction of step 2, for the quinone produced, the absorbance at 600nm was measured and the concentration was calculated by comparison with the absorbance of the reference solution.

Experimental example 1.11 confirmation of Effect of composition for in vivo administration confirmation of 4-lipolytic ability and fat Comparison of cell sizes

The method for confirming the effect of the composition for in vivo administration administered in experimental example 1.7 on the adipocyte size and the adipocyte degradation capacity of the test subject by Hormone Sensitive Lipase (HSL) is as follows:

1. isolation of adipocytes

1-1) epididymal fat pad was sheared with scissors, 4mL/1g KRB buffer containing 2% FBS, 2mM glucose and 1mg/mL collagenase was added, and shaken and allowed to react at 37℃for 1 hour while shaking.

1-2) after the completion of the reaction, the resultant was filtered through a 300 μm nylon sieve to remove adipose tissue residues and adipose tissue, and then the filtrate was again passed through a 40 μm nylon sieve to separate adipocytes and macrophages.

1-3) washing the fat cells filtered in 1-2) by adding DMEM containing 10% FBS and 1% AA, and removing the lower layer of liquid with a syringe to obtain collagenase-removed fat cells.

2. Comparison of lipolytic Capacity

2-1) at 1.0X10 ⁵ Individual cells/well the adipocytes obtained in 1-3) were inoculated into a 48-well plate, and 1mL total DMEM (10% FBS,1% AA) was added thereto for 5% co at 37 ℃ ₂ Incubate for two hours.

2-2) for HSL Activity-inducing wells, norepinephrine is added to a final concentration of 10 ^-5 M。

2-3) after completion of the reaction, 100. Mu.L of supernatant per well was reacted with 100. Mu.L of free glycerol reagent, and absorbance at 540nm was measured.

3. Observation of adipocyte size

3-1) 1.0X10 per well ⁵ Individual cells/mL the adipocytes obtained in 1-3) were inoculated into 48-well plates, treated with 10 μm DAPI, allowed to react for two hours, and observed under a microscope.

3-2) to confirm whether DAPI-stained cells were adipocytes, lipids were stained with nuclei and observed. Specifically, cells were treated with 10. Mu.M DAPI and 1:1000HCS LipidTOX and allowed to react for 24 hours, and then observed under a microscope.

Experimental example 2 confirmation of peptide Effect 1

Experimental example 2.1 preparation of peptides and experiments thereof

After the peptides according to [ Table 1] were prepared according to Experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. Compositions for in vivo administration comprising peptides according to [ table 1] were prepared according to experimental example 1.5.

TABLE 1 peptides used in Experimental example 2 and compositions for in vivo administration comprising the same

Label (Label)	Peptide sequences	SEQ ID NO
			Example 1	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ	56
Example 2	ZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF	57

Test subjects shown in [ table 2] were prepared according to experimental example 1.6.

TABLE 2 test subjects used in Experimental example 2

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period is as follows: 7 weeks of age, 9 weeks of age, 12 weeks of age, 15 weeks of age and 18 weeks of age.

Experimental example 2.2 confirmation of the Experimental results

To confirm the experimental result of experimental example 2.1, the body weight of the test subject was measured for each experimental group disclosed in [ table 2] according to experimental example 1.8.

The experimental results are shown in fig. 1 to 3.

Experimental example 3 confirmation of peptide Effect 2

Experimental example 3.1, peptide preparation and experiments

After the peptides according to [ Table 3] were prepared according to experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. Compositions for in vivo administration comprising peptides according to [ table 3] were prepared according to experimental example 1.5.

TABLE 3 peptides used in Experimental example 3 and compositions for in vivo administration comprising the same

Label (Label)	Peptide sequences	SEQ ID NO
			Example 3	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	108

Test subjects shown in [ table 4] were prepared according to experimental example 1.6.

Table 4 test subjects used in experimental example 3

In particular, lean represents a control group having normal body weight, obese represents an obese group induced by a high fat diet, and blank represents a group given placebo (hereinafter).

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period is as follows: 8 weeks of age, 10 weeks of age, 12 weeks of age and 14 weeks of age.

Experimental example 3.2 confirmation of Experimental results

In order to confirm the experimental results of experimental example 3.1, the following experiments were performed on the test subjects of each experimental group disclosed in [ table 4 ].

(1) The body weight of the test subjects of each experimental group was measured according to experimental example 1.8.

(2) According to experimental example 1.9, the antibody titer observed in the test subjects of each experimental group was confirmed.

(3) Blood lipid concentrations of test subjects of each experimental group were measured according to experimental example 1.10.

(4) According to experimental example 1.11, the lipolytic ability of the test subjects of each experimental group was confirmed, and the size of adipocytes was observed.

The experimental results are shown in fig. 4 to 9.

Experimental example 4 confirmation of peptide Effect 3

Experimental example 4.1, peptide preparation and experiments

After the peptides according to [ Table 5] were prepared according to Experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. Compositions for in vivo administration comprising peptides according to [ table 5] were prepared according to experimental example 1.5.

TABLE 5 peptides used in Experimental example 4 and compositions for in vivo administration comprising the same

Label (Label)	Peptide sequences	SEQ ID NO
			Example 3	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	108
Example 4	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	108

Specifically, in example 4, the final peptide concentration was 30 μg/100 μl.

Test subjects shown in [ table 6] were prepared according to experimental example 1.6.

TABLE 6 test subjects used in Experimental example 4

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period is as follows: 8 weeks of age, 11 weeks of age, 14 weeks of age, 17 weeks of age and 20 weeks of age.

Experimental example 4.2 confirmation of Experimental results

In order to confirm the experimental results of experimental example 4.1, the following experiments were performed on the test subjects of each experimental group disclosed in [ table 6 ].

(1) The body weight of the test subjects of each experimental group was measured according to experimental example 1.8.

(2) According to experimental example 1.9, the antibody titer observed in the test subjects of each experimental group was confirmed.

The experimental results are shown in fig. 10 and 11.

Experimental example 5 confirmation of peptide Effect 4

Experimental example 5.1, peptide preparation and experiments

After the peptides according to [ Table 7] were prepared according to Experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. Compositions for in vivo administration comprising peptides according to [ table 7] were prepared according to experimental example 1.5.

TABLE 7 peptides used in Experimental example 5 and compositions for in vivo administration comprising the same

Label (Label)	Peptide sequences	SEQ ID NO
			Example 3	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	108

Test subjects shown in [ table 8] were prepared according to experimental example 1.6.

TABLE 8 test subjects used in Experimental example 5

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period is as follows: 11 weeks of age, 13 weeks of age, 15 weeks of age, and 17 weeks of age.

Experimental example 5.2 confirmation of Experimental results

To confirm the experimental result of experimental example 5.1, the body weight of the test subject was measured for each experimental group disclosed in [ table 8] according to experimental example 1.8.

The experimental results are shown in fig. 12.

Experimental example 6 confirmation of peptide Effect 5

Experimental example 6.1, peptide preparation and experiments

After the peptides according to [ Table 9] were prepared according to Experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. Compositions for in vivo administration comprising peptides according to [ table 9] were prepared according to experimental example 1.5.

TABLE 9 peptides used in Experimental example 6 and compositions for in vivo administration comprising the same

Label (Label)	Peptide sequences	SEQ ID NO
			Example 3	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	108

Test subjects shown in [ table 10] were prepared according to experimental example 1.6.

Table 10 test subjects used in experimental example 6

* The C57BL/6J-Rag2em1hwl/Korl mouse is a mouse in which the Rag2 gene is knocked out, and Rag2 is a gene involved in the antibody production ability in the C57BL/6J mouse.

* Wild type (+/+) refers to wild type mice without genetic mutation, hetero (+/-) refers to heterozygous mice, and Homo (-/-) refers to homozygous mice.

* Homo (-/-) mice have no capacity to produce antibodies in vivo.

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration cycle is as follows: 8 weeks of age, 10 weeks of age, 12 weeks of age and 14 weeks of age.

Experimental example 6.2 confirmation of the Experimental results

To confirm the experimental result of experimental example 6.1, the body weight of the test subject was measured for each experimental group disclosed in [ table 10] according to experimental example 1.8.

The experimental results are shown in fig. 13.

Experimental example 7, confirmation of peptide Effect 6

Experimental example 7.1, peptide preparation and experiments

After the peptides according to [ Table 11] were prepared according to Experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. Compositions for in vivo administration comprising peptides according to [ table 11] were prepared according to experimental example 1.5.

TABLE 11 peptides used in Experimental example 7 and compositions for in vivo administration comprising the same

Label (Label)	Peptide sequences	SEQ ID NO
			Example 5	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	108
Example 6	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZGSHHHHHHGSDDDDK	68
			Example 7	GSHHHHHHGSDDDDKZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF	69
Example 8	KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	114
			Example 9	RNVPPIFNDVYWIAFCRFRGLISLSOVYLSZaK(Cha)VAAWTLKAAaZ	84
Example 10	RNVPPIFNDVYWIAFZPKYVKQNTLKLATZCRFRGLISLSQVYLS	121
			Example 11	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ	56
Example 12	RNVPPIFNDVYWIAFK(Cha)VAAWTLKAA	62
			Example 13	RNVPPIFNDVYWIAFK(Cha)VAAWTLKAAHHHHHH	67

Test subjects shown in [ table 12] were prepared according to experimental example 1.6.

Table 12 test subjects used in experimental example 7

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period is as follows: 8 weeks of age, 10 weeks of age, 12 weeks of age and 14 weeks of age.

Experimental example 7.2 confirmation of the Experimental results

In order to confirm the experimental results of experimental example 7.1, the following experiments were performed on the test subjects of each experimental group disclosed in [ table 12 ].

(1) The body weight of the test subjects of each experimental group was measured according to experimental example 1.8.

(2) According to experimental example 1.9, antibody titers observed in test subjects of the respective experimental groups at 11 weeks, 16 weeks and 19 weeks were confirmed. Specifically, RNVPPIFNDVYWIAF (SEQ ID NO: 6) was used to determine the target antigen.

The experimental results are shown in fig. 14 to 25.

As a result of the experiment, all of the experimental groups 6-1 (P1) to 6-9 (P9) showed a remarkable weight loss effect as compared with the control group (obesity) fed with a high fat diet.

The results of the antibody titer test according to the experimental group can be explained as follows:

no antibody titer was shown since no antigen was given to the control group (i.e., lean and obese).

Considering the experimental design, in the experimental group, it was mainly confirmed that the sequence of SEQ ID NO: antibody titer of 6. Although NO separate confirmation is made of the sequence other than the sequence of SEQ ID NO: antibody titers of sequences other than 6, but together confirmed the weight loss effect due to humoral immunity caused by these peptides.

Specific results will be described below.

For the case of experimental group 6-1 (P1), depending on the individuals, there were individuals showing a large antibody titer, and also individuals showing no antibody titer. These results can be explained as follows: for some individuals of experimental group 6-1 (P1), humoral immunity to RNVPPIFNDVYWIAF (SEQ ID NO: 6) contained in example 6 was induced, thus showing both the observed weight loss effect and antibody titer; whereas for some individuals humoral immunity to CRFRGLISLSQVYLS (SEQ ID NO: 7) contained in example 6 was induced, resulting in weight loss, the antigen used in the enzyme-linked immunosorbent assay (ELISA) consisted of RNVPPIFNDVYWIAF (SEQ ID NO: 6) alone, and NO other antigen (i.e., the antigen of SEQ ID NO: 7), and therefore, NO antibody titer according to the above experiment was observed even in the presence of antibodies.

