Peptides for use in immunotherapeutics

Abstract

To provide a new immunotherapeutic agent useful for treating obesity.SOLUTION: The pharmaceutical composition contains a peptide having a specific amino acid sequence containing a B cell epitope. Preferably the composition includes an aluminium salt (Alhydrogel (Al (OH) 3) and monophosphoryl lipid A as adjuvants. Intramuscular administration of the composition to a subject results in the production of antibodies capable of binding to ApoB-100 in vivo, and the antibodies exert a therapeutic effect on obesity.SELECTED DRAWING: Figure 14

Description

[Technical Field]

[0001] TECHNICAL FIELD The present disclosure relates to the field of immunotherapeutics, which is peptides that are injected into a subject's body to generate humoral immunity. [Background technology]

[0002] The purpose of immunotherapeutics is to introduce them into a subject's body to induce humoral immunity against the immunotherapeutic agent itself, thereby treating a specific disease or disorder with the resulting antibodies. In particular, "treatment" also includes the prevention of a specific disease or disorder. Immunotherapeutics are similar to vaccines in that they induce antibody production in a subject's body through an antigen-antibody reaction. However, they differ from vaccines in that the antibodies not only have the ability to bind to the immunotherapeutic agent itself, but also have the ability to bind to specific targets in the body (e.g., specific tissues and cells in the body, or substances produced in metabolic processes), thereby treating specific diseases and disorders and allowing repeated administration. Summary of the Invention [Problem to be solved by the invention]

[0003] [Disclosure]

[0004] The present disclosure provides peptides that have the function of inducing pre-designed antibodies in a subject.

[0005] The present disclosure provides immunotherapeutic compositions comprising the peptides.

[0006] The disclosure provides nucleic acid sequences encoding the peptides.

[0007] The disclosure provides uses of the peptides and immunotherapeutic compositions comprising the peptides. [Means for solving the problem]

[0008] According to one aspect of the present disclosure, there is provided a peptide unit (peptide block) having a length of 23-71 mer, recognized by CD4+ T cells, and capable of inducing humoral immunity, the peptide unit comprising: at least one Th epitope, wherein the Th epitope is 8-mer to 32-mer in length; and At least one B-cell epitope Here, the B-cell epitope is a fragment or mimotope of apolipoprotein B-100, which B-cell epitope is capable of inducing antibodies that target apolipoprotein B-100.

[0009] In one embodiment, the peptide units have lengths ranging from 26mer to 50mer, and the Th epitopes have lengths ranging from 11mer to 13mer.

[0010] In one embodiment, the peptide unit comprises one B cell epitope and one Th epitope, and the peptide unit has a length ranging from 26mer to 45mer.

[0011] In one embodiment, the peptide unit comprises one B cell epitope and two Th epitopes (referred to as the first Th epitope and the second Th epitope, respectively), the peptide unit has a length ranging from 37mer to 50mer, and the first Th epitope is linked between the B cell epitope and the second Th epitope.

[0012] In one embodiment, 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 unit having a length ranging from 45mer to 50mer, and the second B cell epitope being linked between the first B cell epitope and the Th epitope.

[0013] In one embodiment, 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 unit having a length ranging from 45mer to 50mer, and the Th epitope being linked between the first B cell epitope and the second B cell epitope.

[0014] The present disclosure provides nucleic acids encoding peptide units or peptides that do not contain non-standard amino acids.

[0015] The present disclosure provides peptides having two or more peptide units and five or fewer peptide units linked together.

[0016] The present disclosure provides a pharmaceutical composition for treating obesity comprising: a peptide unit or peptide and an adjuvant.

[0017] The present disclosure provides a method of treating obesity comprising administering a pharmaceutical composition to a subject.

[0018] The present disclosure provides the use of a peptide unit or peptide for treating obesity.

[0019] The present disclosure provides the use of a peptide unit or peptide for preparing a medicament for treating obesity.

[0020] Advantageous Effects of the Invention

[0021] When the peptides provided in the present disclosure are injected into the body of a subject, the peptides have the effect of inducing the production of antibodies with specific physiological functions that specifically bind to pre-designed antigenic sites. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the results of an experiment to confirm the effect of a peptide in Experimental Example 2, and is a graph showing the measured values ​​of weight change by age in weeks for each experimental group. [Figure 2] FIG. 1 shows the results of an experiment to confirm the effect of a peptide in Experimental Example 2, and is a graph showing the measured values ​​of weight change by age in weeks for each experimental group. [Figure 3] FIG. 1 shows the results of an experiment to confirm the effect of a peptide in Experimental Example 2, and is a graph showing the measured values ​​of weight change by age in weeks for each experimental group. [Figure 4] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 3, and is a graph showing the weight measurements of the test subjects by week of age in each experimental group, where ``thin'' refers to the control group with a normal weight, ``obese'' refers to the obese group induced by a high-fat diet, ``mock'' refers to the placebo-administered group, and ``3H-OTP'' refers to Group 2-1. [Figure 5] This figure shows the results of the peptide effect confirmation experiment in Experimental Example 3, and is a graph showing the measured antibody titers observed in the test subjects for each experimental group, where obesity indicates the obesity group induced by a high-fat diet, mock indicates the placebo-administered group, and 3H-OTP indicates group 2-1. [Figure 6] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 3. It is a graph showing the measured values ​​of the lipolytic ability of hormone-sensitive lipase in the adipocytes of the test subjects for each experimental group, where basal indicates the case where no norepinephrine was treated, hormone indicates the case where norepinephrine was treated, lean indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, mock indicates the placebo-administered group, and 3H-OTP indicates Group 2-1 ((a) concentration of secreted glycerol per 105 adipocytes, (b) concentration of secreted glycerol per 1 g of adipocytes). [Figure 7] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 3, and is an image showing the measured values ​​of the size of adipocytes in the test subjects for each experimental group. The lean group represents the control group with a normal weight, and the obese group represents the obese group induced by a high-fat diet (representing a DAPI-stained image, a LipidTOX-stained image, and a merged image, respectively). [Figure 8]This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 3, and is an image showing the measured size of the fat cells of the test subjects for each experimental group (showing DAPI-stained images of the nuclei and lipids of the fat cells for each experimental group), where lean indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, mock indicates the placebo-administered group, and 3H-OTP indicates Group 2-1. [Figure 9] FIG. 1 shows the results of the peptide effect confirmation experiment in Experimental Example 3, and is a graph showing the measured values ​​of blood lipid concentrations of test subjects for each experimental group, in which TG indicates triglyceride, NEFA indicates non-esterified fatty acid, CHOL indicates cholesterol, HDL indicates high-density lipoprotein, and LDL indicates low-density lipoprotein. [Figure 10] 1 shows the results of the experiment to confirm the effect of peptides in Experimental Example 4, and is a graph showing the measured weight of test subjects by age in weeks for each experimental group, where "thin" indicates the control group with normal weight, "obese" indicates the obese group induced by a high-fat diet, "mock" indicates the placebo group, "3H-OTP 30 μg" indicates Group 3-2, and "3H-OTP 50 g" indicates Group 3-1. For reference, a graph for "3H-OTP-2W 50 μg" representing Group 2-1 is also shown. [Figure 11] FIG. 1 shows the results of an experiment to confirm the effect of peptides in Experimental Example 4, and is a graph showing the measured antibody titers for each experimental group by age in weeks of the test subjects, in which "thin" indicates the control group with a normal weight, "obese" indicates the obese group induced by a high-fat diet, "mock" indicates the placebo-administered group, "3H-OTP 30 μg" indicates Group 3-2, and "3H-OTP 50 g" indicates Group 3-1. [Figure 12] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 5, and is a graph showing the measured weight of the test subjects by week of age for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, and 3H-OTP indicates Group 4-1. [Figure 13]This figure shows the results of an experiment to confirm the effect of a peptide in Experimental Example 6. It is a graph showing the weight increase at 16 weeks of age compared to the weight at 11 weeks of age after measuring the weight of the test subjects at each week of age for each experimental group by age. Wild-type (+ / +)-lean indicates the control group with a normal weight, wild-type (+ / +) indicates group 5-1, heterozygous (+ / -) indicates group 5-2, and homozygous (- / -) indicates group 5-3. [Figure 14] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 15] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 16] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 17]This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 18] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 19] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 20] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 21]This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 22] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a graph showing the weight of the test subjects by week of age measured for each experimental group, where thin indicates the control group with a normal weight, obese indicates the obese group induced by a high-fat diet, P1 indicates group 6-1, P2 indicates group 6-2, P3 indicates group 6-3, P4 indicates group 6-4, P5 indicates group 6-5, P6 indicates group 6-6, P7 indicates group 6-7, P8 indicates group 6-8, and P9 indicates group 6-9. [Figure 23] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a table listing the antibody titer measurements for each experimental group at 11, 16, and 19 weeks of age for the test subjects. "Lean" refers to the normal weight control group, "Obese" refers to the high-fat diet-induced obesity group, P1 refers to Group 6-1, P2 refers to Group 6-2, P3 refers to Group 6-3, P4 refers to Group 6-4, P5 refers to Group 6-5, P6 refers to Group 6-6, P7 refers to Group 6-7, P8 refers to Group 6-8, and P9 refers to Group 6-9. Furthermore, the values ​​identified by the labels in the "No." column for each experimental group in each table indicate the experimental results for each individual subject in each experimental group, "ave" refers to the overall average, "sd" refers to the overall standard deviation, and "se" refers to the overall standard error. [Figure 24]This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a table listing the antibody titer measurements for each experimental group at 11, 16, and 19 weeks of age for the test subjects. "Lean" refers to the normal weight control group, "Obese" refers to the high-fat diet-induced obesity group, P1 refers to Group 6-1, P2 refers to Group 6-2, P3 refers to Group 6-3, P4 refers to Group 6-4, P5 refers to Group 6-5, P6 refers to Group 6-6, P7 refers to Group 6-7, P8 refers to Group 6-8, and P9 refers to Group 6-9. Furthermore, the values ​​identified by the labels in the "No." column for each experimental group in each table indicate the experimental results for each individual subject in each experimental group, "ave" refers to the overall average, "sd" refers to the overall standard deviation, and "se" refers to the overall standard error. [Figure 25] This figure shows the results of the experiment to confirm the effect of peptides in Experimental Example 7, and is a table listing the antibody titer measurements for each experimental group at 11, 16, and 19 weeks of age for the test subjects. "Lean" refers to the normal weight control group, "Obese" refers to the high-fat diet-induced obesity group, P1 refers to Group 6-1, P2 refers to Group 6-2, P3 refers to Group 6-3, P4 refers to Group 6-4, P5 refers to Group 6-5, P6 refers to Group 6-6, P7 refers to Group 6-7, P8 refers to Group 6-8, and P9 refers to Group 6-9. Furthermore, the values ​​identified by the labels in the "No." column for each experimental group in each table indicate the experimental results for each individual subject in each experimental group, "ave" refers to the overall average, "sd" refers to the overall standard deviation, and "se" refers to the overall standard error. DETAILED DESCRIPTION OF THE INVENTION

[0023] The subject matter disclosed herein will now be described in more detail with reference to several specific embodiments and examples, with reference to the accompanying drawings. It should be noted that the accompanying drawings encompass some, but not all, embodiments of the present disclosure. The subject matter disclosed herein 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 present disclosure will occur to those skilled in the art to which the subject matter disclosed herein pertains. Therefore, it is to be understood that the subject matter disclosed herein is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0024] Definitions of common terms.

[0025] about. As used herein, the term "about" refers to a degree of proximity to an amount, and refers to an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies to the extent of 30%, 25%, 20%, 25%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0026] peptide. 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 mainly used to distinguish it from protein.Although there is no clear standard for distinguishing between protein and peptide, as used herein, unless otherwise defined, a polymer of about 200 amino acids will be called a peptide, while one with more than that will be called a protein.The term "peptide" can also include all other meanings recognized by those skilled in the art.

[0027] subject. As used herein, the term "subject" refers to a target organism exposed to a specific substance (e.g., a peptide, etc.). The subject may refer to an independent organism (e.g., a human, an animal, etc.) or a partial component of an independent organism (e.g., a part of a tissue, a cell, etc.). This meaning may be interpreted appropriately depending on the context. Furthermore, the term "subject" may further include all meanings recognized by those skilled in the art.

[0028] Immunotherapy drugs. As used herein, the term "immunotherapeutic agent" is a concept distinct from general therapeutic agents or vaccines. Immunotherapeutic agents are similar to existing vaccines in that they are injected into a subject's body to induce a humoral immune response against the immunotherapeutic agent itself. However, immunotherapeutic agents differ from existing vaccines in that the antibodies induced as a result of the humoral immune response can bind not only to the immunotherapeutic agent itself but also to specific tissues and cells (e.g., cell surface receptors) in the body or specific substances produced during metabolism (e.g., peptides, lipids, proteins, and / or sugars), thereby enabling the immunotherapeutic agent to treat specific diseases or disorders and allowing continuous and repeated administration. Accordingly, immunotherapeutic agents generally contain antigens designed to induce antibodies capable of binding to specific target tissues, cells, or substances in the body. Unless otherwise defined, the term "immunotherapeutic agent" is intended to include all antigens (e.g., peptides, proteins, lipids, sugars, and / or complexes thereof) having the above functions that can be used appropriately by those skilled in the art. The term "immunotherapeutic agent" may be more specifically referred to as "humoral immunotherapeutic agent." Furthermore, the term "immunotherapeutic agent" may include all meanings recognized by those of skill in the art.

[0029] Treatment or cure. As used herein, the term "treatment" collectively refers to any direct or indirect action or means for eliminating, alleviating, reducing, suppressing, or improving a subject's disease, illness, disorder, and / or symptoms, or any direct or indirect action or means for inducing the result of preventing a disease, illness, disorder, and / or symptoms. As used herein, the term "therapeutic agent" refers to various substances (e.g., compounds or peptides) that can exert a "therapeutic" effect when administered to a subject in an appropriate manner. Furthermore, the terms "treatment" or "therapeutic agent" can include all other meanings recognized by those skilled in the art.

[0030] Immunogenicity. As used herein, the term "immunogenicity" generally refers to the "property of acting as an antigen capable of inducing an immune response." There are various methods for measuring the immunogenicity of a specific antigen, and these methods can be appropriately adopted or designed depending on the purpose. Examples of methods include, but are not limited to, 1) determining whether IgG, IgA, and / or IgE antibodies are produced in a subject's body when the antigen is administered to the subject; 2) determining the timing of IgG, IgA, and / or IgE antibody production according to the administration cycle; 3) determining the titer of induced antibodies against the antigen; and 4) determining the effect according to the mechanism of action of the induced antibody once the mechanism of action has been determined. The term "enhanced immunogenicity" can be used interchangeably with, for example, "enhanced effect in inducing an immune response," "improved ability to induce antibodies," and "enhanced efficacy as an immunotherapeutic agent," and includes all expressions that can be appropriately interpreted by a person skilled in the art depending on the context.

[0031] mer. As used herein, the term "mer" generally refers to the number of units of a high molecular weight polymer.As used herein, the term "mer" generally refers to a peptide length, such as "a peptide of length N mer", which refers to a peptide polymerized with N amino acids.The unit represented by the term "mer" should be interpreted appropriately in the context, and includes all other meanings that can be recognized by those skilled in the art.

[0032] Standard amino acids. As used herein, the term "standard amino acids" refers to the 20 amino acids synthesized in living organisms through the process of gene transcription and translation. 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 (Gln, 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 the common one-letter or three-letter code of amino acids. The objects referred to by the term standard amino acids should be interpreted appropriately according to the context, and they include all other meanings that can be recognized by those skilled in the art.

[0033] Non-standard amino acids. As used herein, the term "non-standard amino acid" refers to an amino acid other than the standard amino acids. Non-standard amino acids include artificial amino acids and unnatural amino acids, as well as amino acids chemically modified through post-translational modification in living organisms. Non-standard amino acids include, for example, D-alanine, L-cyclohexylalanine, 6-aminohexanoic acid, etc. Non-standard amino acids do not have corresponding DNA codons and therefore cannot be represented by the one-letter or three-letter symbols of common amino acids. Instead, they are represented using other letters and explained by additional descriptions. The subject referred to by the term non-standard amino acid should be interpreted appropriately according to the context and includes all other meanings that can be recognized by those skilled in the art.

[0034] Description of peptide sequences. Unless otherwise specified, when describing a peptide sequence in this specification, one-letter or three-letter amino acid codes are used, and they are written in the direction from the N-terminus to the C-terminus. For example, the expression "RNVP" refers to a peptide in which arginine, asparagine, valine, and proline are linked in the order from the N-terminus to the C-terminus. In another example, the expression "Thr-Leu-Lys" refers to a peptide in which threonine, leucine, and lysine are linked in the order from the N-terminus to the C-terminus. For amino acids that cannot be represented by one-letter codes, other letters will be used to represent these amino acids, and additional explanations will be provided.

[0035] When a peptide is represented as a structural formula, N- and -C are used to specify the N-terminus or C-terminus, and parentheses can be used to distinguish between the N-terminus and / or the C-terminus. For example, when a peptide's structural formula is represented as (N)-BTA-(C), the "(N)-" at the beginning and the "-(C)" at the end are symbols to clarify the direction of the N-terminus and the C-terminus, unless otherwise specified. This refers to a peptide in which the sequences represented by B, T, and A are linked in the direction from the N-terminus to the C-terminus.

[0036] Background-humoral immunity. Humoral immunity mediated by immunoglobulin M (IgM).

[0037] Among humoral immune responses, IgM-induced immune responses are innate immune functions that are primarily activated in the primary immune response and occur rapidly in the early stages of infection. IgM is primarily secreted in the form of a pentamer, theoretically possessing 10 antigen-binding sites, and thus capable of simultaneously binding to multiple antigens. IgM can bind to a wide variety of antigens, but the affinity and avidity of binding are limited by the intrinsic affinity of the IgM itself. Therefore, the affinity and avidity of IgM for antigens are significantly lower than those of antibodies such as IgG, which are generated with the assistance of helper T cells.

[0038] Restriction of humoral immunity by IgM. IgM-derived humoral immunity plays an important role in the initial immune response; however, 1) the amount of IgM produced by B cells is lower than that of other types of antibodies (e.g., IgG produced by differentiated B cells), 2) the specific binding ability of IgM to antigens is lower than that of IgG, and 3) the degree of secondary immune response upon re-exposure to the same antigen is weak. Therefore, from the perspective of designing an antigen that induces an immune response, if an antigen injected into the subject's body induces only IgM-mediated humoral immunity, the desired effect is unlikely to be achieved. Therefore, it is extremely important to design an antigen that induces IgG-mediated humoral immunity.

[0039] Humoral immunity via immunoglobulin G (IgG)1 - an overview. Humoral immunity, which produces IgG, primarily occurs in germinal centers in the spleen or lymph nodes and is driven by the combined actions of B cells, helper T cells, and antigen-presenting cells (APCs). The overall process is as follows: 1) B cells recognize invading antigens (mainly proteins or peptides). 2) After antigen-presenting cells endocytose the antigen (or its fragments), they intracellularly cleave the antigen into smaller fragments and present some of the fragments on the MHC class II surface of the antigen-presenting cells. 3) Helper T cells recognize the antigen fragments presented on the MHC class II. 4) Helper T cells transmit differentiation signals to B cells (antigen-recognizing cells). 5) B cells are activated, and some differentiate into plasma cells, producing IgG antibodies with high specific binding affinity to antigens. 6) As a result of B cell activation, some differentiate into memory B cells, which are stored in the body so that they can quickly trigger an immune response that produces IgG antigens if the same antigen is re-invaded.

[0040] IgG2-mediated humoral immunity - antigen-recognizing cells. Antigen-presenting cells are a collective term for cells that can endocytose protein fragments or peptides, cleave them into shorter peptide fragments, load them onto MHC class II, and present them on their surface. Major antigen-presenting cells include B cells, macrophages, and dendritic cells. Antigen-presenting cells transport endocytosed antigen fragments from the site of infection to lymph nodes, where they present the antigen fragments to helper T cells via MHC class II, thereby activating the helper T cells that recognize the antigen fragments, thereby inducing an immune response.

[0041] Humoral immunity via IgG3-MHC class II. MHC class II is a molecule expressed on the surface of antigen-presenting cells and has a heterodimer structure consisting of α / β chains. Due to its structure, MHC class II can bind to peptides of a certain length and present the peptides. Antigen-presenting cells bind peptide fragments derived from foreign antigens to MHC class II and present the peptide fragments on their cell surface. The HLA gene complex (human leukocyte antigen gene complex) is involved in the expression of human MHC class II, and among these, gene complexes such as HLA-DP, DQ, and DR are known to be involved in the expression of MHC class II cell surface receptors on the surface of antigen-presenting cells. In humans, various alleles of the HLA-DR gene are known to exist depending on the race, with approximately 12 types of HLA-DR genes being known to be the most frequently occurring alleles.

[0042] Humoral immunity mediated by IgG4 - MHC class II presentation by antigen-presenting cells. Although there are some differences depending on the literature, it is known that the length of peptides presented to MHC class II ranges from approximately 17mers to approximately 24mers. Therefore, antigen-presenting cells do not present endocytosed antigen protein or peptide fragments directly to MHC class II, but rather undergo a cleavage process to smaller fragments of 17mers to 24mers. The antigen fragments (protein or peptide fragments) endocytosed by antigen-presenting cells reside in endosomes, which fuse with the lysosomes of the antigen-presenting cells. The antigen fragments are then cleaved into shorter peptides by various degradative enzymes present in the lysosomes. Examples of degradative enzymes include endopeptidases and exopeptidases. While endopeptidases act on the internal peptide bonds of antigen fragments to cleave them, exopeptidases act primarily on the peptide bonds at both ends of the antigen fragments to cleave them. After the antigen fragments are cleaved into peptides of appropriate sizes through the above process, some of them bind to MHC class II present in the inner membrane of the lysosome. The lysosomes return to the cell surface and fuse with the plasma membrane, exposing MHC class II and the bound peptide fragments on the surface of the antigen-presenting cell. This series of processes is also known as the "process by which antigen-presenting cells present antigens."

[0043] IgG5-mediated humoral immunity - helper T cells. Helper T lymphocytes are also known as CD4+ cells because they express CD4. Helper T cells express a T cell receptor (TCR) capable of binding to MHC class II on their surface. The T cell receptor generally forms a complex with CD3. When antigens (e.g., peptide fragments) delivered to lymph nodes by antigen-presenting cells are presented via MHC class II, helper T cells recognize the presented antigen fragments. This recognition process involves the T cell receptor-CD3 complex and CD4. Once helper T cells successfully recognize the antigen fragments, they become activated, secrete various cytokines, and differentiate. The secreted cytokines are involved in the differentiation of B cells, as described below.

[0044] IgG6-mediated humoral immunity - B cell differentiation. Under the influence of cytokines secreted by helper T cells (e.g., interleukin-4 (IL-4)), B cells undergo immunoglobulin class switching, which changes the antibody isotype they produce (e.g., from IgM to IgG). Furthermore, some B cells differentiate into memory B cells, which are stored to induce a rapid immune response when the same antigen is introduced again, while others differentiate into plasma cells, which actively produce IgG antibodies.

[0045] Humoral immunity by IgG7 - a condition for IgG production. For IgG-mediated humoral immunity to occur, it is essential that 1) a specific three-dimensional structure of the antigen be recognized by B cells and 2) a fragment of the antigen be recognized by helper T cells via MHC class II. Generally, the portions of an antigen recognized by B cells and the portions recognized by helper T cells are different and activate immune responses via different pathways. However, it is generally known that an immune response occurs only when there is at least a certain degree of association between the portions recognized by B cells (B cell epitopes) and the portions recognized by helper T cells (Th epitopes). For example, the B cell epitopes and Th epitopes may be contained in a single molecule, may form a conjugate, or may have other associations.

[0046] Prior Art Limitations.

[0047] Considerations when designing peptides for use as immunotherapeutics.

[0048] As described above, immunotherapeutic drugs are required to have the following properties: 1) the ability to stably induce an immune response in the subject's body, 2) the ability to uniformly induce only the intended antibody in the subject's body and minimize side effects, and 3) ease of synthesis and reasonable manufacturing costs for commercialization of the therapeutic drug. Therefore, when designing peptides that can be used as immunotherapeutic drugs, the following three conditions must essentially be taken into consideration: 1) the peptide must exhibit a certain level of immunogenicity, 2) the peptide must induce an immune response in the subject's body that uniformly induces the intended antigen recognition specificity of the antibody, the isotype that controls the physiological function of the antibody, and so on, and 3) the peptide must be easy to synthesize, taking into account economic feasibility.

[0049] Prior Art Limitations.

[0050] As disclosed in the previously filed patent applications U.S. Patent Application Publication No. 10 / 378,707 and PCT / KR2005 / 000784, as well as Kim et al. (2016, An apolipoprotein B100 mimotope prevents obesity in mice, Clinical Science 130, 105-116), it is known that antibodies specific to artificially produced peptides with specific sequences can also bind to exposed sites of the ApoB-100 protein in LDL molecules, thereby functioning as immunotherapeutics. Taking advantage of this property, immunotherapeutics containing peptides have been designed and are disclosed in the above patent applications and elsewhere. However, prior art has focused primarily on improving the immunogenicity of peptides, for example, by 1) preparing long, contiguous identical sequences of peptides (concatamers) and 2) designing immunotherapeutics by linking helper T cell epitopes (sufficiently long at the protein level) to the concatamers. Accordingly, conventionally designed immunotherapeutic drugs have been limited by the following two factors: 1) the existence of various epitopes (antigenic determinants) leads to the induction of various types of antibodies, reducing uniformity; and 2) high manufacturing costs make them economically unfeasible.

[0051] The need for establishing peptide design methods.

[0052] Regarding peptides used as immunotherapeutics, there are no established principles for designing peptides that 1) uniformly induce only the intended immune response and 2) are easy to synthesize and inexpensive to produce. Accordingly, this specification provides technical considerations and methods for designing peptides to be used as immunotherapeutics.

[0053] peptide.

[0054] Overview of peptides.

[0055] The peptides provided herein comprise at least one peptide unit (peptide block). A peptide unit comprises at least one B cell epitope, at least one Th epitope, and an appropriate number of auxiliary moieties. In one embodiment, a peptide may comprise one peptide unit. In another embodiment, a peptide may comprise two or more peptide units.

[0056] Characteristics of peptide 1 - It contains peptide units.

[0057] The peptide units are designed to 1) exhibit a certain level of immunogenicity and 2) uniformly induce only the intended antibodies. Thus, the peptide units provided herein have properties suitable for use as immunotherapeutics.

[0058] Characteristics of peptide 2: The length of the peptide unit is relatively short.

[0059] Since the peptide units are designed to be relatively short, they are easy to synthesize and have low production costs. Peptides are designed using peptide units as their building blocks, specifically, in the form of one or more linked peptide units. When a peptide contains only a small number of peptide units, the overall length of the peptide is short, which has the advantage of being easy to synthesize. Even in the case of a peptide having a relatively long sequence containing multiple peptide units, the peptide units themselves are designed to be easy to synthesize, so that the peptide can be prepared by synthesizing the peptide units in parallel and then linking these peptide units. As a result, the peptides provided herein have the above-mentioned characteristics of the peptide units as well as the characteristic of being easy to synthesize, making them suitable for use as immunotherapeutic peptides.

[0060] Peptide function.

[0061] When this peptide is injected into a subject's body, it has the function of uniformly inducing only antibodies that can specifically bind to the B cell epitope contained in the peptide.

[0062] B cell epitopes.

[0063] Definition of B-cell epitopes.

[0064] The peptide provided herein comprises 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 kind of homogeneous antibody.Therefore, when the peptide that comprises B cell epitope is injected into the body of a subject, it will result in the predominant induction of one kind of antibody for each kind of B cell epitope.

[0065] Structure of B cell epitopes.

[0066] A B-cell epitope comprises a portion that forms a three-dimensional structure and a portion adjacent to it. The portion forming the three-dimensional structure is a portion that forms a peptide with a higher-order structure, and this portion is designed so that B cells can recognize the peptide with the higher-order structure and produce antibodies that can specifically bind to the peptide. The adjacent portion is a portion that directly or indirectly affects the portion forming the three-dimensional structure and stably forms the higher-order structure. Specifically, the adjacent portion may have various functions, such as 1) a function that allows the portion forming the three-dimensional structure to form a specific structure, 2) a linker function that does not affect the portion forming the three-dimensional structure when the B cell epitope is linked to another portion within the peptide unit, or 3) a function that protects the portion forming the three-dimensional structure, but these functions are not limited to these. In one embodiment, the B cell epitope may have a sequence in which a first portion forming the three-dimensional structure and its first adjacent portion are sequentially linked in the N- to C-terminal direction. In another embodiment, the B cell epitope may have a sequence in which a second adjacent portion, a second portion forming the three-dimensional structure, and a third adjacent portion are sequentially linked in the N- to C-terminal direction. In yet another embodiment, the B-cell epitope may have a sequence in which a third portion and a fourth adjacent portion that form a three-dimensional structure are linked sequentially in the N-terminal to C-terminal direction.

[0067] Design of B cell epitope 1 - Design of the part that forms the three-dimensional structure.

[0068] A B cell epitope should be capable of uniformly inducing the production of antibodies capable of recognizing and specifically binding to a three-dimensional structure on B cells. The three-dimensional structure recognized by B cells can be expressed by an appropriate peptide having a higher-order structure. Therefore, a B cell epitope is designed to contain a three-dimensional structure-forming portion that forms a peptide having a higher-order structure. The three-dimensional structure-forming portion can form a peptide having a desired higher-order structure depending on the purpose. In one embodiment, the three-dimensional structure-forming portion may include an α-helical structure. In another embodiment, the three-dimensional structure-forming portion may include a β-structure. In yet another embodiment, the three-dimensional structure-forming portion may include an α-helical structure and / or a β-structure. In another embodiment, the three-dimensional structure-forming portion may include a peptide having a tertiary structure. In yet another embodiment, the three-dimensional structure-forming portion may include a peptide having a quaternary structure.

[0069] Design of B cell epitope 2 - adjacent part

[0070] When designing a B cell epitope, it is not essential that the entire sequence form a peptide with a higher-order structure. In other words, the B cell epitope may be designed to include an adjacent portion in addition to the portion that forms the three-dimensional structure. The adjacent moiety can affect the moiety that forms the three-dimensional structure so as to stably form a higher-order structure. The adjacent moiety may have various other functions, and its role may overlap with that of the auxiliary moiety. In one embodiment, the adjacent moiety may have a linker function. In another embodiment, the adjacent moiety may have a protective function for the moiety that forms the three-dimensional structure. In yet another embodiment, the adjacent moiety may have one or more functions.

[0071] B cell epitope length.

[0072] B cell epitopes should be 1) large enough to be recognized by B cells, and 2) have one or only a few types of antibodies that specifically bind to the B cell epitope. The length of the B cell epitope should be limited to an appropriate level. If the length of the B cell epitope is too short, it will not be recognized by B cells and will not induce antibodies, whereas if the length of the B cell epitope is too long, various types of antibodies will be induced, which may deviate from the intended purpose. In one embodiment, the length of the B cell epitope may be about 8 mer, about 9 mer, about 10 mer, about 11 mer, about 12 mer, about 13 mer, about 14 mer, about 15 mer, about 16 mer, about 17 mer, about 18 mer, about 20 mer, about 21 mer, about 22 mer, about 23 mer, about 24 mer, about 25 mer, about 26 mer, about 27 mer, about 28 mer, about 29 mer, or about 30 mer.

[0073] In another embodiment, the length of the B-cell epitope may have a value within the two numerical ranges selected in the immediately preceding sentence.

[0074] Embodiments of B-cell epitopes.

[0075] In one embodiment, the B cell epitope may be one 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 may be The externally exposed site of apolipoprotein B-100 contained in low-density lipoprotein (LDL); and the externally exposed site of apolipoprotein B-100 contained in very-low-density lipoprotein (VLDL), The present invention is characterized in that it induces antibodies that target a site selected from the group consisting of:

[0076] Embodiments of sequences of B-cell epitopes.

