RU2812911C2 - Antigene peptides for cancer prevention and treatment - Google Patents

Abstract

FIELD: immunotherapy.

SUBSTANCE: invention relates to immunotherapy based on the use of antigens, more specifically to cancer immunotherapy. In particular, the invention relates to antigenic peptides similar in amino acid composition to fragments of human tumor antigens, but different from them. The invention also relates to immunogenic compounds, cells and pharmaceutical compositions containing such antigenic peptides and nucleic acids encoding such antigenic peptides.

EFFECT: invention provides alternative methods of treating cancer that will overcome existing limitations.

53 cl, 13 dwg, 10 tbl, 9 ex

Description

The present invention relates to the field of cancer treatment, more specifically to immunotherapeutic methods. In particular, the present invention relates to various peptides that are useful for cancer immunotherapy.

Cancer is one of the leading causes of death in people around the world. According to the World Health Organization (WHO), in 2012 alone, there were 14 million new cases and 8.2 million deaths attributed to cancer worldwide, with the number of new cases expected to increase by approximately 70% in the next second decade. . To date, more than 60% of new cancer cases each year occur in Africa, Asia and Central and South America. The contribution of these regions to global mortality is 70%. Among men, the most common cancers are the following five sites: lung cancer, prostate cancer, colorectal cancer, stomach cancer and liver cancer; while in women, breast cancer, colorectal cancer, lung cancer, cervical cancer and stomach cancer predominate.

Cancer treatment includes surgery, radiation therapy, cytotoxic chemotherapy, and endocrine manipulation; these methods are usually combined in a sequential manner for better disease control. However, the major limitations to the true effectiveness of these standard treatments are their unclear specificity, resulting in collateral damage to healthy tissue due to treatment, slow cure rates, and acquired drug resistance.

Recent years have seen tremendous progress in the development of cancer treatments, particularly with significant advances in expression profiling of tumors and normal cells, as well as recent research and early clinical results of immunotherapies or molecular targeted therapies, which are beginning to change our perception of this disease.

Promising anticancer immunotherapies are now a reality, and evidence that the host immune system can recognize tumor antigens has led to the development of anticancer drugs that are now approved by regulatory agencies such as the Food and Drug Administration (FDA). ) and the European Medicines Regulatory Organization (EMA). Various therapeutic approaches include, but are not limited to, adoptive ex vivo transfer of expanded tumor infiltrating lymphocytes (TILs), antitumor vaccines, immunostimulatory cytokines and their variants, pattern recognition receptor (PRR) agonists, and immunomodulatory monoclonal drugs. antibodies directed against tumor antigens or immune checkpoints. (Galuzzi et al., Classification of current anticancer immunotherapies. Oncotarget. 2014 Dec 30;5(24):12472-508).

Unfortunately, a significant number of patients still have primary resistance to some of these immunotherapies or develop secondary resistance during treatment. For example, the 3-year survival rate for unresectable or metastatic melanoma treated with the anti-CTLA-4 antibody, ipilimumab, was reported to be approximately 20% (Snyder et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4;371(23):2189-2199; Schadendorf et al., Pooled Analysis of Long-Term Survival Data from Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol. 2015 Jun 10 ;33(17): 1889-94), with 3-year survival also reported with another checkpoint inhibitor, Nivolumab, directed against PD-1, which was about 44% in renal cell carcinoma (RCC) and 18% in non-small cell lung carcinoma (NSCLC) (MC Dermott et al., Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin Oncol. 2015 Jun 20;33(18):2013- 20; Gettinger et al., Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients with Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015 Jun 20;33(18):2004-12). Thus, fundamental drug resistance represents a significant barrier to the effectiveness of these immunotherapies. It is clear that new and different approaches are required to overcome this barrier.

The lack of response in a large number of subjects treated with these immunotherapeutic methods may be due to an insufficient antitumor immune response (eg, a defect in antigen presentation by antigen presenting cells (APCs) or antigen recognition by T cells). In other words, a positive response to immunotherapy correlates with the ability of the immune system to produce specific subpopulations of lymphocytes capable of recognizing major histocompatibility complex class I (MHC class I)-restricted antigens expressed by human cancer cells (Kvistborg et al., Human cancer regression antigens. Curr. Opin Immunol 2013 Apr;25(2):284-90). This hypothesis is strongly supported by data demonstrating that the response to adoptive transfer of tumor-infiltrating lymphocytes (TILs) directly correlates with the number of CD8+ T cells transferred to the patient (Besser et al., Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res. 2013 Sep 1; 19(17):4792-800). A strong antitumor response will thus depend on the presentation of immunoreactive peptides and the presence of sufficient numbers of reactive cells trained to recognize these antigens.