In the case of experimental group 6-2 (P2), the antibody titer against RNVPPIFNDVYWIAF (SEQ ID NO: 6) contained in example 7 was observed, and a weight loss effect was exhibited, which could be interpreted as that the B cell epitope contained in the peptide of example 7 induced humoral immunity thereto well.

For the case of experimental group 6-3 (P3), the antibody titer of RNVPPIFNDVYWIAF (SEQ ID NO: 6) contained in example 8 was observed, and a weight loss effect was exhibited, which could be interpreted as that the B cell epitope contained in the peptide of example 8 induced humoral immunity thereto well.

In the case of experimental group 6-4 (P4), it can be interpreted that humoral immunity to KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8) and/or CRFRGLISLSQVYLS (SEQ ID NO: 7) contained in example 9 was induced, and thus antibody titer against RNVPPIFNDVYWIAF (SEQ ID NO: 6) was not shown, but there was a weight loss effect.

These results can be interpreted as that for some individuals of experimental group 6-5 (P5), humoral immunity against RNVPPIFNDVYWIAF (SEQ ID NO: 6) contained in example 10 was induced, so that both weight loss effect and antibody titer were observed; for other individuals of experimental group 6-5 (P5), humoral immunity against CRFRGLISLSQVYLS (SEQ ID NO: 7) contained in example 10 was induced, so that a weight loss effect was observed, but NO antibody titer according to the above experiment was observed.

In the case of experimental groups 6-7 (P7), antibodies against RNVPPIFNDVYWIAF (SEQ ID NO: 6) were observed and a weight loss effect was seen, although there was some difference between individuals, and therefore, it could be interpreted that the B cell epitope contained in the peptide of example 11 induced humoral immunity well.

In the case of experimental groups 6 to 8 (P8), since the antibody titer against RNVPPIFNDVYWIAF (SEQ ID NO: 6) contained in example 12 was shown and the weight loss effect was shown, it could be interpreted that the B cell epitope contained in the peptide of example 12 induced humoral immunity well.

In the case of experimental groups 6-9 (P9), there were some differences between individuals. However, since an antibody against RNVPPIFNDVYWIAF (SEQ ID NO: 6) was observed and a weight loss effect was exhibited, it could be interpreted that the B cell epitope contained in the peptide of example 13 induced humoral immunity well.

Experimental example 8, confirmation of peptide Effect 7

Experimental example 8.1, peptide preparation and experiments

After the peptides according to [ Table 13] were prepared according to Experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. Compositions for in vivo administration comprising peptides according to [ table 13] were prepared according to experimental example 1.5.

TABLE 13 peptides used in Experimental example 8 and compositions for in vivo administration comprising the same

Label (Label)	Peptide sequences	SEQ ID NO
			Example 5	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	108
Example 14	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS	160
			Example 15	RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAACR	161

Test subjects shown in [ table 14] were prepared according to experimental example 1.6.

Table 14 test subjects used in experimental example 8

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period, administration time, and administration frequency may be appropriately modified according to the experimental design. For example, for a test subject of 8 weeks of age, four compositions may be administered at two week intervals, but are not limited thereto.

The above experimental method may be appropriately modified as needed.

Experimental example 8.2 confirmation of the Experimental results

In order to confirm the experimental results of experimental example 8.1, the following experiments were performed on the test subjects of each experimental group disclosed in [ table 14 ].

(1) The body weight of the test subjects of each experimental group was measured according to experimental example 1.8.

(2) According to experimental example 1.9, the antibody titer observed in the test subjects of each experimental group was confirmed.

(3) Blood lipid concentrations of test subjects of each experimental group were measured according to experimental example 1.10.

(4) According to experimental example 1.11, the lipolytic ability of the test subjects in each experimental group was confirmed, and the size of adipocytes was observed.

Experimental example 9, confirmation of peptide Effect 8

Experimental example 9.1, peptide preparation and experiments

According to experimental example 1.1, a peptide represented by one or more sequences selected from the group consisting of: SEQ ID NO:56-SEQ ID NO: 158. SEQ ID NO:160-SEQ ID NO:161 and SEQ ID NO:198-SEQ ID NO:220.

the peptides prepared were confirmed according to experimental examples 1.2 to 1.4. According to experimental example 1.5, a composition for in vivo administration comprising the prepared peptide was prepared.

Specifically, peptides can be prepared by selecting only some sequences from the group of the above sequences, and repeated experiments can be performed using various combinations as needed.

Test subjects of the prepared peptides were prepared according to experimental example 1.6. Specifically, examples of the control group and the experimental group to be used are shown in [ table 15], and each experimental group is determined with reference to the conditions of experimental examples 1.6 and [ table 15 ].

Table 15 test subjects used in experimental example 9

Specifically, the experimental groups prepared were as large as the number of peptides prepared.

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period, administration time, and administration frequency may be appropriately modified according to the experimental design. For example, for a test subject of 8 weeks of age, four compositions may be administered at two week intervals, but are not limited thereto.

The above experimental method may be appropriately modified as needed.

Experimental example 9.2 confirmation of the Experimental results

In order to confirm the experimental result of experimental example 9.1, the following experiment was performed on the test subjects of each experimental group.

(1) The body weight of the test subjects of each experimental group was measured according to experimental example 1.8.

(2) According to experimental example 1.9, the antibody titer observed in the test subjects of each experimental group was confirmed.

(3) Blood lipid concentrations of test subjects of each experimental group were measured according to experimental example 1.10.

(4) According to experimental example 1.11, the lipolytic ability of the test subjects in each experimental group was confirmed, and the size of adipocytes was observed.

Experimental example 10, confirmation of peptide Effect 9

Experimental example 10.1, peptide preparation and experiments

After the peptides according to examples 81 to 90 in the "possible examples of the invention" paragraph were prepared according to experimental example 1.1, the prepared peptides were confirmed according to experimental examples 1.2 to 1.4. According to experimental example 1.5, a composition for in vivo administration comprising the prepared peptide was prepared.

Specifically, only a part of the peptides according to the paragraphs examples 81 to 90 of "possible examples of the present invention" may be selected and prepared, and experiments of various combinations may be repeated as necessary.

Test subjects of the prepared peptides were prepared according to experimental example 1.6. Specifically, the control group and the experimental group to be used were determined with reference to the conditions of experimental example 1.6 and [ table 15 ].

According to experimental example 1.7, a composition for in vivo administration was administered to a test subject. Specifically, the administration period, administration time, and administration frequency may be appropriately modified according to the experimental design. For example, for a test subject of 8 weeks of age, four compositions may be administered at two week intervals, but are not limited thereto.

The above experimental method may be appropriately modified as needed.

Experimental example 10.2, confirmation of Experimental results

To confirm the experimental result of experimental example 10.1, the following experiments were performed on the test subjects of each experimental group.

(1) The body weight of the test subjects of each experimental group was measured according to experimental example 1.8.

(2) According to experimental example 1.9, the antibody titer observed in the test subjects of each experimental group was confirmed.

(3) Blood lipid concentrations of test subjects of each experimental group were measured according to experimental example 1.10.

(4) According to experimental example 1.11, the lipolytic ability of the test subjects in each experimental group was confirmed, and the size of adipocytes was observed.

INDUSTRIAL APPLICABILITY

The peptide units, peptides and/or nucleic acids encoding the peptide units and peptides provided herein are useful in the preparation of immunotherapeutic agents, particularly agents for the treatment of obesity, and which can exhibit therapeutic effects by generating a desired humoral immunity when administered into a subject.

<110> 3H biological Co., ltd (3 HBio)

<120> peptide for immunotherapeutic agent

<130> CP20-047

<160> 309

<170> KoPatentIn 3.0

<210> 1

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(11)

<223> amino acid at position 2 (Xaa) is L-cyclohexylalanine

<400> 1

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 2

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 2

Pro Lys Tyr Val Lys Gln Asn Thr Leu Lys Leu Ala Thr

1 5 10

<210> 3

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 3

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile

1 5 10 15

<210> 4

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 4

Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln Ala Ile Pro

1 5 10 15

<210> 5

<211> 32

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 5

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro

1 5 10 15

Met Gly Leu Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

20 25 30

<210> 6

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 6

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10 15

<210> 7

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 7

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

1 5 10 15

<210> 8

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 8

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His

20

<210> 9

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 9

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr

1 5 10

<210> 10

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 10

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln

1 5 10

<210> 11

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 11

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys

1 5 10

<210> 12

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 12

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

1 5 10

<210> 13

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 13

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val

1 5 10

<210> 14

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 14

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys

<210> 15

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 15

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile

1 5 10

<210> 16

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 16

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr

1 5 10

<210> 17

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 17

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn

<210> 18

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 18

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10

<210> 19

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 19

Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

1 5 10

<210> 20

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 20

Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn Lys His

1 5 10 15

<210> 21

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 21

Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10

<210> 22

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 22

Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

1 5 10

<210> 23

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 23

Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn Lys

1 5 10 15

His

<210> 24

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 24

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10

<210> 25

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 25

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

1 5 10

<210> 26

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 26

Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn

1 5 10 15

Lys His

<210> 27

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 27

Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala

1 5 10

<210> 28

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 28

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu

1 5 10

<210> 29

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 29

Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn

1 5 10 15

<210> 30

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile

1 5 10

<210> 31

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 31

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr

1 5 10

<210> 32

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 32

Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn

1 5 10 15

<210> 33

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 33

Pro Pro Ile Phe Asn Asp Val Tyr Trp

1 5

<210> 34

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 34

Arg Gly Leu Ile Ser Leu Ser Gln Val

1 5

<210> 35

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 35

Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys

1 5 10

<210> 36

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid 1 (Xaa) is 6-aminocaproic acid

<400> 36

Xaa Arg Asn Val

1

<210> 37

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid 1 (Xaa) is D-alanine, amino acid 2 (Xaa) is

6-aminocaproic acid

<400> 37

Xaa Xaa Arg Asn

1

<210> 38

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid at position 4 (Xaa) is 6-aminocaproic acid

<400> 38

Ile Ala Phe Xaa

1

<210> 39

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid at position 3 (Xaa) is 6-aminocaproic acid, amino acid at position 4

The acid (Xaa) is D-alanine.

<400> 39

Ala Phe Xaa Xaa

1

<210> 40

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 40

Arg Asn Val Pro

1

<210> 41

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 41

Trp Ile Ala Phe

1

<210> 42

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid 1 (Xaa) is 6-aminocaproic acid

<400> 42

Xaa Cys Arg Phe

1

<210> 43

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid 1 (Xaa) is D-alanine, amino acid 2 (Xaa) is

6-aminocaproic acid

<400> 43

Xaa Xaa Cys Arg

1

<210> 44

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid at position 4 (Xaa) is 6-aminocaproic acid

<400> 44

Tyr Leu Ser Xaa

1

<210> 45

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid at position 3 (Xaa) is 6-aminocaproic acid, amino acid at position 4

The acid (Xaa) is D-alanine.