[0077] In one embodiment, the B-cell epitope is selected from the group consisting of RNVPPIFNDVYWIAF (SEQ ID NO:6), CRFRGLISLSQVYLS (SEQ ID NO:7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO:8), RNVPPIFNDVY (SEQ ID NO:9), CRFRGLISLSQ (SEQ ID NO:10), KTTKQSFDLSVK (SEQ ID NO:11), RNVPPIFNDVYW (SEQ ID NO:12), CRFRGLISLSQV (SEQ ID NO:13), KTTKQSFDLSVKAQYKK (SEQ ID NO:14), RNVPPIFNDVYWI (SEQ ID NO:15), CRFRGLISLSQVY (SEQ ID NO:16), KTTKQSFDLSVKAQYKKN (SEQ ID NO:17), PIFNDVYWIAF (SEQ ID NO:18), NO:18), GLISLSQVYLS(SEQ ID NO:19), QSFDLSVKAQYKKNKH(SEQ ID NO:20), PPIFNDVYWIAF(SEQ ID NO:21), RGLISLSQVYLS(SEQ ID NO:22), KQSFDLSVKAQYKKNKH(SEQ ID NO:23), VPPIFNDVYWIAF(SEQ ID NO:24), FRGLISLSQVYLS(SEQ ID NO:25), TKQSFDLSVKAQYKKNKH(SEQ ID NO:26), NVPPIFNDVYWIA(SEQ ID NO:27), RFRGLISLSQVYL(SEQ ID NO:28), TKQSFDLSVKAQYKKN(SEQ ID NO:29), VPPIFNDVYWI(SEQ ID NO:30), FRGLISLSQVY(SEQ ID and a peptide comprising a sequence selected from the group consisting of: TKQSFDLSVKAQYKKN (SEQ ID NO: 31), TKQSFDLSVKAQYKKN (SEQ ID NO: 32), PPIFNDVYW (SEQ ID NO: 33), RGLISLSQV (SEQ ID NO: 34), KQSFDLSVKAQYKK (SEQ ID NO: 35), RFRGLISLSQVYLDP (SEQ ID NO: 221), and SVCGCPVGHHDVVGL (SEQ ID NO: 222).

[0078] In another embodiment, the B cell epitope may be a peptide comprising an epitope contained in a peptide selected from the group consisting of SEQ ID NOS:6-35 and 221-222.

[0079] Sequences similar to exemplary sequences of B-cell epitopes.

[0080] Disclosed herein are sequences similar to exemplary sequences of B cell epitopes. In one embodiment, a B cell epitope 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 a sequence selected from the group consisting of SEQ ID NOs: 6-34 and 221-222. In another embodiment, a B cell epitope may have a sequence that is identical to the selected sequence beyond the value selected in the immediately preceding sentence. For example, a B cell epitope may have a sequence that is 90% or more identical to SEQ ID NO: 6.

[0081] Th epitope.

[0082] Definition of Th epitopes.

[0083] The Th epitope contained in the peptides provided herein refers to a portion designed to function so as to be recognized by helper T cells (Th, helper T lymphocytes) during the process in which the peptide is endocytosed by an antigen-presenting cell, binds to MHC class II, and is presented on the surface of the antigen-presenting cell by MHC class II. The antigen presentation process in which the endocytosed peptide is processed by the antigen-presenting cell and binds to MHC class II is as described above. In other words, the Th epitope is the portion that plays a role in being recognized by helper T cells when the peptide is injected into the body of a subject, and therefore plays a direct role in inducing IgG-type antibodies against the peptide.

[0084] Design of Th epitope 1-anchor residues.

[0085] The Th epitope is designed to have an anchor residue in its sequence that can bind to MHC class II. Whether or not the anchor residue is included in the sequence is an important factor affecting the function of the Th epitope. In one embodiment, the Th epitope may contain 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) as anchor residues.

[0086] Design of Th epitope 2—species-specific Th epitopes.

[0087] The Th epitope can be selected depending on the purpose, from those capable of binding to the MHC class II of a specific species. In one embodiment, the Th epitope may be a Th epitope capable of binding to human MHC class II. In another embodiment, the Th epitope may be a Th epitope capable of binding to the MHC class II of a mammalian species. Specifically, the Th epitope may be a Th epitope capable of binding to mouse MHC class II.

[0088] Design of Th epitope 3—gene-specific Th epitopes.

[0089] Due to the diverse traits of the HLA gene complex, the structure of MHC class II may vary among races and individuals. Accordingly, it is possible to design Th epitopes that have the ability to bind to the MHC class II molecules HLA-DP, HLA-DQ, and / or HLA-DR of a specific genotype. In one embodiment, the Th epitope may be a peptide sequence having high binding affinity to MHC class II expressed by one or more HLA-DR genes selected from HLA-DR1 alleles 2w2b, 2w2a, 3, 4w4, 4w14, 5, 7, 52a, 52b, 52c, and 53.

[0090] In one embodiment, the Th epitope may be a peptide sequence having high binding affinity to MHC class II expressed by one or more genes selected from HLA-DQ5, HLA-DR, HLA-DR1 to HLA-DR8, HLA-DR11, HLA-DR13, HLA-DR14, HLA-DRw52, HLA-DR2w15, HLA-DPw4, HLA-DRB1 subtypes (e.g., 0301, 01, 03, 04, 07, 08, 09, 11, 12, 13, 15, and 0301), and HLA-DRB5.

[0091] In another embodiment, the Th epitope may be the sequence designated HA307-312 disclosed in Cara C. Wilson et al. (2001, Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes, Journal of Virology, 75(9)4195-4207).

[0092] In yet another embodiment, the Th epitope may be one of the HLA class II restricted epitopes disclosed in Table 2 of Christopher P Desmond et al. (2008, A systematic review of T-cell epitopes in hepatitis B virus: identification, genotypic variation and relevance to antiviral therapeutics, Antiviral Therapy 13:161-175).

[0093] Design of Th epitope 4—gene-nonspecific Th epitope.

[0094] Th epitopes capable of binding to various MHC class IIs are known regardless of the traits of the HLA gene complex, and it is possible to design Th epitopes capable of binding to various MHC class IIs regardless of genetic traits. In one embodiment, the Th epitope may be a sequence designated as a "pan DR-binding peptide" disclosed in U.S. Patent Application No. 305,871.

[0095] Design of Th epitope 5 - Elimination of the possibility of acting as a B cell epitope.

[0096] Th epitope is designed to be presented by MHC class II of antigen-presenting cell and recognized by helper T cell.Therefore, Th epitope generally has very high binding ability to MHC class II, and therefore the probability that Th epitope can act as B cell epitope is very low.In other words, Th epitope is designed not to induce the antibody that specifically binds to the three-dimensional structure of Th epitope itself.

[0097] Designing the length of the Th epitope

[0098] Th epitopes should be designed to have an appropriate length so that they can bind to a single MHC class II molecule. Generally, the length of a single Th epitope capable of directly binding to MHC class II is approximately 30 mer (Abbas, A.K., Lichtman, A.H., and Pillai, S., Cellular and molecular immunology (pp. 124-126), 7th Ed. (2012), Philadelphia, PA, Elsevier, Saunders, et al.). Furthermore, 1) if the Th epitope is too short, there is a risk that the Th epitope will lose its ability to bind to MHC class II; 2) if the Th epitope is too long, the Th epitope may function independently as a B cell epitope, thereby defeating its intended purpose. Therefore, it is necessary to design Th epitopes of appropriate length.

[0099] Th epitope length range.

[0100] In one embodiment, the length of the Th epitope may be a 7-mer, 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, 32-mer, or 33-mer. In another embodiment, the length of the Th epitope may have a value within the two numerical ranges selected in the immediately preceding sentence. For example, the length of the Th epitope may be in the range of 8-mer to 32-mer. In another example, the length of the Th epitope may be in the range of 11-mer to 13-mer.

[0101] The epitope embodiment - PADRE design.

[0102] In one embodiment, the Th epitope may be the peptide designated "pan DR-binding peptide" disclosed in U.S. Patent Application No. 305,871. In another embodiment, the Th epitope may be one of the peptides disclosed in Tables VIIIA and IX of U.S. Patent No. 6,413,935. In yet another embodiment, the Th epitope may have a peptide sequence satisfying the following structural formula I:

[0103] [Formula I] (N)-Lys-X1-X2-Ala-Ala-X3-Thr-X4-X5-Ala-Ala-(C)

[0104] wherein X1 may be, but is not limited to, tyrosine (Tyr), phenylalanine (Phe), or L-cyclohexylalanine.

[0105] X2 may be, but is not limited to, a hydrophobic amino acid, or leucine (Leu) or isoleucine (Ile).

[0106] X3 may be, but is not limited to, an aromatic or cyclic amino acid, or may be phenylalanine (Phe), tyrosine (Tyr) or histidine (His).

[0107] X4 may be an aliphatic long-chain amino acid, or may be, but is not limited to, isoleucine (Ile) or valine (Val).

[0108] X5 may be a charged amino acid or may be, but is not limited to, arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly).

[0109] In one embodiment, the Th epitope may have a peptide sequence satisfying the following structural formula II:

[0110] [Formula II] (N)-X1-X2-Val-X3-Ala-X4-Thr-Leu-Lys-Ala-Ala-(C)

[0111] In the formula, X1 is lysine (Lys) or arginine (Arg).

[0112] X2 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine;

[0113] X3 is lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met);

[0114] X4 is asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys), or alanine (Ala).

[0115] Embodiments of the sequence of the Th epitope.

[0116] In one embodiment, the Th epitope is 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), MQWNSTTFHQTLQDPRVRGLYFPAGG (SEQ ID NO: 165), FFLLTRILTI (SEQ ID NO: 166), FFLLTRILTIPQSLD (SEQ ID NO: 167), TSLNFLGGTTVCLGQ (SEQ ID NO: 168), TSLNFLGGTTVCLGQ (SEQ ID NO: 169), TSLNFLGGTTVCLGQ (SEQ ID NO: 200), TSLNFLGGTTVCLGQ (SEQ ID NO: 2010), TSLNFLGGTTVCLGQ (SEQ ID NO: 2011), TSLNFLGGTTVCLGQ (SEQ ID NO: 2012), TSLNFLGGTTVCLGQ (SEQ ID NO: 2013), TSLNFLGGTTVCLGQ (SEQ ID NO: 2014), TSLNFLGGTTVCLGQ (SEQ ID NO: 2015), TSLNFLGGTTVCLGQ (SEQ ID NO: 2016), TSLNFLGGTTVCLGQ (SEQ ID NO: 2017), TSLNFLGGTTVCLGQ (SEQ ID NO: 2018), TSLNFLGGTTVCLGQ (SEQ ID NO: 2020). NO:168), QSPTSNHSPTSCPPIC(SEQ ID NO:169), IIFLFILLLCLIFLLVLLD(SEQ ID NO:170), CTTPAQGNSMFPSC(SEQ ID NO:171), CTKPTDGN(SEQ ID NO:172), WASVRFSW(SEQ ID NO:173), LLPIFFCLW(SEQ ID NO:174), MDIDPYKEFGATVELLSFLP(SEQ ID NO:175), FLPSDFFPSV(SEQ ID NO:176), RDLLDTASALYREALESPEH(SEQ ID NO:177), PHHTALRQAILCWGELMTLA(SEQ ID NO:178), GRETVIEYLVSFGVW(SEQ ID NO:179), EYLVSFGVWIRTPPA(SEQ ID NO:180), VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181), TVVRRRGRSP(SEQ ID NO:182), VGPLTVNEKRRLKLI(SEQ ID NO:183), RHYLHTLWKAGILYK(SEQ ID NO:184), ESRLVVDFSQFSRGN(SEQ ID NO:185), LQSLTNLLSSNLSWL(SEQ ID NO:186), SSNLSWLSLDVSAAF(SEQ ID NO:187), LHLYSHPIILGFRKI(SEQID NO:188)、KQCFRKLPVNRPIDW(SEQ ID NO:189)、LCQVFADATPTGWGL(SEQ ID NO:190)、AANWILRGTSFVYVP(SEQ ID NO:191)、EIRLKVFVLGGCRHK(SEQ ID NO:192) NO:195)、KYVAAWTLKAA(SEQ ID NO:196)、DIEKKIAKMEKASSVFNVVNS(SEQ ID NO:223)、YSGPLKAEIAQRLEDV(SEQ ID NO:224)、K(Cha)VKANTLKAA(SEQ ID NO:225)、K(Cha)VKANTLKAA(SEQ ID NO:225) NO:226)、K(Cha)VKAWTLKAA(SEQ ID NO:227)、K(Cha)VKAWTLKAA(SEQ ID NO:228)、K(Cha)VWANTLKAA(SEQ ID NO:229)、K(Cha)VWANTLKAA(SEQ ID NO:229) NO:230)、K(Cha)VWAYTLKAA(SEQ ID NO:231)、K(Cha)VWAVTLKAA(SEQ ID NO:232)、K(Cha)VYAWTLKAA(SEQ ID NO:233)、K(Cha)VYAWTLKAA(SEQ ID NO:234)、K(Cha)VYAWTLKAA(SEQ ID NO:234) ID NO:235)、K(Cha)VKAHTLKAA(SEQ ID NO:236)、K(Cha)VKAHTLKAA(SEQ ID NO:237)、K(Cha)VAANTLKAA(SEQ ID NO:238)、K(Cha)VAANTLKAA(SEQ ID NO:239)、K(Cha)VAANTLKAA(SEQ ID NO:239) NO:240)、K(Cha)VAAYTLKAA(SEQ ID NO:241)、K(Cha)VAAWTLKAA(SEQ ID NO:242)、K(Cha)VAAKTLKAA(SEQ ID NO:243)、K(Cha)VAAHTLKAA(SEQ ID NO:244)、K(Cha)VAAHTLKAA(SEQ ID NO:244) NO:245)、K(Cha)VAAWTLKAA(SEQ ID NO:246)、、よびK(Cha)VMAATLKAA(SEQ IDNO:247), where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, and "(Cha)" represents L-cyclohexylalanine.

[0117] Sequences similar to exemplary sequences of Th epitopes.

[0118] Disclosed herein are sequences similar to exemplary sequences of Th epitopes. In one embodiment, the Th epitope may have a sequence having 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO:1 to SEQ ID NO:5, SEQ ID NO:162 to SEQ ID NO:192, SEQ ID NO:195 to SEQ ID NO:196, and SEQ ID NO:223 to SEQ ID NO:247, a sequence satisfying Formula I above, or a sequence satisfying Formula II above. In another embodiment, the Th epitope may have a sequence corresponding to SEQ ID NO:1-5, SEQ ID NO:162-192, SEQ ID NO:195-196, and SEQ ID NO:223-247, as selected in the immediately preceding sentence, a sequence satisfying Formula I above, or a sequence satisfying Formula II above. For example, the Th epitope may have a sequence having 90% or greater identity to the sequence of SEQ ID NO:1.

[0119] auxiliary part.

[0120] Definition of auxiliary parts.

[0121] The peptides disclosed herein may contain one or more auxiliary moieties. An auxiliary moiety is a general term for an additional moiety that can directly or indirectly affect the peptide and induce a desired immune response in the subject's body. The auxiliary moiety may have one or more functions, and the structure and / or position of the peptide sequence can be appropriately designed depending on the purpose.

[0122] Function of auxiliary moiety 1 - function as a linker.

[0123] The auxiliary moiety can function as a linker connecting the B cell epitope and the Th epitope. The B cell epitope and the Th epitope may be directly linked or may be linked via an auxiliary moiety that functions as a linker. Furthermore, the auxiliary moiety may be designed to have a linker function connecting multiple units contained in the peptide. In one embodiment, the sequence of the auxiliary moiety may be located between the sequence of the B cell epitope and the sequence of the Th epitope. In particular, the auxiliary moiety has a linker function connecting 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. In particular, the auxiliary moiety has a linker function connecting the first peptide unit and the second peptide unit.

[0124] Function of auxiliary part 2 - function to protect.

[0125] The peptide units provided herein are characterized by having a relatively short sequence length. Accordingly, when a peptide containing the peptide unit is injected into a subject's body, the Th epitope sequence may be degraded before being recognized by helper T cells, which may result in the failure to provoke the intended immune response. In one embodiment, the protective unit may protect the Th epitope from being cleaved by an enzyme in the subject's body. For example, the enzyme in the subject's body may be a peptidase. Specifically, the peptidase may be an exopeptidase and / or an endopeptidase, but is not limited thereto. In another embodiment, the auxiliary moiety may be linked to the N-terminus and / or C-terminus of the Th epitope. In particular, the auxiliary moiety has the function of protecting the Th epitope. In yet another embodiment, the auxiliary moiety may include at least one non-standard amino acid.

[0126] Function of auxiliary part 3 - to form an annular body.

[0127] The auxiliary moieties may be designed to be linked to both ends of the peptide unit, thereby allowing the peptide to form a cyclic structure. In one embodiment, the peptide may include 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 include one or more cysteines (S). In another embodiment, the peptide may exist in a cyclic structure. In particular, the N-terminus and C-terminus of the peptide may be linked via the auxiliary moieties.

[0128] Auxiliary Part 3 Functions - Other Functions.

[0129] The auxiliary moiety may have additional functions in addition to the above functions. In one embodiment, the auxiliary moiety may contain hydrophilic amino acids 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 biologically inactive in the subject's body. In particular, the auxiliary moiety may have a dummy function to extend the length of the peptide without affecting the function of the B cell epitope and the Th epitope. Specifically, the peptide may be, but is not limited to, a His-tag.

[0130] It can perform multiple functions.

[0131] Ancillary moieties may have one or more functions: In one embodiment, ancillary moieties may have a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function.

[0132] Non-standard amino acids may be included.

[0133] The auxiliary moiety may include one or more non-standard amino acids. The artificial amino acids may be necessary for the auxiliary moiety to perform a linker function, a protective function, and / or other function. In one embodiment, the auxiliary moiety may include 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-aminohexanoic acid, but is not limited thereto.

[0134] The length of the auxiliary part.

[0135] The auxiliary part may be designed to have an appropriate length depending on its function. When the auxiliary part has multiple functions, it may be designed to have an appropriate length to perform all of the multiple functions. In one embodiment, the length of the auxiliary portion may be 1 mer, 2 mer, 3 mer, 4 mer, 5 mer, 6 mer, 7 mer, 8 mer, 9 mer, 10 mer, 11 mer, 12 mer, 13 mer, 14 mer, 15 mer, 16 mer, 17 mer, 18 mer, 19 mer, 20 mer, 21 mer, 22 mer, 23 mer, 24 mer, 25 mer, 26 mer, 27 mer, 28 mer, 29 mer, 30 mer, or 31 mer, or longer. In another embodiment, the length of the auxiliary portion may have a value within the two numerical ranges of the immediately preceding sentence. For example, the length of the auxiliary portion may range from 1 mer to 8 mer. In another example, the length of the auxiliary portion may range from 15 mer to 26 mer.

[0136] Characteristics of the auxiliary moiety - have little effect on the function of the B cell epitope.

[0137] The auxiliary moieties do not significantly affect the ability of the peptide units and / or peptides disclosed herein to induce antibodies in a subject that specifically bind to a B-cell epitope.

[0138] An embodiment of an array of auxiliary moieties.

[0139] In one embodiment, the auxiliary moiety is 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), or any of the following: The peptide may be selected from the group consisting of GSHHHHHHGSDDDDK (SEQ ID NO:51), GSHHHHHHGSDDDDK (SEQ ID NO:52), HHHHHH (SEQ ID NO:53), MRGSHHHHHHGSDDDDKIVD (SEQ ID NO:54), GGGGSGGGGGGSS (SEQ ID NO:55), RRRRRR (SEQ ID NO:159), GSHHHHHHGSDDDDKaZ (SEQ ID NO:193), and ZaGSHHHHHHGSDDDDK (SEQ ID NO:194). In particular, "a" represents D-alanine and "Z" represents 6-aminohexanoic acid.

[0140] Peptide unit design - the big picture.

[0141] Possible peptide units and methods for designing their forms are described below. Each unit may contain at least one B cell epitope and at least one Th epitope, and may contain an appropriate number of auxiliary moieties. The linking order of the B cell epitope, Th epitope, and auxiliary moiety is illustrated for each type. Unless otherwise specified, the design of each moiety contained in the peptide unit basically follows the above design principles.

[0142] Unit A design.

[0143] Structure of Unit A1 - Overview.

[0144] As a peptide unit provided herein, a peptide unit that can include 1) one B cell epitope and one Th epitope, and 2) one or more auxiliary moieties is referred to as "unit A." The function of the auxiliary moiety is not particularly limited as long as it does not impair the functions of the B cell epitope and the Th epitope, and can be appropriately designed as needed.

[0145] In one embodiment, the unit A may be a first B cell epitope and a first Th epitope linked sequentially from the N-terminus to the C-terminus.

[0146] Furthermore, unit A may further comprise a first auxiliary moiety. When unit A comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located N-terminal to the sequence of the first B-cell epitope within the sequence of unit A. In particular, the first auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the first auxiliary moiety are not limited thereto.

[0147] Furthermore, unit A may further comprise a second auxiliary moiety. When unit A comprises a second auxiliary moiety, the sequence of the second auxiliary moiety is located between the sequence of the first B cell epitope and the sequence of the first Th epitope within the sequence of unit A. In particular, the second auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the second auxiliary moiety are not limited thereto.

[0148] Furthermore, unit A may further comprise a third auxiliary moiety. When unit A comprises a third auxiliary moiety, the sequence of the third auxiliary moiety is located C-terminal to the sequence of the first Th epitope in the sequence of unit A. In particular, the third auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, a protective function, and / or a cyclization function, but the functions of the third auxiliary moiety are not limited thereto.

[0149] In another embodiment, the unit A may be a second Th epitope and a second B cell epitope linked sequentially from the N-terminus to the C-terminus.

[0150] Furthermore, unit A may further comprise a fourth auxiliary moiety. When unit A comprises a fourth auxiliary moiety, the sequence of the fourth auxiliary moiety is located N-terminal to the sequence of the second Th epitope within the sequence of unit A. In particular, the fourth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but is not limited to these.

[0151] Furthermore, unit A may further comprise a fifth auxiliary moiety. When unit A comprises a fifth auxiliary moiety, the sequence of the fifth auxiliary moiety 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. In particular, the fifth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the fifth auxiliary moiety are not limited thereto.

[0152] Furthermore, unit A may further comprise a sixth auxiliary moiety. When unit A comprises a sixth auxiliary moiety, the sequence of the sixth auxiliary moiety is located C-terminal to the sequence of the second B-cell epitope within the sequence of unit A. In particular, the sixth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the sixth auxiliary moiety are not limited to these.

[0153] Unit A2 - structure of formula.

[0154] In one embodiment, unit A is a peptide represented by the following formula A or formula A':

[0155] [Formula A] (N)-A1-B1-A2-T1-A3-(C)

[0156] [Formula A'] (N)-A4-T2-A5-B2-A6-(C)

[0157] B1 and B2 are B cell epitopes and follow the design principles described above.

[0158] T1 and T2 are Th epitopes and follow the design principles described above.

[0159] A1 to A6 are auxiliary parts and can be omitted.

[0160] In particular, A1 to A6 may have a dummy function, a solubility-improving function, a linker function, and / or a ring-forming function, but A1 to A6 are not limited thereto.

[0161] Length of unit A.

[0162] In one embodiment, the length of unit A is about 16 mer, about 17 mer, about 18 mer, about 19 mer, about 20 mer, about 21 mer, about 22 mer, about 23 mer, about 24 mer, about 25 mer, about 26 mer, about 27 mer, about 28 mer, about 29 mer, about 30 mer, about 31 mer, about 32 mer, about 33 mer, about 34 mer, about 35 mer, about 36 mer, about 37 mer, about 38 mer, about 39 mer, about 40 mer, about 41 mer, about 42 mer, about 43 mer, about 44 mer, about 45 mer, about 46 mer, about 47 mer, about 48 mer, about 49 mer, about 50 mer, about 51 mer, about 52 mer, about 53 mer, about 54 mer, about 55 mer, about 56 mer, about 57 mer, It may be about a 58-mer, about 59-mer, about 60-mer, about 61-mer, about 62-mer, about 63-mer, about 64-mer, about 65-mer, about 66-mer, about 67-mer, about 68-mer, about 69-mer, about 70-mer, about 71-mer, about 72-mer, about 73-mer, about 74-mer, about 75-mer, about 76-mer, about 77-mer, about 78-mer, about 79-mer, about 80-mer, about 81-mer, about 82-mer, about 83-mer, about 84-mer, about 85-mer, about 86-mer, about 87-mer, about 88-mer, about 89-mer, about 90-mer, about 91-mer, about 92-mer, about 93-mer, about 94-mer, about 95-mer, about 96-mer, about 97-mer, about 98-mer, about 99-mer, or about 100-mer. In another embodiment, the length of unit A may have a value within the two numerical ranges selected in the immediately preceding sentence. For example, the length of unit A may be in the range of about 16-mer to about 30-mer. In another example, the length of unit A may be in the range of about 23-mer to about 60-mer.

[0163] Unit A - Exemplary design embodiment.

[0164] In one embodiment, unit A may comprise a sequence in which a first B cell epitope, a first auxiliary moiety and a first Th epitope are linked in sequence, in particular the first auxiliary moiety has a linker function and comprises one or more artificial amino acids.

[0165] In another embodiment, unit A may comprise a sequence in which a second auxiliary moiety, a second B cell epitope, a third auxiliary moiety and a second Th epitope are linked in sequence, in particular, the second auxiliary moiety is a His-tag and the third auxiliary moiety has a linker function and comprises one or more artificial amino acids.

[0166] In yet another embodiment, unit A may have a sequence in which a third B cell epitope, a fourth auxiliary moiety, a third Th epitope, and a fifth auxiliary moiety are linked in sequence. In particular, the fourth auxiliary moiety has a linker function and a protective function, and the fifth auxiliary moiety has a protective function. The fourth auxiliary moiety and the fifth auxiliary moiety each comprise one or more artificial amino acids.

[0167] In yet another embodiment, unit A may have a sequence in which a sixth auxiliary moiety, a fourth B cell epitope, a seventh auxiliary moiety, a fourth Th epitope and an eighth auxiliary moiety are linked in sequence, in particular, the sixth auxiliary moiety is a His-tag, the seventh auxiliary moiety has a linker function and a protective function, and the eighth auxiliary moiety has a protective function. The seventh and eighth auxiliary portions comprise one or more artificial amino acids.

[0168] An embodiment of an arrangement of units A.

[0169] One of the main ingredients is RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:56) and ZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:57)、CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:58)、KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:59). NO:60)、ZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:61)、RNVPPIFNDVYWIAFK(Cha)VAAWTLKAA(SEQ ID NO:62)、K(Cha)VAAWTLKAARNVPPIFNDVYWIAF(SEQ ID NO:62). NO:63)、RNVPPIFNDVYK(Cha)VAAWTLKAA(SEQ ID NO:64)、PIFNDVYWIAFK(Cha)VAAWTLKAA(SEQ ID NO:65). NO:66); NO:68)、GSHHHHHHGSDDDDKZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:69)、RNVPPIFNDVYWIAFGSHHHHHHGSDDDDKZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:70)、GSHHHHHHGSDDDDKZAK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS(SEQ ID NO:71)、GSHHHHHHGSDDDDKCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:71). NO:72) CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZGSHHHHHHGSDDDDK(SEQ IDNO:73)、GSHHHHHHGSDDDDKZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:74)、GSHHHHHHGSDDDDKKTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:75)、KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZGSHHHHHHGSDDDDK(SEQ ID NO:76)、MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:77)、MRGSHHHHHHGSDDDDKIVDGSHHHHHHGSDDDDKRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:78)、MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZGSHHHHHHGSDDDDK(SEQ ID NO:79)、RNVPPIFNDVYWIAFILMQYIKANSKFIGI(SEQ ID NO:80)、RNVPPIFNDVYWIAFILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ(SEQ ID NO:81)、CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZC(SEQ ID NO:82)、RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAACR(SEQ ID NO:161)、RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXGSHHHHHHGSDDDDK(SEQ ID NO:199)、GSHHHHHHGSDDDDKXXKXVAAWTLKAAXXRNVPPIFNDVYWIAF(SEQ ID NO:200)、RNVPPIFNDVYWIAFXXKXVAAWTLKAAXX(SEQ ID NO:204)、RNVPPIFNDVYWIAFKXVAAWTLKAA(SEQ ID NO:205)、RNVPPIFNDVYWIAFKXVAAWTLKAAHHHHHH(SEQ ID NO:206)、RNVPPIFNDVYWIAFXXKXVAAWTLKAACR(SEQ ID NO:208)、RNVPPIFNDVYWIAFXXKFVAAWTLKAAXX(SEQ IDand RNVPPIFNDVYWIAFXXKFVAAWTLKAACR (SEQ ID NO: 210), RNVPPIFNDVYWIAFXXKFVAAWTLKAACR (SEQ ID NO: 212), RNVPPIFNDVYWIAFCTKPTDGN (SEQ ID NO: 213), RNVPPIFNDVYWIAFLLPIFFCLW (SEQ ID NO: 214), RNVPPIFNDVYWIAFFLPSDFFPSV (SEQ ID NO: 215), RNVPPIFNDVYWIAFILMQYIKANSKFIGIHHHHHH (SEQ ID NO: 219), and RNVPPIFNDVYWIAFMDIDPYKEFGATVELLSFLPHHHHHH (SEQ ID NO: 220), where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, "(Cha)" represents L-cyclohexylalanine, and "X" represents any standard amino acid.

[0170] Unit B design.

[0171] Structure of Unit B1 - Overview.

[0172] The peptide units provided herein are referred to as "unit B" as those that 1) contain two B cell epitopes and one Th epitope, 2) 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 contain one or more auxiliary moieties. The function of the auxiliary moiety is not particularly limited as long as it does not impair the functions of the B cell epitopes and the Th epitope, and may be appropriately designed as needed.

[0173] In one embodiment, unit B may be a first B cell epitope, a second B cell epitope, and a first Th epitope linked sequentially from the N-terminus to the C-terminus.

[0174] Furthermore, unit B may further comprise a first auxiliary moiety. When unit B comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located N-terminal to the sequence of the first B-cell epitope within the sequence of unit B. In particular, the first auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the first auxiliary moiety are not limited to these.

[0175] Furthermore, unit B may further comprise a second auxiliary moiety. When unit B comprises a second auxiliary moiety, the sequence of the second auxiliary moiety is located between the sequence of the first B-cell epitope and the sequence of the second B-cell epitope within the sequence of unit B. In particular, the second auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the second auxiliary moiety are not limited to these.

[0176] Furthermore, unit B may further comprise a third auxiliary moiety. When unit B comprises a third auxiliary moiety, the sequence of the third auxiliary moiety 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. In particular, the third auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the third auxiliary moiety are not limited thereto.

[0177] Furthermore, unit B may further comprise a fourth auxiliary moiety. When unit B comprises a fourth auxiliary moiety, the sequence of the fourth auxiliary moiety is located C-terminal to the sequence of the first Th epitope in the sequence of unit B. In particular, the fourth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the fourth auxiliary moiety are not limited thereto.

[0178] In another embodiment, unit B may comprise a second Th epitope, a third B cell epitope and a fourth B cell epitope linked sequentially from the N-terminus to the C-terminus.

[0179] Furthermore, unit B may further comprise a fifth auxiliary moiety. When unit B comprises a fifth auxiliary moiety, the sequence of the fifth auxiliary moiety is located N-terminal to the sequence of the second Th epitope within the sequence of unit B. In particular, the fifth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a ring-forming function, but the function of the fifth auxiliary moiety is not limited to these.