Vaccination with tumor antigen drugs is a unique approach to cancer therapy that is of great interest because it allows the patient's own immune system to be recruited to recognize, attack and destroy tumors in a specific and reliable manner. Indeed, tumor cells are known to express a large number of peptide antigens that are recognized by the immune system. Vaccines based on such antigens thus offer great potential not only for improving overall patient survival, but also for monitoring immune responses and obtaining GMP-approved products due to their low toxicity and small molecular weight of tumor antigens. Examples of tumor antigens include, among others, by-products of proteins transcribed from normally silent or overexpressed genes, as well as proteins expressed by oncoviruses (Kvistborg et al., Human cancer regression antigens. Curr Opin Immunol. 2013 Apr; 25(2) :284-90), as well as neoantigens obtained as a result of point mutations of cellular proteins. The latter are of particular interest because they have been shown to be directly associated with increased overall survival in patients treated with CTLA-4 inhibitors (Snyder et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4; 371(23):2189-2199; Brown et al., Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014 May; 24(5):743-50).

However, the number of human tumor antigens on which cancer vaccines can be developed is limited. In particular, antigens derived from mutated or modified self-proteins may induce immune tolerance and/or unwanted side effects associated with autoimmune reactions.

Thus, there is a need in the field to find alternative cancer treatments that overcome current limitations.

The purpose of the invention is to satisfy the above needs. This object is achieved by the summary of the invention set forth below, in particular the embodiments of the present invention and the accompanying claims.

OBJECTS OF THE INVENTION

The present invention specifically provides the following objects:

1. An antigenic peptide comprising the amino acid sequence as defined in any one of SEQ ID NOs 1-580 and 861-887.

2. The antigenic peptide of claim 1, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 1-580.

3. The antigenic peptide of claim 1, consisting of or including an amino acid sequence as set forth in any of SEQ ID NOs 861,887.

4. An antigenic peptide according to claim 1 or claim 2, consisting of or including the amino acid sequence as specified in any of SEQ ID NOs 1-160, 162-253 and 255-580.

5. The antigenic peptide of claim 2 or claim 4, wherein said antigenic peptide consists of or includes an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524.

6. Antigenic peptide according to any one of paragraphs. 1-5, wherein said antigenic peptide consists of or includes an amino acid sequence as indicated by any of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524.

7. Antigenic peptide according to any one of paragraphs. 1-6, wherein said antigenic peptide consists of or includes an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524.

8. Antigenic peptide according to any one of paragraphs. 1-7, wherein said antigenic peptide consists of or includes an amino acid sequence as defined in any one of SEQ ID NOs 30, 32, 87, 97, and 194.

9. Antigenic peptide according to any one of paragraphs. 1-2, wherein said antigenic peptide consists of or includes an amino acid sequence as defined in any one of SEQ ID NOs 30, 32, 194, 220, 254 or 255.

10. An immunogenic compound comprising an antigenic peptide according to any one of paragraphs. 1-9.

11. An immunogenic compound according to claim 10, wherein the antigenic peptide is linked to a carrier molecule.

12. The immunogenic compound according to claim 11, wherein the carrier molecule is a carrier protein or a carrier peptide.

13. Immunogenic compound according to any one of paragraphs. 10-12, consisting of or including a polypeptide of formula (I)

PepNt-CORE-PepCt (I)

Where:

- "PepNt" consists of a polypeptide with a length of 0 to 500 amino acid residues and a polypeptide of formula (I) located at the N-terminus;

-CORE consists of an antigenic peptide as defined in any one of claims. 1-6; And

- "PepCt" consists of a polypeptide with a length of 0 to 500 amino acid residues and a polypeptide of formula (I) located at the C-terminus.

14. Nanoparticle loaded

- at least one antigenic peptide according to any one of paragraphs. 1-9, or

- at least one immunogenic compound according to any one of claims. 10-13;

and optionally an adjuvant.