<400> 45

Leu Ser Xaa Xaa

1

<210> 46

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 46

Cys Arg Phe Arg

1

<210> 47

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 47

Val Tyr Leu Ser

1

<210> 48

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid 1 (Xaa) is 6-aminocaproic acid

<400> 48

Xaa Lys Thr Thr

1

<210> 49

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid 1 (Xaa) is D-alanine, amino acid 2 (Xaa) is

6-aminocaproic acid

<400> 49

Xaa Xaa Lys Thr

1

<210> 50

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid at position 4 (Xaa) is 6-aminocaproic acid

<400> 50

Asn Lys His Xaa

1

<210> 51

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(4)

<223> amino acid at position 3 (Xaa) is 6-aminocaproic acid, amino acid at position 4

The acid (Xaa) is D-alanine

<400> 51

Lys His Xaa Xaa

1

<210> 52

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 52

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys

1 5 10 15

<210> 53

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 53

His His His His His His

1 5

<210> 54

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 54

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp

20

<210> 55

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 55

Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser

1 5 10

<210> 56

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 56

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

20 25 30

<210> 57

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> amino acid 1 (Xaa) is 6-aminocaproic acid, amino acid 2

The acid (Xaa) is D-alanine and the amino acid at position 4 (Xaa) is

L-cyclohexylalanine, amino acid 14 (Xaa) is D-alanine.

Amino acid at position 15 (Xaa) is 6-aminocaproic acid

<400> 57

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg

1 5 10 15

Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

20 25 30

<210> 58

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

Amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 58

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

20 25 30

<210> 59

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> amino acid 1 (Xaa) is 6-aminocaproic acid, amino acid 2

The acid (Xaa) is D-alanine and the 4th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 14 (Xaa) being D-alanine,

amino acid at position 15 (Xaa) is 6-aminocaproic acid

<400> 59

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

20 25 30

<210> 60

<211> 35

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(35)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 60

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa

35

<210> 61

<211> 35

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(35)

<223> amino acid 1 (Xaa) is 6-aminocaproic acid, amino acid 2

The acid (Xaa) is D-alanine and the amino acid at position 4 (Xaa) is

L-cyclohexylalanine, amino acid 14 (Xaa) being D-alanine,

amino acid at position 15 (Xaa) is 6-aminocaproic acid

<400> 61

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Lys

1 5 10 15

Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys

20 25 30

Asn Lys His

35

<210> 62

<211> 26

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(26)

<223> amino acid at position 17 (Xaa) is L-cyclohexylalanine

<400> 62

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys

1 5 10 15

Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

20 25

<210> 63

<211> 26

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(26)

<223> amino acid at position 2 (Xaa) is L-cyclohexylalanine

<400> 63

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Arg Asn Val Pro Pro

1 5 10 15

Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

20 25

<210> 64

<211> 22

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(22)

<223> amino acid at position 13 (Xaa) is L-cyclohexylalanine

<400> 64

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Lys Xaa Val Ala Ala

1 5 10 15

Trp Thr Leu Lys Ala Ala

20

<210> 65

<211> 22

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(22)

<223> amino acid at position 13 (Xaa) is L-cyclohexylalanine

<400> 65

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys Xaa Val Ala Ala

1 5 10 15

Trp Thr Leu Lys Ala Ala

20

<210> 66

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(20)

<223> amino acid 11 (Xaa) is L-cyclohexylalanine

<400> 66

Pro Pro Ile Phe Asn Asp Val Tyr Trp Lys Xaa Val Ala Ala Trp Thr

1 5 10 15

Leu Lys Ala Ala

20

<210> 67

<211> 32

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(32)

<223> amino acid at position 17 (Xaa) is L-cyclohexylalanine

<400> 67

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys

1 5 10 15

Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala His His His His His His

20 25 30

<210> 68

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 68

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Gly Ser

20 25 30

His His His His His His Gly Ser Asp Asp Asp Asp Lys

35 40 45

<210> 69

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

Amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 69

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn

20 25 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

35 40 45

<210> 70

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid 31 (Xaa) is 6-aminocaproic acid, amino acid 32

The acid (Xaa) is D-alanine and the 34 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 44 (Xaa) being D-alanine,

amino acid (Xaa) at position 45 is 6-aminocaproic acid

<400> 70

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Gly

1 5 10 15

Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

35 40 45

<210> 71

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 71

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 72

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid 31 (Xaa) is 6-aminocaproic acid, amino acid 32

The acid (Xaa) is D-alanine and the 34 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 44 (Xaa) being D-alanine,

amino acid (Xaa) at position 45 is 6-aminocaproic acid

<400> 72

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

35 40 45

<210> 73

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 73

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Gly Ser

20 25 30

His His His His His His Gly Ser Asp Asp Asp Asp Lys

35 40 45

<210> 74

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 74

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Lys Thr

20 25 30

Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn

35 40 45

Lys His

50

<210> 75

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 75

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Lys

1 5 10 15

Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys

20 25 30

Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa

50

<210> 76

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 76

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Gly Ser His His His His His His Gly Ser Asp Asp Asp

35 40 45

Asp Lys

50

<210> 77

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 77

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa

50

<210> 78

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 51 (Xaa) is 6-aminocaproic acid, amino at position 52

The acid (Xaa) is D-alanine and the amino acid at position 54 (Xaa) is

L-cyclohexylalanine, amino acid 64 (Xaa) being D-alanine,

amino acid 65 (Xaa) is 6-aminocaproic acid

<400> 78

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Gly Ser His His His His His His Gly Ser Asp Asp

20 25 30

Asp Asp Lys Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile

35 40 45

Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa

50 55 60

Xaa

65

<210> 79

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 79

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

50 55 60

Lys

65

<210> 80

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 80

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Ile

1 5 10 15

Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile

20 25 30

<210> 81

<211> 47

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 81

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Ile

1 5 10 15

Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro Met

20 25 30

Gly Leu Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

35 40 45

<210> 82

<211> 32

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(32)

<223> amino acid at position 17 (Xaa) is 6-aminocaproic acid, amino at position 18

The acid (Xaa) is D-alanine and the amino acid at position 20 (Xaa) is

L-cyclohexylalanine, amino acid 30 (Xaa) being D-alanine,

amino acid 31 (Xaa) is 6-aminocaproic acid

<400> 82

Cys Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10 15

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys

20 25 30

<210> 83

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid 31 (Xaa) is 6-aminocaproic acid, amino acid 32

The acid (Xaa) is D-alanine and the 34 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 44 (Xaa) being D-alanine,

amino acid (Xaa) at position 45 is 6-aminocaproic acid

<400> 83

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Arg

1 5 10 15

Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

35 40 45

<210> 84

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid 31 (Xaa) is 6-aminocaproic acid, amino acid 32

The acid (Xaa) is D-alanine and the 34 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 44 (Xaa) being D-alanine,

amino acid (Xaa) at position 45 is 6-aminocaproic acid

<400> 84

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

35 40 45

<210> 85

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 85

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys

1 5 10 15

Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys

20 25 30

Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa

50

<210> 86

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid 31 (Xaa) is 6-aminocaproic acid, amino acid 32

The acid (Xaa) is D-alanine and the 34 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 44 (Xaa) being D-alanine,

amino acid (Xaa) at position 45 is 6-aminocaproic acid

<400> 86

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Arg

1 5 10 15

Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

35 40 45

<210> 87

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid 31 (Xaa) is 6-aminocaproic acid, amino acid 32

The acid (Xaa) is D-alanine and the 34 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 44 (Xaa) being D-alanine,

amino acid (Xaa) at position 45 is 6-aminocaproic acid

<400> 87

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

35 40 45

<210> 88

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 88

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Lys

1 5 10 15

Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys

20 25 30

Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa

50

<210> 89

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 89

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa

50

<210> 90

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 90

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val

20 25 30

Tyr Leu Ser Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa

50

<210> 91

<211> 55

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(55)

<223> amino acid at position 41 (Xaa) is 6-aminocaproic acid, amino at position 42

The acid (Xaa) is D-alanine and the amino acid at position 44 (Xaa) is

L-cyclohexylalanine, amino acid 54 (Xaa) being D-alanine,

Amino acid 55 (Xaa) is 6-aminocaproic acid

<400> 91

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys

20 25 30

Ala Gln Tyr Lys Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp

35 40 45

Thr Leu Lys Ala Ala Xaa Xaa

50 55

<210> 92

<211> 41

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(41)

<223> amino acid at position 32 (Xaa) is L-cyclohexylalanine

<400> 92

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Lys Xaa

20 25 30

Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40

<210> 93

<211> 33

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(33)

<223> amino acid at position 24 (Xaa) is L-cyclohexylalanine

<400> 93

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Gly Leu Ile Ser Leu

1 5 10 15

Ser Gln Val Tyr Leu Ser Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala

<210> 94

<211> 33

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(33)

<223> amino acid at position 24 (Xaa) is L-cyclohexylalanine

<400> 94

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Cys Arg Phe Arg Gly

1 5 10 15

Leu Ile Ser Leu Ser Gln Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala

<210> 95

<211> 33

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(33)

<223> amino acid at position 24 (Xaa) is L-cyclohexylalanine

<400> 95

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys Arg Phe Arg Gly

1 5 10 15

Leu Ile Ser Leu Ser Gln Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala

<210> 96

<211> 29

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(29)

<223> amino acid at position 20 (Xaa) is L-cyclohexylalanine

<400> 96

Pro Pro Ile Phe Asn Asp Val Tyr Trp Arg Gly Leu Ile Ser Leu Ser

1 5 10 15

Gln Val Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

20 25

<210> 97

<211> 47

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(47)

<223> amino acid at position 32 (Xaa) is L-cyclohexylalanine

<400> 97

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Lys Xaa

20 25 30

Val Ala Ala Trp Thr Leu Lys Ala Ala His His His His His His

35 40 45

<210> 98

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 51 (Xaa) is 6-aminocaproic acid, amino at position 52

The acid (Xaa) is D-alanine and the amino acid at position 54 (Xaa) is

L-cyclohexylalanine, amino acid 64 (Xaa) being D-alanine,

amino acid 65 (Xaa) is 6-aminocaproic acid

<400> 98

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr

35 40 45

Leu Ser Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa

50 55 60

Xaa

65

<210> 99

<211> 63

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(63)

<223> amino acid at position 51 (Xaa) is 6-aminocaproic acid, amino at position 52

The acid (Xaa) is D-alanine and the amino acid at position 54 (Xaa) is

L-cyclohexylalanine, amino acid 64 (Xaa) being D-alanine,

amino acid 65 (Xaa) is 6-aminocaproic acid

<400> 99

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr

35 40 45

Leu Ser Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

50 55 60

<210> 100

<211> 43

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(43)

<223> amino acid 31 (Xaa) is 6-aminocaproic acid, amino acid 32

The acid (Xaa) is D-alanine and the 34 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 44 (Xaa) being D-alanine,

amino acid (Xaa) at position 45 is 6-aminocaproic acid

<400> 100

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40

<210> 101

<211> 76

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(76)

<223> amino acid 64 (Xaa) is 6-aminocaproic acid, amino acid 65

The acid (Xaa) is D-alanine and the 67 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 77 (Xaa) being D-alanine,

amino acid (Xaa) at position 78 is 6-aminocaproic acid

<400> 101

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser

35 40 45

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

50 55 60

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

65 70 75

<210> 102

<211> 56

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(56)

<223> amino acid at position 44 (Xaa) is 6-aminocaproic acid, amino at position 45

The acid (Xaa) is D-alanine and the 47 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 57 (Xaa) being D-alanine,

Amino acid 58 at position 14 (Xaa) is 6-aminocaproic acid

<400> 102

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser Arg Asn Val Pro

20 25 30

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa Xaa Lys Xaa Val

35 40 45

Ala Ala Trp Thr Leu Lys Ala Ala

50 55

<210> 103

<211> 58

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(58)

<223> amino acid at position 44 (Xaa) is 6-aminocaproic acid, amino at position 45