[0180] Furthermore, unit B may further comprise a sixth auxiliary moiety. When unit B comprises a sixth auxiliary moiety, the sequence of the sixth auxiliary moiety 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. In particular, the sixth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the sixth auxiliary moiety are not limited thereto.

[0181] Furthermore, unit B may further comprise a seventh auxiliary moiety. 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 sequence of unit B. In particular, the seventh auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the seventh auxiliary moiety are not limited to these.

[0182] Furthermore, unit B may further comprise an eighth auxiliary moiety. When unit B comprises an eighth auxiliary moiety, the sequence of the eighth auxiliary moiety is located C-terminal to the sequence of the fourth B-cell epitope in the sequence of unit B. In particular, the eighth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the eighth auxiliary moiety are not limited to these.

[0183] Unit B2 - Structure of formulas.

[0184] In one embodiment, unit B is a peptide represented by the following formula B or B': [Formula B] (N)-A1-B1-A2-B2-A3-T1-A4-(C) [Formula B'] (N)-A5-T2-A6-B3-A7-B4-A8-(C)

[0185] B1 to B4 are B cell epitopes and follow the above design principles.

[0186] T1 and T2 are Th epitopes and follow the design principles described above.

[0187] A1 to A8 are auxiliary parts and can be omitted.

[0188] In particular, A1 to A8 may have a dummy function, a solubility-improving function, a linker function, and / or a ring-forming function, but A1 to A8 are not limited thereto.

[0189] Length of unit B

[0190] In one embodiment, the length of unit B is about 24 mer, about 25 mer, about 26 mer, about 27 mer, about 28 mer, about 29 mer, about 30 mer, about 31 mer, about 32 mer, about 33 mer, about 34 mer, about 35 mer, about 36 mer, about 37 mer, about 38 mer, about 39 mer, about 40 mer, about 41 mer, about 42 mer, about 43 mer, about 44 mer, about 45 mer, about 46 mer, about 47 mer, about 48 mer, about 49 mer, about 50 mer, about 51 mer, about 52 mer, about 53 mer, about 54 mer, about 55 mer, about 56 mer, about 57 mer, about 58 mer, about 59 mer, about 60 mer, about 61 mer, It may be about a 62-mer, about 63-mer, about 64-mer, about 65-mer, about 66-mer, about 67-mer, about 68-mer, about 69-mer, about 70-mer, about 71-mer, about 72-mer, about 73-mer, about 74-mer, about 75-mer, about 76-mer, about 77-mer, about 78-mer, about 79-mer, about 80-mer, about 81-mer, about 82-mer, about 83-mer, about 84-mer, about 85-mer, about 86-mer, about 87-mer, about 88-mer, about 89-mer, about 90-mer, about 91-mer, about 92-mer, about 93-mer, about 94-mer, about 95-mer, about 96-mer, about 97-mer, about 98-mer, about 99-mer, or about 100-mer. In another embodiment, the length of unit B may have a value within the two numerical ranges selected in the immediately preceding sentence. For example, the length of unit B may be in the range of about 24mer to about 45mer. In another example, the length of unit A may be in the range of about 40mer to about 80mer.

[0191] Unit B - an exemplary design embodiment.

[0192] In one embodiment, unit B may have a sequence of a first auxiliary moiety, a first B cell epitope, a second B cell epitope, a second auxiliary moiety, and a first Th epitope, in which the first auxiliary moiety is a His-tag and the second auxiliary moiety comprises one or more artificial amino acids.

[0193] In another embodiment, unit B may have a sequence in which a third B cell epitope, a fourth B cell epitope, a third auxiliary moiety and a second Th epitope are linked in sequence. In particular, the third auxiliary part has a linker function and it comprises one or more artificial amino acids.

[0194] In another embodiment, unit B may have a sequence in which a fourth auxiliary moiety, a fifth B-cell epitope, a sixth B-cell epitope, a fifth auxiliary moiety, a third Th epitope, and a sixth auxiliary moiety are linked in sequence, in particular, the fourth auxiliary moiety is a His-tag, the fifth auxiliary moiety has a linker function and a protective function and comprises one or more artificial amino acids, and the sixth auxiliary moiety has a protective function and comprises one or more artificial amino acids.

[0195] In yet another embodiment, unit B may have a sequence in which a seventh B cell epitope, an eighth B cell epitope, a seventh auxiliary moiety, a fourth Th epitope, and an eighth auxiliary moiety are linked in sequence. In particular, the seventh auxiliary part has a linker function, a protective function and comprises one or more artificial amino acids, and the eighth auxiliary part has a protective function and comprises one or more artificial amino acids.

[0196] In yet another embodiment, unit B may comprise a sequence of an eighth auxiliary moiety, a ninth B-cell epitope, a ninth auxiliary moiety, a tenth B-cell epitope, a tenth auxiliary moiety and a fifth Th epitope, in which 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.

[0197] In yet another embodiment, unit B may comprise a sequence of an eleventh B cell epitope, an eleventh auxiliary moiety, a twelfth B cell epitope, a twelfth auxiliary moiety and a sixth Th epitope, in which 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.

[0198] In yet another embodiment, unit B may comprise a sequence of a 13th B cell epitope, a 13th auxiliary moiety, a 14th B cell epitope, a 14th auxiliary moiety, a 7th Th epitope and a 15th auxiliary moiety, linked in sequence, where in particular the 13th auxiliary moiety has a linker function, the 14th auxiliary moiety has a linker function and a protective function and comprises one or more artificial amino acids, and the 15th auxiliary moiety has a protective function and comprises one or more artificial amino acids.

[0199] An embodiment of an arrangement of unit B.

[0200] In one case, unit B is RNVPPIFNDVYWIAFRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:83)、RNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:84) NO:85) CRFRGLISLSQVYLSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:86). NO:87) CRFRGLISLSQVYLSKTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:88)、KTTKQSFDLSVKAQYKKNKHRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:89)、KTTKQSFDLSVKAQYKKNKHCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:90)、KTTKQSFDLSVKAQYKKNKHKTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:91)、RNVPPIFNDVYWIAFCRFRGLISLSQVYLSK(Cha)VAAWTLKAA(SEQ ID NO:92)、PIFNDVYWIAFGLISLSQVYLSK(Cha)VAAWTLKAA(SEQ ID NO:93)、RNVPPIFNDVYCRFRGLISLSQK(Cha)VAAWTLKAA(SEQ ID NO:93). NO:94)、PIFNDVYWIAFCRFRGLISLSQK(Cha)VAAWTLKAA(SEQ ID NO:95)、PPIFNDVYWRGLISLSQVK(Cha)VAAWTLKAA(SEQ ID NO:96)、RNVPPIFNDVYWIAFCRFRGLISLSQVYLSK(Cha)VAAWTLKAAHHHHHH(SEQ ID NO:96).NO:97), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:98), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAA(SEQ ID NO:99), RNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAA(SEQ ID NO:100), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAA(SEQ ID NO:101), RNVPPIFNDVYWIAFGGGGSGGGGGGSSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAA(SEQ ID NO:102), RNVPPIFNDVYWIAFGGGGSGGGGGGSSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:103), RNVPPIFNDVYWIAFRNVPPIFNDVYWIAFILMQYIKANSKFIGI(SEQ ID NO:104), RNVPPIFNDVYWIAFRNVPPIFNDVYWIAFILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ(SEQ ID NO:105), CRNVPPIFNFDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZC(SEQ ID NDC 106), and RNVPPIFNDVYWIAFCRFRGLISLSQVYLSXXK(Cha)VAAWTLKAAXX (SEQ ID NO:202), where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, "(Cha)" represents L-cyclohexylalanine, and "X" represents any standard amino acid.

[0201] Unit C design.

[0202] Structure of Unit C1 - Overview.

[0203] The peptide unit provided herein is referred to as "unit C," which is a peptide unit that 1) contains two B cell epitopes and one Th epitope, 2) the sequence of the Th epitope is located between the sequence of one of the two B cell epitopes and the sequence of the other B cell epitope, and 3) optionally contains one or more auxiliary moieties. The function of the auxiliary moiety is not particularly limited as long as it does not impair the functions of the B cell epitope and the Th epitope, and can be appropriately designed as needed.

[0204] In one embodiment, unit C may be a first B cell epitope, a first Th epitope, and a second B cell epitope linked sequentially from the N-terminus to the C-terminus.

[0205] Furthermore, unit C may further comprise a first auxiliary moiety. When unit C comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located N-terminal to the sequence of the first B-cell epitope within the sequence of unit C. In particular, the first auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a ring-forming function, but the function of the first auxiliary moiety is not limited to these.

[0206] Furthermore, unit C may further comprise a second auxiliary moiety. When unit C comprises a second auxiliary moiety, the sequence of the second auxiliary moiety 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. In particular, the second auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the second auxiliary moiety are not limited thereto.

[0207] Additionally, unit C may further comprise a third auxiliary moiety. When unit C comprises a third auxiliary moiety, the sequence of the third auxiliary moiety 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. In particular, the third auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the third auxiliary moiety are not limited to these.

[0208] Furthermore, unit C may further comprise a fourth auxiliary moiety. When unit C comprises a fourth auxiliary moiety, the sequence of the fourth auxiliary moiety is located C-terminal to the sequence of the second B-cell epitope within the sequence of unit C. In particular, the fourth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the fourth auxiliary moiety are not limited to these.

[0209] Unit C2 - structure of formula.

[0210] In one embodiment, unit C is a peptide represented by the following formula C: [Formula C] (N)-A1-B1-A2-T1-A3-B2-A4-(C)

[0211] B1 and B2 are B cell epitopes and follow the design principles described above.

[0212] T1 is a Th epitope and follows the design principles described above.

[0213] A1, A2, A3, and A4 are auxiliary parts, which can be omitted.

[0214] In particular, A1, A2, A3, and A4 may have dummy functions, solubility-enhancing functions, linker functions, and / or cyclization functions, but A1, A2, A3, and A4 are not limited thereto.

[0215] Length of unit C.

[0216] In one embodiment, the length of unit C is about 24 mer, about 25 mer, about 26 mer, about 27 mer, about 28 mer, about 29 mer, about 30 mer, about 31 mer, about 32 mer, about 33 mer, about 34 mer, about 35 mer, about 36 mer, about 37 mer, about 38 mer, about 39 mer, about 40 mer, about 41 mer, about 42 mer, about 43 mer, about 44 mer, about 45 mer, about 46 mer, about 47 mer, about 48 mer, about 49 mer, about 50 mer, about 51 mer, about 52 mer, about 53 mer, about 54 mer, about 55 mer, about 56 mer, about 57 mer, about 58 mer, about 59 mer, about 60 mer, about 61 mer r, about 62-mer, about 63-mer, about 64-mer, about 65-mer, about 66-mer, about 67-mer, about 68-mer, about 69-mer, about 70-mer, about 71-mer, about 72-mer, about 73-mer, about 74-mer, about 75-mer, about 76-mer, about 77-mer, about 78-mer, about 79-mer, about 80-mer, about 81-mer, about 82-mer, about 83-mer, about 84-mer, about 85-mer, about 86-mer, about 87-mer, about 88-mer, about 89-mer, about 90-mer, about 91-mer, about 92-mer, about 93-mer, about 94-mer, about 95-mer, about 96-mer, about 97-mer, about 98-mer, about 99-mer, or about 100-mer. In another embodiment, the length of unit C may have a value within the two numerical ranges selected in the immediately preceding sentence. For example, the length of unit C may be in the range of about 24-mer to about 45-mer. In another example, the length of unit A may range from about a 40-mer to about an 80-mer.

[0217] Unit C - Exemplary design embodiment.

[0218] In one embodiment, unit C may have a sequence in which a first B cell epitope, a first auxiliary moiety, a first Th epitope, a second auxiliary moiety, and a second B cell epitope are linked in sequence. In particular, the first auxiliary moiety and the second auxiliary moiety each have a linker function and a protective function. The first auxiliary moiety and the second auxiliary moiety each comprise one or more artificial amino acids.

[0219] In another embodiment, unit C may have a sequence in which a third auxiliary moiety, a third B cell epitope, a fourth auxiliary moiety, a second Th epitope, a fifth auxiliary moiety, and a fourth B cell epitope are linked in sequence. In particular, the third auxiliary moiety is a His-tag, and the fourth and fifth auxiliary moieties have linker and protective functions, respectively. Each of the fourth and fifth auxiliary moieties comprises one or more artificial amino acids.

[0220] An embodiment of an arrangement of unit C.

[0221] In one embodiment, the unit C is selected from the group consisting of RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF (SEQ ID NO: 107), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS (SEQ ID NO: 108), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 109), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF (SEQ ID NO: 110), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS (SEQ ID NO: 111). NO:111), RNVPPIFNFDVYWIAFZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:112), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZRNVPPIFNFDVYWIAF(SEQ ID NO:113), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS(SEQ ID NO:114), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:115), PIFNDVYWIAFK(Cha)VAAWTLKAACRFRGLISLSQ(SEQ ID NO:116), PPIFNDVYWK(Cha)VAAWTLKAARGLISLSQV(SEQ ID NO:117), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNFDVYWIAF(SEQ ID NO:118), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSILMQYIKANSKFIGIPMGLPQSIALSSLMVAQGGGGSGGGGGGSSCRFRGLISLSQVYLS(SEQ ID NO:119), RNVPPIFNDVYWIAFILMQYIKANSKFIGICRFRGLISLSQVYLS(SEQ IDNO:120), RNVPPIFNDVYWIAFZPKYVKQNTLKLATZCRFRGLISLSQVYLS(SEQ ID NO:121), CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFC(SEQ ID NO:122), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:160), RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:198), KTTKQSFDLSVKAQYKKNKHXXKXVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:201), RNVPPIFNFDVYWIAFXPKYVKQNTLKLATXCRFRGLISLSQVYLS(SEQ ID NO:203), RNVPPIFNDVYWIAFXXKXVAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:207), RNVPPIFNDVYWIAFXXKFVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:209), RNVPPIFNDVYWIAFXXKFVAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:211), KTTKQSFDLSVKAQYKKNKHZaWPEANQVGAGAFGPGFaZCRFRGLISLSQVYLS(SEQ ID NO:216), KTTKQSFDLSVKAQYKKNKHZaMDIDPYKEFGATVELLSFLPaZCRFRGLISLSQVYLS(SEQ ID and KTTKQSFDLSVKAQYKKNKHZaILMQYIKANSKFIGIPMGLPQSIALSSLMVAQaZCRFRGLISLSQVYLS (SEQ ID NO:217), and KTTKQSFDLSVKAQYKKNKHZaILMQYIKANSKFIGIPMGLPQSIALSSLMVAQaZCRFRGLISLSQVYLS (SEQ ID NO:218), where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, "(Cha)" represents L-cyclohexylalanine, and "X" represents any standard amino acid.

[0222] Unit D Design.

[0223] Structure of Unit D1 - Overview.

[0224] The peptide units provided herein are referred to as "unit C" as peptide units that 1) contain one B cell epitope and two Th epitopes, 2) 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 contain one or more auxiliary moieties. The function of the auxiliary moiety is not particularly limited as long as it does not impair the functions of the B cell epitope and the Th epitope, and may be appropriately designed as needed.

[0225] In one embodiment, the D unit may comprise a first B cell epitope, a first Th epitope and a second Th epitope linked sequentially from the N-terminus to the C-terminus.

[0226] Furthermore, unit D may further comprise a first auxiliary moiety. When unit D comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located N-terminal to the sequence of the first B-cell epitope within the sequence of unit D. In particular, the first auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the first auxiliary moiety are not limited to these.

[0227] Furthermore, unit D may further comprise a second auxiliary moiety. When unit D comprises a second auxiliary moiety, the sequence of the second auxiliary moiety 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. In particular, the second auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the second auxiliary moiety are not limited to these.

[0228] Furthermore, unit D may further comprise a third auxiliary moiety. When unit D comprises a third auxiliary moiety, the sequence of the third auxiliary moiety is located between the sequence of the first Th epitope and the sequence of the second Th epitope within the sequence of unit D. In particular, the third auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the third auxiliary moiety are not limited thereto.

[0229] Furthermore, unit D may further comprise a fourth auxiliary moiety. When unit D comprises a fourth auxiliary moiety, the sequence of the fourth auxiliary moiety is located C-terminal to the sequence of the second Th epitope in the sequence of unit D. In particular, the fourth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but is not limited to these.

[0230] In another embodiment, unit D may be a third Th epitope, a fourth Th epitope and a second B cell epitope linked sequentially from the N-terminus to the C-terminus.

[0231] Furthermore, unit D may further comprise a fifth auxiliary moiety. When unit D comprises a fifth auxiliary moiety, the sequence of the fifth auxiliary moiety is located N-terminal to the sequence of the third Th epitope in the sequence of unit D. In particular, the fifth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but is not limited to these.

[0232] Furthermore, unit D may further comprise a sixth auxiliary moiety. When unit D comprises a sixth auxiliary moiety, the sequence of the sixth auxiliary moiety is located between the sequence of the third Th epitope and the sequence of the fourth Th epitope in the sequence of unit D. In particular, the sixth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the functions of the sixth auxiliary moiety are not limited thereto.

[0233] Furthermore, unit D may further comprise a seventh auxiliary moiety, in which case the sequence of the seventh auxiliary moiety is located within the sequence of unit D between the sequence of the fourth Th epitope and the sequence of the second B cell epitope. In particular, the seventh auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the function of the seventh auxiliary moiety is not limited to these.

[0234] Furthermore, unit D may further comprise an eighth auxiliary moiety. When unit D comprises an eighth auxiliary moiety, the sequence of the eighth auxiliary moiety is located C-terminal to the sequence of the second B-cell epitope in the sequence of unit D. In particular, the eighth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the eighth auxiliary moiety are not limited to these.

[0235] Unit D2 - Structure of formula.

[0236] In one embodiment, unit B is a peptide represented by the following formula D or D': [Formula D] (N)-A1-B1-A2-T1-A3-T2-A4-(C) [Formula D'] (N)-A5-T3-A6-T4-A7-B2-A8-(C)

[0237] B1 and B2 are B cell epitopes and follow the design principles described above.

[0238] T1 to T4 are Th epitopes and follow the above design principles.

[0239] A1 to A8 are auxiliary parts and can be omitted.

[0240] In particular, A1 to A8 may have a dummy function, a solubility-improving function, a linker function, and / or a ring-forming function, but A1 to A8 are not limited thereto.

[0241] Length of unit D

[0242] In one embodiment, the length of unit D is about 24 mer, about 25 mer, about 26 mer, about 27 mer, about 28 mer, about 29 mer, about 30 mer, about 31 mer, about 32 mer, about 33 mer, about 34 mer, about 35 mer, about 36 mer, about 37 mer, about 38 mer, about 39 mer, about 40 mer, about 41 mer, about 42 mer, about 43 mer, about 44 mer, about 45 mer, about 46 mer, about 47 mer, about 48 mer, about 49 mer, about 50 mer, about 51 mer, about 52 mer, about 53 mer, about 54 mer, about 55 mer, about 56 mer, about 57 mer, about 58 mer, about 59 mer, about 60 mer, or about 61 mer , about 62-mer, about 63-mer, about 64-mer, about 65-mer, about 66-mer, about 67-mer, about 68-mer, about 69-mer, about 70-mer, about 71-mer, about 72-mer, about 73-mer, about 74-mer, about 75-mer, about 76-mer, about 77-mer, about 78-mer, about 79-mer, about 80-mer, about 81-mer, about 82-mer, about 83-mer, about 84-mer, about 85-mer, about 86-mer, about 87-mer, about 88-mer, about 89-mer, about 90-mer, about 91-mer, about 92-mer, about 93-mer, about 94-mer, about 95-mer, about 96-mer, about 97-mer, about 98-mer, about 99-mer, or about 100-mer. In another embodiment, the length of unit B may have a value within the two numerical ranges selected in the immediately preceding sentence. For example, the length of unit D may be in the range of about 24-mer to about 45-mer. In another example, the length of unit A may range from about a 40-mer to about an 80-mer.

[0243] Unit D - Exemplary design embodiment.

[0244] In one embodiment, unit D may have a sequence in which a first auxiliary moiety, a first B cell epitope, a second auxiliary moiety, a first Th epitope, a third auxiliary moiety, and a second Th epitope are linked in sequence. In particular, the first auxiliary moiety is a His-tag, and the second and third auxiliary moieties each have a linker function. The second and third auxiliary moieties each comprise one or more artificial amino acids.

[0245] In another embodiment, unit D may have a sequence in which a fourth auxiliary moiety, a second B-cell epitope, a fifth auxiliary moiety, a third Th epitope, a sixth auxiliary moiety, a fourth Th epitope, and a seventh auxiliary moiety are linked in sequence. In particular, the fourth auxiliary moiety is a His-tag, the fifth and sixth auxiliary moieties each have a linker function, and the seventh auxiliary moiety has a protective function. The fifth, sixth, and seventh auxiliary moieties each comprise one or more artificial amino acids.

[0246] In yet another embodiment, unit D comprises a third B cell epitope, an eighth auxiliary moiety, a fifth Th epitope, a ninth auxiliary moiety, and a sixth Th epitope. In particular, the eighth and ninth auxiliary moieties each have a linker function. The eighth and ninth auxiliary moieties each have a protective function and each comprise one or more artificial amino acids.

[0247] In yet another embodiment, unit D comprises a fourth B-cell epitope, a tenth auxiliary moiety, a seventh Th epitope, an eleventh auxiliary moiety, an eighth Th epitope, and a twelfth auxiliary moiety. In particular, the tenth auxiliary moiety and the eleventh auxiliary moiety each have a linker function. The twelfth auxiliary moiety has a protection function. The tenth auxiliary moiety, the eleventh auxiliary moiety, and the twelfth auxiliary moiety each comprise one or more artificial amino acids.

[0248] An embodiment of an array of units D.

[0249] In one embodiment, unit D is RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI (SEQ ID NO:123), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI (SEQ ID NO:124), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI (SEQ ID NO:125), ILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF (SEQ ID NO:126), ILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS (SEQ ID NO:127), ILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH (SEQ ID NO:128), PIFNDVYWIAFK(Cha)VAAWTLKAAK(Cha)VAAWTLKAA (SEQ ID NO:129), PPIFNDVYWK(Cha)VAAWTLKAAK(Cha)VAAWTLKAA (SEQ ID NO:130), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI (SEQ ID NO:131), MRGSHHHHHHGSDDDDKIVDILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZ (SEQ ID NO:132), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI (SEQ ID NO:133), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSILMQYIKANSKFIGIPMGLPQSIALSSLMVAQGGGGSGGGGGGSSILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ (SEQ ID NO:134), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZK(Cha)LAAFTIRAAaZ (SEQ IDand CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIC (SEQ ID NO: 135), and CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIC (SEQ ID NO: 136), where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, "(Cha)" represents L-cyclohexylalanine, and "X" represents any standard amino acid.

[0250] Unit E Design.

[0251] Unit E1 Structure - Overview.

[0252] The peptide units provided herein are referred to as "unit E" as peptide units that 1) contain two B cell epitopes and two Th epitopes, 2) the sequences of the two Th epitopes are located between the sequence of one of the two B cell epitopes and the sequence of the other B cell epitope, and 3) may contain one or more auxiliary moieties. The function of the auxiliary moiety is not particularly limited as long as it does not impair the function of the B cell epitope and the Th epitope, and may be appropriately designed as needed.

[0253] In one embodiment, unit E may be a first B cell epitope, a first Th epitope, a second Th epitope, and a second B cell epitope linked sequentially from the N-terminus to the C-terminus.

[0254] Furthermore, unit E may further comprise a first auxiliary moiety. When unit E comprises a first auxiliary moiety, the sequence of the first auxiliary moiety is located N-terminal to the sequence of the first B-cell epitope within the sequence of unit E. In particular, the first auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but the functions of the first auxiliary moiety are not limited thereto.

[0255] Additionally, unit E may further comprise a second auxiliary moiety. When unit E comprises a second auxiliary moiety, the sequence of the second auxiliary moiety 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. In particular, the second auxiliary moiety may have, but is not limited to, a dummy function, a solubility-enhancing function, a linker function, and / or a protective function.

[0256] Furthermore, unit E may further comprise a third auxiliary moiety. When unit E comprises a third auxiliary moiety, the sequence of the third auxiliary moiety is located between the sequence of the first Th epitope and the sequence of the second Th epitope within the sequence of unit E. In particular, the third auxiliary moiety may have, but is not limited to, a dummy function, a solubility-enhancing function, a linker function, and / or a protective function.

[0257] Furthermore, unit E may further comprise a fourth auxiliary moiety. When unit E comprises a fourth auxiliary moiety, the sequence of the fourth auxiliary moiety is located between the sequences of the second B-cell epitopes in the sequence of unit E. In particular, the fourth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a protective function, but the function of the fourth auxiliary moiety is not limited thereto.

[0258] Furthermore, unit E may further comprise a fifth auxiliary moiety. When unit E comprises a fifth auxiliary moiety, the sequence of the fifth auxiliary moiety is located N-terminal to the sequence of the second B-cell epitope within the sequence of unit E. In particular, the fifth auxiliary moiety may have a dummy function, a solubility-enhancing function, a linker function, and / or a cyclization function, but is not limited to these.

[0259] Unit E2 - Structure of formula

[0260] In one embodiment, unit E is a peptide represented by the following formula E: [Formula E] (N)-A1-B1-A2-T1-A3-T2-A4-B2-A5-(C)

[0261] B1 and B2 are B cell epitopes and follow the design principles described above.

[0262] T1 and T2 are Th epitopes and follow the design principles described above.

[0263] A1, A2, A3, A4, and A5 are auxiliary parts, which can be omitted.

[0264] In particular, A1, A2, A3, A4, and A5 may have a dummy function, a solubility-enhancing function, a linker function, and / or a ring-forming function, but A1, A2, A3, A4, and A5 are not limited thereto.

[0265] Length of unit E.

[0266] In one embodiment, the length of unit E is about 32 mer, about 33 mer, about 34 mer, about 35 mer, about 36 mer, about 37 mer, about 38 mer, about 39 mer, about 40 mer, about 41 mer, about 42 mer, about 43 mer, about 44 mer, about 45 mer, about 46 mer, about 47 mer, about 48 mer, about 49 mer, about 50 mer, about 51 mer, about 52 mer, about 53 mer, about 54 mer, about 55 mer, about 56 mer, about 57 mer, about 58 mer, about 59 mer, about 60 mer, about 61 mer, about 62 mer, about 63 mer, about 64 mer, about 65 mer, The length of unit E may be about 66-mer, about 67-mer, about 68-mer, about 69-mer, about 70-mer, about 71-mer, about 72-mer, about 73-mer, about 74-mer, about 75-mer, about 76-mer, about 77-mer, about 78-mer, about 79-mer, about 80-mer, about 81-mer, about 82-mer, about 83-mer, about 84-mer, about 85-mer, about 86-mer, about 87-mer, about 88-mer, about 89-mer, about 90-mer, about 91-mer, about 92-mer, about 93-mer, about 94-mer, about 95-mer, about 96-mer, about 97-mer, about 98-mer, about 99-mer, or about 100-mer. In another embodiment, the length of unit E may be within the two numerical ranges selected in the immediately preceding sentence. For example, the length of unit E may be in the range of about 32-mer to about 60-mer. In another example, the length of unit A may be in the range of about 50-mer to about 100-mer.

[0267] Unit E - an exemplary design embodiment.

[0268] In one embodiment, unit E may have a sequence in which a first auxiliary moiety, a first B cell epitope, a second auxiliary moiety, a first Th epitope, a third auxiliary moiety, a second Th epitope, a fourth auxiliary moiety, and a second B cell epitope are linked in sequence. In particular, the first auxiliary moiety is a His-tag. The second and fourth auxiliary moieties have a linker function and a protective function, respectively. The third auxiliary moiety has a linker function. The second, third, and fourth auxiliary moieties comprise one or more artificial amino acids.

[0269] In another embodiment, unit E may have a sequence in which a third B cell epitope, a fifth auxiliary moiety, a third Th epitope, a sixth auxiliary moiety, a fourth Th epitope, a seventh auxiliary moiety, and a fourth B cell epitope are linked in sequence. In particular, the fifth auxiliary moiety and the seventh auxiliary moiety have a linker function and a protective function, respectively. The sixth auxiliary moiety has a linker function. The fifth auxiliary moiety, the sixth auxiliary moiety, and the seventh auxiliary moiety comprise one or more artificial amino acids.

[0270] An embodiment of an array of units E.

[0271] In one embodiment, the unit E is selected from the group consisting of RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF (SEQ ID NO: 137), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGICRFRGLISLSQVYLS (SEQ ID NO: 138), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIKTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 139), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF (SEQ ID NO: 139). NO:140), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGICRFRGLISLSQVYLS(SEQ ID NO:141), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:142), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF(SEQ ID NO:143), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGICRFRGLISLSQVYLS(SEQ ID NO:144), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:145), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF(SEQ IDNo. 146), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSILMQYIKANSKFIGIPMGLPQSIALSSLMVAQILMQYIKANSKFIGIPMGLPQSIALSSLMVAQGGGGSGGGGGGSSCRFRGLISLSQVYLS (SEQ ID NO: 147), PIFNDVYWIAFK(Cha)VAAWTLKAAK(Cha)VAAWTLKAACRFRGLISLSQ (SEQ ID NO: 148), PPIFNDVYWK(Cha)VAAWTLKAAK(Cha)VAAWTLKAARGLISLSQV (SEQ ID NO: 149), and CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAFC (SEQ ID NO: 150). In this case, "a" indicates D-alanine, "Z" indicates 6-aminohexanoic acid, and "(Cha)" indicates L-cyclohexylalanine.

[0272] Peptide design.

[0273] Peptide design - an overview.

[0274] The peptides provided herein can be designed using one or more of the peptide units disclosed above. These peptides contain one or more peptide units, and may contain one or more types of peptide units. For example, peptides can be designed by 1) including only one peptide unit, 2) designing a concatemer by linking multiple peptide units of the same type having the same sequence, 3) designing a peptide in the form of a daisy chain by linking one or more types of peptide units having different sequences, 4) combining the design methods 1) to 3) above, or 5) designing a cyclic peptide by linking both ends of a peptide designed by the above method, but the design method is not limited to these. Each design method is described in detail below.

[0275] 1 unit design.

[0276] The peptide may be designed to contain only one of the above peptide units. In one embodiment, the peptide may contain one peptide unit selected from the group consisting of unit A, unit B, unit C, unit D, and unit E. In particular, the peptide unit has the above configuration.

[0277] Concatemer Design 1- Overview.

[0278] Peptides can be designed in the form of a concatemer, in which multiple peptide units having the same sequence are linked together. A peptide designed in the form of a concatemer consists of 1) one type of peptide unit and 2) multiple peptide units having the same or equivalent sequences.

[0279] In particular, two peptide units "having equivalent sequences" refer to 1) the presence of an auxiliary moiety at each of the N-terminus and / or C-terminus of the two peptides, and 2) the presence of an auxiliary moiety, if any, means that the sequences of the two peptides are different but the remaining sequences are identical. For example, if a first peptide has a sequence in which the first auxiliary moiety and the first unit A are linked N- to C-terminally, a second peptide has a sequence in which the first unit A and the first auxiliary moiety are linked N- to C-terminally, a third peptide has a sequence in which the second auxiliary moiety, the first unit A, and the third auxiliary moiety are linked N- to C-terminally, and a fourth peptide has the sequence of the first unit A, then the first to fourth peptides are said to have equivalent sequences.

[0280] In one embodiment, the peptide may comprise a first peptide unit sequentially linked to a second peptide unit, in particular, 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.

[0281] In another embodiment, the peptide may include a third peptide unit, a fourth peptide unit, and a fifth peptide unit linked sequentially in a sequence. In particular, 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 a sequence identical or equivalent to the third peptide unit.

[0282] In yet another embodiment, the peptide may comprise a sixth, seventh, eighth, and ninth peptide unit linked in sequence, wherein 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, eighth, and ninth peptide units each have a sequence identical or equivalent to the sixth peptide unit.