15. A cell loaded with an antigenic peptide according to any one of paragraphs. 1-9, or an immunogenic compound according to any one of paragraphs. 10-13.

16. The cell of claim 15, wherein said cell is an antigen presenting cell (APC), preferably a dendritic cell.

17. Nucleic acid encoding an antigenic peptide according to any one of paragraphs. 1-9, a polypeptide of formula (I) as defined in paragraph 13, or an immunogenic compound according to any one of claims. 10-13, wherein said immunogenic compound is a peptide or protein.

18. Nucleic acid according to claim 17, wherein the nucleic acid is a DNA molecule or an RNA molecule; preferably selected from genomic DNA; cDNA; miRNA; rRNA; mRNA; antisense DNA; antisense RNA; ribozyme; complementary RNA and/or DNA sequences; RNA and/or DNA sequences with or without expression elements, regulatory elements and/or promoters; vector; as well as their combinations.

19. A host cell containing the nucleic acid of claim 17 or claim 18.

20. The host cell according to claim 19, wherein the nucleic acid is a vector.

21. Host cell according to any one of paragraphs. 19-20, wherein said host cell is a bacterial cell, preferably a bacterial cell of the intestinal microflora

22. Pharmaceutical composition comprising:

- antigenic peptide according to any one of paragraphs. 1-9,

- immunogenic compound according to any one of paragraphs. 10-13,

- nanoparticle according to claim 14,

- a cage according to clause 15 or clause 16,

- nucleic acid according to claim 17 or claim 18, and/or

- a host cell according to any one of paragraphs. 19-21,

and optionally one or more pharmaceutically available excipients or carriers.

23. The pharmaceutical composition according to claim 22, further comprising one or more immunostimulating agents.

24. The pharmaceutical composition according to claim 23, wherein the immunostimulating agent is selected from the group consisting of immunoadjuvants and antigen-presenting cells.

25. The pharmaceutical composition according to claim 24, wherein the antigen presenting cell is a dendritic cell.

26. Pharmaceutical composition according to any one of paragraphs. 22-25, and the composition includes:

(a) at least two different antigenic peptides according to any one of claims. 1-9;

(b) at least two different immunogenic compounds according to any one of claims. 10-13;

(c) at least two different nanoparticles according to claim 14; and/or

(d) at least two different nucleic acids according to claim 17 or claim 18.

27. Set including

- antigenic peptide according to any one of paragraphs. 1-9,

- immunogenic compound according to any one of paragraphs. 10-13,

- nanoparticle according to claim 14,

- a cage according to clause 15 or clause 16,

- nucleic acid according to claim 17 or claim 18,

- a host cell according to any one of paragraphs. 19-21, and/or

- a pharmaceutical composition according to any one of paragraphs. 22-26.

28. The kit of claim 27 further comprising a package insert or instructions for use with recommendations for the prevention and treatment of cancer by use of an antigenic peptide, immunogenic compound, nanoparticle, cell, nucleic acid, host cell and/or pharmaceutical composition.

29. The set according to claim 27 or claim 28, wherein the set contains at least two different antigenic peptides according to any of claims. 1-9.

30. The kit according to claim 27 or claim 28, wherein the set contains at least two different immunogenic compounds according to any one of claims. 10-13.

31. The set according to claim 27 or claim 28, wherein the set contains at least two different nanoparticles according to claim 14.

32. The kit according to claim 27 or claim 28, wherein the kit contains at least two different nucleic acids according to claim 15 or 16.

33. Antigenic peptide according to any one of paragraphs. 1-9,

- immunogenic compound according to any one of paragraphs. 10-13,

- nanoparticle according to claim 14,

- cage according to item 15 or 16,

- nucleic acid according to claim 17 or 18,

- host cell according to clauses 19-21,

- pharmaceutical composition according to any one of paragraphs. 22-26 or

- set according to any of paragraphs. 27-32

for use in the prevention and/or treatment of cancer.

34. An antigenic peptide, immunogenic compound, nanoparticle, cell, nucleic acid, host cell, pharmaceutical composition or kit for use according to claim 33, wherein the cancer is selected from glioma, kidney cancer, skin cancer, more specifically melanoma, lung cancer, ovarian cancer , breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial cancer and prostate cancer.

35. A combination of at least two different antigenic peptides according to any one of claims. 1-9 for use in the prevention and/or treatment of cancer.