The acid (Xaa) is D-alanine and the 47 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 57 (Xaa) being D-alanine,

amino acid (Xaa) at position 58 is 6-aminocaproic acid

<400> 103

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser Arg Asn Val Pro

20 25 30

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa Xaa Lys Xaa Val

35 40 45

Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

50 55

<210> 104

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 104

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Arg

1 5 10 15

Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile

35 40 45

<210> 105

<211> 62

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 105

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Arg

1 5 10 15

Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro Met Gly

35 40 45

Leu Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

50 55 60

<210> 106

<211> 47

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(47)

<223> amino acid (Xaa) at position 32 is 6-aminocaproic acid, amino acid at position 33

The acid (Xaa) is D-alanine and the 35 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 45 (Xaa) being D-alanine,

amino acid (Xaa) at position 46 is 6-aminocaproic acid

<400> 106

Cys Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10 15

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

20 25 30

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys

35 40 45

<210> 107

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

Amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 107

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn

20 25 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

35 40 45

<210> 108

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 108

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 109

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 109

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Lys Thr

20 25 30

Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn

35 40 45

Lys His

50

<210> 110

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 110

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn

20 25 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

35 40 45

<210> 111

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 111

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 112

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 112

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Lys Thr

20 25 30

Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn

35 40 45

Lys His

50

<210> 113

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 113

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile

35 40 45

Ala Phe

50

<210> 114

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 114

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr

35 40 45

Leu Ser

50

<210> 115

<211> 55

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(55)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 115

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala

35 40 45

Gln Tyr Lys Lys Asn Lys His

50 55

<210> 116

<211> 33

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(33)

<223> amino acid at position 13 (Xaa) is L-cyclohexylalanine

<400> 116

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys Xaa Val Ala Ala

1 5 10 15

Trp Thr Leu Lys Ala Ala Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser

20 25 30

Gln

<210> 117

<211> 29

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 117

Pro Pro Ile Phe Asn Asp Val Tyr Trp Lys Xaa Val Ala Ala Trp Thr

1 5 10 15

Leu Lys Ala Ala Arg Gly Leu Ile Ser Leu Ser Gln Val

20 25

<210> 118

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 118

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala

50 55 60

Phe

65

<210> 119

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 119

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser

35 40 45

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro

50 55 60

Met Gly Leu Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

65 70 75 80

Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser Cys Arg Phe

85 90 95

Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

100 105

<210> 120

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 120

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Ile

1 5 10 15

Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 121

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 121

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Pro Lys Tyr Val Lys Gln Asn Thr Leu Lys Leu Ala Thr Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 122

<211> 47

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(47)

<223> amino acid at position 17 (Xaa) is 6-aminocaproic acid, amino at position 18

The acid (Xaa) is D-alanine and the amino acid at position 20 (Xaa) is

L-cyclohexylalanine, amino acid 30 (Xaa) being D-alanine,

amino acid 31 (Xaa) is 6-aminocaproic acid

<400> 122

Cys Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10 15

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg

20 25 30

Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

35 40 45

<210> 123

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 123

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile

35 40 45

<210> 124

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 124

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile

35 40 45

<210> 125

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 125

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile

35 40 45

Gly Ile

50

<210> 126

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 126

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn

20 25 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

35 40 45

<210> 127

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 127

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 128

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 128

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Lys Thr

20 25 30

Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn

35 40 45

Lys His

50

<210> 129

<211> 33

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(33)

<223> amino acid at position 13 (Xaa) is L-cyclohexylalanine, amino acid at position 24 (Xaa)

Is L-cyclohexylalanine

<400> 129

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys Xaa Val Ala Ala

1 5 10 15

Trp Thr Leu Lys Ala Ala Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala

<210> 130

<211> 31

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(31)

<223> amino acid 11 (Xaa) is L-cyclohexylalanine, amino acid 21 (Xaa)

Is L-cyclohexylalanine.

<400> 130

Pro Pro Ile Phe Asn Asp Val Tyr Trp Lys Xaa Val Ala Ala Trp Thr

1 5 10 15

Leu Lys Ala Ala Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

20 25 30

<210> 131

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 131

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly

50 55 60

Ile

65

<210> 132

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 132

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe

20 25 30

Ile Gly Ile Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa

50

<210> 133

<211> 78

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(78)

<223> amino acid at position 49 (Xaa) is 6-aminocaproic acid, amino acid at position 50

The acid (Xaa) is D-alanine and the 52 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 62 (Xaa) being D-alanine,

amino acid 63 (Xaa) is 6-aminocaproic acid

<400> 133

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser

35 40 45

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile

50 55 60

Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile

65 70 75

<210> 134

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 134

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser

35 40 45

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro

50 55 60

Met Gly Leu Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

65 70 75 80

Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser Ile Leu Met

85 90 95

Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro Met Gly Leu

100 105 110

Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

115 120 125

<210> 135

<211> 43

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(43)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid, amino acid at position 32

The acid (Xaa) is L-cyclohexylalanine

<400> 135

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Lys Xaa

20 25 30

Leu Ala Ala Phe Thr Ile Arg Ala Ala Xaa Xaa

35 40

<210> 136

<211> 47

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(47)

<223> amino acid at position 17 (Xaa) is 6-aminocaproic acid, amino at position 18

The acid (Xaa) is D-alanine and the amino acid at position 20 (Xaa) is

L-cyclohexylalanine, amino acid 30 (Xaa) being D-alanine,

amino acid 31 (Xaa) is 6-aminocaproic acid

<400> 136

Cys Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10 15

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile

20 25 30

Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Cys

35 40 45

<210> 137

<211> 60

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(60)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 137

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Arg Asn Val

35 40 45

Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

50 55 60

<210> 138

<211> 60

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(60)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 138

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Cys Arg Phe

35 40 45

Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

50 55 60

<210> 139

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

Amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 139

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Lys Thr Thr

35 40 45

Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn Lys

50 55 60

His

65

<210> 140

<211> 60

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(60)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 140

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Arg Asn Val

35 40 45

Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

50 55 60

<210> 141

<211> 60

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(60)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 141

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Cys Arg Phe

35 40 45

Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

50 55 60

<210> 142

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 16 (Xaa) is 6-aminocaproic acid, amino at position 17

The acid (Xaa) is D-alanine and the 19 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 29 (Xaa) being D-alanine,

amino acid (Xaa) at position 30 is 6-aminocaproic acid

<400> 142

Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Lys Thr Thr

35 40 45

Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys Lys Asn Lys

50 55 60

His

65

<210> 143

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 143

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile

35 40 45

Gly Ile Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala

50 55 60

Phe

65

<210> 144

<211> 65

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(65)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 144

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile

35 40 45

Gly Ile Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu

50 55 60

Ser

65

<210> 145

<211> 70

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(70)

<223> amino acid at position 21 (Xaa) is 6-aminocaproic acid, amino at position 22

The acid (Xaa) is D-alanine and the 24 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 34 (Xaa) being D-alanine,

amino acid (Xaa) at position 35 is 6-aminocaproic acid

<400> 145

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile

35 40 45

Gly Ile Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln

50 55 60

Tyr Lys Lys Asn Lys His

65 70

<210> 146

<211> 80

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(80)

<223> amino acid at position 36 (Xaa) is 6-aminocaproic acid, amino at position 37

The acid (Xaa) is D-alanine and the 39 th amino acid (Xaa) is

L-cyclohexylalanine, amino acid 49 (Xaa) is D-alanine,

amino acid (Xaa) at position 50 is 6-aminocaproic acid

<400> 146

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly

50 55 60

Ile Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

65 70 75 80

<210> 147

<211> 140

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 147

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser

35 40 45

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro

50 55 60

Met Gly Leu Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

65 70 75 80

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Pro

85 90 95

Met Gly Leu Pro Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser Ser Cys Arg Phe

115 120 125

Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

130 135 140

<210> 148

<211> 44

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(44)

<223> amino acid at position 13 (Xaa) is L-cyclohexylalanine, amino acid at position 24 (Xaa)

Is L-cyclohexylalanine

<400> 148

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys Xaa Val Ala Ala

1 5 10 15

Trp Thr Leu Lys Ala Ala Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln

35 40

<210> 149

<211> 40

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(40)

<223> amino acid 11 (Xaa) is L-cyclohexylalanine, amino acid 22 (Xaa)

Is L-cyclohexylalanine

<400> 149

Pro Pro Ile Phe Asn Asp Val Tyr Trp Lys Xaa Val Ala Ala Trp Thr

1 5 10 15

Leu Lys Ala Ala Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Arg

20 25 30

Gly Leu Ile Ser Leu Ser Gln Val

35 40

<210> 150

<211> 62

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(62)

<223> amino acid at position 17 (Xaa) is 6-aminocaproic acid, amino at position 18

The acid (Xaa) is D-alanine and the amino acid at position 20 (Xaa) is

L-cyclohexylalanine, amino acid 30 (Xaa) being D-alanine,

amino acid 31 (Xaa) is 6-aminocaproic acid

<400> 150

Cys Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

1 5 10 15

Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile

20 25 30

Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Arg Asn

35 40 45

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

50 55 60

<210> 151

<211> 80

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(80)

<223> amino acid 36, 50, 66 and 80 (Xaa) are each

6-aminocaproic acid, amino groups 37, 49, 67 and 79

The acids (Xaa) are each D-alanine, amino groups 39 and 69

The acids (Xaa) are each L-cyclohexylalanine

<400> 151

Met Arg Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys Ile Val Asp Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

20 25 30

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

35 40 45

Xaa Xaa Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala

50 55 60

Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

65 70 75 80

<210> 152

<211> 90

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(90)

<223> amino acid 31, 45, 76 and 90 (Xaa) are each

6-aminocaproic acid, amino groups 32, 44, 77 and 89

The acids (Xaa) are each D-alanine, amino groups 34 and 79

The acids (Xaa) are each L-cyclohexylalanine

<400> 152

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn Val

35 40 45

Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys Arg Phe Arg

50 55 60

Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa Lys Xaa Val

65 70 75 80

Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

85 90

<210> 153

<211> 90

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(90)

<223> amino acid (Xaa) at position 16, 30, 61 and 75 each

6-aminocaproic acid, amino groups at positions 17, 29, 62 and 74

The acids (Xaa) are each D-alanine, amino groups 19 and 64

The acids (Xaa) are each L-cyclohexylalanine

<400> 153

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Arg Asn Val

35 40 45

Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa Xaa Lys Xaa

50 55 60

Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg Phe Arg Gly

65 70 75 80

Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

85 90

<210> 154

<211> 90

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(90)

<223> amino acid (Xaa) at position 16, 30, 61 and 75 each

6-aminocaproic acid, amino groups at positions 17, 29, 62 and 74

The acids (Xaa) are each D-alanine, amino groups 19 and 64

The acids (Xaa) are each L-cyclohexylalanine

<400> 154

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Arg Asn Val

35 40 45

Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa Xaa Lys Xaa

50 55 60

Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu Met Gln Tyr

65 70 75 80

Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile

85 90

<210> 155

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(120)

<223> amino acid (Xaa) at position 16, 30, 76 and 90, respectively

6-aminocaproic acid, amino groups at positions 17, 29, 77 and 89

The acids (Xaa) are each D-alanine, amino groups 19 and 79

The acids (Xaa) are each L-cyclohexylalanine

<400> 155

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu

20 25 30

Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Arg Asn Val

35 40 45

Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Arg Asn Val Pro

50 55 60

Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa Xaa Lys Xaa Val

65 70 75 80

Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Ile Leu Met Gln Tyr Ile

85 90 95

Lys Ala Asn Ser Lys Phe Ile Gly Ile Arg Asn Val Pro Pro Ile Phe

100 105 110

Asn Asp Val Tyr Trp Ile Ala Phe

115 120

<210> 156

<211> 75

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(75)

<223> amino acid (Xaa) at position 16, 30, 61 and 75 each

6-aminocaproic acid, amino groups at positions 17, 29, 62 and 74

The acids (Xaa) are each D-alanine, amino groups 19 and 64

The acids (Xaa) are each L-cyclohexylalanine

<400> 156

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn

20 25 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys Arg Phe

35 40 45

Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa Lys Xaa

50 55 60

Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

65 70 75

<210> 157

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> 16 th, 30 th, 46 th, 62 th, 76 th, 92 th, 108 th and

amino acid 122 (Xaa) is 6-aminocaproic acid, 17, 29, 63,

Amino acid (Xaa) at position 75, 109 and 121 are each D-alanine, 19

Amino acid (Xaa) at position 65 and 111 are each L-cyclohexylalanine.