[0283] Concatemer Design 2-Formula

[0284] In one embodiment, the peptide may be a peptide represented by the following formula 1: [Formula 1] (N)-U1-U2-…-U n -(C) In the formula, U1~U n are peptide units selected from the group consisting of unit A, unit B, unit C, unit D, and unit E, each of which has the constituent elements of the peptide units described above.

[0285] U1~U n have the same or equivalent sequence.

[0286] n is an integer equal to or greater than 2.

[0287] Concatamer Design 3 - Exemplary Sequences

[0288] In one embodiment, the peptide is MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ (SEQ ID NO:151), RNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ (SEQ ID NO:152), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS(SEQ ID NO:153). and RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI (SEQ ID NO:153), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAFRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF (SEQ ID NO:155), where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, and "(Cha)" represents L-cyclohexylalanine.

[0289] Chain Design 1-Outline

[0290] Peptides can be designed in the form of a daisy chain in which multiple peptide units with different sequences are linked together. A daisy chain designed peptide consists of 1) at least one type of peptide unit and 2) multiple peptide units with different sequences.

[0291] In one embodiment, the peptide may comprise a first peptide unit and a second peptide unit linked in sequence, wherein the first peptide unit and the second peptide unit are each a peptide unit 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 different sequences from each other.

[0292] In another embodiment, the peptide may comprise a third peptide unit, a fourth peptide unit, and a fifth peptide unit linked in sequence, wherein the third peptide unit, the fourth peptide unit, and the fifth peptide unit are each a peptide unit 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 different sequences from each other.

[0293] In yet another embodiment, the peptide may comprise a sixth, seventh, eighth, and ninth peptide unit linked in sequence, wherein the sixth, seventh, eighth, and ninth peptide units are each a peptide unit selected from the group consisting of unit A, unit B, unit C, unit D, and unit E, and the sixth, seventh, eighth, and ninth peptide units have sequences different from each other.

[0294] Chain Design 2-type

[0295] In one embodiment, the peptide may be a peptide represented by the following formula 2: [Formula 2] (N)-U1-U2-…-U n -(C)

[0296] In the formula, U1~U n are peptide units selected from the group consisting of unit A, unit B, unit C, unit D, and unit E, each of which has the constituent elements of the peptide units described above.

[0297] U1~U n have the same or equivalent sequence.

[0298] n is an integer equal to or greater than 2.

[0299] String Design 3 - Exemplary Array

[0300] In one embodiment, the peptide may be RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ (SEQ ID NO:156), where "a" represents D-alanine, Z represents 6-aminohexanoic acid, and (Cha) represents L-cyclohexylalanine.

[0301] Combination Design 1 - Overview

[0302] The peptide may be designed by appropriately combining the above-mentioned 1) single-unit design, 2) concatemer design, and 3) daisy-chain design. In one embodiment, the peptide may be designed by first designing a unit peptide according to the above-mentioned design method, and then linking multiple unit peptides.

[0303] In one embodiment, the peptide may be formed by sequentially linking a first and second unit peptide, wherein the first and second unit peptides each have peptide components according to one of a single-unit design, a concatemer design, and a daisy-chain design, and the sequences of the first and second unit peptides are different from each other.

[0304] In another embodiment, the peptide may be formed by sequentially linking a third, fourth, and fifth peptide unit. In particular, the third, fourth, and fifth peptide unit each have peptide components according to one of a single-unit design, a concatemer design, and a daisy-chain design, and the sequences of the third, fourth, and fifth peptide unit are different from one another.

[0305] In yet another embodiment, the peptide may be formed by sequentially linking a sixth, seventh, eighth, and ninth peptide unit. In particular, the sixth, seventh, eighth, and ninth peptide unit units each have peptide components according to one of a single-unit design, a concatemer design, and a daisy-chain design, and the sequences of the sixth, seventh, eighth, and ninth peptide unit units are different from one another.

[0306] Combination Design 2-Formula

[0307] In one embodiment, the peptide may be a peptide represented by the following formula 3: [Formula 3] (N)-P1-P2-…-P n -(C)

[0308] In the formula, P1~P n are unit peptides designed by a method selected from the group consisting of single-unit design, concatemer design, and daisy-chain design, each of which has the above-mentioned peptide design and constituent elements.

[0309] n is an integer equal to or greater than 2.

[0310] Combinatorial Design 3 - Exemplary Sequences

[0311] In one embodiment, the peptides are RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFZRNVPPI FNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIZRNVPPIFNDVY WIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGICRFRGLISLSQVYLS (SEQ ID NO: 157), and RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFCRFRGLI and SLSQVYLSZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFZRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIZRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ ILMQYIKANSKFIGICRFRGLISLSQVYLS (SEQ ID NO:158), where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, and "(Cha)" represents L-cyclohexylalanine.

[0312] Annular design.

[0313] The peptide may be designed to form a cyclic structure. A cyclic peptide has improved stability in the subject's body, and therefore, when used as an immunotherapeutic agent, a cyclic peptide can be expected to have improved efficacy. In one embodiment, with respect to a peptide designed by a design method selected from the group consisting of single-unit design, concatemer design, daisy-chain design, and combinatorial design, the peptide may be designed to further have auxiliary moieties at the N-terminus and C-terminus that function to form a cyclic structure. In another embodiment, with respect to a peptide designed by a design method selected from the group consisting of single-unit design, concatemer design, daisy-chain design, and combinatorial design, the peptide may further comprise an auxiliary moiety and be designed to form a cyclic structure via the auxiliary moiety.

[0314] Other designs.

[0315] In addition to the above-mentioned design methods, the peptide may be designed by other methods as needed. In one embodiment, for peptides designed by a design method selected from the group consisting of unitary design, concatemer design, daisy-chain design, and combinatorial design methods, the peptide may further include one or more auxiliary moieties, one or more B cell epitopes, and / or one or more Th epitopes.

[0316] Disclosed peptide units and / or peptide-like sequences.

[0317] Disclosed herein are peptide units and / or peptides having sequences similar to those disclosed above in the "Unit A Design," "Unit B Design," "Unit C Design," "Unit D Design," "Unit E Design," and "Peptide Design" sections.

[0318] In one embodiment, the peptide unit may have a sequence that has 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of the sequences disclosed in the sections "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 is at least numerically identical to any one of the sequences disclosed in the sections "Unit A Design," "Unit B Design," "Unit C Design," "Unit D Design," and "Unit E Design," as selected in the immediately preceding sentence. In yet another embodiment, the 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 one selected from SEQ ID NO:56-SEQ ID NO:150, SEQ ID NO:160-SEQ ID NO:161, and SEQ ID NO:198-SEQ ID NO:220. In yet another embodiment, the peptide unit may have a sequence that is at least numerically identical to any one of the disclosed sequences selected from SEQ ID NO:56-SEQ ID NO:150, SEQ ID NO:160-SEQ ID NO:161, and SEQ ID NO:198-SEQ ID NO:220, as selected in the immediately preceding sentence. For example, the peptide unit may have a sequence that is 90% or greater identical to SEQ ID NO:56.

[0319] In yet another embodiment, the 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 one of the sequences disclosed in the "Peptide Design" section. In yet another embodiment, the peptide may have a sequence that matches any one of the sequences disclosed in the "Peptide Design" section by at least the numerical values ​​selected in the immediately preceding sentence. In yet another embodiment, the 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 one selected from SEQ ID NO:151-158. In yet another embodiment, the peptide may have a sequence that matches at least the numerically selected number in the immediately preceding sentence to any one of SEQ ID NO:151-158. For example, the peptide may have a sequence that is 90% or more identical to SEQ ID NO:151.

[0320] Use of peptides.

[0321] Uses of peptides - an overview.

[0322] The peptides provided herein are suitable as immunotherapeutic agents because, when introduced into a subject's body, they have the following properties: 1) they induce the production of antibodies that specifically bind to intentionally designed B cell epitopes, and 2) they induce the production of homogeneous antibodies. Therefore, the peptides can be used as immunotherapeutic agents. In one embodiment, the peptides provided herein can be used as immunotherapeutic agents for obesity. In another embodiment, the peptide units provided herein and / or peptides comprising same can be used for the treatment of obesity.

[0323] Use of peptides for the treatment of obesity.

[0324] The peptides provided herein contain a B cell epitope. In one embodiment, the B cell epitope may be a B cell epitope included in SEQ ID NOS:41-75. In particular, B cell epitopes are known to induce antibodies capable of binding to ApoB-100 (U.S. Patent Application 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). It is known from the above-mentioned prior literature that antibodies capable of binding to ApoB-100, when induced in a subject by a B cell epitope, have an immunotherapeutic effect against obesity. Accordingly, the present specification discloses the use of peptides and methods for treating obesity. To explain the immunotherapeutic effect of peptides on obesity, US Patent Application 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. If there is any discrepancy between the referenced portion and the description in this specification, the description in this specification shall be interpreted as taking precedence over the referenced portion.

[0325] A pharmaceutical composition comprising a peptide.

[0326] This specification discloses pharmaceutical compositions containing the above-mentioned peptides. These peptides can be used as immunotherapeutic agents and have a common feature with vaccines in that they induce humoral immunity when injected into the body. Therefore, those skilled in the art can add appropriate components to pharmaceutical compositions containing peptides for the administration of general vaccines and / or to enhance the effect of inducing an immune response. For example, pharmaceutical compositions can include, but are not limited to, formulated peptides, pharmaceutically acceptable carriers, supplements, and / or adjuvants. Specifically, the pharmaceutical composition may contain water, saline, dextrose, ethanol, glycerol, sodium chloride, dextrose, mannitol, sorbitol, lactose, gelatin, albumin, aluminum hydroxide, Freund's incomplete and complete adjuvant (Pifco Laboratories, Detroit, Michigan), Merck Adjuvant 65 (Merck and Company, Inc., Rahway, New Jersey), aluminum hydroxide gel (Alum), or aluminum salts, such as aluminum phosphate, AS04 series, MF, squalene, MF59, QS21, calcium, iron, or zinc salts, acylated tyrosine, insoluble suspensions of acylated fructose, cation- or anion-derived polysaccharides, polyphosphazenes, biodegradable microspheres, Quil A, toll-like receptor (TLR) agonists, PHADs [Avanti polar], and the like. lipid, monophosphoryl lipid A (synthetic)], monophosphoryl lipid A (MPL, monophosphoryl lipid A), synthetic lipid A, lipid A mimic or analog, aluminum salt, cytokine, saponin, prolactin, growth hormone deoxycholate, beta-glucan, polyribonucleotide, muramyl dipeptide (MDP) derivative, CpG oligo, Gram-negative bacterial lipopolysaccharide (LPS), polyphosphazene, emulsion, virosome, cochleate, poly(lactide-co-glycolide) (PLG) microparticle, poloxamer particle, microparticle, liposome, or suitable combination thereof.

[0327] Methods for producing peptides.

[0328] The peptides provided herein can be prepared by known methods that can be adopted by those skilled in the art, and the preparation method is not particularly limited. In one embodiment, the peptides may be prepared by recombinant protein preparation methods. In another embodiment, the peptides may be chemically synthesized. Specifically, the peptides can be synthesized by liquid phase peptide synthesis, solid phase peptide synthesis, convergence of small peptide fragments, etc., but the methods are not limited thereto.

[0329] Peptide units and / or nucleic acids encoding peptides.

[0330] Peptide units and / or nucleic acids encoding peptides - Overview.

[0331] The present specification discloses nucleic acids (hereinafter referred to as "encoding nucleic acids") that encode the peptide units and / or peptides disclosed above. The peptide units and peptides disclosed herein may contain non-standard amino acids, but codons corresponding to non-standard amino acids do not exist in nature. Therefore, non-standard amino acids cannot be encoded using a general method. Accordingly, these non-standard amino acids must be replaced with appropriate standard amino acids and encoded in the form of nucleic acids. If the peptide units and / or peptides do not contain non-standard amino acids, the encoding nucleic acids can be designed using nucleic acid codons corresponding to each standard amino acid.

[0332] For ease of explanation, peptide units and / or peptides that contain non-standard amino acids substituted with appropriate standard amino acids, as well as peptide units and / or peptides that contain only standard amino acids, will be referred to herein as encoded target peptides, and DNA and / or RNA that encodes the encoded target peptides will be referred to as encoding nucleic acids. In particular, if the peptide units and / or peptides do not contain non-standard amino acids, the peptide units and / or peptides will have the same amino acid sequence as the encoded target peptide.

[0333] As used herein, the term "encoded target peptide" is a conceptual term introduced to easily describe the resulting encoding nucleic acid, and is independent of the method or procedure for preparing the encoding nucleic acid.

[0334] Design of the encoded target peptide.

[0335] When the peptide units and peptides disclosed herein contain non-standard amino acids, the encoded target peptide is designed by replacing the peptide with the appropriate standard amino acid. When the peptide units and peptides disclosed herein do not contain non-standard amino acids, the encoded corresponding target peptide has the same sequence as the peptide units and peptides. In one embodiment, the encoded target peptide may have the non-standard amino acid replaced with any standard amino acid. In another embodiment, the encoded target peptide may have the non-standard amino acid replaced with a standard amino acid having the same or equivalent function. In yet another embodiment, the encoded target peptide may have the same sequence as the peptide units and / or peptides. In particular, the peptide units and / or peptides are characterized by not having any non-standard amino acids.

[0336] Embodiments for designing encoded target peptides—including PADRE.

[0337] The peptide units and peptides disclosed herein contain one or more Th epitopes. In particular, when the Th epitope is a sequence designated PADRE as disclosed in U.S. Patent Application No. 305,871, it may contain the non-standard amino acid L-cyclohexylalanine. According to the literature, L-cyclohexylalanine is believed to have both the function of protecting PADRE from peptidolytic enzymes and the function of an anchor residue capable of binding to MHC class II. Therefore, the encoded target peptide is designed by replacing L-cyclohexylalanine with an appropriate standard amino acid with the same or equivalent function. In one embodiment, L-cyclohexylalanine may be substituted with any standard amino acid. In another embodiment, L-cyclohexylalanine may be substituted with phenylalanine or tyrosine. In yet another embodiment, the sequence of the encoded target peptide corresponding to PADRE may be KFVAAWTLKAA (SEQ ID NO:195), KYVAAWTLKAA (SEQ ID NO:196), or KXVAAWTLKAA (SEQ ID NO:197), where X represents any standard amino acid.

[0338] 1. An embodiment of the sequence of the encoded target peptide.

[0339] In one embodiment, the sequences of the encoded target peptides are RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXCRFRGLISLSQVYLS (SEQ ID NO: 198), RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXGSHHHHHHGSDDDDK (SEQ ID NO: 199), GSHHHHHHGSDDDDKXXKXVAAWTLKAAXXRNVPPIFNDVYWIAF (SEQ ID NO: 200), KTTKQSFDLSVKAQYKKNKHXXKXVAAWTLKAAXXCRFRGLISLSQVYLS (SEQ ID NO: 201), RNVPPIFNDVYWIAFCRFRGLISLSQVYLSXXK(Cha)VAAWTLKAAXX (SEQ ID NO: 202), RNVPPIFNDVYWIAFXPKYVKQNTLKLATXCRFRGLISLSQVYLS (SEQ ID NO: 203). NO:203), RNVPPIFNDVYWIAFXXKXVAAWTLKAAXX(SEQ ID NO:204), RNVPPIFNDVYWIAFKXVAAWTLKAA(SEQ ID NO:205), RNVPPIFNDVYWIAFKXVAAWTLKAAHHHHHH(SEQ ID NO:206), RNVPPIFNDVYWIAFXXKXVAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:207), RNVPPIFNDVYWIAFXXKXVAAWTLKAACR(SEQ ID NO:208), RNVPPIFNDVYWIAFXXKFVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:209), RNVPPIFNFDVYWIAFXXKFVAAWTLKAAXX(SEQ ID NO:210), RNVPPIFNDVYWIAFXXKFVAAWTLKAACRFRGLISLSQVYLS (SEQ ID NO:211), and RNVPPIFNDVYWIAFXXKFVAAWTLKAACR (SEQ ID NO:212), where "X" represents any standard amino acid.

[0340] Design of coding nucleic acid 1 - based on nucleic acid codons.

[0341] The encoding nucleic acid disclosed herein refers to the nucleic acid codons that encode the target peptide. Because the sequence of the encoded target peptide is all standard amino acids, the encoding nucleic acid is designed based on the nucleic acid codons corresponding to each amino acid of the encoded target peptide. In particular, since one or more nucleic acid codons can correspond to one standard amino acid, two or more encoding nucleic acids can ultimately be designed to encode one encoded target peptide. In one embodiment, the encoding nucleic acid may be a DNA and / or RNA codon that encodes the encoded target peptide. In another embodiment, the encoding nucleic acid may have a DNA and / or RNA sequence that can complementarily bind to the DNA and / or RNA codon that encodes the encoded target peptide.

[0342] The encoding nucleic acid sequence may be codon optimized, as described in more detail below.

[0343] Design of coding nucleic acid 2 - codon optimization.

[0344] As described above, by simply linking nucleic acid codons corresponding to each amino acid of the target peptide to be encoded, multiple coding nucleic acids can be designed for one target nucleic acid. Because an average of one to six nucleic acid codons correspond to each standard amino acid, the number of possible nucleic acid codon combinations increases exponentially as the length of the amino acid sequence increases. However, not all of these combinations are equally important. Generally, there are nucleic acid codon combinations that can enhance intracellular expression of the encoded target peptide. These combinations may vary depending on the higher-order structure of the sequence itself, the type of target cell into which the coding nucleic acid is injected, and other factors. Discovering such nucleic acid codon combinations and designating them as the sequence of the coding nucleic acid is called codon optimization. A single coding target peptide does not necessarily require only one codon-optimized sequence; two or more codon-optimized sequences may exist.

[0345] In one embodiment, 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.

[0346] Codon optimization of coding nucleic acids 1 - Consideration of the higher-order structure of coding nucleic acids.

[0347] Codon optimization of the encoding nucleic acid may be performed taking into account the higher-order structure of the nucleic acid sequence itself. In one embodiment, the encoding 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 is less than about 1%, about 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%, or about 45%. Approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 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%, 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 immediately preceding sentence. For example, the sequence of the encoding nucleic acid may have a GC content ranging from about 20% to about 50%. In yet another embodiment, the sequence of the encoding nucleic acid may have a GC content less than the numerical range selected in the immediately preceding sentence. For example, the sequence of the encoding nucleic acid may have a GC content less than about 25%.

[0348] Codon optimization of coding nucleic acid 2 - Consideration of target cells for expression.

[0349] Codon optimization of the encoding nucleic acid may be achieved by taking into consideration the cells into which the encoding nucleic acid is to be injected and expressed. In one embodiment, codon optimization of the encoding nucleic acid may be achieved by taking into consideration the codon usage in prokaryotic or eukaryotic cells. In another embodiment, codon optimization of the encoding nucleic acid may be achieved by taking into consideration the codon usage of animal cells. In yet another embodiment, codon optimization of the encoding nucleic acid may be achieved by taking into consideration mammalian codon usage. In yet another embodiment, codon optimization of the encoding nucleic acid may be achieved by taking into consideration human codon usage. In yet another embodiment, the encoding nucleic acid may be codon optimized for E. coli. In yet another embodiment, the encoding nucleic acid may be codon optimized for mammals. In yet another embodiment, the encoding nucleic acid may be codon optimized for humans.

[0350] Embodiments of the coding nucleic acid sequence.

[0351] In one embodiment, the coding nucleic acid is 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCTTTCCGTGGACTGATTTCCCGTTCCCAGGTTTATCTGTCC-3' (SEQ ID NO:248), 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCTGTTTCCGTGGACTGATTTCCCGTTCCCAGGTTTATCTGTCC-3' (SEQ ID NO:249), 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCTGTTTCCGTGGACTGATTTCCCGTTCCCAGGTTTATCTGTCC-3' (SEQ ID NO:249) NO:250)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNGGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAG-3'(SEQ ID NO:251)、5'-ACGTAATGTTCCTCCTATCTTCAATGATGTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNGGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAG-3'(SEQ ID NO:252)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNGGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAG-3'(SEQ IDNO:253)、5'-GGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAGNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNCGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTC-3'(SEQ ID NO:254)、5'-GGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAGNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNCGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTC-3'(SEQ ID NO:255)、5'-GGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAGNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNCGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTC-3'(SEQ ID NO:256)、5'-AAAACGACAAAGCAATCATTTGATTTAAGTGTAAAAGCTCAGTATNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:257)、5'-AAAACGACAAAGCAATCATTTGATTTAAGTGTAAAAGCTCAGTATNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:258)、5'-AAAACGACAAAGCAATCATTTGATTTAAGTGTAAAAGCTCAGTATNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ IDNO:259)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:260)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:261)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:262)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNCCTAAGTATGTGAAGCAGAATACACTGAAGCTGGCAACCNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:263)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:264)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:265)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ IDNO:266)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCA-3'(SEQ ID NO:267)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCA-3'(SEQ ID NO:268)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCA-3'(SEQ ID NO:269)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCACATCACCATCACCATCAC-3'(SEQ ID NO:270)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCACATCACCATCACCATCAC-3'(SEQ ID NO:271)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCACATCACCATCACCATCAC-3'(SEQ ID NO:272)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:273)、5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ IDNO:274), 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:275), 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGT-3'(SEQ ID No. 277), and 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGT-3' (SEQ ID No. 278).

[0352] In one embodiment, the encoding nucleic acid can be represented by an RNA sequence equivalent to a sequence selected from SEQ ID NO:248 to SEQ ID NO:278.

[0353] In another embodiment, the encoding nucleic acid may be a sequence selected from SEQ ID NO: 248 to SEQ ID NO: 278 in which at least one codon has been replaced with a codon encoding the same amino acid. For example, the encoding nucleic acid may be a sequence in which the first codon (the first to third nucleic acids at the 5' end) of SEQ ID NO: 248 (i.e., CGT) has been replaced with CGC, CGG, CGA, AGA, or AGG.

[0354] In yet another embodiment, the encoding nucleic acid can be represented by an RNA sequence equivalent to a sequence selected from SEQ ID NO:248 to SEQ ID NO:278, in which one or more codons are replaced with codons encoding the same amino acid.

[0355] Pharmaceutical compositions comprising peptide units and / or nucleic acids encoding the peptides.

[0356] Pharmaceutical compositions containing coding nucleic acids - Overview.

[0357] The present specification provides pharmaceutical compositions comprising peptide units and / or nucleic acids encoding peptides (i.e., coding nucleic acids). In order to deliver the coding nucleic acids to a subject to exert the intended effect of inducing an immune response, the coding nucleic acids must be formulated by an appropriate method. The encoding nucleic acid can be prepared by known methods, for example, as described in WKKIM (2019, mRNA vaccine - a 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), Reichmuth 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.

[0358] A pharmaceutical composition comprising an encoding nucleic acid may further comprise an adjuvant and / or additional ingredients in addition to the formulated encoding nucleic acid, hi one embodiment, a pharmaceutical composition comprising an encoding nucleic acid comprises a formulated encoding nucleic acid, optionally an adjuvant, and optionally additional ingredients.

[0359] Formulated coding nucleic acids.

[0360] The formulated encoding nucleic acid can be formulated by one skilled in the art by selecting an appropriate delivery vehicle (vector) for the encoding nucleic acid. The encoding nucleic acid can be formulated using a viral vector and / or a non-viral vector. In one embodiment, the formulated encoding nucleic acid may comprise a viral vector. In another embodiment, the formulated encoding nucleic acid may comprise a non-viral vector. Specifically, non-viral vectors may include, but are not limited to, lipids, polymers, and inorganic nanoparticles.

[0361] In yet another embodiment, the formulated encoding nucleic acid may comprise one or more selected from the following:

[0362] These include naked nucleic acids, cationic peptide-complexed nucleic acids (protamine), positively charged oil-water cationic nanoemulsions (cationic nanoemulsions), nucleic acids bound 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 complexed with cationic polymers (e.g., polyethyleneimine (PEI)) (cationic polymers), nucleic acids complexed with cationic polymers such as PEI and lipid components (cationic polymer liposomes), nucleic acids complexed with polysaccharide polymers (e.g., chitosan) (polysaccharide particles), 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).

[0363] In yet another embodiment, the formulated encoding nucleic acid may comprise a lipid nanoparticle (LNP). In certain embodiments of the above, the lipid nanoparticle may be an ionizable cationic lipid, a phospholipid, cholesterol, and / or a lipid-anchored polyethylene glycol. Specifically, the ionizable cationic lipid may be one or more selected from 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), COVID-19 vaccine lipids ALC-0315 and SM-102, TT3 and biodegradable derivative FTT5 (Anderson Group), vitamin-derived lipids ssPalmE and VcLNP; A9 (Acuitas), L5 (Moderna), A18 lipid; ATX lipid (LUNAR® composition, Arcturus) and LP01 (Intellia Therapeutics). Specifically, the phospholipid may be one or more selected from 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0364] In certain embodiments, the formulated encoding nucleic acid may comprise a polymer-based delivery system, which may comprise one or more selected from polyethyleneimine (PEI), polyamidoamine (PAMAM), polypropyleneimine, and a polymer-based dendrimer.

[0365] In yet another embodiment, the formulated encoding nucleic acid may comprise a peptide-based delivery system. In certain embodiments, the peptide-based delivery system may include protamine. Specifically, the formulated encoding nucleic acid may be a protamine-mRNA complex.

[0366] In yet another embodiment, the formulated encoding nucleic acid may comprise a cationic lipid comprising a liposome, lipoplex, and / or cationic emulsion (CNE). In certain embodiments, the cationic lipid may be 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and / or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP).

[0367] Adjuvant.

[0368] In one embodiment, the pharmaceutical composition comprising the encoding nucleic acid may include as adjuvants lipid nanoparticles (LNPs), aluminum salts, 1,2-dioleyl-3-trimethylammonium-propane chloride, MF59 (Novartis) adjuvant, CD70, CD40 ligand (CD40L), TriMix, protamine acting through TLR7 signaling, and / or bacterially derived monophosphoryl lipid A.

[0369] component.

[0370] In one embodiment, the pharmaceutical composition comprising the encoding nucleic acid may optionally include various additional components. In another embodiment, the additional components may be one or more selected from the following:

[0371] lipids; salts to balance acidity in the body; sucrose to maintain stability during repeated freeze-thaw cycles; and vaccine stability enhancers.

[0372] Specifically, the lipid may be, but is not limited to, SM-102, PEG2000-DMG, DPSC, cholesterol, and / or ALC-0315. Specifically, the salt may be, but is not limited to, sodium acetate, potassium chloride, monobasic potassium phosphate, sodium chloride, and / or dibasic sodium phosphate anhydrous. Specifically, the vaccine stability enhancer may be, but is not limited to, acetic acid, an acid stabilizer (tromethamine), and / or ethanol.

[0373] Peptides - Overview.

[0374] The peptides provided herein comprise at least one peptide unit, which comprises at least one B cell epitope and at least one Th epitope, and may comprise an appropriate number of auxiliary moieties. The peptide unit is designed to uniformly induce only the intended antibody while exhibiting a certain level of immunogenicity in the subject's body. Furthermore, the peptide unit is designed to be relatively short, which allows for easy synthesis and low production costs. Due to the above-mentioned properties of the peptide unit, the peptide has properties suitable for use as an immunotherapeutic agent. The design principles of peptides and peptide units are disclosed in detail herein.

[0375] The names of each portion (e.g., auxiliary portion) of the peptides disclosed herein are provided for convenience of description. Accordingly, the scope and name of each portion may vary depending on the perspective. For example, auxiliary portions may be referred to as, but are not limited to, a protection portion, a dummy portion, and / or a linker. In another example, B-cell epitopes may be referred to as, but are not limited to, a Th-epitope protection epitope.

[0376] Possible embodiments of the present invention.

[0377] The following are possible examples of the present invention provided herein. The following examples provided in this section merely correspond to embodiments of the present invention. Therefore, the present invention provided herein cannot be construed as being limited to the following examples.

[0378] Symbols used in each example.

[0379] In the following, in addition to the numbers for distinguishing each embodiment, symbols used in a brief description of each embodiment will be explained.

[0380] "B" indicates a B cell epitope. "T" indicates a Th epitope. "A" indicates an auxiliary part. "U" indicates a peptide unit.

[0381] When each component is connected with "-", it means that the components on both sides of the "-" are directly connected or connected via any other component. For example, when written as BT, it includes all peptides in which a B cell epitope and a Th epitope are directly connected, and all peptides in which a B cell epitope and a Th epitope are connected via any other sequence.

[0382] Optionally, each component may be given a subscript number to indicate that the two components are different, for example, B1-B2-T, where B1 and B2 represent different B-cell epitopes.

[0383] The above symbols are merely used to roughly explain the embodiments, and the embodiments should not be construed as being limited by these symbols.

[0384] Peptide unit 1.

[0385] Example 1. Peptide units capable of inducing humoral immunity.

[0386] A peptide unit capable of inducing humoral immunity by being recognized by CD4+ T cells, comprising at least one Th epitope and at least one B cell epitope, wherein the length of the Th epitope is 8 mer, 9 mer, 10 mer, 11 mer, 12 mer, 13 mer, 14 mer, 15 mer, 16 mer, 17 mer, 18 mer, 19 mer, 20 mer, 21 mer, 22 mer, 23 mer, 24 mer, 25 mer, 26 mer, 27 mer, 28 mer, 29 mer, or 3 0-mer, and the length of the B-cell epitope is 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer, and the length of the peptide unit is 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer. 5mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, 32mer, 33mer, 34mer, 35mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer , 65mer, 66mer, 67mer, 68mer, 69mer, 70mer, 71mer, 72mer, 73mer, 74mer, 75mer, 76mer, 77mer, 78mer, 79mer, 80mer, 81mer, 82mer, 83mer, 84mer, 85mer, 86mer, 87mer, 88mer, 89mer, 90mer, 91mer, 92mer, 93mer, 94mer, 95mer, 96mer, 97mer, 98mer, 99mer, or 100mer.

[0387] Example 2. Peptide units that induce antibodies targeting apolipoprotein B-100.

[0388] A peptide unit capable of inducing humoral immunity by being recognized by CD4+ T cells, comprising at least one Th epitope and at least one B cell epitope, wherein the length of the Th epitope is 8 mer, 9 mer, 10 mer, 11 mer, 12 mer, 13 mer, 14 mer, 15 mer, 16 mer, 17 mer, 18 mer, 19 mer, 20 mer, 21 mer, 22 mer, 23 mer, 24 mer, 25 mer, or 30 mer. mer, 26mer, 27mer, 28mer, 29mer, or 30mer, and the B cell epitope is capable of inducing an antibody that targets apolipoprotein B-100, and the length of the peptide unit is 16mer, 17mer, 18mer, 19mer, 20mer, 21mer, 22mer, 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, 32mer, 33mer, 34mer, 35mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer, 65mer, 66mer, 67mer, 68mer, 69mer, 70mer, 71mer, 72mer, 73mer, 74mer, 75mer, 76mer, 77mer, 78mer, 79mer, 80mer, 81mer, 82mer, 83mer, 84mer, 85mer, 86mer, 87mer, 88mer, 89mer, 90mer, 91mer, 92mer, 93mer, 94mer, 95mer, 96mer, 97mer, 98mer, 99mer, 100mer, 101mer, 102mer, 103mer, 10 mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer r, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer, 65mer, 66mer, 67mer, 68mer, 69mer, A peptide unit characterized in that it is a 70mer, 71mer, 72mer, 73mer, 74mer, 75mer, 76mer, 77mer, 78mer, 79mer, 80mer, 81mer, 82mer, 83mer, 84mer, 85mer, 86mer, 87mer, 88mer, 89mer, 90mer, 91mer, 92mer, 93mer, 94mer, 95mer, 96mer, 97mer, 98mer, 99mer, or 100mer.