36. A combination of at least two different immunogenic compounds according to any one of claims. 10-13 for use in the prevention and/or treatment of cancer.

37. A combination of at least two different nanoparticles according to any one of claims. 14 for use in the prevention and/or treatment of cancer.

38. A combination of at least two different nucleic acids according to claim 17 or claim 18 for use in the prevention and/or treatment of cancer.

39. Combination for use according to any one of paragraphs. 35-38, wherein at least two different components are present in different compositions.

40. Combination for use according to any of paragraphs. 35-38, wherein at least two different components are included in one composition.

41. Combination for use according to any of paragraphs. 35-39, wherein at least two different components are introduced in different ways.

42. Combination for use according to any of paragraphs. 35-40, wherein at least two different components are administered in the same manner.

43. Combination for use according to any of paragraphs. 35-39, 41 and 42, wherein at least two different components are introduced sequentially.

43. Combination for use according to any of paragraphs. 35-42, wherein at least two different components are introduced at approximately the same time.

44. A method of preventing and/or treating cancer, or initiating, enhancing or prolonging an antitumor response in a subject in need thereof, comprising administering to the subject

- antigenic peptide according to any one of paragraphs. 1-9,

- immunogenic compound according to any one of paragraphs. 10-13,

- nanoparticles according to clause 14,

- cells according to clause 15 or clause 16,

- nucleic acid according to claim 17 or claim 18,

- host cell according to any one of paragraphs. 19-21,

- pharmaceutical composition according to any one of paragraphs. 22-26, and/or

- combinations as defined in any of paragraphs. 35-44.

45. The method of claim 45, wherein the cancer is selected from glioma, kidney cancer, skin cancer, more specifically melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, cancer urothelium and prostate cancer.

46. Peptide-MHC multimer (pMHC), including an antigenic peptide according to any one of paragraphs. 1-9.

The invention and in particular the objects listed above are described in detail in the text of the application below.

DEFINITIONS

Unless otherwise defined further, scientific and technical terms used herein will have meanings that are generally well known to those skilled in the art. In addition, unless otherwise specified, the conventions used in the description, as well as cell and tissue culture techniques, are well known to those skilled in the art.

Such techniques are described in detail in the literature, for example by Owen et al. (Kuby Immunology, 7 ^th , edition, 2013 - WH Freeman) and Sambrook et al. (Molecular cloning: A laboratory manual 4th edition, Cold Spring Harbor Laboratory Press - Cold Spring Harbor, NY, USA, 2012).

However, as various terms are used herein, the following specific definitions are more applicable.