<400> 157

Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

20 25 30

<210> 158

<211> 272

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<220>

<221> MISC_FEATURE

<222> (1)..(272)

<223> 16 th, 30 th, 61 th, 75 th, 106 th, 120 th, 136 th, 150 th,

166, 182, 196, 212, 228 and 242 amino acids (Xaa) are each

6-aminocaproic acid, position 17, 29, 62, 74, 107, 119, 137,

Amino acids 149, 183, 195, 229 and 241 (Xaa) are each

<400> 158

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn

20 25 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys Arg Phe

35 40 45

Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa Lys Xaa

50 55 60

Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn Val Pro Pro

65 70 75 80

Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys Arg Phe Arg Gly Leu

85 90 95

Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa Lys Xaa Val Ala Ala

100 105 110

Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn Val Pro Pro Ile Phe Asn

115 120 125

Asp Val Tyr Trp Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr

130 135 140

Leu Lys Ala Ala Xaa Xaa Arg Asn Val Pro Pro Ile Phe Asn Asp Val

145 150 155 160

Tyr Trp Ile Ala Phe Xaa Arg Asn Val Pro Pro Ile Phe Asn Asp Val

165 170 175

Tyr Trp Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys

180 185 190

Ala Ala Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe

195 200 205

Ile Gly Ile Xaa Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp

210 215 220

Ile Ala Phe Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

225 230 235 240

Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly

245 250 255

Ile Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

260 265 270

<210> 159

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> Artificial sequence

<400> 159

Arg Arg Arg Arg Arg Arg

1 5

<210> 160

<211> 43

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(43)

<223> Xaa at position 19 is L-cyclohexylalanine

<400> 160

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Cys Arg Phe Arg

20 25 30

Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40

<210> 161

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> Xaa at position 19 is L-cyclohexylalanine

<400> 161

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Cys Arg

20 25 30

<210> 162

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 162

Pro Leu Gly Phe Phe Pro Asp His Gln Leu

1 5 10

<210> 163

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 163

Trp Pro Glu Ala Asn Gln Val Gly Ala Gly Ala Phe Gly Pro Gly Phe

1 5 10 15

<210> 164

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 164

Met Gln Trp Asn Ser Thr Ala Leu His Gln Ala Leu Gln Asp Pro

1 5 10 15

<210> 165

<211> 26

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 165

Met Gln Trp Asn Ser Thr Thr Phe His Gln Thr Leu Gln Asp Pro Arg

1 5 10 15

Val Arg Gly Leu Tyr Phe Pro Ala Gly Gly

20 25

<210> 166

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 166

Phe Phe Leu Leu Thr Arg Ile Leu Thr Ile

1 5 10

<210> 167

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 167

Phe Phe Leu Leu Thr Arg Ile Leu Thr Ile Pro Gln Ser Leu Asp

1 5 10 15

<210> 168

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 168

Thr Ser Leu Asn Phe Leu Gly Gly Thr Thr Val Cys Leu Gly Gln

1 5 10 15

<210> 169

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 169

Gln Ser Pro Thr Ser Asn His Ser Pro Thr Ser Cys Pro Pro Ile Cys

1 5 10 15

<210> 170

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 170

Ile Ile Phe Leu Phe Ile Leu Leu Leu Cys Leu Ile Phe Leu Leu Val

1 5 10 15

Leu Leu Asp

<210> 171

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 171

Cys Thr Thr Pro Ala Gln Gly Asn Ser Met Phe Pro Ser Cys

1 5 10

<210> 172

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 172

Cys Thr Lys Pro Thr Asp Gly Asn

1 5

<210> 173

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 173

Trp Ala Ser Val Arg Phe Ser Trp

1 5

<210> 174

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 174

Leu Leu Pro Ile Phe Phe Cys Leu Trp

1 5

<210> 175

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 175

Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu

1 5 10 15

Ser Phe Leu Pro

20

<210> 176

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 176

Phe Leu Pro Ser Asp Phe Phe Pro Ser Val

1 5 10

<210> 177

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 177

Arg Asp Leu Leu Asp Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu

1 5 10 15

Ser Pro Glu His

20

<210> 178

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 178

Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu Leu

1 5 10 15

Met Thr Leu Ala

20

<210> 179

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 179

Gly Arg Glu Thr Val Ile Glu Tyr Leu Val Ser Phe Gly Val Trp

1 5 10 15

<210> 180

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 180

Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr Pro Pro Ala

1 5 10 15

<210> 181

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 181

Val Ser Phe Gly Val Trp Ile Arg Thr Pro Pro Ala Tyr Arg Pro Pro

1 5 10 15

Asn Ala Pro Ile

20

<210> 182

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 182

Thr Val Val Arg Arg Arg Gly Arg Ser Pro

1 5 10

<210> 183

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 183

Val Gly Pro Leu Thr Val Asn Glu Lys Arg Arg Leu Lys Leu Ile

1 5 10 15

<210> 184

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 184

Arg His Tyr Leu His Thr Leu Trp Lys Ala Gly Ile Leu Tyr Lys

1 5 10 15

<210> 185

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 185

Glu Ser Arg Leu Val Val Asp Phe Ser Gln Phe Ser Arg Gly Asn

1 5 10 15

<210> 186

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 186

Leu Gln Ser Leu Thr Asn Leu Leu Ser Ser Asn Leu Ser Trp Leu

1 5 10 15

<210> 187

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 187

Ser Ser Asn Leu Ser Trp Leu Ser Leu Asp Val Ser Ala Ala Phe

1 5 10 15

<210> 188

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 188

Leu His Leu Tyr Ser His Pro Ile Ile Leu Gly Phe Arg Lys Ile

1 5 10 15

<210> 189

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 189

Lys Gln Cys Phe Arg Lys Leu Pro Val Asn Arg Pro Ile Asp Trp

1 5 10 15

<210> 190

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 190

Leu Cys Gln Val Phe Ala Asp Ala Thr Pro Thr Gly Trp Gly Leu

1 5 10 15

<210> 191

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 191

Ala Ala Asn Trp Ile Leu Arg Gly Thr Ser Phe Val Tyr Val Pro

1 5 10 15

<210> 192

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 192

Glu Ile Arg Leu Lys Val Phe Val Leu Gly Gly Cys Arg His Lys

1 5 10 15

<210> 193

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> auxiliary portion

<220>

<221> MISC_FEATURE

<222> (1)..(17)

<223> Xaa at position 17 is D-alanine, xaa at position 16 is 6-aminocaproic acid

<400> 193

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Xaa

1 5 10 15

Xaa

<210> 194

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> auxiliary portion

<220>

<221> MISC_FEATURE

<222> (1)..(17)

<223> Xaa at position 1 is D-alanine and Xaa at position 2 is 6-aminocaproic acid

<400> 194

Xaa Xaa Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp

1 5 10 15

Lys

<210> 195

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 195

Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 196

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 196

Lys Tyr Val Ala Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 197

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 197

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 198

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> all Xaa are standard amino acids

<400> 198

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 199

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> all Xaa are standard amino acids

<400> 199

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Gly Ser

20 25 30

His His His His His His Gly Ser Asp Asp Asp Asp Lys

35 40 45

<210> 200

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> all Xaa are standard amino acids

<400> 200

Gly Ser His His His His His His Gly Ser Asp Asp Asp Asp Lys Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Arg Asn

20 25 30

Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe

35 40 45

<210> 201

<211> 50

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(50)

<223> all Xaa are standard amino acids

<400> 201

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala

20 25 30

Ala Xaa Xaa Cys Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr

35 40 45

Leu Ser

50

<210> 202

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> all Xaa are standard amino acids

<400> 202

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

1 5 10 15

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser Xaa Xaa

20 25 30

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

35 40 45

<210> 203

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> all Xaa are standard amino acids

<400> 203

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Pro Lys Tyr Val Lys Gln Asn Thr Leu Lys Leu Ala Thr Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 204

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> all Xaa are standard amino acids

<400> 204

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

20 25 30

<210> 205

<211> 26

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(26)

<223> all Xaa are standard amino acids

<400> 205

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys

1 5 10 15

Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

20 25

<210> 206

<211> 32

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(32)

<223> all Xaa are standard amino acids

<400> 206

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Lys

1 5 10 15

Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala His His His His His His

20 25 30

<210> 207

<211> 43

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(43)

<223> all Xaa are standard amino acids

<400> 207

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Cys Arg Phe Arg

20 25 30

Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40

<210> 208

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> all Xaa are standard amino acids

<400> 208

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Cys Arg

20 25 30

<210> 209

<211> 45

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(45)

<223> all Xaa are standard amino acids

<400> 209

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa Cys Arg

20 25 30

Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40 45

<210> 210

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> all Xaa are standard amino acids

<400> 210

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa Xaa

20 25 30

<210> 211

<211> 43

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(43)

<223> all Xaa are standard amino acids

<400> 211

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Cys Arg Phe Arg

20 25 30

Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

35 40

<210> 212

<211> 30

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(30)

<223> all Xaa are standard amino acids

<400> 212

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Xaa

1 5 10 15

Xaa Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Cys Arg

20 25 30

<210> 213

<211> 23

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<400> 213

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Cys

1 5 10 15

Thr Lys Pro Thr Asp Gly Asn

20

<210> 214

<211> 24

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<400> 214

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Leu

1 5 10 15

Leu Pro Ile Phe Phe Cys Leu Trp

20

<210> 215

<211> 25

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<400> 215

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Phe

1 5 10 15

Leu Pro Ser Asp Phe Phe Pro Ser Val

20 25

<210> 216

<211> 55

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(55)

<223> Xaa at positions 22 and 39 is D-alanine and Xaa at positions 21 and 40 is 6-aminocaproic acid

<400> 216

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Trp Pro Glu Ala Asn Gln Val Gly Ala Gly

20 25 30

Ala Phe Gly Pro Gly Phe Xaa Xaa Cys Arg Phe Arg Gly Leu Ile Ser

35 40 45

Leu Ser Gln Val Tyr Leu Ser

50 55

<210> 217

<211> 59

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(59)

<223> Xaa at positions 22 and 43 is D-alanine, xaa at positions 21 and 44 6-aminocaproic acid

<400> 217

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly

20 25 30

Ala Thr Val Glu Leu Leu Ser Phe Leu Pro Xaa Xaa Cys Arg Phe Arg

35 40 45

Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Ser

50 55

<210> 218

<211> 71

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<220>

<221> MISC_FEATURE

<222> (1)..(71)

<223> Xaa at positions 22 and 55 is D-alanine and Xaa at positions 21 and 56 is 6-aminocaproic acid