[0389] Example 3. Peptide units that induce antibodies targeting apolipoprotein B-100 contained in LDL and / or VLDL.

[0390] A peptide unit described in Example 2, characterized in that the B cell epitope induces an antibody that targets a site selected from the externally exposed site of apolipoprotein B-100 contained in low-density lipoprotein (LDL) and the externally exposed site of apolipoprotein B-100 contained in very-low-density lipoprotein (VLDL).

[0391] Example 4, Restrictions on Type B.

[0392] A peptide unit according to example 2, characterized in that the B-cell epitope is a fragment of apolipoprotein B-100 and / or a mimotope of apolipoprotein B-100.

[0393] Example 5, Restrictions on the Sequence of B.

[0394] The peptide unit according to Example 4, characterized in that the B-cell epitope is an epitope contained in a sequence selected from the group consisting of RNVPPIFNDVYWIAF (SEQ ID NO: 7), CRFRGLISLSQVYLS (SEQ ID NO: 7), KTTKQSFDLSVKAQYKKNKH (SEQ ID NO: 8), RFRGLISLSQVYLDP (SEQ ID NO: 221), and SVCGCPVGHHDVVGL (SEQ ID NO: 222), or a sequence selected from SEQ ID NOs: 6 to 8 and 221 to 222.

[0395] Example 6. Restrictions on full-length sequence length of peptide units.

[0396] The peptide unit according to any one of Examples 1 to 5, characterized in that the length of the peptide unit is 23-mer to 71-mer or 26-mer to 50-mer.

[0397] Peptide unit 2 - unit A.

[0398] Example 7, BT and TB.

[0399] A peptide unit according to any one of Examples 1 to 4, characterized in that the peptide unit comprises one B cell epitope and one Th epitope.

[0400] Example 8: Constraints on Sequence B, Constraints on Length T, and Constraints on Length U

[0401] The peptide unit according to Example 7, characterized in that the peptide unit is 26-mer to 45-mer in length, the B cell epitope is selected from RNVPPIFNDVYWIAF (SEQ ID NO: 6), NVPPIFNDVYWIAF (SEQ ID NO: 6), NVPPIFNDVYWIAF (SEQ ID NO: 6), RFRGLISLSQVYLDP (SEQ ID NO: 221), and SVCGCPVGHHDVVGL (SEQ ID NO: 222), and the Th epitope is 11-mer to 13-mer in length.

[0402] Example 9, Restrictions on Sequence T.

[0403] The Th epitope is 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); MQWNSTTFHQTLQDPRVRGLYFPAGG (SEQ ID NO: 165); FFLLTRILTI (SEQ ID NO: 166); FFLLTRILTIPQSLD (SEQ ID NO: 167); TSLNFLGGTTVCLGQ (SEQ ID NO: 168); NO:168);QSPTSNHSPTSCPPIC(SEQ ID NO:169);IIFLFILLLCLIFLLVLLD(SEQ ID NO:170);CTTPAQGNSMFPSC(SEQ ID NO:171);CTKPTDGN(SEQ ID NO:172);WASVRFSW(SEQ ID NO:173);LLPIFFCLW(SEQ ID NO:174);MDIDPYKEFGATVELLSFLP(SEQ ID NO:175);FLPSDFFPSV(SEQ ID NO:176);RDLLDTASALYREALESPEH(SEQ ID NO:177);PHHTALRQAILCWGELMTLA(SEQ ID NO:178);GRETVIEYLVSFGVW(SEQ ID NO:179);EYLVSFGVWIRTPPA(SEQ ID NO:180);VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181);TVVRRRGRSP(SEQ ID NO:182);VGPLTVNEKRRLKLI(SEQ ID NO:183);RHYLHTLWKAGILYK(SEQ ID NO:184);ESRLVVDFSQFSRGN(SEQ ID NO:185);LQSLTNLLSSNLSWL(SEQ ID NO:186);SSNLSWLSLDVSAAF(SEQ ID NO:187);A peptide unit according to any one of Examples 7 and 8, characterized in that it is selected from the group consisting of LHLYSHPIILGFRKI (SEQ ID NO: 188); KQCFRKLPVNRPIDW (SEQ ID NO: 189); LCQVFADATPTGWGL (SEQ ID NO: 190); AANWILRGTSFVYVP (SEQ ID NO: 191); and EIRLKVFVLGGCRHK (SEQ ID NO: 192), in which (Cha) represents L-cyclohexylalanine.

[0404] Example 10, BAT and TAB.

[0405] A peptide unit according to any one of Examples 7 and 8, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the B cell epitope and the Th epitope.

[0406] Example 11, Restrictions on A containing non-standard amino acids.

[0407] 11. The peptide unit of Example 10, wherein the auxiliary moiety comprises one or more non-standard amino acids.

[0408] Example 12. Restrictions on sequences of A containing non-standard amino acids.

[0409] The peptide unit of Example 11, wherein the peptide unit is characterized in that the auxiliary moieties are selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193), and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0410] Example 13, Restrictions on Sequence A that does not contain non-standard amino acids.

[0411] A peptide unit according to Example 10, characterized in that the peptide unit has auxiliary moieties selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0412] Peptide unit 3 - unit D.

[0413] Example 14, B-T1-T2 and T2-T1-B.

[0414] 5. The peptide unit according to any one of Examples 1 to 4, characterized in that it comprises one B cell epitope and two Th epitopes, referred to as the first Th epitope and the second Th epitope, respectively, and the first Th epitope is linked between the B cell epitope and the second Th epitope.

[0415] Example 15, constraints on sequence B, constraints on length T, and constraints on length U.

[0416] The peptide unit according to Example 14, wherein the peptide unit is 37-mer to 50-mer in length, 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 and second Th epitopes are each 11-mer to 13-mer in length.

[0417] Example 16: Restrictions on sequence T.

[0418] The Th epitope is 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); MQWNSTTFHQTLQDPRVRGLYFPAGG (SEQ ID NO: 165); FFLLTRILTI (SEQ ID NO: 166); FFLLTRILTIPQSLD (SEQ ID NO: 167); TSLNFLGGTTVCLGQ (SEQ ID NO: 168); NO:168);QSPTSNHSPTSCPPIC(SEQ ID NO:169);IIFLFILLLCLIFLLVLLD(SEQ ID NO:170);CTTPAQGNSMFPSC(SEQ ID NO:171);CTKPTDGN(SEQ ID NO:172);WASVRFSW(SEQ ID NO:173);LLPIFFCLW(SEQ ID NO:174);MDIDPYKEFGATVELLSFLP(SEQ ID NO:175);FLPSDFFPSV(SEQ ID NO:176);RDLLDTASALYREALESPEH(SEQ ID NO:177);PHHTALRQAILCWGELMTLA(SEQ ID NO:178);GRETVIEYLVSFGVW(SEQ ID NO:179);EYLVSFGVWIRTPPA(SEQ ID NO:180);VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181);TVVRRRGRSP(SEQ ID NO:182);VGPLTVNEKRRLKLI(SEQ ID NO:183);RHYLHTLWKAGILYK(SEQ ID NO:184);ESRLVVDFSQFSRGN(SEQ ID NO:185);LQSLTNLLSSNLSWL(SEQ ID NO:186);SSNLSWLSLDVSAAF(SEQ ID NO:187);A peptide unit according to any one of Examples 14 and 15, characterized in that it is selected from the group consisting of LHLYSHPIILGFRKI (SEQ ID NO: 188); KQCFRKLPVNRPIDW (SEQ ID NO: 189); LCQVFADATPTGWGL (SEQ ID NO: 190); AANWILRGTSFVYVP (SEQ ID NO: 191); and EIRLKVFVLGGCRHK (SEQ ID NO: 192), in which a denotes D-alanine, (Cha) denotes L-cyclohexylalanine, and Z denotes 6-aminohexanoic acid;

[0419] Example 17, BAT1-T2 and T2-T1AB.

[0420] A peptide unit according to any one of Examples 14 and 15, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the B cell epitope and the first Th epitope.

[0421] Example 18, B-T1AT2 and T2AT1-B.

[0422] A peptide unit described in any one of Examples 14 and 15, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the first Th epitope and the second Th epitope.

[0423] Example 19, Restrictions on A containing non-standard amino acids.

[0424] 19. The peptide unit of any one of Examples 17 and 18, wherein the auxiliary moiety comprises one or more non-standard amino acids.

[0425] Example 20, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0426] The peptide unit of Example 19, characterized in that the peptide unit has auxiliary moieties selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0427] Example 21, Restrictions on Sequence A that does not contain non-standard amino acids.

[0428] A peptide unit according to any one of Examples 17 and 18, characterized in that the peptide unit has an ancillary moiety selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0429] Example 22, BAT1AT2 and T2AT1AB.

[0430] 16. The peptide unit of any one of Examples 14 and 15, characterized in that the peptide unit further comprises a first auxiliary moiety and a second auxiliary moiety, the first auxiliary moiety being linked between the B cell epitope and the Th epitope, and the second auxiliary moiety being linked between the first Th epitope and the second Th epitope.

[0431] Example 23, Restrictions on A containing non-standard amino acids.

[0432] 23. The peptide unit of Example 22, wherein the first auxiliary moiety and / or the second auxiliary moiety comprises one or more non-standard amino acids.

[0433] Example 24, Restrictions on sequences of A containing non-standard amino acids.

[0434] The peptide unit of Example 23, wherein the ancillary moieties comprising one or more non-standard amino acids are independently selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193), and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0435] Example 25, Restrictions on Sequence A that does not contain non-standard amino acids.

[0436] The peptide unit of Example 22, wherein the first auxiliary moiety and / or the second auxiliary moiety are independently selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0437] Peptide unit 4 - unit B.

[0438] Example 26, B1-B2-T and T-B2-B1.

[0439] 5. A peptide unit according to any one of Examples 1 to 4, characterized in that the peptide unit comprises two B cell epitopes, referred to as a first B cell epitope and a second B cell epitope, respectively, and the second B cell epitope is linked between the first B cell epitope and the Th epitope.

[0440] Example 27, constraints on sequence B, constraints on length T, and constraints on length U.

[0441] 27. The peptide unit of Example 26, wherein the peptide unit is 45-mer to 50-mer in length, 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 11-mer to 13-mer in length.

[0442] Example 28, Restrictions on Sequence T.

[0443] The Th epitope is 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); MQWNSTTFHQTLQDPRVRGLYFPAGG (SEQ ID NO: 165); FFLLTRILTI (SEQ ID NO: 166); FFLLTRILTIPQSLD (SEQ ID NO: 167); TSLNFLGGTTVCLGQ (SEQ ID NO: 168); NO:168);QSPTSNHSPTSCPPIC(SEQ ID NO:169);IIFLFILLLCLIFLLVLLD(SEQ ID NO:170);CTTPAQGNSMFPSC(SEQ ID NO:171);CTKPTDGN(SEQ ID NO:172);WASVRFSW(SEQ ID NO:173);LLPIFFCLW(SEQ ID NO:174);MDIDPYKEFGATVELLSFLP(SEQ ID NO:175);FLPSDFFPSV(SEQ ID NO:176);RDLLDTASALYREALESPEH(SEQ ID NO:177);PHHTALRQAILCWGELMTLA(SEQ ID NO:178);GRETVIEYLVSFGVW(SEQ ID NO:179);EYLVSFGVWIRTPPA(SEQ ID NO:180);VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181);TVVRRRGRSP(SEQ ID NO:182);VGPLTVNEKRRLKLI(SEQ ID NO:183);RHYLHTLWKAGILYK(SEQ ID NO:184);ESRLVVDFSQFSRGN(SEQ ID NO:185);LQSLTNLLSSNLSWL(SEQ ID NO:186);SSNLSWLSLDVSAAF(SEQ ID NO:187);A peptide unit according to any one of Examples 26 and 27, characterized in that it is selected from the group consisting of LHLYSHPIILGFRKI (SEQ ID NO: 188); KQCFRKLPVNRPIDW (SEQ ID NO: 189); LCQVFADATPTGWGL (SEQ ID NO: 190); AANWILRGTSFVYVP (SEQ ID NO: 191); and EIRLKVFVLGGCRHK (SEQ ID NO: 192), in which a denotes D-alanine, (Cha) denotes L-cyclohexylalanine, and Z denotes 6-aminohexanoic acid;

[0444] Example 29, B1-B2AT and TAB2-B1.

[0445] 28. The peptide unit of any one of Examples 26 and 27, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the second B cell epitope and the Th epitope.

[0446] Example 30, B1AB2-T and T-B2AB1.

[0447] 28. The peptide unit of any one of Examples 26 and 27, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the first B-cell epitope and the second B-cell epitope.

[0448] Example 31, Restrictions on A containing non-standard amino acids.

[0449] 31. The peptide unit of any one of Examples 29 and 30, wherein the auxiliary moiety comprises one or more non-standard amino acids.

[0450] Example 32, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0451] The peptide unit of Example 31, characterized in that the peptide unit has auxiliary moieties selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0452] Example 33, A, Restrictions on sequences that do not contain non-standard amino acids.

[0453] A peptide unit according to any one of Examples 29 and 30, characterized in that the auxiliary moieties are selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0454] Example 34, B1A1B2A2T and TA2B2A1B1.

[0455] 28. The peptide unit of any one of Examples 26 and 27, characterized in that the peptide unit further comprises a first auxiliary moiety and a second auxiliary moiety, the first auxiliary moiety being linked between the first B-cell epitope and the second B-cell epitope, and the second auxiliary moiety being linked between the second B-cell epitope and the Th epitope.

[0456] Example 35, Restrictions on A containing non-standard amino acids.

[0457] The peptide unit of Example 34, wherein the first auxiliary moiety and / or the second auxiliary moiety comprises one or more non-standard amino acids.

[0458] Example 36, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0459] The peptide unit of Example 35, wherein the peptide unit is characterized in that the auxiliary moieties comprising one or more non-standard amino acids are each independently selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0460] Example 37, Restrictions on Sequence A that does not contain non-standard amino acids.

[0461] The peptide unit of Example 34, wherein the first auxiliary moiety and / or the second auxiliary moiety are each independently selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0462] Peptide unit 5 - unit C.

[0463] Example 38, B1-T-B2.

[0464] 5. A peptide unit according to any one of Examples 1 to 4, characterized in that the peptide unit comprises two B cell epitopes, called the first B cell epitope and the second B cell epitope, and one Th epitope, wherein the Th epitope is linked between the first B cell epitope and the second B cell epitope.

[0465] Example 39, constraints on sequence B, constraints on length T, and constraints on length U.

[0466] The peptide unit according to Example 38, wherein the peptide unit is 45-mer to 50-mer in length, 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 11-mer to 13-mer in length.

[0467] Example 40: Restrictions on sequence T.

[0468] The Th epitope is 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); MQWNSTTFHQTLQDPRVRGLYFPAGG (SEQ ID NO: 165); FFLLTRILTI (SEQ ID NO: 166); FFLLTRILTIPQSLD (SEQ ID NO: 167); TSLNFLGGTTVCLGQ (SEQ ID NO: 168); NO:168);QSPTSNHSPTSCPPIC(SEQ ID NO:169);IIFLFILLLCLIFLLVLLD(SEQ ID NO:170);CTTPAQGNSMFPSC(SEQ ID NO:171);CTKPTDGN(SEQ ID NO:172);WASVRFSW(SEQ ID NO:173);LLPIFFCLW(SEQ ID NO:174);MDIDPYKEFGATVELLSFLP(SEQ ID NO:175);FLPSDFFPSV(SEQ ID NO:176);RDLLDTASALYREALESPEH(SEQ ID NO:177);PHHTALRQAILCWGELMTLA(SEQ ID NO:178);GRETVIEYLVSFGVW(SEQ ID NO:179);EYLVSFGVWIRTPPA(SEQ ID NO:180);VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181);TVVRRRGRSP(SEQ ID NO:182);VGPLTVNEKRRLKLI(SEQ ID NO:183);RHYLHTLWKAGILYK(SEQ ID NO:184);ESRLVVDFSQFSRGN(SEQ ID NO:185);LQSLTNLLSSNLSWL(SEQ ID NO:186);SSNLSWLSLDVSAAF(SEQ ID NO:187);A peptide unit according to any one of Examples 38 and 39, characterized in that it is selected from the group consisting of LHLYSHPIILGFRKI (SEQ ID NO: 188); KQCFRKLPVNRPIDW (SEQ ID NO: 189); LCQVFADATPTGWGL (SEQ ID NO: 190); AANWILRGTSFVYVP (SEQ ID NO: 191); and EIRLKVFVLGGCRHK (SEQ ID NO: 192), in which a denotes D-alanine, (Cha) denotes L-cyclohexylalanine, and Z denotes 6-aminohexanoic acid;

[0469] Example 41, B1AT-B2 and B2-TAB1.

[0470] A peptide unit according to any one of Examples 38 and 39, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the first B cell epitope and the Th epitope.

[0471] Example 42, Restrictions on A containing non-standard amino acids.

[0472] 42. The peptide unit of Example 41, wherein the auxiliary moiety comprises one or more non-standard amino acids.

[0473] Example 43, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0474] The peptide unit of Example 42, wherein the peptide unit is characterized in that the auxiliary moieties are selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0475] Example 44, Restrictions on Sequence A that does not contain non-standard amino acids.

[0476] A peptide unit according to Example 41, characterized in that the auxiliary moieties are selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0477] Example 45, B1A1TA2B2.

[0478] 40. The peptide unit of any one of Examples 38 and 39, characterized in that the peptide unit further comprises a first auxiliary moiety and a second auxiliary moiety, the first auxiliary moiety being linked between the first B cell epitope and the Th epitope, and the second auxiliary moiety being linked between the second B cell epitope and the Th epitope.

[0479] Example 46, Restrictions on A containing non-standard amino acids.

[0480] The peptide unit of Example 45, wherein the first auxiliary moiety and / or the second auxiliary moiety comprises one or more non-standard amino acids.

[0481] Example 47, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0482] The peptide unit of Example 46, wherein the peptide unit is characterized in that the auxiliary moieties comprising one or more non-standard amino acids are each independently selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0483] Example 48, Restrictions on Sequence A that does not contain non-standard amino acids.

[0484] The peptide unit of Example 45, wherein the first auxiliary moiety and / or the second auxiliary moiety are each independently selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0485] Peptide unit 6 - unit E.

[0486] Example 49, B1-T1-T2-B2.

[0487] 5. The peptide unit according to any one of Examples 1 to 4, characterized in that the peptide unit comprises two B cell epitopes, referred to as the first B cell epitope and the second B cell epitope, respectively, and two Th epitopes, referred to as the first Th epitope and the second Th epitope, respectively, and the first B cell epitope, the first Th epitope, the second Th epitope, and the second B cell epitope are linked sequentially from the N-terminus to the C-terminus.

[0488] Example 50, constraints on sequence B, constraints on length T, and constraints on length U.

[0489] 49. The peptide unit according to Example 49, wherein the peptide unit is 52-mer to 90-mer in length, 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 11-mer to 13-mer in length.

[0490] Example 51, Restrictions on sequence T.

[0491] The first Th epitope and the second Th epitope are 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); MQWNSTTFHQTLQDPRVRGLYFPAGG (SEQ ID NO: 165); FFLLTRILTI (SEQ ID NO: 166); FFLLTRILTIPQSLD (SEQ ID NO: 167); TSLNFLGGTTVCLGQ (SEQ ID NO: 168); NO:168);QSPTSNHSPTSCPPIC(SEQ ID NO:169);IIFLFILLLCLIFLLVLLD(SEQ ID NO:170);CTTPAQGNSMFPSC(SEQ ID NO:171);CTKPTDGN(SEQ ID NO:172);WASVRFSW(SEQ ID NO:173);LLPIFFCLW(SEQ ID NO:174);MDIDPYKEFGATVELLSFLP(SEQ ID NO:175);FLPSDFFPSV(SEQ ID NO:176);RDLLDTASALYREALESPEH(SEQ ID NO:177);PHHTALRQAILCWGELMTLA(SEQ ID NO:178);GRETVIEYLVSFGVW(SEQ ID NO:179);EYLVSFGVWIRTPPA(SEQ ID NO:180);VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181);TVVRRRGRSP(SEQ ID NO:182);VGPLTVNEKRRLKLI(SEQ ID NO:183);RHYLHTLWKAGILYK(SEQ ID NO:184);ESRLVVDFSQFSRGN(SEQ ID NO:185);LQSLTNLLSSNLSWL(SEQ ID NO:186);SSNLSWLSLDVSAAF(SEQ ID NO:187);Peptide units according to example 50, characterized in that they are each independently selected from the group consisting of LHLYSHPIILGFRKI (SEQ ID NO: 188); KQCFRKLPVNRPIDW (SEQ ID NO: 189); LCQVFADATPTGWGL (SEQ ID NO: 190); AANWILRGTSFVYVP (SEQ ID NO: 191); and EIRLKVFVLGGCRHK (SEQ ID NO: 192), in which a represents D-alanine, (Cha) represents L-cyclohexylalanine, and Z represents 6-aminohexanoic acid;

[0492] Example 52, B1AT1-T2-B2 and B2-T2-T1AB1.

[0493] A peptide unit according to any one of Examples 49 and 50, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the first B cell epitope and the first Th epitope.

[0494] Example 53, B1-T1AT2-B2.

[0495] A peptide unit described in any one of Examples 49 and 50, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the first Th epitope and the second Th epitope.

[0496] Example 54, B1-T1-T2AB2 and B2AT2-T1-B1.

[0497] A peptide unit described in any one of Examples 49 and 50, characterized in that the peptide unit further comprises an auxiliary moiety, the auxiliary moiety being linked between the second Th epitope and the second B cell epitope.

[0498] Example 55, Restrictions on A containing non-standard amino acids.

[0499] 55. The peptide unit of any one of Examples 52 to 54, wherein the auxiliary moiety comprises one or more non-standard amino acids.

[0500] Example 56, Restrictions on A containing non-standard amino acids.

[0501] 55. The peptide unit according to any one of Examples 52 to 54, wherein the auxiliary moieties are selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0502] Example 57, Restrictions on Sequence A that does not contain non-standard amino acids.

[0503] 55. The peptide unit according to any one of Examples 52 to 54, characterized in that the auxiliary moieties are selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0504] Example 58, B1A1T1A2T2-B2 and B2-T2A2T1A1B1.

[0505] 51. The peptide unit of any one of Examples 49 and 50, characterized in that the peptide unit further comprises a first auxiliary portion and a second auxiliary portion, the auxiliary portion being linked between the first B cell epitope and the first Th epitope, and the second auxiliary portion being linked between the first Th epitope and the second Th epitope.

[0506] Example 59, B1A1T1-T2A2B2.

[0507] 51. The peptide unit of any one of Examples 49 and 50, characterized in that the peptide unit further comprises a first auxiliary moiety and a second auxiliary moiety, wherein the auxiliary moiety is linked between the first B cell epitope and the first Th epitope, and the second auxiliary moiety is linked between the second Th epitope and the second B cell epitope.

[0508] Example 60, B1-T1A1T2A2B2 and B2-T2A2T1A1B1.

[0509] 51. The peptide unit of any one of Examples 49 and 50, characterized in that the peptide unit further comprises a first auxiliary portion and a second auxiliary portion, the auxiliary portion being linked between the first Th epitope and the second Th epitope, and the first Th epitope and the second Th epitope being linked between the second Th epitope and the second B cell epitope.

[0510] Example 61, Restrictions on A containing non-standard amino acids.

[0511] 61. The peptide unit of any one of Examples 58 to 60, wherein the first auxiliary moiety and / or the second auxiliary moiety comprises one or more non-standard amino acids.

[0512] Example 62, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0513] 61. The peptide unit of any one of Examples 58 to 60, wherein the peptide unit is characterized in that the auxiliary moieties comprising one or more non-standard amino acids are each independently selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193), and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0514] Example 63, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0515] 61. The peptide unit of any one of Examples 58 to 60, wherein the first auxiliary moiety and / or the second auxiliary moiety are each independently selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0516] Example 64, B1A1T1A2T2A3B2.

[0517] 51. The peptide unit of any one of Examples 49 and 50, characterized in that the peptide unit further comprises a first auxiliary moiety, a second auxiliary moiety, and a third auxiliary moiety, wherein the first auxiliary moiety is linked between the first B cell epitope and the first Th epitope, the second auxiliary moiety is linked between the first Th epitope and the second Th epitope, and the third auxiliary moiety is linked between the second Th epitope and the second B cell epitope.

[0518] Example 65, Restrictions on A containing non-standard amino acids.

[0519] The peptide unit of Example 64, wherein the first auxiliary portion, the second auxiliary portion, and / or the third auxiliary portion comprises one or more non-standard amino acids.

[0520] Example 66, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0521] The peptide unit of Example 65, wherein the peptide unit is characterized in that the auxiliary moieties comprising one or more non-standard amino acids are each independently selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193), and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0522] Example 67, Restrictions on Sequence A that does not contain non-standard amino acids.

[0523] The peptide unit of Example 64, wherein 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).

[0524] Peptide unit 7-unit and additional auxiliary moieties.

[0525] Example 68, AU and UA.

[0526] A peptide unit comprising a peptide unit according to any one of Examples 1 to 67 and an additional auxiliary moiety.

[0527] Example 69, Restrictions on A containing non-standard amino acids.

[0528] 68. The peptide unit of Example 67, wherein the additional auxiliary moiety comprises one or more non-standard amino acids.

[0529] Example 70, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0530] The peptide unit of Example 69, characterized in that the peptide unit further comprises an additional auxiliary moiety selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0531] Example 71, Restrictions on Sequence A that does not contain non-standard amino acids.

[0532] The peptide unit according to Example 68, characterized in that the additional auxiliary moiety is selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0533] Example 72, AUA.

[0534] A peptide unit comprising a peptide unit according to any one of Examples 1 to 67 and a first additional ancillary moiety and a second additional ancillary moiety, in particular, the peptide unit is linked between the first additional ancillary moiety and the second additional ancillary moiety.

[0535] Example 73, Restrictions on A containing non-standard amino acids.

[0536] The peptide unit of Example 72, wherein the first additional auxiliary moiety and / or the second additional auxiliary moiety comprises one or more non-standard amino acids.

[0537] Example 74, Restrictions on Sequence A Containing Non-Canonical Amino Acids.

[0538] The peptide unit of Example 73, wherein the peptide unit is characterized in that the additional auxiliary moieties comprising one or more non-standard amino acids are each independently selected from a, Z, aZ, Za, GSHHHHHHGSDDDKZa (SEQ ID NO: 193) and aZGSHHHHHHGSDDDK (SEQ ID NO: 194).

[0539] Example 75, Restrictions on Sequence A that does not contain non-standard amino acids.

[0540] The peptide unit of Example 72, wherein the first additional auxiliary moiety and / or the second additional auxiliary moiety are each independently selected from CR, HHHHHH (SEQ ID NO: 53) and RRRRRR (SEQ ID NO: 159).

[0541] Restrictions on peptide unit 8-unit sequences.

[0542] Example 76, Restrictions on the Sequence of Unit A.

[0543] Material: RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:56); NO:58);ZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS(SEQ ID NO:59);KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:60);ZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:61);RNVPPIFNDVYWIAFK(Cha)VAOUT(SEQ ID NO:62);K(Cha)VAOUTVPPIFNDVYWIAF(SEQ ID NO:63);RNVPPIFNDVYK(Cha)VAOUT(SEQ ID NO:64); NO:65);PPIFNDVYWK(Cha)VAOTLKAA(SEQ ID NO:66);RNVPPIFNDVYWIAFK(Cha)VAOTLKAAHHHHHH(SEQ ID NO:67); NO:68);GSHHHHHHGSDDDDKZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:69); NO:70);GSHHHHHHGSDDDDKZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS(SEQ ID NO:71); NO:72);CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZGSHHHHHGGSDDDDK(SEQ ID NO:73);GSHHHHHHGSDDDDKZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:74);GSHHHHHHGSDDDDKKTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:75);KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZGSHHHHHHGSDDDDK(SEQ ID NO:76);MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:77);MRGSHHHHHHGSDDDDKIVDGSHHHHHHGSDDDDKRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:78);MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZGSHHHHHHGSDDDDK(SEQ ID NO:79);RNVPPIFNDVYWIAFILMQYIKANSKFIGI(SEQ ID NO:80);RNVPPIFNDVYWIAFILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ(SEQ ID NO:81);CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZC(SEQ ID NO:82);RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAACR(SEQ ID NO:161);RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXGSHHHHHHGSDDDDK(SEQ ID NO:199);GSHHHHHHGSDDDDKXXKXVAAWTLKAAXXRNVPPIFNDVYWIAF(SEQ ID NO:200);RNVPPIFNDVYWIAFXXKXVAAWTLKAAXX(SEQ ID NO:204);RNVPPIFNDVYWIAFKXVAAWTLKAA(SEQ ID NO:205);RNVPPIFNDVYWIAFKXVAAWTLKAAHHHHHH(SEQ ID NO:206);RNVPPIFNDVYWIAFXXKXVAAWTLKAACR(SEQ ID NO:208);RNVPPIFNDVYWIAFXXKFVAAWTLKAAXX (SEQ ID NO: 210); RNVPPIFNDVYWIAFXXKFVAAWTLKAACR (SEQ ID NO: 212); RNVPPIFNDVYWIAFCTKPTDGN (SEQ ID NO: 213); RNVPPIFNDVYWIAFLLPIFFCLW (SEQ ID NO: 214); RNVPPIFNDVYWIAFFLPSDFFPSV (SEQ ID NO: 215); RNVPPIFNDVYWIAFILMQYIKANSKFIGIHHHHHH (SEQ ID NO: 219); and RNVPPIFNDVYWIAFMDIDPYKEFGATVELLSFLPHHHHHH (SEQ ID NO: 219) NO:220) (wherein a represents D-alanine, Z represents 6-aminohexanoic acid, (Cha) represents L-cyclohexylalanine, and X represents any standard amino acid);

[0544] Example 77, Restrictions on the arrangement of unit D.

[0545] The peptide units are: RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI(SEQ ID NO:123); CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI(SEQ ID NO:124); KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI(SEQ ID NO:125); ILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:126); ILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS(SEQ ID NO:127); ILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:128); PIFNDVYWIAFK(Cha)VAAWTLKAAK(Cha)VAAWTLKAA(SEQ ID NO:129); PPIFNDVYWK(Cha)VAAWTLKAAK(Cha)VAAWTLKAA(SEQ ID NO:130); MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI(SEQ ID NO:131); MRGSHHHHHHGSDDDDKIVDILMQYIKANSKFIGIZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:132); MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGI(SEQ ID NO:133); MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSILMQYIKANSKFIGIPMGLPQSIALSSLMVAQGGGGSGGGGGGSSILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ(SEQ ID NO:134); RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZK(Cha)LAAFTIRAAaZ(SEQ ID NO:135);and CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIC (SEQ ID NO: 136), where a represents D-alanine, Z represents 6-aminohexanoic acid, and (Cha) represents L-cyclohexylalanine;

[0546] Example 78, Restrictions on the Sequence of Unit B.