The terms "peptide", "polypeptide", "protein" and various variations of these terms refer to peptides, oligopeptides, polypeptides or proteins comprising at least two amino acids linked together, preferably by a conventional peptide bond or, alternatively, by a modified peptide bond, as, for example, in the case of isosteric peptides. The term "(poly)peptide" refers to a peptide and/or polypeptide. In particular, the terms "peptide", "polypeptide" and "protein" refer to a sequential chain of amino acids of any length, the amino acids being linked together by peptide bonds (-NHCO-). Peptides, polypeptides and proteins can play structural and/or functional roles in cells in vitro and/or in vivo. The terms "peptide", "polypeptide", "protein" preferably combine amino acid chains that are from 2 to at least about 1000 amino acid residues in length. The term "peptide" preferably encompasses amino acid chains that are less than about 30 amino acids in length, with the terms "polypeptide" and "protein" preferably encompassing amino acid chains that are at least 30 amino acids in length. The terms "polypeptide" and "protein" are used interchangeably herein. According to a preferred embodiment of the invention, the terms "peptide", "polypeptide" and "protein" also include "peptidomimetics", which are defined as peptide analogues containing non-peptide structural elements, such peptides being capable of mimicking or counteracting the biological activity of the natural parent peptide. . Peptidomimetics do not have the properties of classical proteins, such as peptide bonds that are cleaved by enzymes. In particular, a peptide, polypeptide or protein may, in addition to basic amino acids, include amino acids that differ from the 20 amino acids encoded in the genetic code, or it may consist entirely of amino acids different from the 20 encoded in the genetic code. In particular, a peptide, polypeptide or protein in the context of the present invention may equally consist of amino acids modified by natural means, such as post-translational maturation processes or chemical processes, which are well known to those skilled in the art. Such modifications are described in detail in the literature. Such modifications can be located anywhere in the polypeptide: in the peptide backbone, in the amino acid chain, or even at the carboxy- or amino-terminal regions. In particular, the peptide or polypeptide may be branched after ubiquitination or be cyclic, with or without branching. This type of modification may result from natural or synthetic post-translational processes, which are well known to those skilled in the art. The terms "peptide", "polypeptide", "protein" in the context of the present invention, in particular, also include modified peptides, polypeptides and proteins. For example, modifications of a peptide, polypeptide or protein may include acetylation, acylation, ADP-ribosylation, amidation, covalent addition of a nucleotide or nucleotide derivative, covalent addition of a lipid or lipid derivative, covalent addition of phosphatidylinositol, covalent or non-covalent cross-linking, cyclization, disulfide bond formation, demethylation , glycosylation, including PEGylation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processes, phosphorylation, prenylation, racemization, seneloylation, sulfation, addition of amino acids such as arginylation or ubiquitination. Such modifications are described in detail in the literature (Proteins Structure and Molecular Properties (1993) 2nd Ed., T. E. Creighton, New York; Post-translational Covalent Modifications of Proteins (1983) V. C. Johnson, Ed., Academic Press, New York; Seifter et al. (1990) Analysis for protein modifications and nonprotein cofactors, Meth. Enzymol. 182: 626-646 and Rattan et al., (1992) Protein Synthesis: Post-translational Modifications and Aging, Ann NY Acad Sci , 663: 48-62). Accordingly, the terms "peptide", "polypeptide", "protein" preferably also include, for example, lipopeptides, lipoproteins, glycopeptides, glycoproteins and the like.

According to a preferred embodiment of the invention, the (poly)peptide or protein is a "classical" (poly)peptide or protein, wherein the "classical" (poly)peptide or protein typically consists of amino acids selected from the 20 amino acids encoded in the genetic code, connected with each other via a normal peptide bond.

As is well known in the art, peptides, polypeptides and proteins can be encoded by nucleic acids. The terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", "nucleotide sequence" are used interchangeably herein and refer to the exact sequence of natural nucleotides (e.g. A, T, G, C and U) or synthetic nucleotides, that is, a chain consisting of at least two nucleotides. In particular, the terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", "nucleotide sequence" refer to DNA or RNA. Nucleic acids preferably include single-stranded, double-stranded or partially double-stranded DNA or RNA, preferably selected from genomic DNA (gDNA), complementary DNA (cDNA), ribosomal DNA (rDNA), as well as a transcription product of said DNA, such as RNA. Preferred examples of nucleic acids include ribosomal RNA (rRNA), messenger RNA (mRNA); antisense DNA, antisense RNA; complementary RNA and/or DNA sequences, ribozymes, (complementary) RNA/DNA sequences with and without expression elements, vector; mini-gene, gene fragments, regulatory elements, promoters, as well as their combinations. Additional preferred examples of nucleic acids (molecules) and/or polynucleotides include, for example, a recombinant polynucleotide, a vector, an oligonucleotide, an RNA molecule such as rRNA, mRNA or transfer RNA (tRNA), or a DNA molecule as described above. Thus, it is preferable that the nucleic acid (molecule) is a DNA molecule or an RNA molecule; preferably selected from the group of gDNA; cDNA; rRNA; mRNA; antisense DNA; antisense RNA; complementary RNA and/or DNA sequences; RNA and/or DNA sequences with or without expression elements, regulatory elements, and/or promoters; vector; as well as their combinations. It is easy for one skilled in the art to determine a nucleotide sequence that may encode a specific amino acid sequence.

Polypeptides and/or nucleic acids in accordance with the present invention can be obtained using any method known in the art, including, without limitation, any recombinant method, any ex vivo synthesis method and the like, as well as any combination thereof. Such techniques are described in detail in the literature, as mentioned above.

The term "antigenic peptide" as used in the present invention refers to a peptide that is capable of eliciting/inducing, enhancing, prolonging or maintaining an immune response in a subject to which it is administered. More specifically, an antigenic peptide is a sequence variant (fragment/epitope) of a (human) tumor antigen. In other words, the antigenic peptide is preferably different from the (fragment/epitope) tumor antigen (human), but preferably has amino acid similarity to the (fragment/epitope) tumor antigen (human). Preferably, the immune response induced/triggered, enhanced, prolonged or maintained by the antigenic peptide (also) targets the corresponding (fragment/epitope) of the (human) tumor antigen.