<400> 218

Lys Thr Thr Lys Gln Ser Phe Asp Leu Ser Val Lys Ala Gln Tyr Lys

1 5 10 15

Lys Asn Lys His Xaa Xaa Ile Leu Met Gln Tyr Ile Lys Ala Asn Ser

20 25 30

Lys Phe Ile Gly Ile Pro Met Gly Leu Pro Gln Ser Ile Ala Leu Ser

35 40 45

Ser Leu Met Val Ala Gln Xaa Xaa Cys Arg Phe Arg Gly Leu Ile Ser

50 55 60

Leu Ser Gln Val Tyr Leu Ser

65 70

<210> 219

<211> 36

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<400> 219

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Ile

1 5 10 15

Leu Met Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile His His

20 25 30

His His His His

35

<210> 220

<211> 41

<212> PRT

<213> artificial sequence

<220>

<223> Unit peptide

<400> 220

Arg Asn Val Pro Pro Ile Phe Asn Asp Val Tyr Trp Ile Ala Phe Met

1 5 10 15

Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu Ser

20 25 30

Phe Leu Pro His His His His His His

35 40

<210> 221

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> B cell epitope

<400> 221

Arg Phe Arg Gly Leu Ile Ser Leu Ser Gln Val Tyr Leu Asp Pro

1 5 10 15

<210> 222

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> B cell epitope

<400> 222

Ser Val Cys Gly Cys Pro Val Gly His His Asp Val Val Gly Leu

1 5 10 15

<210> 223

<211> 21

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 223

Asp Ile Glu Lys Lys Ile Ala Lys Met Glu Lys Ala Ser Ser Val Phe

1 5 10 15

Asn Val Val Asn Ser

20

<210> 224

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 224

Tyr Ser Gly Pro Leu Lys Ala Glu Ile Ala Gln Arg Leu Glu Asp Val

1 5 10 15

<210> 225

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 225

Lys Xaa Val Lys Ala Asn Thr Leu Lys Ala Ala

1 5 10

<210> 226

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 226

Lys Xaa Val Lys Ala Asn Thr Leu Lys Ala Ala

1 5 10

<210> 227

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 227

Lys Xaa Val Lys Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 228

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 228

Lys Xaa Val Lys Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 229

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 229

Lys Xaa Val Trp Ala Asn Thr Leu Lys Ala Ala

1 5 10

<210> 230

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 230

Lys Xaa Val Trp Ala Asn Thr Leu Lys Ala Ala

1 5 10

<210> 231

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 231

Lys Xaa Val Trp Ala Tyr Thr Leu Lys Ala Ala

1 5 10

<210> 232

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 232

Lys Xaa Val Trp Ala Val Thr Leu Lys Ala Ala

1 5 10

<210> 233

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 233

Lys Xaa Val Tyr Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 234

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 234

Lys Xaa Val Tyr Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 235

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 235

Arg Xaa Val Arg Ala Asn Thr Leu Lys Ala Ala

1 5 10

<210> 236

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 236

Lys Xaa Val Lys Ala His Thr Leu Lys Ala Ala

1 5 10

<210> 237

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 237

Lys Xaa Val Lys Ala His Thr Leu Lys Ala Ala

1 5 10

<210> 238

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 238

Lys Xaa Val Ala Ala Asn Thr Leu Lys Ala Ala

1 5 10

<210> 239

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 239

Lys Xaa Val Ala Ala Asn Thr Leu Lys Ala Ala

1 5 10

<210> 240

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 240

Lys Xaa Val Ala Ala Tyr Thr Leu Lys Ala Ala

1 5 10

<210> 241

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 241

Lys Xaa Val Ala Ala Tyr Thr Leu Lys Ala Ala

1 5 10

<210> 242

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 242

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 243

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 243

Lys Xaa Val Ala Ala Lys Thr Leu Lys Ala Ala

1 5 10

<210> 244

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 244

Lys Xaa Val Ala Ala His Thr Leu Lys Ala Ala

1 5 10

<210> 245

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 245

Lys Xaa Val Ala Ala Ala Thr Leu Lys Ala Ala

1 5 10

<210> 246

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 246

Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala

1 5 10

<210> 247

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Th epitope

<400> 247

Lys Xaa Val Met Ala Ala Thr Leu Lys Ala Ala

1 5 10

<210> 248

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 248

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagnnngtg 60

gcagcttgga ccctgaaggc agcannnnnn tgccgtttcc gtggactgat ttccctgtcc 120

caggtttatc tgtcc 135

<210> 249

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 249

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagttcgtg 60

gcagcttgga ccctgaaggc agcannnnnn tgccgtttcc gtggactgat ttccctgtcc 120

caggtttatc tgtcc 135

<210> 250

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 250

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagtatgtg 60

gcagcttgga ccctgaaggc agcannnnnn tgccgtttcc gtggactgat ttccctgtcc 120

caggtttatc tgtcc 135

<210> 251

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 251

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagnnngtg 60

gcagcttgga ccctgaaggc agcannnnnn ggatcgcatc accatcacca tcacggatcc 120

gatgatgatg acaag 135

<210> 252

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 252

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagttcgtg 60

gcagcttgga ccctgaaggc agcannnnnn ggatcgcatc accatcacca tcacggatcc 120

gatgatgatg acaag 135

<210> 253

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 253

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagtatgtg 60

gcagcttgga ccctgaaggc agcannnnnn ggatcgcatc accatcacca tcacggatcc 120

gatgatgatg acaag 135

<210> 254

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 254

ggatcgcatc accatcacca tcacggatcc gatgatgatg acaagnnnnn naagnnngtg 60

gcagcttgga ccctgaaggc agcannnnnn cgtaatgttc ctcctatctt caatgatgtt 120

tattggattg cattc 135

<210> 255

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 255

ggatcgcatc accatcacca tcacggatcc gatgatgatg acaagnnnnn naagttcgtg 60

gcagcttgga ccctgaaggc agcannnnnn cgtaatgttc ctcctatctt caatgatgtt 120

tattggattg cattc 135

<210> 256

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 256

ggatcgcatc accatcacca tcacggatcc gatgatgatg acaagnnnnn naagtatgtg 60

gcagcttgga ccctgaaggc agcannnnnn cgtaatgttc ctcctatctt caatgatgtt 120

tattggattg cattc 135

<210> 257

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 257

aaaacgacaa agcaatcatt tgatttaagt gtaaaagctc agtatnnnnn naagnnngtg 60

gcagcttgga ccctgaaggc agcannnnnn tgccgtttcc gtggactgat ttccctgtcc 120

caggtttatc tgtcc 135

<210> 258

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 258

aaaacgacaa agcaatcatt tgatttaagt gtaaaagctc agtatnnnnn naagttcgtg 60

gcagcttgga ccctgaaggc agcannnnnn tgccgtttcc gtggactgat ttccctgtcc 120

caggtttatc tgtcc 135

<210> 259

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 259

aaaacgacaa agcaatcatt tgatttaagt gtaaaagctc agtatnnnnn naagtatgtg 60

gcagcttgga ccctgaaggc agcannnnnn tgccgtttcc gtggactgat ttccctgtcc 120

caggtttatc tgtcc 135

<210> 260

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 260

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattctgccg tttccgtgga 60

ctgatttccc tgtcccaggt ttatctgtcc nnnnnnaagn nngtggcagc ttggaccctg 120

aaggcagcan nnnnn 135

<210> 261

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 261

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattctgccg tttccgtgga 60

ctgatttccc tgtcccaggt ttatctgtcc nnnnnnaagt tcgtggcagc ttggaccctg 120

aaggcagcan nnnnn 135

<210> 262

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 262

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattctgccg tttccgtgga 60

ctgatttccc tgtcccaggt ttatctgtcc nnnnnnaagt atgtggcagc ttggaccctg 120

aaggcagcan nnnnn 135

<210> 263

<211> 135

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 263

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnncc taagtatgtg 60

aagcagaata cactgaagct ggcaaccnnn tgccgtttcc gtggactgat ttccctgtcc 120

caggtttatc tgtcc 135

<210> 264

<211> 90

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 264

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagnnngtg 60

gcagcttgga ccctgaaggc agcannnnnn 90

<210> 265

<211> 90

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 265

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagttcgtg 60

gcagcttgga ccctgaaggc agcannnnnn 90

<210> 266

<211> 90

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 266

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagtatgtg 60

gcagcttgga ccctgaaggc agcannnnnn 90

<210> 267

<211> 78

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 267

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcaagnn ngtggcagct 60

tggaccctga aggcagca 78

<210> 268

<211> 78

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 268

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcaagtt cgtggcagct 60

tggaccctga aggcagca 78

<210> 269

<211> 78

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 269

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcaagta tgtggcagct 60

tggaccctga aggcagca 78

<210> 270

<211> 96

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 270

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcaagnn ngtggcagct 60

tggaccctga aggcagcaca tcaccatcac catcac 96

<210> 271

<211> 96

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 271

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcaagtt cgtggcagct 60

tggaccctga aggcagcaca tcaccatcac catcac 96

<210> 272

<211> 96

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 272

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcaagta tgtggcagct 60

tggaccctga aggcagcaca tcaccatcac catcac 96

<210> 273

<211> 129

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 273

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagnnngtg 60

gcagcttgga ccctgaaggc agcatgccgt ttccgtggac tgatttccct gtcccaggtt 120

tatctgtcc 129

<210> 274

<211> 129

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 274

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagttcgtg 60

gcagcttgga ccctgaaggc agcatgccgt ttccgtggac tgatttccct gtcccaggtt 120

tatctgtcc 129

<210> 275

<211> 129

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 275

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagtatgtg 60

gcagcttgga ccctgaaggc agcatgccgt ttccgtggac tgatttccct gtcccaggtt 120

tatctgtcc 129

<210> 276

<211> 90

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 276

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagnnngtg 60

gcagcttgga ccctgaaggc agcatgccgt 90

<210> 277

<211> 90

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 277

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagttcgtg 60

gcagcttgga ccctgaaggc agcatgccgt 90

<210> 278

<211> 90

<212> DNA

<213> artificial sequence

<220>

<223> DNA encoding Unit peptide

<400> 278

cgtaatgttc ctcctatctt caatgatgtt tattggattg cattcnnnnn naagtatgtg 60

gcagcttgga ccctgaaggc agcatgccgt 90

<210> 279

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 279

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naagnnngug 60

gcagcuugga cccugaaggc agcannnnnn ugccguuucc guggacugau uucccugucc 120

cagguuuauc ugucc 135

<210> 280

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 280

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguucgug 60

gcagcuugga cccugaaggc agcannnnnn ugccguuucc guggacugau uucccugucc 120