[0547] Download RNVPPIFNDVYWIAFRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:83) NO:84) CRFRGLISLSQVYLSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:85) NO:86)、CRFRGLISLSQVYLSCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:87)、CRFRGLISLSQVYLSKTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:88) KTTKQSFDLSVKAQYKKNKHCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:89). NO:90)、KTTKQSFDLSVKAQYKKNKHKTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:91)、RNVPPIFNDVYWIAFCRFRGLISLSQVYLSK(Cha)VAAWTLKAA(SEQ ID NO:92)、PIFNDVYWIAFGLISLSQVYLSK(Cha)VAAWTLKAA(SEQ ID NO:93)、RNVPPIFNDVYCRFRGLISLSQK(Cha)VAAWTLKAA(SEQ ID NO:94). NO:95) 、PPIFNDVYWRGLISLSQVK(CHA)VAUTLKAA(SEQ ID NO:96)、RNVPPIFNDVYWIAFCRFRGLISLSQVYLSK(Cha)VAUTLKAAHHHHHH(SEQ IDNO:97), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:98), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAA(SEQ ID NO:99), RNVPPIFNDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAA(SEQ ID NO:100), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAA(SEQ ID NO:101), RNVPPIFNDVYWIAFGGGGSGGGGGGSSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAA(SEQ ID NO:102), RNVPPIFNDVYWIAFGGGGSGGGGGGSSRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZ(SEQ ID NO:103), RNVPPIFNDVYWIAFRNVPPIFNDVYWIAFILMQYIKANSKFIGI(SEQ ID NO:104), RNVPPIFNDVYWIAFRNVPPIFNDVYWIAFILMQYIKANSKFIGIPMGLPQSIALSSLMVAQ(SEQ ID NO:105), CRNVPPIFNFDVYWIAFCRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZC(SEQ ID NO:106), and RNVPPIFNDVYWIAFCRFRGLISLSQVYLSXXK(Cha)VAAWTLKAAXX (SEQ ID NO:202), where a represents D-alanine, (Cha) represents L-cyclohexylalanine, Z represents 6-aminohexanoic acid, and X represents any standard amino acid.

[0548] Example 79, Restrictions on the Sequence of Unit C.

[0549] Material: RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:107); NO:108);RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:109);CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:110);CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZCRFRGLISLSQVYLS(SEQ ID NO:111); NO:112);KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:113); NO:114);KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZKTTKQSFDLSVKAQYKKNKH(SEQ ID NO:115);PIFNDVYWIAFK(Cha)VAAWTLKAACRFRGLISLSQ(SEQ ID NO:116);PPIFNDVYWK(Cha)VAAWTLKAARGLISLSQV(SEQ ID NO:117);MRGSHHHHHHGSDDDDKIVD RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAF(SEQ ID NO:118); GGGGSGGGGGGSSCRFRGLISLSQVYLS(SEQ ID NO:119);RNVPPIFNDVYWIAFILMQYIKANSKFIGICRFRGLISLSQVYLS(SEQ ID NO:120);RNVPPIFNDVYWIAFZPKYVKQNTLKLATZCRFRGLISLSQVYLS(P5:SEQ ID NO:121);CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZRNVPPIFNDVYWIAFC(SEQ ID NO:122);RNVPPIFNFDVYWIAFZaK(Cha)VAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:160);RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:198);KTTKQSFDLSVKAQYKKNKHXXKXVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:201);RNVPPIFNDVYWIAFXPKYVKQNTLKLATXCRFRGLISLSQVYLS(SEQ ID NO:203);RNVPPIFNDVYWIAFXXKXVAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:207);RNVPPIFNDVYWIAFXXKFVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:209);RNVPPIFDVYWIAFXXKFVAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:211);KTTKQSFDLSVKAQYKKNKHZaWPEANQVGAGAFGPGaZCRFRGLISLSQVYLS(SEQ ID NO:216);KTTKQSFDLSVKAQYKKNKHZaMDIDPYKEFGATVELLSFLPaZCRFRGLISLSQVYLS(SEQ ID NO:217); and KTTKQSFDLSVKAQYKKNKHZaILMQYIKANSKFIGIPMGLPQSIALSSLMVAQaZCRFRGLISLSQVYLS (SEQ ID NO:218), where a represents D-alanine, (Cha) represents L-cyclohexylalanine, Z represents 6-aminohexanoic acid, and X represents any standard amino acid.

[0550] Example 80, Restrictions on the Sequence of Unit E.

[0551] The peptide units are RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF (SEQ ID NO:137), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGICRFRGLISLSQVYLS (SEQ ID NO:138), RNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIKTTKQSFDLSVKAQYKKNKH (SEQ ID NO:139), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF (SEQ ID NO:140), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGICRFRGLISLSQVYLS (SEQ ID NO:141), CRFRGLISLSQVYLSZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIKTTKQSFDLSVKAQYKKNKH (SEQ ID NO:142), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF (SEQ ID NO:143), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGICRFRGLISLSQVYLS (SEQ ID NO:144), KTTKQSFDLSVKAQYKKNKHZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIKTTKQSFDLSVKAQYKKNKH (SEQ ID NO:145), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAF (SEQ IDNO:146), MRGSHHHHHHGSDDDDKIVDRNVPPIFNDVYWIAFGGGGSGGGGGGSSILMQYIKANSKFIGIPMGLPQSIALSSLMVAQILMQYIKANSKFIGIPMGLPQSIALSSLMVAQGGGGSGGGGGGSSCRFRGLISLSQVYLS(SEQ ID NO:147), PIFNDVYWIAFK(Cha)VAAWTLKAAK(Cha)VAAWTLKAACRFRGLISLSQ(SEQ ID NO:148), PPIFDVYWK(Cha)VAAWTLKAAK(Cha)VAAWTLKAARGLISLSQV(SEQ ID NO:149), and CRNVPPIFNDVYWIAFZaK(Cha)VAAWTLKAAaZILMQYIKANSKFIGIRNVPPIFNDVYWIAFC(SEQ ID NO:150) (wherein a represents D-alanine, (Cha) represents L-cyclohexylalanine, and Z represents 6-aminohexanoic acid).

[0552] Peptide unit 9 - Formula.

[0553] Example 81, Higher level concepts of unit A formula.

[0554] A peptide unit according to any one of Examples 1 and 2, wherein the peptide unit is represented by the following [Formula A] or [Formula A'].

[0555] [Formula A]A1-B-A2-T-A3.

[0556] [Formula A']A1-T-A2-B-A3. wherein the peptide unit is capable of inducing humoral immunity by being recognized by CD4+ T cells and has a length of 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, 32mer, 33mer, 34mer, 35mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer, 65mer, 66mer, 67mer, 68mer, 69mer, 70mer, or 71mer; wherein A1 is a first ancillary moiety or is absent, wherein the first ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally a non-standard amino acid; A2 is a second ancillary moiety or is absent, wherein the second ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A3 is a third ancillary moiety or is absent, wherein the third ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; B, a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100 and can elicit antibodies that target apolipoprotein B-100; The Th epitope, T, can be recognized by CD4+ T cells and is an 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer in length.

[0557] Example 82, combination of sequences of unit A.

[0558] In Example 81 A1, A2, and A3 are 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 wherein a represents D-alanine and Z represents 6-aminohexanoic acid; B is RNVPPIFNDVYWIAF(SEQ ID NO:6), CRFRGLISLSQVYLS(SEQ ID NO:7), KTTKQSFDLSVKAQYKKNKH(SEQ ID NO:8), RNVPPIFNDVY(SEQ ID NO:9), CRFRGLISLSQ(SEQ ID NO:10), KTTKQSFDLSVK(SEQ ID NO:11), RNVPPIFNDVYW(SEQ ID NO:12), CRFRGLISLSQV(SEQ ID NO:13), KTTKQSFDLSVKAQYKK(SEQ ID NO:14), RNVPPIFNDVYWI(SEQ ID NO:15), CRFRGLISLSQVY(SEQ ID NO:16), KTTKQSFDLSVKAQYKKN(SEQ ID NO:17), PIFNDVYWIAF(SEQ ID NO:18), GLISLSQVYLS(SEQ ID NO:19), QSFDLSVKAQYKKNKH(SEQ ID NO:20), PPIFNDVYWIAF(SEQ ID NO:21), RGLISLSQVYLS(SEQ ID NO:22), KQSFDLSVKAQYKKNKH(SEQ ID NO:23), VPPIFNDVYWIAF(SEQ ID NO:24), FRGLISLSQVYLS(SEQ ID NO:25), TKQSFDLSVKAQYKKNKH(SEQ ID NO:26), NVPPIFNDVYWIA(SEQ ID NO:27), RFRGLISLSQVYL(SEQ ID NO:28), TKQSFDLSVKAQYKKN(SEQ ID NO:29), VPPIFNDVYWI(SEQ ID NO:30), FRGLISLSQVY(SEQ ID NO:31), TKQSFDLSVKAQYKKN (SEQ ID NO:32), PPIFNDVYW (SEQ ID NO:33), RGLISLSQV (SEQ ID NO:34), KQSFDLSVKAQYKK (SEQ ID NO:35), RFRGLISLSQVYLDP (SEQ ID NO:221), and SVCGCPVGHHDVVGL (SEQ ID NO:222); an epitope contained in any one of SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222; or Sequences that are 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 identical to any one of SEQ ID NOs:6 to 35, and SEQ ID NOs:221 to 222. (wherein a represents D-alanine, Z represents 6-aminohexanoic acid, T is 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)、MQWNSTTFHQTLQDPRVRGLYFPAGG(SEQ ID NO:165)、FFLLTRILTI(SEQ ID NO:166)、FFLLTRILTIPQSLD(SEQ ID NO:167)、TSLNFLGGTTVCLGQ(SEQ ID NO:168)、QSPTSNHSPTSCPPIC(SEQ ID NO:169)、IIFLFILLLCLIFLLVLLD(SEQ ID NO:170)、CTTPAQGNSMFPSC(SEQ ID NO:171)、CTKPTDGN(SEQ ID NO:172)、WASVRFSW(SEQ ID NO:173)、LLPIFFCLW(SEQ ID NO:174)、MDIDPYKEFGATVELLSFLP(SEQ ID NO:175)、FLPSDFFPSV(SEQ ID NO:176)、RDLLDTASALYREALESPEH(SEQ ID NO:177)、PHHTALRQAILCWGELMTLA(SEQ ID NO:178)、GRETVIEYLVSFGVW(SEQ ID NO:179)、EYLVSFGVWIRTPPA(SEQ ID NO:180)、VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181)、TVVRRRGRSP(SEQ ID NO:182)、VGPLTVNEKRRLKLI(SEQ ID NO:183)、RHYLHTLWKAGILYK(SEQ ID NO:184)、ESRLVVDFSQFSRGN(SEQ ID NO:185)、LQSLTNLLSSNLSWL(SEQ ID NO:186)、SSNLSWLSLDVSAAF(SEQ ID NO:187)、LHLYSHPIILGFRKI(SEQ IDNO:188)、KQCFRKLPVNRPIDW(SEQ ID NO:189)、LCQVFADATPTGWGL(SEQ ID NO:190)、AANWILRGTSFVYVP(SEQ ID NO:191)、EIRLKVFVLGGCRHK(SEQ ID NO:192) NO:195)、KYVAAWTLKAA(SEQ ID NO:196)、DIEKKIAKMEKASSVFNVVNS(SEQ ID NO:223)、YSGPLKAEIAQRLEDV(SEQ ID NO:224)、K(Cha)VKANTLKAA(SEQ ID NO:225)、K(Cha)VKANTLKAA(SEQ ID NO:225) NO:226)、K(Cha)VKAWTLKAA(SEQ ID NO:227)、K(Cha)VKAWTLKAA(SEQ ID NO:228)、K(Cha)VWANTLKAA(SEQ ID NO:229)、K(Cha)VWANTLKAA(SEQ ID NO:229) NO:230)、K(Cha)VWAYTLKAA(SEQ ID NO:231)、K(Cha)VWAVTLKAA(SEQ ID NO:232)、K(Cha)VYAWTLKAA(SEQ ID NO:233)、K(Cha)VYAWTLKAA(SEQ ID NO:234)、K(Cha)VYAWTLKAA(SEQ ID NO:234) ID NO:235)、K(Cha)VKAHTLKAA(SEQ ID NO:236)、K(Cha)VKAHTLKAA(SEQ ID NO:237)、K(Cha)VAANTLKAA(SEQ ID NO:238)、K(Cha)VAANTLKAA(SEQ ID NO:239)、K(Cha)VAANTLKAA(SEQ ID NO:239) NO:240)、K(Cha)VAAYTLKAA(SEQ ID NO:241)、K(Cha)VAAWTLKAA(SEQ ID NO:242)、K(Cha)VAAKTLKAA(SEQ ID NO:243)、K(Cha)VAAHTLKAA(SEQ ID NO:244)、K(Cha)VAAHTLKAA(SEQ ID NO:244) NO:245)、K(Cha)VAAWTLKAA(SEQ ID NO:246)、K(Cha)VMAATLKAA(SEQ ID NO:247) A sequence represented by the following formula I or II: [Formula I](N)-Lys-X1-X2-Ala-Ala-X3-Thr-X4-X5-Ala-Ala-(C) wherein X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is a hydrophobic amino acid, or leucine (Leu), or isoleucine (Ile), X3 is an aromatic or cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr), or histidine (His); X4 is an aliphatic long-chain amino acid, or isoleucine (Ile) or valine (Val), X5 is a charged amino acid or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly); [Formula II](N)-Lys-X1-Val-X2-Ala-X3-Thr-Leu-Lys-Ala-Ala-(C) wherein X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); X3 is asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys), or alanine (Ala); a sequence that is 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 identical to any one of SEQ ID NOs:1 to 5, SEQ ID NOs:162 to 192, SEQ ID NOs:195 to 196, SEQ ID NOs:223 to 247, and the sequences represented by [Formula I] or [Formula II]; (where (Cha) represents L-cyclohexylalanine and X represents any standard amino acid) It has.

[0559] Example 83, higher level concept of the formula for unit B.

[0560] The peptide unit according to any one of Examples 1 and 2, wherein the peptide unit is represented by the following [Formula B] or [Formula B']:

[0561] [Formula B] A1-B1-A2-B2-A3-T-A4

[0562] [Formula B']A1-T-A2-B1-A3-B2-A4 wherein the peptide unit is capable of inducing humoral immunity by being recognized by CD4+ T cells and is characterized in that its length is 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, 32mer, 33mer, 34mer, 35mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer, 65mer, 66mer, 67mer, 68mer, 69mer, 70mer, or 71 mer; A1 is a first ancillary moiety or is absent, wherein the first ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A2 is a second ancillary moiety or is absent, wherein the second ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A3 is a third ancillary moiety or is absent, wherein the third ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A4 is a fourth ancillary moiety or is absent, wherein the fourth ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; B1, a B cell epitope, is a fragment or mimotope of apolipoprotein B-100 and can induce antibodies that target apolipoprotein B-100; B2, a B cell epitope, is a fragment or mimotope of apolipoprotein B-100 and can induce antibodies that target apolipoprotein B-100; The Th epitope, T, can be recognized by CD4+ T cells and is an 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer in length.

[0563] Example 84, combination of sequences of unit B.

[0564] In Example 83, A1, A2, and A3 are 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 wherein a represents D-alanine and Z represents 6-aminohexanoic acid; B1 and B2 are RNVPPIFNDVYWIAF(SEQ ID NO:6), CRFRGLISLSQVYLS(SEQ ID NO:7), KTTKQSFDLSVKAQYKKNKH(SEQ ID NO:8), RNVPPIFNDVY(SEQ ID NO:9), CRFRGLISLSQ(SEQ ID NO:10), KTTKQSFDLSVK(SEQ ID NO:11), RNVPPIFNDVYW(SEQ ID NO:12), CRFRGLISLSQV(SEQ ID NO:13), KTTKQSFDLSVKAQYKK(SEQ ID NO:14), RNVPPIFNDVYWI(SEQ ID NO:15), CRFRGLISLSQVY(SEQ ID NO:16), KTTKQSFDLSVKAQYKKN(SEQ ID NO:17), PIFNDVYWIAF(SEQ ID NO:18), GLISLSQVYLS(SEQ ID NO:19), QSFDLSVKAQYKKNKH(SEQ ID NO:20), PPIFNDVYWIAF(SEQ ID NO:21), RGLISLSQVYLS(SEQ ID NO:22), KQSFDLSVKAQYKKNKH(SEQ ID NO:23), VPPIFNDVYWIAF(SEQ ID NO:24), FRGLISLSQVYLS(SEQ ID NO:25), TKQSFDLSVKAQYKKNKH(SEQ ID NO:26), NVPPIFNDVYWIA(SEQ ID NO:27), RFRGLISLSQVYL(SEQ ID NO:28), TKQSFDLSVKAQYKKN(SEQ ID NO:29), VPPIFNDVYWI(SEQ ID NO:30), FRGLISLSQVY(SEQ ID each independently selected from the group consisting of: TKQSFDLSVKAQYKKN (SEQ ID NO: 31), TKQSFDLSVKAQYKKN (SEQ ID NO: 32), PPIFNDVYW (SEQ ID NO: 33), RGLISLSQV (SEQ ID NO: 34), KQSFDLSVKAQYKK (SEQ ID NO: 35), RFRGLISLSQVYLDP (SEQ ID NO: 221), and SVCGCPVGHHDVVGL (SEQ ID NO: 222); an epitope contained in any one of SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222; or a sequence that is 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 identical to any one of SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222; (wherein a represents D-alanine, Z represents 6-aminohexanoic acid, T is 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)、MQWNSTTFHQTLQDPRVRGLYFPAGG(SEQ ID NO:165)、FFLLTRILTI(SEQ ID NO:166)、FFLLTRILTIPQSLD(SEQ ID NO:167)、TSLNFLGGTTVCLGQ(SEQ ID NO:168)、QSPTSNHSPTSCPPIC(SEQ ID NO:169)、IIFLFILLLCLIFLLVLLD(SEQ ID NO:170)、CTTPAQGNSMFPSC(SEQ ID NO:171)、CTKPTDGN(SEQ ID NO:172)、WASVRFSW(SEQ ID NO:173)、LLPIFFCLW(SEQ ID NO:174)、MDIDPYKEFGATVELLSFLP(SEQ ID NO:175)、FLPSDFFPSV(SEQ ID NO:176)、RDLLDTASALYREALESPEH(SEQ ID NO:177)、PHHTALRQAILCWGELMTLA(SEQ ID NO:178)、GRETVIEYLVSFGVW(SEQ ID NO:179)、EYLVSFGVWIRTPPA(SEQ ID NO:180)、VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181)、TVVRRRGRSP(SEQ ID NO:182)、VGPLTVNEKRRLKLI(SEQ ID NO:183)、RHYLHTLWKAGILYK(SEQ ID NO:184)、ESRLVVDFSQFSRGN(SEQ ID NO:185)、LQSLTNLLSSNLSWL(SEQ ID NO:186)、SSNLSWLSLDVSAAF(SEQ ID NO:187)、LHLYSHPIILGFRKI(SEQ IDNO:188)、KQCFRKLPVNRPIDW(SEQ ID NO:189)、LCQVFADATPTGWGL(SEQ ID NO:190)、AANWILRGTSFVYVP(SEQ ID NO:191)、EIRLKVFVLGGCRHK(SEQ ID NO:192) NO:195)、KYVAAWTLKAA(SEQ ID NO:196)、DIEKKIAKMEKASSVFNVVNS(SEQ ID NO:223)、YSGPLKAEIAQRLEDV(SEQ ID NO:224)、K(Cha)VKANTLKAA(SEQ ID NO:225)、K(Cha)VKANTLKAA(SEQ ID NO:225) NO:226)、K(Cha)VKAWTLKAA(SEQ ID NO:227)、K(Cha)VKAWTLKAA(SEQ ID NO:228)、K(Cha)VWANTLKAA(SEQ ID NO:229)、K(Cha)VWANTLKAA(SEQ ID NO:229) NO:230)、K(Cha)VWAYTLKAA(SEQ ID NO:231)、K(Cha)VWAVTLKAA(SEQ ID NO:232)、K(Cha)VYAWTLKAA(SEQ ID NO:233)、K(Cha)VYAWTLKAA(SEQ ID NO:234)、K(Cha)VYAWTLKAA(SEQ ID NO:234) ID NO:235)、K(Cha)VKAHTLKAA(SEQ ID NO:236)、K(Cha)VKAHTLKAA(SEQ ID NO:237)、K(Cha)VAANTLKAA(SEQ ID NO:238)、K(Cha)VAANTLKAA(SEQ ID NO:239)、K(Cha)VAANTLKAA(SEQ ID NO:239) NO:240)、K(Cha)VAAYTLKAA(SEQ ID NO:241)、K(Cha)VAAWTLKAA(SEQ ID NO:242)、K(Cha)VAAKTLKAA(SEQ ID NO:243)、K(Cha)VAAHTLKAA(SEQ ID NO:244)、K(Cha)VAAHTLKAA(SEQ ID NO:244) NO:245)、K(Cha)VAAWTLKAA(SEQ ID NO:246)、K(Cha)VMAATLKAA(SEQ ID NO:247) A sequence represented by the following formula I or II: [Formula I](N)-Lys-X1-X2-Ala-Ala-X3-Thr-X4-X5-Ala-Ala-(C) X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is a hydrophobic amino acid, or leucine (Leu), or isoleucine (Ile), X3 is an aromatic or cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr), or histidine (His); X4 is an aliphatic long-chain amino acid, or isoleucine (Ile) or valine (Val), X5 is a charged amino acid or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly); [Formula II](N)-Lys-X1-Val-X2-Ala-X3-Thr-Leu-Lys-Ala-Ala-(C) X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); X3 is asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys), or alanine (Ala); a sequence that is 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 identical to any one of SEQ ID NOs:1 to 5, SEQ ID NOs:162 to 192, SEQ ID NOs:195 to 196, SEQ ID NOs:223 to 247, and the sequences represented by [Formula I] or [Formula II]; (where (Cha) represents L-cyclohexylalanine and X represents any standard amino acid) It has.

[0565] Example 85, higher level concept of the formula of unit C.

[0566] The peptide unit according to any one of Examples 1 and 2, wherein the peptide unit is represented by the following formula C: [Formula C]A1-B1-A2-T-A3-B2-A4 wherein the peptide unit is capable of inducing humoral immunity by being recognized by CD4+ T cells and is characterized in that its length is 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, 32mer, 33mer, 34mer, 35mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer, 65mer, 66mer, 67mer, 68mer, 69mer, 70mer, or 71 mer; A1 is a first ancillary moiety or is absent, wherein the first ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A2 is a second ancillary moiety or is absent, wherein the second ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A3 is a third ancillary moiety or is absent, wherein the third ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A4 is a fourth ancillary moiety or is absent, wherein the fourth ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; B1, a B cell epitope, is a fragment or mimotope of apolipoprotein B-100 and can induce antibodies that target apolipoprotein B-100; B2, a B cell epitope, is a fragment or mimotope of apolipoprotein B-100 and can induce antibodies that target apolipoprotein B-100; The Th epitope, T, can be recognized by CD4+ T cells and is an 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer in length.

[0567] Example 86, combination of sequences of unit C.

[0568] In Example 85, A1, A2, A3, and A4 are 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 wherein a represents D-alanine and Z represents 6-aminohexanoic acid; B1 and B2 each independently have one selected from the group consisting of: RNVPPIFNDVYWIAF(SEQ ID NO:6), CRFRGLISLSQVYLS(SEQ ID NO:7), KTTKQSFDLSVKAQYKKNKH(SEQ ID NO:8), RNVPPIFNDVY(SEQ ID NO:9), CRFRGLISLSQ(SEQ ID NO:10), KTTKQSFDLSVK(SEQ ID NO:11), RNVPPIFNDVYW(SEQ ID NO:12), CRFRGLISLSQV(SEQ ID NO:13), KTTKQSFDLSVKAQYKK(SEQ ID NO:14), RNVPPIFNDVYWI(SEQ ID NO:15), CRFRGLISLSQVY(SEQ ID NO:16), KTTKQSFDLSVKAQYKKN(SEQ ID NO:17), PIFNDVYWIAF(SEQ ID NO:18), GLISLSQVYLS(SEQ ID NO:19), QSFDLSVKAQYKKNKH(SEQ ID NO:20), PPIFNDVYWIAF(SEQ ID NO:21), RGLISLSQVYLS(SEQ ID NO:22), KQSFDLSVKAQYKKNKH(SEQ ID NO:23), VPPIFNDVYWIAF(SEQ ID NO:24), FRGLISLSQVYLS(SEQ ID NO:25), TKQSFDLSVKAQYKKNKH(SEQ ID NO:26), NVPPIFNDVYWIA(SEQ ID NO:27), RFRGLISLSQVYL(SEQ ID NO:28), TKQSFDLSVKAQYKKN(SEQ ID NO:29), VPPIFNDVYWI(SEQ ID NO:30), FRGLISLSQVY(SEQ ID NO:31), TKQSFDLSVKAQYKKN (SEQ ID NO:32), PPIFNDVYW (SEQ ID NO:33), RGLISLSQV (SEQ ID NO:34), KQSFDLSVKAQYKK (SEQ ID NO:35), RFRGLISLSQVYLDP (SEQ ID NO:221), and SVCGCPVGHHDVVGL (SEQ ID NO:222); an epitope contained in any one of SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222; a sequence that is 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 identical to any one of the sequences represented by SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222; (where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, T is 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)、MQWNSTTFHQTLQDPRVRGLYFPAGG(SEQ ID NO:165)、FFLLTRILTI(SEQ ID NO:166)、FFLLTRILTIPQSLD(SEQ ID NO:167)、TSLNFLGGTTVCLGQ(SEQ ID NO:168)、QSPTSNHSPTSCPPIC(SEQ ID NO:169)、IIFLFILLLCLIFLLVLLD(SEQ ID NO:170)、CTTPAQGNSMFPSC(SEQ ID NO:171)、CTKPTDGN(SEQ ID NO:172)、WASVRFSW(SEQ ID NO:173)、LLPIFFCLW(SEQ ID NO:174)、MDIDPYKEFGATVELLSFLP(SEQ ID NO:175)、FLPSDFFPSV(SEQ ID NO:176)、RDLLDTASALYREALESPEH(SEQ ID NO:177)、PHHTALRQAILCWGELMTLA(SEQ ID NO:178)、GRETVIEYLVSFGVW(SEQ ID NO:179)、EYLVSFGVWIRTPPA(SEQ ID NO:180)、VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181)、TVVRRRGRSP(SEQ ID NO:182)、VGPLTVNEKRRLKLI(SEQ ID NO:183)、RHYLHTLWKAGILYK(SEQ ID NO:184)、ESRLVVDFSQFSRGN(SEQ ID NO:185)、LQSLTNLLSSNLSWL(SEQ ID NO:186)、SSNLSWLSLDVSAAF(SEQ ID NO:187)、LHLYSHPIILGFRKI(SEQ IDThose selected from the group consisting of NO:188), KQCFRKLPVNRPIDW (SEQ ID NO:189), LCQVFADATPTGWGL (SEQ ID NO:190), AANWILRGTSFVYVP (SEQ ID NO:191), EIRLKVFVLGGCRHK (SEQ ID NO:192), KFVAAWTLKAA (SEQ ID NO:195), KYVAAWTLKAA (SEQ ID NO:196), DIEKKIAKMEKASSVFNVVNS (SEQ ID NO:223), YSGPLKAEIAQRLEDV (SEQ ID NO:224), K(Cha)VKANTLKAA (SEQ ID NO:225), K(Cha)VKANTLKAA (SEQ ID NO:226), K(Cha)VKAWTLKAA (SEQ ID NO:227), K(Cha)VKAWTLKAA (SEQ ID NO:228), K(Cha)VWANTLKAA (SEQ ID NO:229), K(Cha)VWANTLKAA (SEQ ID NO:230), K(Cha)VWAYTLKAA (SEQ ID NO:231), K(Cha)VWAVTLKAA (SEQ ID NO:232), K(Cha)VYAWTLKAA (SEQ ID NO:233), K(Cha)VYAWTLKAA (SEQ ID NO:234), R(Cha)VRANTLKAA (SEQ ID NO:235), K(Cha)VKAHTLKAA (SEQ ID NO:236), K(Cha)VKAHTLKAA (SEQ ID NO:237), K(Cha)VAANTLKAA (SEQ ID NO:238), K(Cha)VAANTLKAA (SEQ ID NO:239), K(Cha)VAAYTLKAA (SEQ ID NO:240), K(Cha)VAAYTLKAA (SEQ ID NO:241), K(Cha)VAAWTLKAA (SEQ ID NO:242), K(Cha)VAAKTLKAA (SEQ ID NO:243), K(Cha)VAAHTLKAA (SEQ ID NO:244), K(Cha)VAAATLKAA (SEQ ID NO:245), K(Cha)VAAWTLKAA (SEQ ID NO:246), and K(Cha)VMAATLKAA (SEQ ID NO:247); A sequence represented by the following formula I or II: [Formula I](N)-Lys-X1-X2-Ala-Ala-X3-Thr-X4-X5-Ala-Ala-(C) X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is a hydrophobic amino acid, or leucine (Leu), or isoleucine (Ile), X3 is an aromatic or cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr), or histidine (His); X4 is an aliphatic long-chain amino acid, or isoleucine (Ile) or valine (Val), X5 is a charged amino acid or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly); [Formula II](N)-Lys-X1-Val-X2-Ala-X3-Thr-Leu-Lys-Ala-Ala-(C) X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); X3 is asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys), or alanine (Ala); Sequences that are 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 identical to any one of SEQ ID NOs: 1 to 5, SEQ ID NOs: 162 to 192, SEQ ID NOs: 195 to 196, SEQ ID NOs: 223 to 247, and the sequences represented by [Formula I] or [Formula II]. (where (Cha) represents L-cyclohexylalanine and X represents any standard amino acid) It has.

[0569] Example 87, Higher level concept of the formula of unit D.

[0570] The peptide unit according to any one of Examples 1 and 2, wherein the peptide unit is represented by the following formula I or II: [Formula D] A1-B-A2-T1-A3-T2-A4 [Formula D']A1-T1-A2-T2-A3-B-A4 wherein the peptide unit is capable of inducing humoral immunity by being recognized by CD4+ T cells and is characterized in that its length is 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, 32mer, 33mer, 34mer, 35mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer, 65mer, 66mer, 67mer, 68mer, 69mer, 70mer, or 71 mer; A1 is a first ancillary moiety or is absent, wherein the first ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A2 is a second ancillary moiety or is absent, wherein the second ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A3 is a third ancillary moiety or is absent, wherein the third ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A4 is a fourth ancillary moiety or is absent, wherein the fourth ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; B, a B cell epitope, is a fragment of apolipoprotein B-100 or a mimotope of apolipoprotein B-100 and is capable of inducing antibodies that target apolipoprotein B-100; the Th epitope, T1, can be recognized by CD4+ T cells and is an 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer in length; The Th epitope, T2, can be recognized by CD4+ T cells and is an 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer in length.

[0571] Example 88, combination of sequences of unit D.