As used herein, the term “tumor antigen” refers to tumor-specific antigens and tumor-associated antigens. In general, the term “tumor antigen” as used herein refers to an antigenic substance produced by tumor cells and sometimes healthy cells that can initiate an immune response when administered to a subject. In humans, antigens are classified according to their expression pattern, function, or genetic nature, and include, but are not limited to, overexpressed autoantigens (such as HER2/neu and its variant dHER2, p53, Wilms tumor 1, Ephrin receptor, Proteinase-3, mucin -1, mesothelin, EGFR, CD20); testicular cancer antigens (such as MAGE-1, BAGE, GAGE, NY-ESO-1); mutational antigens also known as neoantigens (such as mutants MUM-1, bcr-abl, ras, b-raf, p53, CDK-4, CDC27, beta-catenin, alpha-actenin-4); tissue-specific differentiation antigens (such as melanoma antigens Melan A/MART-1, tyrosinase, TRP1/pg75, TRP2, gp100 and gangliosides GM3, GM2, GD2 and GD3; prostate cancer antigens PSMA, PSA and PAP); viral antigens expressed by oncoviruses (such as HPV, EBV); oncofetal antigens (such as alpha-fetoprotein AFP and carcinoembryonic antigen CEA); as well as universal antigens (telomerase, hTERT, survivin, mdm-2, CYP-1B1) (Srinivasan and Wolchok, Tumor antigens for cancer immunotherapy: therapeutic potential of xenogeneic DNA vaccines. J Transl Med. 2004 Apr 16;2(1): 12). Accordingly, human tumor antigens are well known to those skilled in the art. In particular, interleukin-13 alpha subunit (IL-13Rα2 or IL13RA2) is a membrane-bound protein that is encoded by the IL13RA2 gene in humans. IL13RA2 has been reported to be a potential target for immunotherapy (see, Beard et at; Clin Cancer Res; 72(11); 2012). High IL13RA2 expression has also been associated with invasion, liver metastasis, and poor prognosis in colorectal cancer (Barderas et al.; Cancer Res; 72(11); 2012). In particular, the antigenic peptides in accordance with the present invention are preferably sequence variants (epitope/fragment) of the tumor antigens presented in Table 1 B, and can be used, in particular, in diseases corresponding to a specific tumor antigen from Table 1 B.

The term "microbiota" as used herein refers to the symbiotic microorganisms that can be found in all multicellular organisms studied to date, both plant and animal. In particular, it has been found that the microbiota is essential for the immunogenic, hormonal and metabolic homeostasis of the host. Microbiota includes bacteria, archaea, protozoa, fungi and viruses. Accordingly, the term “microbiota sequence variant” is a reference sequence variant (specifically, an epitope/fragment of a human tumor antigen) that exists in the microbiota (eg, contained in a microbiotic protein). A "sequence variant", particularly over the entire length of the sequence, is typically at least 50% identical to a reference sequence, specifically a fragment/epitope of a (reference) tumor antigen. Preferably, the sequence variant is at least 60%, preferably at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least is at least 90%, particularly preferably at least 95%, and most preferably at least 99% identical to the reference sequence of a specific tumor antigen fragment/epitope. Sequence identities can be calculated using methods well known in the art, particularly as described below. Preferably, the sequence variant retains the specific function of the reference sequence, for example, the function of a tumor epitope and/or the ability to induce or maintain an immune response. The microbiota sequence variant is preferably selected from the group consisting of bacterial sequence variants, archaeal sequence variants, protozoan sequence variants, fungal sequence variants and viral sequence variants. More preferably, the microbiota sequence variant is a bacterial sequence variant.

Anatomically, the microbiota is located on the surface of or within a range of tissues and body fluids, including the skin, conjunctiva, breast, vagina, placenta, seminal fluid, uterus, ovarian follicles, lungs, saliva, oral cavity (particularly the oral mucosa), and gastrointestinal tract, in particular the intestines. In the context of the present invention, the microbiota sequence variant is preferably a gastrointestinal microbiota sequence variant (microorganisms inhabiting the gastrointestinal tract), more preferably a gut microbiota sequence variant (microorganisms inhabiting the intestines). Accordingly, it is more preferable that the microbiota sequence variant is a (human) gut bacteria sequence variant (ie, a sequence variant of bacteria inhabiting the (human) gut).