cagguuuauc ugucc 135

<210> 281

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 281

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguaugug 60

gcagcuugga cccugaaggc agcannnnnn ugccguuucc guggacugau uucccugucc 120

cagguuuauc ugucc 135

<210> 282

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 282

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naagnnngug 60

gcagcuugga cccugaaggc agcannnnnn ggaucgcauc accaucacca ucacggaucc 120

gaugaugaug acaag 135

<210> 283

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 283

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguucgug 60

gcagcuugga cccugaaggc agcannnnnn ggaucgcauc accaucacca ucacggaucc 120

gaugaugaug acaag 135

<210> 284

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 284

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguaugug 60

gcagcuugga cccugaaggc agcannnnnn ggaucgcauc accaucacca ucacggaucc 120

gaugaugaug acaag 135

<210> 285

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 285

ggaucgcauc accaucacca ucacggaucc gaugaugaug acaagnnnnn naagnnngug 60

gcagcuugga cccugaaggc agcannnnnn cguaauguuc cuccuaucuu caaugauguu 120

uauuggauug cauuc 135

<210> 286

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 286

ggaucgcauc accaucacca ucacggaucc gaugaugaug acaagnnnnn naaguucgug 60

gcagcuugga cccugaaggc agcannnnnn cguaauguuc cuccuaucuu caaugauguu 120

uauuggauug cauuc 135

<210> 287

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 287

ggaucgcauc accaucacca ucacggaucc gaugaugaug acaagnnnnn naaguaugug 60

gcagcuugga cccugaaggc agcannnnnn cguaauguuc cuccuaucuu caaugauguu 120

uauuggauug cauuc 135

<210> 288

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 288

aaaacgacaa agcaaucauu ugauuuaagu guaaaagcuc aguaunnnnn naagnnngug 60

gcagcuugga cccugaaggc agcannnnnn ugccguuucc guggacugau uucccugucc 120

cagguuuauc ugucc 135

<210> 289

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 289

aaaacgacaa agcaaucauu ugauuuaagu guaaaagcuc aguaunnnnn naaguucgug 60

gcagcuugga cccugaaggc agcannnnnn ugccguuucc guggacugau uucccugucc 120

cagguuuauc ugucc 135

<210> 290

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 290

aaaacgacaa agcaaucauu ugauuuaagu guaaaagcuc aguaunnnnn naaguaugug 60

gcagcuugga cccugaaggc agcannnnnn ugccguuucc guggacugau uucccugucc 120

cagguuuauc ugucc 135

<210> 291

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 291

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucugccg uuuccgugga 60

cugauuuccc ugucccaggu uuaucugucc nnnnnnaagn nnguggcagc uuggacccug 120

aaggcagcan nnnnn 135

<210> 292

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 292

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucugccg uuuccgugga 60

cugauuuccc ugucccaggu uuaucugucc nnnnnnaagu ucguggcagc uuggacccug 120

aaggcagcan nnnnn 135

<210> 293

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 293

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucugccg uuuccgugga 60

cugauuuccc ugucccaggu uuaucugucc nnnnnnaagu auguggcagc uuggacccug 120

aaggcagcan nnnnn 135

<210> 294

<211> 135

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 294

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnncc uaaguaugug 60

aagcagaaua cacugaagcu ggcaaccnnn ugccguuucc guggacugau uucccugucc 120

cagguuuauc ugucc 135

<210> 295

<211> 90

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 295

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naagnnngug 60

gcagcuugga cccugaaggc agcannnnnn 90

<210> 296

<211> 90

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 296

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguucgug 60

gcagcuugga cccugaaggc agcannnnnn 90

<210> 297

<211> 90

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 297

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguaugug 60

gcagcuugga cccugaaggc agcannnnnn 90

<210> 298

<211> 78

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 298

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucaagnn nguggcagcu 60

uggacccuga aggcagca 78

<210> 299

<211> 78

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 299

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucaaguu cguggcagcu 60

uggacccuga aggcagca 78

<210> 300

<211> 78

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 300

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucaagua uguggcagcu 60

uggacccuga aggcagca 78

<210> 301

<211> 96

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 301

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucaagnn nguggcagcu 60

uggacccuga aggcagcaca ucaccaucac caucac 96

<210> 302

<211> 96

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 302

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucaaguu cguggcagcu 60

uggacccuga aggcagcaca ucaccaucac caucac 96

<210> 303

<211> 96

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 303

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucaagua uguggcagcu 60

uggacccuga aggcagcaca ucaccaucac caucac 96

<210> 304

<211> 129

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 304

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naagnnngug 60

gcagcuugga cccugaaggc agcaugccgu uuccguggac ugauuucccu gucccagguu 120

uaucugucc 129

<210> 305

<211> 129

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 305

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguucgug 60

gcagcuugga cccugaaggc agcaugccgu uuccguggac ugauuucccu gucccagguu 120

uaucugucc 129

<210> 306

<211> 129

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 306

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguaugug 60

gcagcuugga cccugaaggc agcaugccgu uuccguggac ugauuucccu gucccagguu 120

uaucugucc 129

<210> 307

<211> 90

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 307

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naagnnngug 60

gcagcuugga cccugaaggc agcaugccgu 90

<210> 308

<211> 90

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 308

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguucgug 60

gcagcuugga cccugaaggc agcaugccgu 90

<210> 309

<211> 90

<212> RNA

<213> artificial sequence

<220>

<223> RNA encoding Unit peptide

<400> 309

cguaauguuc cuccuaucuu caaugauguu uauuggauug cauucnnnnn naaguaugug 60

gcagcuugga cccugaaggc agcaugccgu 90

Claims (26)

1. A peptide unit of length 23mer to 71mer capable of being CD4 ⁺ T cells recognize and thereby induce antibodies targeting apolipoprotein B-100, the peptide unit is represented by formula 1:

[ 1 ]]N-B-A ₁ -T-A ₂ -C

Wherein B is a sequence of a B cell epitope of apolipoprotein B-100 having greater than 90% identity to a sequence selected from the group consisting of RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7) and KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8),

wherein the A ₁ A sequence that is a first auxiliary moiety or is absent, the sequence being Za or Z,

wherein the T is a sequence of a helper T cell epitope (Th epitope) that has greater than 90% identity to a sequence selected from the group consisting of: k (Cha) VAAWTLKAA (SEQ ID NO: 1), PKYVKQNTLKLAT (SEQ ID NO: 2), ILMQYIKANSKFIGI (SEQ ID NO: 3), QSIALSSLMVAQAIP (SEQ ID NO: 4), ILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ (SEQ ID NO: 5), PLGFFPDHQL (SEQ ID NO: 162), WPEANQVGAGAFGPGF (SEQ ID NO: 163), MQWNSTALHQALQDP (SEQ ID NO: 164), MQWNSTALHQALQDP (SEQ ID NO: 165), MQWNSTALHQALQDP (SEQ ID NO: 166), MQWNSTALHQALQDP (SEQ ID NO: 167), MQWNSTALHQALQDP (SEQ ID NO: 168), MQWNSTALHQALQDP (SEQ ID NO: 169), MQWNSTALHQALQDP (SEQ ID NO: 170), MQWNSTALHQALQDP (SEQ ID NO: 171), CTKPTDGN (SEQ ID NO: 172), WASVRFSW (SEQ ID NO: 173), MQWNSTALHQALQDP (SEQ ID NO: 174), MQWNSTALHQALQDP (SEQ ID NO: 175), MQWNSTALHQALQDP (SEQ ID NO: 176), MQWNSTALHQALQDP (SEQ ID NO: 177), MQWNSTALHQALQDP (SEQ ID NO: 178), MQWNSTALHQALQDP (SEQ ID NO: 179), MQWNSTALHQALQDP (SEQ ID NO: 180), MQWNSTALHQALQDP (SEQ ID NO: 184), MQWNSTALHQALQDP (SEQ ID NO: 188), AANWILRGTSFVYVP (SEQ ID NO: 191), and EIRLKVFVLGGCRHK (SEQ ID NO: 192),

Wherein the A ₂ The sequence of the second auxiliary moiety, which is aZ, CR, HHHHHH (SEQ ID NO: 53) or aZGSHHHHHHHTGSDDDDDDK (SEQ ID NO: 194), or the absence thereof,

wherein said a represents D-alanine, said (Cha) represents L-cyclohexylalanine, and said Z represents 6-aminocaproic acid.

2. The peptide unit according to claim 1,

wherein the A ₁ Is the value of Za, which is the value of Za,

the A is ₂ For aZGSHHHHHHTGSDDDDDK (SEQ ID NO: 194)

The B cell epitope is KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8).

3. The peptide unit of claim 2, wherein the peptide unit is RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZGSHHHHHHHGSDDDDK (SEQ ID NO: 68).

4. The peptide unit according to claim 1,

wherein the A ₁ Is the value of Za, which is the value of Za,

the A is ₂ Is aZ, and

the B cell epitope is RNVPPIFNDVYWIAF (SEQ ID NO: 6).

5. The peptide unit of claim 4, wherein the peptide unit is RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 56).

6. The peptide unit according to claim 1,

wherein the A ₁ There is no time for the existence of the non-woven fabric,

the A is ₂ HHHHH (SEQ ID NO: 53)

The B cell epitope is RNVPPIFNDVYWIAF (SEQ ID NO: 6).

7. The peptide unit of claim 6, wherein the peptide unit is RNVPPIFNDVYWIAFK (Cha) VAAWTLKAAHHHHHH (SEQ ID NO: 67).

8. The peptide unit according to claim 1,

wherein the A ₁ Is the value of Za, which is the value of Za,

the A is ₂ Is CR, and

the B cell epitope is RNVPPIFNDVYWIAF (SEQ ID NO: 6).

9. The peptide unit of claim 8, wherein the peptide unit is RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAACR (SEQ ID NO: 161).

10. A peptide unit of length 23mer to 71mer capable of being CD4 ⁺ T cells recognize and thereby induce antibodies targeting apolipoprotein B-100, the peptide unit is represented by formula 2:

[ 2 ]]N-B ₁ -A ₁ -T-A ₂ -B ₂ -C

Wherein B is ₁ And B ₂ Each being a B cell epitope of apolipoprotein B-100, said sequences being independently selected from the group consisting of RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7) and KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8),

wherein the A ₁ A sequence of a first auxiliary moiety, said sequence being Za or Z,

wherein T is a sequence of a helper T cell epitope (Th epitope) having a sequence selected from the group consisting of: k (Cha) VAAWTLKAA (SEQ ID NO: 1), PKYVKQNTLKLAT (SEQ ID NO: 2), ILMQYIKANSKFIGI (SEQ ID NO: 3), QSIALSSLMVAQAIP (SEQ ID NO: 4), ILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ (SEQ ID NO: 5), PLGFFPDHQL (SEQ ID NO: 162), WPEANQVGAGAFGPGF (SEQ ID NO: 163), MQWNSTALHQALQDP (SEQ ID NO: 164), MQWNSTALHQALQDP (SEQ ID NO: 165), MQWNSTALHQALQDP (SEQ ID NO: 166), MQWNSTALHQALQDP (SEQ ID NO: 167), MQWNSTALHQALQDP (SEQ ID NO: 168), MQWNSTALHQALQDP (SEQ ID NO: 169), MQWNSTALHQALQDP (SEQ ID NO: 170), MQWNSTALHQALQDP (SEQ ID NO: 171), CTKPTDGN (SEQ ID NO: 172), WASVRFSW (SEQ ID NO: 173), MQWNSTALHQALQDP (SEQ ID NO: 174), MQWNSTALHQALQDP (SEQ ID NO: 175), MQWNSTALHQALQDP (SEQ ID NO: 176), MQWNSTALHQALQDP (SEQ ID NO: 177), MQWNSTALHQALQDP (SEQ ID NO: 178), MQWNSTALHQALQDP (SEQ ID NO: 179), MQWNSTALHQALQDP (SEQ ID NO: 180), MQWNSTALHQALQDP (SEQ ID NO: 184), MQWNSTALHQALQDP (SEQ ID NO: 188), AANWILRGTSFVYVP (SEQ ID NO: 191), and EIRLKVFVLGGCRHK (SEQ ID NO: 192),

Wherein the A ₂ A sequence which is a second auxiliary moiety, said sequence being aZ or Z,

wherein said a represents D-alanine, said (Cha) represents L-cyclohexylalanine, and said Z represents 6-aminocaproic acid.