[0572] In Example 87, A1, A2, A3, and A4 are 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 wherein a represents D-alanine and Z represents 6-aminohexanoic acid; B is RNVPPIFNDVYWIAF(SEQ ID NO:6), CRFRGLISLSQVYLS(SEQ ID NO:7), KTTKQSFDLSVKAQYKKNKH(SEQ ID NO:8), RNVPPIFNDVY(SEQ ID NO:9), CRFRGLISLSQ(SEQ ID NO:10), KTTKQSFDLSVK(SEQ ID NO:11), RNVPPIFNDVYW(SEQ ID NO:12), CRFRGLISLSQV(SEQ ID NO:13), KTTKQSFDLSVKAQYKK(SEQ ID NO:14), RNVPPIFNDVYWI(SEQ ID NO:15), CRFRGLISLSQVY(SEQ ID NO:16), KTTKQSFDLSVKAQYKKN(SEQ ID NO:17), PIFNDVYWIAF(SEQ ID NO:18), GLISLSQVYLS(SEQ ID NO:19), QSFDLSVKAQYKKNKH(SEQ ID NO:20), PPIFNDVYWIAF(SEQ ID NO:21), RGLISLSQVYLS(SEQ ID NO:22), KQSFDLSVKAQYKKNKH(SEQ ID NO:23), VPPIFNDVYWIAF(SEQ ID NO:24), FRGLISLSQVYLS(SEQ ID NO:25), TKQSFDLSVKAQYKKNKH(SEQ ID NO:26), NVPPIFNDVYWIA(SEQ ID NO:27), RFRGLISLSQVYL(SEQ ID NO:28), TKQSFDLSVKAQYKKN(SEQ ID NO:29), VPPIFNDVYWI(SEQ ID NO:30), FRGLISLSQVY(SEQ ID NO:31), TKQSFDLSVKAQYKKN (SEQ ID NO:32), PPIFNDVYW (SEQ ID NO:33), RGLISLSQV (SEQ ID NO:34), KQSFDLSVKAQYKK (SEQ ID NO:35), RFRGLISLSQVYLDP (SEQ ID NO:221), and SVCGCPVGHHDVVGL (SEQ ID NO:222); an epitope contained in any one of SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222; A sequence that is 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 identical to any one of the sequences represented by SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222. (where "a" represents D-alanine, "Z" represents 6-aminohexanoic acid, T1 and T2 are each independently 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)、MQWNSTTFHQTLQDPRVRGLYFPAGG(SEQ ID NO:165)、FFLLTRILTI(SEQ ID NO:166)、FFLLTRILTIPQSLD(SEQ ID NO:167)、TSLNFLGGTTVCLGQ(SEQ ID NO:168)、QSPTSNHSPTSCPPIC(SEQ ID NO:169)、IIFLFILLLCLIFLLVLLD(SEQ ID NO:170)、CTTPAQGNSMFPSC(SEQ ID NO:171)、CTKPTDGN(SEQ ID NO:172)、WASVRFSW(SEQ ID NO:173)、LLPIFFCLW(SEQ ID NO:174)、MDIDPYKEFGATVELLSFLP(SEQ ID NO:175)、FLPSDFFPSV(SEQ ID NO:176)、RDLLDTASALYREALESPEH(SEQ ID NO:177)、PHHTALRQAILCWGELMTLA(SEQ ID NO:178)、GRETVIEYLVSFGVW(SEQ ID NO:179)、EYLVSFGVWIRTPPA(SEQ ID NO:180)、VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181)、TVVRRRGRSP(SEQ ID NO:182)、VGPLTVNEKRRLKLI(SEQ ID NO:183)、RHYLHTLWKAGILYK(SEQ ID NO:184)、ESRLVVDFSQFSRGN(SEQ ID NO:185)、LQSLTNLLSSNLSWL(SEQ ID NO:186)、SSNLSWLSLDVSAAF(SEQ ID NO:187)、LHLYSHPIILGFRKI(SEQ IDThose selected from the group consisting of NO:188), KQCFRKLPVNRPIDW (SEQ ID NO:189), LCQVFADATPTGWGL (SEQ ID NO:190), AANWILRGTSFVYVP (SEQ ID NO:191), EIRLKVFVLGGCRHK (SEQ ID NO:192), KFVAAWTLKAA (SEQ ID NO:195), KYVAAWTLKAA (SEQ ID NO:196), DIEKKIAKMEKASSVFNVVNS (SEQ ID NO:223), YSGPLKAEIAQRLEDV (SEQ ID NO:224), K(Cha)VKANTLKAA (SEQ ID NO:225), K(Cha)VKANTLKAA (SEQ ID NO:226), K(Cha)VKAWTLKAA (SEQ ID NO:227), K(Cha)VKAWTLKAA (SEQ ID NO:228), K(Cha)VWANTLKAA (SEQ ID NO:229), K(Cha)VWANTLKAA (SEQ ID NO:230), K(Cha)VWAYTLKAA (SEQ ID NO:231), K(Cha)VWAVTLKAA (SEQ ID NO:232), K(Cha)VYAWTLKAA (SEQ ID NO:233), K(Cha)VYAWTLKAA (SEQ ID NO:234), R(Cha)VRANTLKAA (SEQ ID NO:235), K(Cha)VKAHTLKAA (SEQ ID NO:236), K(Cha)VKAHTLKAA (SEQ ID NO:237), K(Cha)VAANTLKAA (SEQ ID NO:238), K(Cha)VAANTLKAA (SEQ ID NO:239), K(Cha)VAAYTLKAA (SEQ ID NO:240), K(Cha)VAAYTLKAA (SEQ ID NO:241), K(Cha)VAAWTLKAA (SEQ ID NO:242), K(Cha)VAAKTLKAA (SEQ ID NO:243), K(Cha)VAAHTLKAA (SEQ ID NO:244), K(Cha)VAAATLKAA (SEQ ID NO:245), K(Cha)VAAWTLKAA (SEQ ID NO:246), and K(Cha)VMAATLKAA (SEQ ID NO:247); A sequence represented by the following formula I or II: [Formula I](N)-Lys-X1-X2-Ala-Ala-X3-Thr-X4-X5-Ala-Ala-(C) X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is a hydrophobic amino acid, or leucine (Leu), or isoleucine (Ile), X3 is an aromatic or cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr), or histidine (His); X4 is an aliphatic long-chain amino acid, or isoleucine (Ile) or valine (Val), X5 is a charged amino acid or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly); [Formula II](N)-Lys-X1-Val-X2-Ala-X3-Thr-Leu-Lys-Ala-Ala-(C): X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met). X3 is asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys), or alanine (Ala); Sequences that are 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 identical to any one of SEQ ID NOs: 1 to 5, SEQ ID NOs: 162 to 192, SEQ ID NOs: 195 to 196, SEQ ID NOs: 223 to 247, and the sequences represented by [Formula I] or [Formula II]. (where (Cha) represents L-cyclohexylalanine and X represents any standard amino acid) It has.

[0573] Example 89, Higher level concepts of the formula of unit E.

[0574] The peptide unit according to any one of Examples 1 and 2, wherein the peptide unit is represented by the following formula E: [Formula E]A1-B1-A2-T1-A3-T2-A4-B2-A5 wherein the peptide unit is capable of inducing humoral immunity by being recognized by CD4+ T cells and has a length of 23mer, 24mer, 25mer, 26mer, 27mer, 28mer, 29mer, 30mer, 31mer, 32mer, 33mer, 34mer, 35mer, 36mer, 37mer, 38mer, 39mer, 40mer, 41mer, 42mer, 43mer, 44mer, 45mer, 46mer, 47mer, 48mer, 49mer, 50mer, 51mer, 52mer, 53mer, 54mer, 55mer, 56mer, 57mer, 58mer, 59mer, 60mer, 61mer, 62mer, 63mer, 64mer, 65mer, 66mer, 67mer, 68mer, 69mer, 70mer, or 71mer; A1 is a first ancillary moiety or is absent, wherein the first ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A2 is a second ancillary moiety or is absent, wherein the second ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A3 is a third ancillary moiety or is absent, wherein the third ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; A4 is a fourth ancillary moiety or is absent, wherein the fourth ancillary moiety has a linker function, a protecting function, a cyclization function, a dummy function, and / or a solubility-enhancing function, and optionally may have a non-standard amino acid; B1, a B cell epitope, is a fragment or mimotope of apolipoprotein B-100 and can induce antibodies that target apolipoprotein B-100; B2, a B cell epitope, is a fragment or mimotope of apolipoprotein B-100 and can induce antibodies that target apolipoprotein B-100; the Th epitope, T1, can be recognized by CD4+ T cells and is characterized in that its length is an 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer; The Th epitope, T2, can be recognized by CD4+ T cells and is characterized by its length being an 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, 25-mer, 26-mer, 27-mer, 28-mer, 29-mer, 30-mer, 31-mer, or 32-mer.

[0575] Example 90, combination of sequences of unit E.

[0576] In Example 89, A1, A2, A3, and A4 are 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 wherein a represents D-alanine and Z represents 6-aminohexanoic acid; B1 and B2 each independently have one selected from the group consisting of: RNVPPIFNDVYWIAF(SEQ ID NO:6), CRFRGLISLSQVYLS(SEQ ID NO:7), KTTKQSFDLSVKAQYKKNKH(SEQ ID NO:8), RNVPPIFNDVY(SEQ ID NO:9), CRFRGLISLSQ(SEQ ID NO:10), KTTKQSFDLSVK(SEQ ID NO:11), RNVPPIFNDVYW(SEQ ID NO:12), CRFRGLISLSQV(SEQ ID NO:13), KTTKQSFDLSVKAQYKK(SEQ ID NO:14), RNVPPIFNDVYWI(SEQ ID NO:15), CRFRGLISLSQVY(SEQ ID NO:16), KTTKQSFDLSVKAQYKKN(SEQ ID NO:17), PIFNDVYWIAF(SEQ ID NO:18), GLISLSQVYLS(SEQ ID NO:19), QSFDLSVKAQYKKNKH(SEQ ID NO:20), PPIFNDVYWIAF(SEQ ID NO:21), RGLISLSQVYLS(SEQ ID NO:22), KQSFDLSVKAQYKKNKH(SEQ ID NO:23), VPPIFNDVYWIAF(SEQ ID NO:24), FRGLISLSQVYLS(SEQ ID NO:25), TKQSFDLSVKAQYKKNKH(SEQ ID NO:26), NVPPIFNDVYWIA(SEQ ID NO:27), RFRGLISLSQVYL(SEQ ID NO:28), TKQSFDLSVKAQYKKN(SEQ ID NO:29), VPPIFNDVYWI(SEQ ID NO:30), FRGLISLSQVY(SEQ ID NO:31), TKQSFDLSVKAQYKKN (SEQ ID NO:32), PPIFNDVYW (SEQ ID NO:33), RGLISLSQV (SEQ ID NO:34), KQSFDLSVKAQYKK (SEQ ID NO:35), RFRGLISLSQVYLDP (SEQ ID NO:221), and SVCGCPVGHHDVVGL (SEQ ID NO:222); an epitope contained in any one of SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222; A sequence that is 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 identical to any one of the sequences represented by SEQ ID NO:6 to SEQ ID NO:35, and SEQ ID NO:221 to SEQ ID NO:222. (wherein a represents D-alanine, Z represents 6-aminohexanoic acid, T1 and T2 are each independently 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)、MQWNSTTFHQTLQDPRVRGLYFPAGG(SEQ ID NO:165)、FFLLTRILTI(SEQ ID NO:166)、FFLLTRILTIPQSLD(SEQ ID NO:167)、TSLNFLGGTTVCLGQ(SEQ ID NO:168)、QSPTSNHSPTSCPPIC(SEQ ID NO:169)、IIFLFILLLCLIFLLVLLD(SEQ ID NO:170)、CTTPAQGNSMFPSC(SEQ ID NO:171)、CTKPTDGN(SEQ ID NO:172)、WASVRFSW(SEQ ID NO:173)、LLPIFFCLW(SEQ ID NO:174)、MDIDPYKEFGATVELLSFLP(SEQ ID NO:175)、FLPSDFFPSV(SEQ ID NO:176)、RDLLDTASALYREALESPEH(SEQ ID NO:177)、PHHTALRQAILCWGELMTLA(SEQ ID NO:178)、GRETVIEYLVSFGVW(SEQ ID NO:179)、EYLVSFGVWIRTPPA(SEQ ID NO:180)、VSFGVWIRTPPAYRPPNAPI(SEQ ID NO:181)、TVVRRRGRSP(SEQ ID NO:182)、VGPLTVNEKRRLKLI(SEQ ID NO:183)、RHYLHTLWKAGILYK(SEQ ID NO:184)、ESRLVVDFSQFSRGN(SEQ ID NO:185)、LQSLTNLLSSNLSWL(SEQ ID NO:186)、SSNLSWLSLDVSAAF(SEQ ID NO:187)、LHLYSHPIILGFRKI(SEQ IDThose selected from the group consisting of NO:188), KQCFRKLPVNRPIDW (SEQ ID NO:189), LCQVFADATPTGWGL (SEQ ID NO:190), AANWILRGTSFVYVP (SEQ ID NO:191), EIRLKVFVLGGCRHK (SEQ ID NO:192), KFVAAWTLKAA (SEQ ID NO:195), KYVAAWTLKAA (SEQ ID NO:196), DIEKKIAKMEKASSVFNVVNS (SEQ ID NO:223), YSGPLKAEIAQRLEDV (SEQ ID NO:224), K(Cha)VKANTLKAA (SEQ ID NO:225), K(Cha)VKANTLKAA (SEQ ID NO:226), K(Cha)VKAWTLKAA (SEQ ID NO:227), K(Cha)VKAWTLKAA (SEQ ID NO:228), K(Cha)VWANTLKAA (SEQ ID NO:229), K(Cha)VWANTLKAA (SEQ ID NO:230), K(Cha)VWAYTLKAA (SEQ ID NO:231), K(Cha)VWAVTLKAA (SEQ ID NO:232), K(Cha)VYAWTLKAA (SEQ ID NO:233), K(Cha)VYAWTLKAA (SEQ ID NO:234), R(Cha)VRANTLKAA (SEQ ID NO:235), K(Cha)VKAHTLKAA (SEQ ID NO:236), K(Cha)VKAHTLKAA (SEQ ID NO:237), K(Cha)VAANTLKAA (SEQ ID NO:238), K(Cha)VAANTLKAA (SEQ ID NO:239), K(Cha)VAAYTLKAA (SEQ ID NO:240), K(Cha)VAAYTLKAA (SEQ ID NO:241), K(Cha)VAAWTLKAA (SEQ ID NO:242), K(Cha)VAAKTLKAA (SEQ ID NO:243), K(Cha)VAAHTLKAA (SEQ ID NO:244), K(Cha)VAAATLKAA (SEQ ID NO:245), K(Cha)VAAWTLKAA (SEQ ID NO:246), and K(Cha)VMAATLKAA (SEQ ID NO:247); A sequence represented by the following formula I or II: [Formula I](N)-Lys-X1-X2-Ala-Ala-X3-Thr-X4-X5-Ala-Ala-(C) X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X1 is a hydrophobic amino acid, or leucine (Leu), or isoleucine (Ile), X3 is an aromatic or cyclic amino acid, or phenylalanine (Phe), tyrosine (Tyr), or histidine (His); X4 is an aliphatic long-chain amino acid, or isoleucine (Ile) or valine (Val), X5 is a charged amino acid or arginine (Arg), leucine (Leu), aspartic acid (Asp), glutamine (Gln), or glycine (Gly); [Formula II](N)-Lys-X1-Val-X2-Ala-X3-Thr-Leu-Lys-Ala-Ala-(C): X1 is tyrosine (Tyr), phenylalanine (Phe) or L-cyclohexylalanine; X2 is lysine (Lys), tryptophan (Trp), tyrosine (Tyr), arginine (Arg), alanine (Ala), or methionine (Met); X3 is asparagine (Asn), tryptophan (Trp), tyrosine (Tyr), valine (Val), histidine (His), lysine (Lys), or alanine (Ala); a sequence that is 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 identical to any one of SEQ ID NOs:1 to 5, SEQ ID NOs:162 to 192, SEQ ID NOs:195 to 196, SEQ ID NOs:223 to 247, and the sequences represented by [Formula I] or [Formula II]; (where (Cha) represents L-cyclohexylalanine and X represents any standard amino acid) It has.

[0577] A peptide comprising a peptide unit.

[0578] Example 91, Peptides containing two or more peptide units.

[0579] A peptide comprising two or more linked peptide units according to any one of Examples 1 to 90.

[0580] Example 92, peptides containing 2 to 8 peptide units.

[0581] A peptide comprising 2, 3, 4, 5, 6, 7, or 8 linked peptide units according to any one of Examples 1 to 90.

[0582] Example 93, Concatameric Sequences.

[0583] The peptide of Example 91, wherein each of the peptide units has the same or equivalent sequence.

[0584] Example 94, rosary.

[0585] The peptide of Example 91, wherein each of the peptide units has a different sequence.

[0586] Example 95, Cyclic

[0587] The peptide of Example 91, characterized in that the peptide further comprises auxiliary moieties at the N-terminus and C-terminus having cyclization functionality, and the peptide forms a cyclization via the auxiliary moieties.

[0588] Peptide units and / or nucleic acids encoding peptides.

[0589] Example 96, coding nucleic acids that do not contain non-standard amino acids.

[0590] A nucleic acid encoding a peptide unit described in any one of Examples 1 to 6 and / or a peptide described in any one of Examples 91 to 95, wherein the peptide unit and the peptide do not contain any non-standard amino acids.

[0591] Example 97, coding nucleic acids for each unit formula, excluding non-standard amino acids.

[0592] A nucleic acid encoding a peptide unit according to any one of Examples 7 to 10, 14 to 18, 22, 26 to 30, 34, 38 to 41, 45, 49 to 54, 58 to 60, 64, 68, and 72, wherein the peptide unit does not contain a non-standard amino acid.

[0593] Example 98, Restrictions on the sequence of unit peptides.

[0594] 10. The nucleic acid of any one of Examples 96 and 97, wherein the nucleic acid is selected from the group consisting of RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXCRFRGLISLSQVYLS (SEQ ID NO: 198); RNVPPIFNDVYWIAFXXKXVAAWTLKAAXXGSHHHHHHGSDDDDK (SEQ ID NO: 199); GSHHHHHHGSDDDDKXXKXVAAWTLKAAXXRNVPPIFNDVYWIAF (SEQ ID NO: 200); KTTKQSFDLSVKAQYKKNKHXXKXVAAWTLKAAXXCRFRGLISLSQVYLS (SEQ ID NO: 201); RNVPPIFNDVYWIAFCRFRGLISLSQVYLSXXKXVAAWTLKAAXX (SEQ ID NO: 202); RNVPPIFNDVYWIAFXPKYVKQNTLKLATXCRFRGLISLSQVYLS (SEQ ID NO: 203). NO:203);RNVPPIFNFDVYWIAFXXKXVAAWTLKAAXX(SEQ ID NO:204);RNVPPIFNDVYWIAFKXVAAWTLKAA(SEQ ID NO:205);RNVPPIFNDVYWIAFKXVAAWTLKAAHHHHHH(SEQ ID NO:206);RNVPPIFNDVYWIAFXXKXVAAWTLKAACRFRGLISLSQVYLS(SEQ ID NO:207);RNVPPIFNDVYWIAFXXKXVAAWTLKAACR(SEQ ID NO:208);RNVPPIFNDVYWIAFXXKFVAAWTLKAAXXCRFRGLISLSQVYLS(SEQ ID NO:209);RNVPPIFNFDVYWIAFXXKFVAAWTLKAAXX(SEQ ID N0:210); RNVPPIFNDVYWIAFXXKFVAAWTLKAACRFRGLISLSQVYLS (SEQ ID NO:211); and RNVPPIFNDVYWIAFXXKFVAAWTLKAACR (SEQ ID NO:212) (wherein X represents any standard amino acid).

[0595] Example 99, Restrictions on the Sequence of DNA Coding Units.

[0596] The nucleic acid of Example 98, which is a DNA represented by a sequence selected from the following: 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:248);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:249);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:250);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNGGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAG-3'(SEQ ID NO:251);5'-ACGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNGGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAG-3'(SEQ ID NO:252);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNGGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAG-3'(SEQ ID NO:253);5'-GGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAGNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNCGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTC-3'(SEQ ID NO:254);5'-GGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAGNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNCGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTC-3'(SEQ ID NO:255);5'-GGATCGCATCACCATCACCATCACGGATCCGATGATGATGACAAGNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNCGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTC-3'(SEQ ID NO:256);5'-AAAACGACAAAGCAATCATTTGATTTAAGTGTAAAAGCTCAGTATNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:257);5'-AAAACGACAAAGCAATCATTTGATTTAAGTGTAAAAGCTCAGTATNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:258);5'-AAAACGACAAAGCAATCATTTGATTTAAGTGTAAAAGCTCAGTATNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:259);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:260);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:261);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:262);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNCCTAAGTATGTGAAGCAGAATACACTGAAGCTGGCAACCNNNTGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:263);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:264);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:265);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCANNNNNN-3'(SEQ ID NO:266);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCA-3'(SEQ ID NO:267);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCA-3'(SEQ ID NO:268);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCA-3'(SEQ ID NO:269);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCACATCACCATCACCATCAC-3'(SEQ ID NO:270);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCACATCACCATCACCATCAC-3'(SEQ ID NO:271);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCACATCACCATCACCATCAC-3'(SEQ ID NO:272);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:273);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTTCGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:274);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGTTTCCGTGGACTGATTTCCCTGTCCCAGGTTTATCTGTCC-3'(SEQ ID NO:275);5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGNNNGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGT-3'(SEQ ID and 5'-CGTAATGTTCCTCCTATCTTCAATGATGTTTATTGGATTGCATTCNNNNNNAAGTATGTGGCAGCTTGGACCCTGAAGGCAGCATGCCGT-3' (SEQ ID NO:278). ;

[0597] Example 100. Restrictions on the sequence of the unit encoding RNA.

[0598] The nucleic acid of Example 98, wherein the RNA is represented by a sequence selected from the following: 5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:279);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:280);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:281);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNGGAUCGCAUCACCAUCACCAUCACGGAUCCGAUGAUGAUGACAAG-3'(SEQ ID NO:282);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNGGAUCGCAUCACCAUCACCAUCACGGAUCCGAUGAUGAUGACAAG-3'(SEQ ID NO:283);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNGGAUCGCAUCACCAUCACCAUCACGGAUCCGAUGAUGAUGACAAG-3'(SEQ ID NO:284);5'-GGAUCGCAUCACCAUCACCAUCACGGAUCCGAUGAUGAUGACAAGNNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNCGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUC-3'(SEQ ID NO:285);5'-GGAUCGCAUCACCAUCACCAUCACGGAUCCGAUGAUGAUGACAAGNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNCGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUC-3'(SEQ ID NO:286);5'-GGAUCGCAUCACCAUCACCAUCACGGAUCCGAUGAUGAUGACAAGNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNCGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUC-3'(SEQ ID NO:287);5'-AAAACGACAAAGCAAUCAUUUGAUUUAAGUGUAAAAGCUCAGUAUNNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:288);5'-AAAACGACAAAGCAAUCAUUUGAUUUAAGUGUAAAAGCUCAGUAUNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:289);5'-AAAACGACAAAGCAAUCAUUUGAUUUAAGUGUAAAAGCUCAGUAUNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNNUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:290);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCCNNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNN-3'(SEQ ID NO:291);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCCNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNN-3'(SEQ ID NO:292);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCCNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNN-3'(SEQ ID NO:293);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNCCUAAGUAUGUGAAGCAGAAUACACUGAAGCUGGCAACCNNNUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:294);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNN-3'(SEQ ID NO:295);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNN-3'(SEQ ID NO:296);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCANNNNNN-3'(SEQ ID NO:297);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCAAGNNNNGUGGCAGCUUGGACCCUGAAGGCAGCA-3'(SEQ ID NO:298);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCAAGUAUCUGGAGCUUGGACCCUGAAGGCAGCA-3'(SEQ ID NO:299);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCAAGUAUGUUGGCAGCUUGGACCCUGAAGGCAGCA-3'(SEQ ID NO:300);5'-CGUAAUGUUCCUCCUAUCUCAAUGAUGUUUAUUGGAUUGCAUUCAAGNNNNGUGGCAGCUUGGACCCUGAAGGCAGCACAUCACCAUCACCAUCAC-3'(SEQ ID NO:301);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCAAGUUCGUGCAGCUUGGACCCUGAAGGCAGCACAUCACCAUCACCAUCAC-3'(SEQ ID NO:302) NO:302);5'-CGUAAUGUUCCUCCUAUCUCAAUGAUGUUUAUUGGAUUGCAUUCAAGUAUUGGGCAGCUUGGACCCUGAAGGCAGCACAUCACCAUCACCAUCAC-3'(SEQ ID NO:303);5'-CGUAAUGUUCCUCCUAUCUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCAUGCCGUUUCCGUGGACUGAUUUCCCGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:304);5'-CGUAAUGUUCCUCCUAUCUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCAUGCCGUUUCCGUGGACUGAUUUCCGUGGACUGAUUUCCGUGGACUGAUUUCCCUGGCCAGGUUUAUCUCUGUCC-3'(SEQ ID NO:305);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCAUGCCGUUUCCGUGGACUGAUUUCCCUGUCCCAGGUUUAUCUGUCC-3'(SEQ ID NO:306);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGNNNGUGGCAGCUUGGACCCUGAAGGCAGCAUGCCGU-3'(SEQ ID NO:307);5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUUCGUGGCAGCUUGGACCCUGAAGGCAGCAUGCCGU-3'(SEQ ID and 5'-CGUAAUGUUCCUCCUAUCUUCAAUGAUGUUUAUUGGAUUGCAUUCNNNNNNAAGUAUGUGGCAGCUUGGACCCUGAAGGCAGCAUGCCGU-3' (SEQ ID NO:309). ;

[0599] Example 101, Vector.

[0600] A vector comprising the nucleic acid described in any one of Examples 96 to 100.

[0601] Example 102. Restrictions on Vectors.

[0602] The vector of Example 101, wherein the vector is selected from the group consisting of a plasmid, a retrovirus, a lentivirus, an adenovirus, an adeno-associated virus, a vaccinia virus, a poxvirus, and a herpes simplex virus.

[0603] Example 103, Mammalian codon-optimized nucleic acids.

[0604] The nucleic acid of any one of Examples 96 to 98, wherein the nucleic acid is codon-optimized for a species selected from mammals.

[0605] Example 104, human codon-optimized nucleic acids.

[0606] The nucleic acid of any one of Examples 96 to 98, wherein the nucleic acid is human codon optimized.

[0607] Example 105. Prokaryotic codon-optimized nucleic acids.

[0608] The nucleic acid of any one of Examples 96 to 98, wherein the nucleic acid is codon-optimized for a species selected from prokaryotes.

[0609] Example 106, E. coli codon-optimized nucleic acids.

[0610] The nucleic acid of any one of Examples 96 to 98, wherein the nucleic acid is E. coli codon optimized.

[0611] A pharmaceutical composition comprising a peptide.

[0612] Example 107, Pharmaceutical composition for immunotherapy.

[0613] A pharmaceutical composition for immunotherapy comprising: A peptide unit according to any one of Examples 1 to 90 and / or a peptide according to any one of Examples 91 to 95; and

[0614] Adjuvant.

[0615] Example 108: Pharmaceutical composition for treating obesity.

[0616] A pharmaceutical composition for treating obesity, comprising: A peptide unit according to any one of Examples 1 to 90 and / or a peptide according to any one of Examples 91 to 95; and Adjuvant.

[0617] Example 109, Adjuvant Restrictions.

[0618] In any one of Examples 107-108, the adjuvant is selected from the group consisting of water, saline, dextrose, ethanol, glycerol, sodium chloride, dextrose, mannitol, sorbitol, lactose, gelatin, albumin, aluminum hydroxide, Freund's incomplete and complete adjuvant (Pifco Laboratories, Detroit, Michigan), Merck Antigen Adjuvant 65 (Merck and Company, Inc., Rahway, New Jersey), Alhydrogel (Al(OH)), aluminum hydroxide gel (alum) or aluminum salts, such as aluminum phosphate, AS04 series, MF, squalene, MF59, QS21, calcium, iron, or zinc salts, acylated tyrosine, insoluble suspensions of acylated fructose, cationic or anionic derived polysaccharides, polyphosphazenes, biodegradable microspheres, Quil A, toll-like receptor (TLR) agonist, PHAD [Avanti polar lipids, monophosphoryl lipid A (synthetic)], monophosphoryl lipid A (MPL, monophosphoryl lipid A), synthetic lipid A, lipid A mimetic or analog, aluminum salt, cytokine, saponin, prolactin, growth hormone deoxycholate, beta-glucan, polyribonucleotide, muramyl dipeptide (MDP) derivative, CpG oligo, gram-negative bacterial lipopolysaccharide (LPS), polyphosphazene, emulsion, virosome, cochleate, poly(lactide-co-glycolide) (PLG) microparticle, poloxamer particle, microparticle, liposome, or a suitable combination thereof.

[0619] A pharmaceutical composition comprising the encoding nucleic acid.

[0620] Example 110, Formulated Coding Nucleic Acids.

[0621] A formulated encoding nucleic acid, characterized in that the nucleic acid according to any one of Examples 96 to 106 is formulated using a viral vector and / or a non-viral vector.

[0622] Example 111. Restrictions on viral vectors.

[0623] In example 110, the encoding nucleic acid is characterized in that the viral vector is selected from: retroviruses; lentiviruses; adenoviruses; adeno-associated viruses; vaccinia viruses; poxviruses; and herpes simplex viruses.

[0624] Example 112, Restrictions on the Form of Formulated Nucleic Acids.

[0625] In example 110, the encoding nucleic acid is characterized in that the formulated nucleic acid is selected from: These include naked nucleic acids, cationic peptide-complexed nucleic acids (protamine), positively charged oil-water cationic nanoemulsions containing nucleic acids (cationic nanoemulsions), nucleic acids bound 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 complexed with cationic polymers (e.g., polyethyleneimine (PEI)) (cationic polymers), nucleic acids complexed with cationic polymers such as PEI and lipid components (cationic polymer liposomes), nucleic acids complexed with polysaccharide polymers (e.g., chitosan) (polysaccharide particles), 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).

[0626] Example 113, Immunotherapeutic pharmaceutical compositions comprising formulated nucleic acids.

[0627] A pharmaceutical composition for immunotherapy comprising: A formulated nucleic acid according to any one of Examples 100-112; and Adjuvant.

[0628] Example 114: A pharmaceutical composition for treating obesity comprising a formulated nucleic acid.

[0629] A pharmaceutical composition for treating obesity, comprising:

[0630] A formulated nucleic acid according to any one of Examples 100-112; and Adjuvant.

[0631] Example 115, Adjuvant Restrictions.

[0632] 115. A pharmaceutical composition according to any one of Examples 113 and 114, characterized in that the adjuvant is one or more selected from the following: Lipid nanoparticles (LNPs), aluminum salts, 1,2-dioleyl-3-trimethylammonium-propane chloride, MF59 (Novartis) adjuvant, CD70, CD40 ligand (CD40L), TriMix, protamine acting through TLR7 signaling, and / or bacterial-derived monophosphoryl lipid A.

[0633] Example 116 containing additional ingredients.

[0634] The pharmaceutical composition of any one of Examples 113-114, wherein the pharmaceutical composition comprises one or more additional ingredients selected from the following:

[0635] lipids; salts to balance acidity in the body; sucrose to maintain stability during repeated freeze-thaw cycles; and vaccine stability enhancers.

[0636] Example 117, Restrictions on Additional Ingredients

[0637] The pharmaceutical composition of Example 116, 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 phosphate monobasic, sodium chloride, sodium phosphate dibasic anhydrous; A pharmaceutical composition, wherein the vaccine stability enhancing substance is one or more selected from acetic acid, an acid stabilizer (tromethamine), and / or ethanol.

[0638] Use of peptides.

[0639] Example 118, Use in immunotherapy (first medical use).

[0640] Use of a peptide unit described in any one of Examples 1 to 90, a peptide described in any one of Examples 91 to 95, a nucleic acid described in any one of Examples 96 to 106, and / or a pharmaceutical composition described in any one of Examples 107 to 109 and Examples 113 to 117 for immunotherapy.

[0641] Example 119: Use for treating obesity (first medical use).

[0642] Use of a peptide unit described in any one of Examples 1 to 90, a peptide described in any one of Examples 91 to 95, a nucleic acid described in any one of Examples 96 to 106, and / or a pharmaceutical composition described in any one of Examples 107 to 109 and Examples 113 to 117 for the treatment of obesity.

[0643] Example 120, Use in the preparation of immunotherapeutic drugs (second medical use).

[0644] Use of a peptide unit according to any one of Examples 1 to 90, a peptide according to any one of Examples 91 to 95, a nucleic acid according to any one of Examples 96 to 106, and / or a pharmaceutical composition according to any one of Examples 107 to 109 and Examples 113 to 117 for the preparation of an immunotherapeutic agent.

[0645] Example 121: Use in the preparation of a therapeutic drug for the treatment of obesity (second medical use).

[0646] Use of a peptide unit described in any one of Examples 1 to 90, a peptide described in any one of Examples 91 to 95, a nucleic acid described in any one of Examples 96 to 106, and / or a pharmaceutical composition described in any one of Examples 107 to 109 and Examples 113 to 117 for the preparation of a therapeutic agent for the treatment of obesity.

[0647] Peptide-based therapy.