Although microbiota can be found in many multicellular organisms (all multicellular organisms studied to date from plants to animals), in the context of the present invention, microbiota found in and on the human body is preferred. Such microbiota is referred to herein as “human microbiota” (with the term “human” referring specifically to the location/residence of the microbiota). In the context of the present invention, the microbiota sequence variant is a human microbiota sequence variant.

The term "immunogenic compound" refers to a compound containing an antigenic peptide claimed in accordance with the present invention. An "immunogenic compound" is capable of inducing/causing, enhancing, prolonging or maintaining an immune response against a specified antigenic peptide in a subject to which it is administered. In some embodiments, the immunogenic compounds comprise at least one antigenic peptide, or alternatively at least one compound comprising such an antigenic peptide linked to a protein, such as a carrier protein.

A "carrier protein" is typically a protein that is capable of carrying cargo, such as an antigenic peptide of the present invention. For example, a carrier protein can transport its cargo across a membrane. In the context of the present invention, a carrier protein specifically (also) refers to a protein or polypeptide that has the ability to induce an immune response against an antigenic peptide to which it is associated. Carrier proteins are well known in the art.

Alternatively, such a carrier protein or polypeptide may be co-administered in the form of an immune adjuvant.

Preferably, the antigenic peptide described herein may be administered simultaneously or linked, for example by covalent or non-covalent linkage, to a protein/peptide having immunoadjuvant properties, such as providing stimulation of CD4+ Th1 cells. Considering that the antigenic peptide described herein preferentially binds to MHC class I, CD4+ helper epitopes can further be used to stimulate an effective immune response. Th1 helper cells are able to support efficient dendritic cell (DC) activation and specific CTL activation by secreting interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) and interleukin-2 (IL-2) and increasing co-stimulatory signal expression on dendritic cells and T cells (Galaine et al., Interest in Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine. Vaccines (Basel). 2015 Jun 30;3(3):490-502).

For example, the adjuvant peptide/protein may preferably be different from the antigenic peptide claimed in accordance with the present invention. Preferably, the adjuvant peptide/protein is capable of inducing immune memory or providing non-specific help, or being a specific helper protein. Several helper peptides have been described in the literature to help nonspecific T cells, such as tetanus helper protein, keyhole limpet hemocyanin peptide, or PADRE peptide (Adotevi et al., Targeting antitumor CD4 helper T cells with universal tumor-reactive helper peptides derived from telomerase for cancer vaccine. Hum Vaccin Immunother. 2013 May; 9(5): 1073-7, Slingluff CL, The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Cancer J. 2011 Sep -Oct;17(5):343-50). Accordingly, tetanus helper protein, keyhole limpet hemocyanin peptide and PADRE peptide are preferred examples of such adjuvant proteins/peptides. In particular, an antigenic peptide as described herein, or a polypeptide containing said antigenic peptide, may be linked, for example, covalently or non-covalently to an HHD-DR3 peptide with the sequence MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). This peptide is another example of a helper peptide (having immunoadjuvant properties) that is preferred in the context of the present invention. Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh N, Raghava GP (2003) MHCBN: a comprehensive database of MHC binding and non-binding peptides. Bioinformatics 19: 665 666) . Other examples of preferred helper proteins are the UCP2 peptide (e.g. described in WO 2013/135553 A1 or Dosset M, Godet Y, Vauchy C, Beziaud L, Lone YC, Sedlik C, Liard C, Levionnois E, Clerc B, Sandoval F, Daguindau E, Wain-Hobson S, Tartour E, Langlade-Demoyen P, Borg C, Adotévi O: Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor. Clin Cancer Res. 2012 Nov 15;18(22) :6284-95. doi: 10.1158/1078-0432. CCR-12-0896. Epub 2012 Oct 2) and the BIRC5 peptide (for example, as described in EP 2119726 A1 or in Widenmeyer M, Griesemann H, Stevanovic S, Feyerabend S, Klein R, Attig S, Hennenlotter J, Wernet D, Kuprash DV, Sazykin AY, Pascolo S, Stenzl A, Gouttefangeas C, Rammensee HG: Promiscuous survivin peptide induces robust CD4+ T-cell responses in the majority of cancer patients. Int J Cancer. 2012 Jul 1; 131(1): 140-9. doi: 10.1002/ijc.26365. Epub 2011 Sep 14). The most preferred helper peptide is the UCP2 peptide (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859, for example, as described in WO 2013/135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15;18(22):6284 -95).