11. The peptide unit according to claim 10,

wherein the A ₁ Is the value of Za, which is the value of Za,

the A is ₂ In order to be an AZ,

the B is ₁ RNVPPIFNDVYWIAF (SEQ ID NO: 6) or KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), and

the B is ₂ CRFRGLISLSQVYLS (SEQ ID NO: 7).

12. The peptide unit of claim 11, wherein the peptide unit is RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZCRFRGLISLSQVYLS (SEQ ID NO: 108) or KTTKQSFDLSVKAQYKKNKHZaK (Cha) VAAWTLKAAaZCRFRGLISLSQVYLS (SEQ ID NO: 114).

13. The peptide unit according to claim 10,

wherein the A ₁ In the presence of a Z,

the A is ₂ In the presence of a Z,

the B is ₁ RNVPPIFNDVYWIAF (SEQ ID NO: 6)

The B is ₂ CRFRGLISLSQVYLS (SEQ ID NO: 7).

14. The peptide unit of claim 13, wherein the peptide unit is RNVPPINDVYWIAFZPKYKQNTKLATZCTCRGRLISLSQVYLS (SEQ ID NO: 121).

15. A peptide unit of length 23mer to 71mer capable of being CD4 ⁺ T cells recognize and thereby induce antibodies targeting apolipoprotein B-100, the peptide unit is represented by formula 3:

[ 3 ]]N-B ₁ -B ₂ -A ₁ -T-A ₂ -C

Wherein B is ₁ And B ₂ Each being a B cell epitope of apolipoprotein B-100, said sequences being independently selected from the group consisting of RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7) and KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8),

wherein the A ₁ A sequence of a first auxiliary part, the sequence being Za,

wherein T is a sequence of a helper T cell epitope (Th epitope) having a sequence selected from the group consisting of: k (Cha) VAAWTLKAA (SEQ ID NO: 1), PKYVKQNTLKLAT (SEQ ID NO: 2), ILMQYIKANSKFIGI (SEQ ID NO: 3), QSIALSSLMVAQAIP (SEQ ID NO: 4), TLMQYIKANSKFIGIPMGLPQSIALSSLMVAQ (SEQ ID NO: 5), PLGFFPDHQL (SEQ ID NO: 162), WPEANQVGAGAFGPGF (SEQ ID NO: 163), MQWNSTALHQALQDP (SEQ ID NO: 164), MQWNSTALHQALQDP (SEQ ID NO: 165), MQWNSTALHQALQDP (SEQ ID NO: 166), MQWNSTALHQALQDP (SEQ ID NO: 167), MQWNSTALHQALQDP (SEQ ID NO: 168), MQWNSTALHQALQDP (SEQ ID NO: 169), MQWNSTALHQALQDP (SEQ ID NO: 170), MQWNSTALHQALQDP (SEQ ID NO: 171), CTKPTDGN (SEQ ID NO: 172), WASVRFSW (SEQ ID NO: 173), MQWNSTALHQALQDP (SEQ ID NO: 174), MQWNSTALHQALQDP (SEQ ID NO: 175), MQWNSTALHQALQDP (SEQ ID NO: 176), MQWNSTALHQALQDP (SEQ ID NO: 177), MQWNSTALHQALQDP (SEQ ID NO: 178), MQWNSTALHQALQDP (SEQ ID NO: 179), MQWNSTALHQALQDP (SEQ ID NO: 180), MQWNSTALHQALQDP (SEQ ID NO: 184), MQWNSTALHQALQDP (SEQ ID NO: 188), AANWILRGTSFVYVP (SEQ ID NO: 191), and EIRLKVFVLGGCRHK (SEQ ID NO: 192).

Wherein the A ₂ A sequence which is a second auxiliary moiety, said sequence being aZ,

wherein said a represents D-alanine, said (Cha) represents L-cyclohexylalanine, and said Z represents 6-aminocaproic acid.

16. The peptide unit according to claim 15,

wherein the B is ₁ RNVPPIFNDVYWIAF (SEQ ID NO: 6)

The B is ₂ CRFRGLISLSQVYLS (SEQ ID NO: 7).

17. The peptide unit of claim 16, wherein the peptide unit is RNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 84).

18. A peptide unit of length 23mer to 71mer capable of being CD4 ⁺ T cells recognize and thereby induce antibodies targeting apolipoprotein B-100, the peptide unit is represented by formula 4:

[ 4 ]]N-A ₁ -T-A ₂ -B-C，

Wherein B is a sequence of a B cell epitope of apolipoprotein B-100 selected from RNVPPIFNDVYWIAF (SEQ ID NO: 6), CRFRGLISLSQVYLS (SEQ ID NO: 7) and KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8),

wherein the A ₁ A sequence which is the first auxiliary moiety, said sequence being GSHHHHHHTGSDDDDKZa (SEQ ID NO: 193),

wherein T is a sequence of a helper T cell epitope (Th epitope) selected from the group consisting of: k (Cha) VAAWTLKAA (SEQ ID NO: 1), PKYVKQNTLKLAT (SEQ ID NO: 2), ILMQYIKANSKFIGI (SEQ ID NO: 3), QSIALSSLMVAQAIP (SEQ ID NO: 4), ILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ (SEQ ID NO: 5), PLGFFPDHQL (SEQ ID NO: 162), WPEANQVGAGAFGPGF (SEQ ID NO: 163), MQWNSTALHQALQDP (SEQ ID NO: 164), MQWNSTALHQALQDP (SEQ ID NO: 165), MQWNSTALHQALQDP (SEQ ID NO: 166), MQWNSTALHQALQDP (SEQ ID NO: 167), MQWNSTALHQALQDP (SEQ ID NO: 168), MQWNSTALHQALQDP (SEQ ID NO: 169), MQWNSTALHQALQDP (SEQ ID NO: 170), MQWNSTALHQALQDP (SEQ ID NO: 171), CTKPTDGN (SEQ ID NO: 172), WASVRFSW (SEQ ID NO: 173), MQWNSTALHQALQDP (SEQ ID NO: 174), MQWNSTALHQALQDP (SEQ ID NO: 175), MQWNSTALHQALQDP (SEQ ID NO: 176), MQWNSTALHQALQDP (SEQ ID NO: 177), MQWNSTALHQALQDP (SEQ ID NO: 178), MQWNSTALHQALQDP (SEQ ID NO: 179), MQWNSTALHQALQDP (SEQ ID NO: 180), MQWNSTALHQALQDP (SEQ ID NO: 184), MQWNSTALHQALQDP (SEQ ID NO: 188), AANWILRGTSFVYVP (SEQ ID NO: 191), and EIRLKVFVLGGCRHK (SEQ ID NO: 192),

Wherein the A ₂ A sequence which is a second auxiliary moiety, said sequence being aZ,

wherein said a represents D-alanine, said (Cha) represents L-cyclohexylalanine, and said Z represents 6-aminocaproic acid.

19. The peptide unit of claim 18, wherein B is RNVPPIFNDVYWIAF (SEQ ID NO: 6).

20. The peptide unit of claim 19, wherein the peptide unit is GSHHHHHHGSDDDDKZaK (Cha) VAAWTLKAAaZRNVPPIFANDVYWIAF (SEQ ID NO: 69).

21. A peptide capable of being bound by CD4 ⁺ T cells recognize and thereby induce antibodies targeting apolipoprotein B-100, wherein 2 to 5 peptide units independently selected from the group consisting of: a peptide unit according to claim 1; the peptide unit of claim 10; the peptide unit of claim 15; and the peptide unit of claim 18.

22. The polypeptide of claim 21, wherein in the polypeptide, 2 or more and 5 or less peptide units independently selected from the group consisting of: RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 56); RNVPPIFNDVYWIAFK (Cha) VAAWTLKAA (SEQ ID NO: 62); RNVPPIFNDVYWIAFK (Cha) VAAWTLKAAHHHHHH (SEQ ID NO: 67); RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZGSHHHHHHHGSDDDDK (SEQ ID NO: 68); GSHHHHHHGSDDDDKZaK (Cha) VAAWTLKAAaZRNVPPIFANDVYWIAF (SEQ ID NO: 69); RNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 84); RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZCRRGLISLSQVYLS (SEQ ID NO: 108); KTTKQSFDLSVKAQYKKNKHZaK (Cha) VAAWTLKAAaZCRFRGLISLSQ VYLS (SEQ ID No: 114); RNVPPINDVYWIAFZPKYVKQNTKLATZCRRFRGLISLSQVYLS (SEQ ID NO: 121); RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAACRFRGLISLSQVYLS (SEQ ID NO: 160) and RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAACR (SEQ ID NO: 161),

Wherein a represents D-alanine, cha represents L-cyclohexylalanine, and Z represents 6-aminocaproic acid.

23. A pharmaceutical composition for treating obesity, the composition comprising: the peptide unit of any one of claims 1, 10, 15 and 18, or the peptide of claim 21; an adjuvant.

24. The pharmaceutical composition of claim 23, wherein the adjuvant is water, saline, dextrose, ethanol, glycerol, sodium chloride, dextrose, mannitol, sorbitol, lactose, gelatin, albumin, aluminum hydroxide, incomplete freund's adjuvant and complete adjuvant (Pifco Laboratories, detroit, mich.), merck antigen adjuvant 65 (Merck and Company, inc., rahway, NJ.), alhydrogel (Al (OH) ₃ ) Aluminum hydroxide gel (Alum) or aluminum salts (e.g., aluminum phosphate), AS04 series, MF, squalene, MF59, QS21, insoluble suspensions of calcium, iron or zinc salts, acylated fructose, cationically or anionically derivatized polysaccharides, polyphosphazenes, biodegradable microspheres, quilA, toll-like receptor (TLR) agonists, PHAD [ Avanti polar lipid, monophosphoryl lipid A (synthetic)]Mono-phosphoryl lipid a (MPL, mono-phosphoryl lipid a), synthetic lipid a, lipid a mimics or analogues, aluminium salts, cytokines, saponins, prolactin, growth hormone deoxycholic acid, beta-glucan, polyribonucleotides, muramyl Dipeptide (MDP) derivatives, cpG oligonucleotides, gram negative bacterial Lipopolysaccharide (LPS), polyphosphazenes, emulsions, virosomes, cochleates, poly (lactide-co-glycolide) (PLG) microparticles, poloxamer particles, microparticles, liposomes or suitable combinations thereof.

25. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprises a peptide unit selected from the group consisting of: RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 56); RNVPPIFNDVYWIAFK (Cha) VAAWTLKAA (SEQ ID NO: 62); RNVPPIFNDVYWIAFK (Cha) VAAWTLKAAHHHHHH (SEQ ID NO: 67); RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZGSHHHHHHHGSDDDDK (SEQ ID NO: 68); GSHHHHHHGSDDDDKZaK (Cha) VAAWTLKAAaZRNVPPIFANDVYWIAF (SEQ ID NO: 69); RNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 84); RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZCRRGLISLSQVYLS (SEQ ID NO: 108); KTTKQSFDLSVKAQYKKNKHZaK (Cha) VAAWTLKAAaZCRFRGLISLSQ VYLS (SEQ ID NO: 114); RNVPPINDVYWIAFZPKYVKQNTKLATZCRRFRGLISLSQVYLS (SEQ ID NO: 121); RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAACRFRGLISLSQVYLS (SEQ ID NO: 160); and RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAACR (SEQ ID NO: 161), wherein a represents D-alanine, cha represents L-cyclohexylalanine, and Z represents 6-aminocaproic acid.

26. A method of treating obesity, the method comprising: administering to a subject the pharmaceutical composition of claim 23.