[0648] Example 122. Peptide-based immunotherapy.

[0649] Immunotherapy drugs, including the following steps: A step of administering into the body of a subject a peptide unit described in any one of Examples 1 to 90, a peptide described in any one of Examples 91 to 95, a nucleic acid described in any one of Examples 96 to 106, and / or a pharmaceutical composition described in any one of Examples 107 to 109 and Examples 113 to 117.

[0650] Example 123: Obesity treatment using peptides.

[0651] Obesity treatment using the following steps: A step of administering into the body of a subject a peptide unit described in any one of Examples 1 to 90, a peptide described in any one of Examples 91 to 95, a nucleic acid described in any one of Examples 96 to 106, and / or a pharmaceutical composition described in any one of Examples 107 to 109 and Examples 113 to 117.

[0652] Peptide units and / or peptide-like sequences.

[0653] Example 124, Sequences Similar to Peptide Units.

[0654] A peptide unit having a sequence that is 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% identical to a peptide unit described in any one of Examples 1-90.

[0655] Example 125, peptide-like sequences.

[0656] A peptide having a sequence that is 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 identical to a peptide unit described in any one of Examples 91-95.

[0657] [Experimental Example]

[0658] The invention provided herein will be described in more detail through experimental examples and examples below. These examples are merely for illustrating the contents disclosed herein, and it will be apparent to those skilled in the art that the scope of the contents disclosed herein should not be construed as being limited by these examples.

[0659] Experimental example 1, experimental method.

[0660] Example 1.1. Preparation of peptides.

[0661] The peptides were obtained through a peptide synthesis company (Anygen, Gwangju, Korea). The peptides of the present invention can be synthesized using conventional techniques (e.g., solution-phase peptide synthesis, solid-phase peptide synthesis, convergence of small peptide fragments, etc.), and the synthesis method is not particularly limited. For example, the OTP3 peptide of the present invention can be synthesized using a convergence method of small peptide fragments, in which a site where coupling of a long peptide can be easily performed is virtually cleaved, various parts are prepared based on this, and then combined with each other to virtually synthesize the desired peptide. The convergence method described above is limited by the requirement that specific amino acids be present in the peptide sequence. Therefore, peptides can also be effectively synthesized using combinatorial peptide synthesis, which appropriately combines solution-phase synthesis and solid-phase peptide synthesis.

[0662] Experimental Example 1.2: Confirmation of prepared peptide 1 - purity analysis.

[0663] The purity of the peptide 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 analytical conditions, the sample was separated and developed in an aqueous solution of 0.05% trifluoroacetic acid (TFA) and 0.05% TFA acetotrile solution at 60°C, and the purity was confirmed by measuring the peak absorbance at a wavelength of 230 nm.

[0664] Experimental Example 1.3: Confirmation of prepared peptide 2 - molecular weight analysis.

[0665] The molecular weight of the peptide prepared in Experimental Example 1.1 was analyzed using a mass spectrometer (AXIMA Assurance, MALDI-TOF, Shimadzu Corporation).

[0666] Experimental Example 1.4: Confirmation and quantification of prepared peptide 2

[0667] The peptides prepared in Experimental Example 1.1 were quantified by measuring the ultraviolet extinction coefficient (Ultrospec 3000 Pro UV / VIS spectrophotometer, Pharmacia). Specifically, quantification was performed using the extinction coefficient at 280 nm.

[0668] Experimental Example 1.5: Preparation of a composition for in vivo administration.

[0669] The peptide prepared in Experimental Example 1.1 was mixed with Alhydrogel (Al(OH)3, manufactured by InvivoGe) and PHAD (manufactured by Avanti) to prepare a composition for in vivo administration. The specific process is as follows:

[0670] (1) The prepared peptide powder was dissolved in 100% dimethyl sulfoxide (DMSO) to obtain a concentration of 100 mg / L.

[0671] (2) PBS was added to the peptide-DMSO solution of (1) and mixed to prepare a peptide at a concentration of 50 mg / mL.

[0672] (3) PHAD was dissolved in 100% DMSO to a concentration of 10 mg / mL, and then diluted with distilled water to a concentration of 1 mg / mL.

[0673] (4) Alhydrogel adjuvant (Invivogen, USA) and PHAD solution were added to the mixture of (2). The concentration of the mixture was 50 g of peptide, 10 g of PHAD, and 10% (v / v) of Alhydrogel adjuvant per 100 μL (a single dose).

[0674] (5) The mixture of (4) was thoroughly mixed, and the resulting mixture was reacted overnight in a cold room (4°C) while stirring with a rotor.

[0675] (6) To wash the DSMO, the reaction mixture from (5) was centrifuged at 1,400 rpm for 15 minutes, and the supernatant was removed except for approximately 1 mL above the pellet. Then, 10 mL of PBS was added and mixed.

[0676] (7) The washing process in (6) was repeated three times.

[0677] (8) After the final washing process, PBS was added to adjust the final concentrations of the composition, specifically, the peptide concentration was 50 μg / 100 L (especially, 30 μg / 100 L in Example 4), the PHAD concentration was 10 μg / 100 L, and the hydrogel adjuvant concentration was 10% (v / v).

[0678] (9) The amount of peptide adsorbed to aluminum gel was measured according to the method described in Experimental Example 2.3. As a result, it was confirmed that the adsorption rate was 95% or higher, and the peptide was used in the experiment.

[0679] Example 1.6, Preparation of Test Subjects.

[0680] To verify the effects of the composition for in vivo administration prepared in Experimental Example 1.5, C57BL / 6, Balbc, and / or ICR mice were used as experimental mice (purchased from Central Lab Animal Inc.). Although there were some differences between species, the purchased mice were an average of 7 weeks old, and were allowed to acclimate for one week before being used in the experiment at 8 weeks of age. The experimental mice were housed under constant temperature and humidity conditions within a temperature range of 23±1°C and a relative humidity of 50±5%, as well as in a controlled environment of 12 hours light and 12 hours dark. Drinking water and food were provided ad libitum. The normal diet (purchased from Central Lab Animal Inc.) consisted of 20% protein, 70% carbohydrate, and 10% fat based on total calories, while the obesogenic diet (purchased from Research Diets) consisted of a high-fat diet containing 20% ​​protein, 20% carbohydrate, and 60% fat based on total calories. The experimental mice were divided into groups with different dietary and composition administration conditions, and experiments were conducted with a statistically acceptable number of individuals for each experimental group. Detailed conditions are as disclosed in each specific experimental example.

[0681] Example 1.7. Administration of a composition containing a peptide to a test subject.

[0682] The test subjects prepared in Experimental Example 1.6 were administered a different composition for each experimental group. All compositions were administered intramuscularly. After disinfecting both thigh muscles of each mouse with an alcohol swab, 50 μL of each composition was injected, for a total of 100 μL.

[0683] Experimental Example 1.8: Confirmation of the effect of the composition for in vivo administration 1 - Body weight measurement.

[0684] To confirm the weight loss effect of the composition for internal administration according to Experimental Example 1.7 on test subjects, the body weight and organ weights of the mice in each experimental group were measured. For each experimental group, the mice were measured three times per week from the time of arrival until the end of the experiment, and the average was calculated to determine the average weight value for each week. After the experiment was completed, each mouse was anesthetized, its organs were dissected, and its weight was measured, and the average for each experimental group was calculated.

[0685] Experimental Example 1.9: Confirmation of the effect of the composition for in vivo administration 2 - Confirmation of antibody titer.

[0686] To determine whether the composition for in vivo administration administered in Experimental Example 1.7 induced antibodies against B cell epitopes, the antibody titer was confirmed using the target antigen as follows. In particular, the target antigen is RNVPPIFNDVYWIAF (SEQ ID NO:6) or ApoB100. The time for checking the antibody titer may be changed as necessary, and the time is specifically described for each experimental example.

[0687] 1.The process of antigen coating reaction.

[0688] 1-1) Each time a composition for in vivo administration is injected into a test subject, approximately 200 L of blood is collected from the subject's tail vein one week after the injection.

[0689] 1-2) After leaving the collected blood at 4°C for 1 hour, the blood sample is centrifuged at 14,000 rpm for 10 minutes to separate the supernatant serum.

[0690] 1-3) The target antigen is diluted with coating buffer (0.05 M bicarbonate, pH 9.6) to a concentration of 50 μg / 100 L, and the antigen is added to a 96-well plate at 50 μg / well and reacted overnight at 4°C to coat the well walls with the peptide.

[0691] 1-4) Wash the target antigen-coated plate three times with 300 L per well of phosphate-buffered saline (PBS)-T (0.05% Tween®-20).

[0692] 2. Blocking reaction process.

[0693] 2-1) Add 300 μL of 0.5% casein blocking solution per well of the plate and allow to react at 4°C overnight.

[0694] 2-2) Wash the plate three times with 300 μL of PBS-T per well.

[0695] 3. The process of primary antibody reaction.

[0696] 3-1) For the primary antibody reaction, dilute the isolated serum to an appropriate concentration, add 100 L per well, and incubate at 37°C for 1 hour. After the first injection, dilute the serum serially to 1 / 20–1 / 1,000, and after the second and third injections, dilute the serum serially to 1 / 500–1 / 10,000 depending on the subject. A purified monoclonal antibody against the peptide of SEQ ID NO: 41 was used as a positive control.

[0697] 3-2) After the reaction in 3-1, wash the plate three times with 300 μL of PBS-T per well.

[0698] 4. Secondary antibody reaction process.

[0699] 4-1) For the secondary antibody reaction, 100 μL per well of horseradish peroxidase (HRP) conjugated to an anti-mouse IgG antibody that recognizes mouse antibodies is added, and the reaction is carried out at 37°C for 1 hour.

[0700] 4-2) After the reaction in 4-1), wash the plate three times with 300 μL of PBS-T per well.

[0701] 5. The process of checking color development and absorbance.

[0702] 5-1) 100 μL of o-phenylenediamine dihydrochloride (OPD) solution is added per well, and after incubation at 37° C. for 10 minutes, the absorbance at OD 450 nm is measured (Synergy HT microplate reader, BioTek).

[0703] The antibody titer in the serum is calculated by converting the measured extinction coefficient based on a monoclonal antibody against the target antibody at a concentration of 1 mg / mL as a positive control.

[0704] Experimental Example 1.10: Confirmation of the effect of the composition for in vivo administration 3 - Confirmation of blood lipid concentration.

[0705] The experimental method for confirming the effect of the composition for in vivo administration administered in Experimental Example 1.7 on the blood lipid levels of the test subjects is as follows.

[0706] (1) One week after administration of each composition, approximately 200 μL of blood is collected from the subject's tail vein.

[0707] (2) Measurement of blood triglyceride (TG) concentration: Triglyzyme-V (Shinyak Chemical Co., Ltd.) was used. i) 4 μL of blood sample was mixed with 300 μL of color-developing reagent, and the mixture was reacted at 37°C for 5 minutes. ii) The absorbance of the generated red quinone was measured at 505 nm, and the concentration was calculated by comparison with a standard solution.

[0708] (3) Measurement of total blood cholesterol concentration: Cholestezyme-V (Shinyak Chemical Co., Ltd.) was used. i) 4 μL of the blood sample was mixed with 300 μL of the color-developing reagent, and the mixture was allowed to react for 5 minutes at 37° C. ii) The absorbance of the generated red quinone was measured at 505 nm, and the concentration was calculated by comparing with that of a standard solution.

[0709] (4) Measurement of blood high-density lipoprotein (HDL) concentration: HDL-C555 (Shinyak Chemical Co., Ltd.) was used. i) 10 μL of blood sample was mixed with 10 μL of precipitating reagent, and the mixture was allowed to react at room temperature for at least 10 minutes. ii) The reaction mixture was centrifuged at 300 rpm or higher, and the supernatant was separated. iii) 4 μL of the supernatant was mixed with 300 μL of color-developing reagent, and the mixture was allowed to react at 37°C for 5 minutes. iv) The absorbance at 555 nm was measured for the above reaction, and the concentration was calculated by comparison with a standard solution.

[0710] (5) Measurement of blood low-density lipoprotein (LDL) concentration. i) The reaction was carried out using a direct LDL cholesterol detection kit (Randox). ii) After the reaction in step 2, the absorbance of the generated quinone was measured at 600 nm, and the concentration was calculated by comparing it with the absorbance of a standard solution.

[0711] Experimental Example 1.11: Confirmation of the effect of composition 4 for in vivo administration - Confirmation of lipolytic ability and comparison of fat cell size.

[0712] The method for confirming the effect of the composition for in vivo administration administered in Experimental Example 1.7 on the ability of hormone-sensitive lipase (HSL) to decompose fat cells of the test subject and on the size of the fat cells is as follows.

[0713] 1. Fat cell isolation.

[0714] 1-1) Cut the epididymal fat pad with scissors, add 4 mL of KRB buffer containing 2% FBS, 2 mM glucose, and 1 mg / mL collagenase per gram, and react with shaking at 37°C for 1 hour.

[0715] 1-2) After the reaction is completed, the resultant is passed through a 300 μm nylon mesh to filter out the adipose tissue residue and the adipose tissue, and then the filtrate is passed through a 40 μm nylon mesh again to separate the adipocytes and macrophages.

[0716] 1-3) Add DMEM containing 10% FBS and 1% AA to the adipocytes filtered in 1-2) to wash them, and remove the underlying liquid with a syringe to obtain adipocytes from which collagenase has been removed.

[0717] 2. Comparison of lipolytic ability.

[0718] 2-1) The adipocytes obtained in 1-3) were plated in a 48-well plate at 1.0 x 10 5 Cells are seeded per well, and a total of 1 mL of DMEM (10% FBS, 1% AA) is added thereto, followed by incubation at 37°C under 5% CO 2 for 2 hours.

[0719] 2-2) In the wells where HSL activity is to be induced, norepinephrine was added to a final concentration of 10 -5 Add to make M.

[0720] 2-3) After the reaction is completed, 100 μL of the supernatant from each well is reacted with 100 μL of free glycerol reagent, and the absorbance is measured at 540 nm.

[0721] 3. Observation of the size of fat cells.

[0722] 3-1) The adipocytes obtained in 1-3) were plated in a 48-well plate at 1.0 x 10 5 The cells are seeded at 1000 cells / mL / well, treated with 10 μM DAPI, and incubated for 2 hours before observation under a microscope.

[0723] 3-2) To confirm whether the cells stained with DAPI are adipocytes, we stained both lipids and nuclei and observed them. Specifically, we treated the cells with 10 μM DAPI and HCS LipidTOX 1:1,000, incubated them for 24 hours, and then observed them under a microscope.

[0724] Experimental example 2, confirmation of peptide effect 1.

[0725] Experimental Example 2.1. Preparation of peptides and their experiments.

[0726] Peptides according to Table 1 were prepared according to Experimental Example 1.1, and then 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 containing a peptide according to [Table 1] was prepared.

[0727] [Table 1] Peptides used in Experimental Example 2 and compositions containing them for in vivo administration. [Table 1]

[0728] The test specimens shown in Table 2 were prepared according to Experimental Example 1.6.

[0729] [Table 2] Test subjects used in Experimental Example 2. [Table 2]

[0730] The in vivo administration composition was administered to the test subjects according to Experimental Example 1.7, specifically at the following administration cycles: 7 weeks, 9 weeks, 12 weeks, 15 weeks, and 18 weeks of age.

[0731] Experimental Example 2.2, Confirmation of Experimental Results.

[0732] To confirm the experimental results of Experimental Example 2.1, the body weight of the test subjects was measured for each experimental group disclosed in Table 2 according to Experimental Example 1.8.

[0733] The experimental results are shown in Figures 1 to 3.

[0734] Experimental example 3, confirmation of peptide effect 2.

[0735] Experimental Example 3.1. Preparation of peptides and their experiments.

[0736] Peptides according to Table 3 were prepared according to Experimental Example 1.1, and then 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 containing a peptide according to [Table 3] was prepared.

[0737] [Table 3] Peptides used in Experimental Example 3 and compositions containing them for in vivo administration. [Table 3]

[0738] The test specimens shown in Table 4 were prepared according to Experimental Example 1.6.

[0739] [Table 4] Test subjects used in Experimental Example 3. [Table 4]

[0740] In particular, "thin" refers to a control group with a normal weight, "obese" refers to a group of subjects with obesity induced by a high-fat diet, and "mock" refers to a group administered with a placebo (the same applies below).

[0741] The in vivo administration composition was administered to the test subjects according to Experimental Example 1.7, specifically at the following administration cycles: 8 weeks, 10 weeks, 12 weeks and 14 weeks of age.

[0742] Experimental Example 3.2, Confirmation of Experimental Results.

[0743] To confirm the experimental results of Experimental Example 3.1, the following experiments were conducted on test subjects for each experimental group disclosed in [Table 4].

[0744] (1) The body weight of the test subjects in each experimental group was measured according to Experimental Example 1.8.

[0745] (2) The antibody titers observed in the test subjects of each experimental group were confirmed according to Experimental Example 1.9.

[0746] (3) According to Experimental Example 1.10, the blood lipid levels of the test subjects in each experimental group were measured.

[0747] (4) According to Experimental Example 1.11, the lipolytic ability of the test subjects in each experimental group was confirmed, and the size of the adipocytes was observed.

[0748] The experimental results are shown in FIGS.

[0749] Experimental Example 4: Confirmation of peptide effect 3

[0750] Experimental Example 4.1: Preparation of peptides and their experiments

[0751] After preparing peptides according to [Table 5] in Experimental Example 1.1, the prepared peptides were confirmed according to Experimental Examples 1.2 to 1.4. A composition for in vivo administration containing the peptides shown in Table 5 in Experimental Example 1.5 was prepared.

[0752] [Table 5] Peptides used in Experimental Example 4 and compositions for in vivo administration containing the same. [Table 5]

[0753] In particular, in Example 4, the final concentration of peptide was 30 g / 100 L.

[0754] The test specimens shown in Table 6 were prepared according to Experimental Example 1.6.

[0755] [Table 6] Test subjects used in Experimental Example 4 [Table 6]

[0756] According to Experimental Example 1.7, the composition for in vivo administration was administered to the test subjects at the following administration intervals: 8 weeks, 11 weeks, 14 weeks, 17 weeks, and 20 weeks of age.

[0757] Experimental Example 4.2, Confirmation of Experimental Results.

[0758] To confirm the experimental results of Experimental Example 4.1, the following experiments were conducted on test subjects for each experimental group disclosed in [Table 6].

[0759] (1) The body weight of the test subjects in each experimental group was measured according to Experimental Example 1.8.

[0760] (2) Confirmation of the antibody titers observed in the test subjects of each experimental group was carried out according to Experimental Example 1.9.

[0761] The experimental results are shown in FIGS.

[0762] Experimental example 5, confirmation of peptide effect 4.

[0763] Experimental Example 5.1. Preparation of peptides and their experiments.

[0764] Peptides according to Table 7 were prepared according to Experimental Example 1.1, and the prepared peptides were confirmed according to Experimental Examples 1.2 to 1.4. Compositions for in vivo administration containing peptides according to Table 7 were prepared according to Experimental Example 1.5.

[0765] [Table 7] Peptides used in Experimental Example 5 and compositions for in vivo administration containing the same. [Table 7]

[0766] The test specimens shown in Table 8 were prepared according to Experimental Example 1.6.

[0767] [Table 8] Test subjects used in Experimental Example 5. [Table 8]

[0768] The in vivo administration composition was administered to the test subjects according to Experimental Example 1.7, specifically at the following administration cycles: 11 weeks of age, 13 weeks of age, 15 weeks of age, and 17 weeks of age.

[0769] Experimental Example 5.2, Confirmation of Experimental Results.

[0770] To confirm the experimental results of Experimental Example 5.1, the body weight of the test subjects was measured for each experimental group disclosed in Table 8 according to Experimental Example 1.8.

[0771] The experimental results are shown in FIG.

[0772] Experimental Example 6: Confirmation of peptide effect 5.

[0773] Example 6.1. Preparation of peptides and their experiments.

[0774] Peptides according to Table 9 were prepared according to Experimental Example 1.1, and the prepared peptides were then characterized according to Experimental Examples 1.2 to 1.4. A composition for in vivo administration containing the peptides according to Table 9 was prepared according to Experimental Example 1.5.

[0775] [Table 9] Peptides used in Experimental Example 6 and compositions for in vivo administration containing the same. [Table 9]

[0776] The test specimens shown in Table 10 were prepared according to Experimental Example 1.6.

[0777] [Table 10] Test subjects used in Experimental Example 6. [Table 10]

[0778] * C57BL / 6J-Rag2<em>1hwl / Korl mice are mice in which the Rag2 gene, which is involved in the antibody production ability of C57BL / 6J mice, has been knocked out.

[0779] ** Wild-type (+ / +) refers to wild-type mice with no gene mutations, heterozygous (+ / -) refers to heterozygous mice, and homozygous (- / -) refers to homozygous mice.

[0780] *** Homozygous (- / -) mice are incapable of producing antibodies in their bodies.

[0781] The in vivo administration composition was administered to the test subjects according to Experimental Example 1.7, specifically at the following administration cycles: 8 weeks, 10 weeks, 12 weeks and 14 weeks of age.

[0782] Experimental Example 6.2, Confirmation of Experimental Results.

[0783] To confirm the experimental results of Experimental Example 6.1, the body weight of the test subjects was measured for each experimental group disclosed in Table 10 according to Experimental Example 1.8.

[0784] The experimental results are shown in FIG.

[0785] Experimental Example 7, Confirmation of Peptide Effect 6.

[0786] Experimental Example 7.1: Preparation of peptides and their experiments.

[0787] Peptides according to Table 11 were prepared according to Experimental Example 1.1, and the prepared peptides were then characterized according to Experimental Examples 1.2 to 1.4. A composition for in vivo administration containing the peptides according to Table 11 was prepared according to Experimental Example 1.5.

[0788] [Table 11] Peptides used in Experimental Example 7 and compositions for in vivo administration containing the same. [Table 11]

[0789] The test specimens shown in Table 12 were prepared according to Experimental Example 1.6. [Table 12] Test subjects used in Experimental Example 7 [Table 12]

[0790] The in vivo administration composition was administered to the test subjects according to Experimental Example 1.7, specifically at the following administration cycles: 8 weeks, 10 weeks, 12 weeks and 14 weeks of age.

[0791] Experimental Example 7.2, Confirmation of Experimental Results.

[0792] To confirm the experimental results of Experimental Example 7.1, the following experiments were conducted on test subjects for each experimental group disclosed in [Table 12].

[0793] (1) The body weight of the test subjects in each experimental group was measured according to Experimental Example 1.8.

[0794] (2) According to Experimental Example 1.9, the antibody titers observed in the test subjects of each experimental group at weeks 11, 16, and 19 were confirmed. In particular, the target antigen was determined using RNVPPIFNDVYWIAF (SEQ ID NO: 6).

[0795] The experimental results are shown in FIGS.

[0796] As a result of the experiment, all experimental groups 6-1 (P1) to 6-9 (P9) showed a clear weight loss effect compared to the control group (obese) fed a high-fat diet.

[0797] The results of the antibody titer tests according to the experimental groups can be interpreted as follows.

[0798] Antibody titers are not shown for the control groups (i.e., lean and obese groups) because they were not administered the antigen.

[0799] Considering the experimental design, the antibody titer against SEQ ID NO: 6 contained in the peptide used was mainly checked in the experimental group. Although antibody titers against sequences other than SEQ ID NO: 6 contained in the peptide used were not separately checked, the weight loss effect due to humoral immunity due to these was also confirmed.

[0800] Specific results will be explained below.

[0801] In experimental group 6-1 (P1), some individuals showed high antibody titers, while others showed no antibody titers. These results can be interpreted as follows: some individuals in experimental group 6-1 (P1) showed induction of humoral immunity against RNVPPIFNDVYWIAF (SEQ ID NO: 6) included in Example 6, resulting in the observation of weight loss and antibody titers. In some individuals, humoral immunity was induced against RNVPPIFNDVYWIAF (SEQ ID NO: 6) included in Example 6, resulting in weight loss. However, because the antigen used in the enzyme-linked immunosorbent assay (ELISA) consisted only of RNVPPIFNDVYWIAF (SEQ ID NO: 6) and no other antigens (i.e., the antigen of SEQ ID NO: 7) were present, antibody titers were not observed in the above experiment, even in the presence of antibodies.

[0802] In the case of experimental group 6-2 (P2), antibody titers against RNVPPIFNDVYWIAF (SEQ ID NO:6) contained in Example 7 were observed, and a weight loss effect was observed, which suggests that the B cell epitope contained in the peptide of Example 7 effectively induced humoral immunity against it.

[0803] In the case of experimental group 6-3 (P3), the antibody titer against RNVPPIFNDVYWIAF (SEQ ID NO:6) contained in Example 8 was observed, and a weight loss effect was observed, which suggests that the B cell epitope contained in the peptide of Example 8 effectively induces humoral immunity.

[0804] In the case of experimental group 6-4 (P4), no weight loss effect was observed, which can be interpreted as indicating that humoral immunity was induced against KTTKQSFDLSVKAQYKKNKH (SEQ ID NO:8) and / or CRFRGLISLSQVYLS (SEQ ID NO:7) included in Example 9, but antibody titers against RNVPPIFNDVYWIAF (SEQ ID NO:6) were observed.

[0805] These results suggest that in some individuals (P5) of experimental group 6-5, humoral immunity was induced against RNVPPIFNDVYWIAF (SEQ ID NO: 6) included in Example 10, such that both a weight loss effect and antibody titer were observed, and in other individuals of experimental group 6-5 (P5), humoral immunity was induced against CRFRGLISLSQVYLS (SEQ ID NO: 7) included in Example 10, such that a weight loss effect was observed, but antibody titer was not observed in the above experiment.

[0806] In experimental group 6-7 (P7), although there were individual differences, antibodies against RNVPPIFNDVYWIAF (SEQ ID NO:6) were observed and a weight loss effect was observed, which suggests that the B cell epitope contained in the peptide of Example 11 effectively induced humoral immunity.

[0807] In the case of experimental group 6-8 (P8), antibody titers against RNVPPIFNDVYWIAF (SEQ ID NO:6) contained in Example 12 were observed, and a weight loss effect was observed. This suggests that the B cell epitope contained in the peptide of Example 12 effectively induced humoral immunity.

[0808] In experimental group 6-9 (P9), there was some individual variation. However, antibodies against RNVPPIFNDVYWIAF (SEQ ID NO: 6) were observed and weight loss was observed, which suggests that the B cell epitope contained in the peptide of Example 13 effectively induces humoral immunity.

[0809] Experimental Example 8, Confirmation of Peptide Effect 7.

[0810] Example 8.1: Preparation of peptides and their experiments.

[0811] After preparing the peptides according to [Table 13] according to Experimental Example 1.1, the prepared peptides are confirmed according to Experimental Examples 1.2 to 1.4. A composition for in vivo administration containing the peptides according to [Table 13] is prepared according to Experimental Example 1.5.

[0812] [Table 13] Peptides used in Experimental Example 8 and compositions for in vivo administration containing the same. [Table 13]

[0813] The test objects shown in Table 14 are prepared according to Example 1.6.

[0814] [Table 14] Test subjects used in Experimental Example 8 [Table 14]

[0815] The composition for in vivo administration is administered to a test subject according to Experimental Example 1.7. In particular, the administration cycle, administration time, and administration frequency can be appropriately changed depending on the experimental design. For example, but not limited to, the composition may be administered to an 8-week-old test subject four times at two-week intervals.

[0816] The above experimental method can be modified as needed.

[0817] Experimental Example 8.2, Confirmation of Experimental Results.

[0818] To confirm the experimental results of Experimental Example 8.1, the following experiment is conducted on test subjects for each experimental group disclosed in [Table 14].

[0819] (1) Measure the body weight of the test subjects in each experimental group according to Experimental Example 1.8.

[0820] (2) Confirm the antibody titers observed in the test subjects of each experimental group according to Experimental Example 1.9.

[0821] (3) Measure the blood lipid levels of the test subjects in each experimental group according to Experimental Example 1.10.

[0822] (4) According to Experimental Example 1.11, the lipolytic ability of the test subjects in each experimental group is confirmed, and the size of the adipocytes is observed.

[0823] Experimental Example 9, Confirmation of Peptide Effect 8.

[0824] Example 9.1: Preparation of peptides and their experiments.

[0825] According to Example 1.1, peptides represented by one or more sequences selected from the group consisting of SEQ ID NOS:56-158, SEQ ID NOS:160-161, and SEQ ID NOS:198-220 are prepared.

[0826] The prepared peptide is confirmed according to Experimental Examples 1.2 to 1.4. A composition for in vivo administration containing the prepared peptide is prepared according to Experimental Example 1.5.

[0827] In particular, peptides may be prepared by selecting only some sequences from the above sequence group, and experiments may be repeated using multiple combinations as necessary.

[0828] Test subjects of the prepared peptides are prepared according to Experimental Example 1.6. In particular, examples of the control group and experimental group used are as shown in [Table 15], and each experimental group is determined by referring to the conditions of Experimental Example 1.6 and [Table 15].

[0829] [Table 15] Test subjects used in Experimental Example 9 [Table 15]

[0830] In particular, the number of experimental groups prepared is equal to the number of peptides prepared.

[0831] The composition for in vivo administration is administered to a test subject according to Experimental Example 1.7. In particular, the administration cycle, administration time, and administration frequency can be appropriately changed depending on the experimental design. For example, but not limited to, the composition may be administered four times at two-week intervals to an 8-week-old test subject.

[0832] The above experimental method can be modified as needed.

[0833] Experimental Example 9.2, Confirmation of Experimental Results

[0834] To confirm the experimental results of Experimental Example 9.1, the following experiment is conducted on test subjects for each experimental group.

[0835] (1) Measure the body weight of the test subjects in each experimental group according to Experimental Example 1.8.

[0836] (2) Confirm the antibody titers observed in the test subjects of each experimental group according to Experimental Example 1.9.

[0837] (3) Measure the blood lipid levels of the test subjects in each experimental group according to Experimental Example 1.10.

[0838] (4) According to Experimental Example 1.11, the lipolytic ability of the test subjects in each experimental group is confirmed, and the size of the adipocytes is observed.

[0839] Experimental Example 10: Confirmation of peptide effect 9

[0840] Experimental Example 10.1: Preparation of peptides and their experiments

[0841] According to Experimental Example 1.1, a peptide is prepared according to Examples 81 to 90 in the "Possible Examples of the Present Invention" section, and then the prepared peptide is confirmed according to Experimental Examples 1.2 to 1.4. A composition for in vivo administration containing the prepared peptide is prepared according to Experimental Example 1.5.

[0842] In particular, only a portion of the peptides may be selected and prepared according to Examples 81 to 90 in the section "Possible Examples of the Present Invention," and experiments may be repeated for multiple combinations as necessary.

[0843] The prepared peptide test subjects are pre...

Claims

1. GSHHHHHHGSDDDDKZaK (Cha) VAAWTLKAAaZRNVPIFNDVYWIAF (SEQ ID NO: 69), RNVPPIFNDVYWIAFZaK (Cha)VAAWTLKAAaZGSHHHHHHGSDDDDK (SEQ ID NO: 68), RNVPPIFNDVYWIAFZaK (Cha) VAAWTLKAAaZ (SEQ ID NO: 56), RNVPPIFNDVYWIAFK(Cha)VAAWTLKAA (SEQ ID NO: 62), and RNVPPIFNDVYWIAFK (Cha) VAAWTLKAAAHHHHHH (SEQ ID NO: 67) a peptide comprising an amino acid sequence selected from the group consisting of: The a represents D-alanine, the (Cha) represents L-cyclohexylalanine, and the Z represents 6-aminohexanoic acid. A pharmaceutical composition for treating obesity.

2. The pharmaceutical composition of claim 1 further comprising an adjuvant.

3. 3. The pharmaceutical composition of claim 2, wherein the adjuvant comprises an aluminum salt and monophosphoryl lipid A.

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