As used herein, the term "immunogenic composition" refers to a composition that has the ability to induce, induce, enhance, prolong or maintain an immune response, particularly a composition that induces, induces, enhances, prolongs or maintains an immune response when administered to a mammal, in primarily when administered to humans. Preferably, the immunogenic composition further contains one or more immunoadjuvant compounds.

The term “pharmaceutically available excipient or carrier” as used herein refers to a pharmaceutical grade compound that improves the delivery, stability or bioavailability of the active ingredient, and can be metabolized in the body of the subject to which it is administered without causing toxicity. Preferred excipients or carriers in accordance with the present invention are any of the excipients or carriers commonly used in pharmaceutical products, such as, for example, water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof . In many cases it will be preferable to use isotonic agents in the composition, for example, sugars, polyalcohols such as mannitol, sorbitol or sodium chloride. Pharmaceutically available excipients or carriers may further contain minimal amounts of auxiliary compounds, such as wetting or emulsifying agents, or preservatives.

The term “vaccine” refers to a composition capable of stimulating the immune system of a living organism so as to provide protection against a harmful antigen, either through prophylaxis or therapy. Preventative vaccines are preferred. Preferably, the vaccine or vaccine composition further contains one or more immunoadjuvant compounds.

In various aspects and embodiments of the invention described herein, the term “subject” or “host” preferably refers to a mammal and, most preferably, a human. The subject may already have cancer, be evaluated for suspected cancer, or be at risk of developing such a disease.

The term "cancer" as used herein refers to a malignant neoplasm. In particular, the term "cancer" refers herein to any condition from the class of diseases or disorders that are characterized by uncontrolled cell division and the ability of those cells to invade other tissues either by directly growing into adjacent tissue through invasion or by implanting into distant sites by metastasis. Metastasis is defined as the stage of the disease in which cancer cells are transported through the blood or lymphatic system. The term includes, among others, esophageal cancer, stomach cancer, duodenal cancer, small intestine cancer, appendix cancer, colon cancer, colon cancer, rectal cancer, colorectal cancer, anal cancer, pancreatic cancer, liver cancer, cancer gallbladder, spleen cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, uterine cancer, endometrial cancer, ovarian cancer, vaginal cancer, vulvar cancer, breast cancer, lung cancer, thyroid cancer, thymus cancer, brain cancer, nervous system cancer, gliomas, oral cavity cancer, skin cancer, blood cancer, lymphomas, eye cancer, bone cancer, bone marrow cancer, muscle cancer, etc. In the context of the present invention, melanoma, head and neck cancer, breast cancer, colorectal cancer or kidney cancer (eg clear cell renal cell carcinoma) are preferred types of cancer.

As used herein, the term "prophylaxis", "avoid" or "prevent", "prevent" generally means actions to avoid or minimize the likelihood of a disease occurring and/or the development of a condition before it occurs, while the term "treating" " or "treat" means to reduce, alleviate, or cure a disease or condition (or the symptoms of a disease or condition) after its onset. The term "prevention" refers to "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence" of a disease.

The term "effective amount" or "effective dose" as used herein means an amount that produces the desired effect. For therapeutic purposes, an effective amount is an amount sufficient to achieve a beneficial or desired clinical result. The preferred effective amount for a given use can be readily determined by one of ordinary skill in the art, taking into account, for example, the size, weight and age of the subject, the type of disease/condition to be prevented or treated, and the time that has passed since the onset of the disease/condition. . In the context of the present invention, with regard to prevention and treatment, an effective amount of the composition is an amount sufficient to induce a humoral/or cell-mediated immune response directed against the disease/condition.

Throughout this specification and the claims below, unless the context otherwise requires, the term "includes" and its derivatives "including" and "including" are to be understood to include the designated components, integers, and steps, but not to exclude other undesignated components, integers and stages. The term "consist" refers to a special case of the term "comprise" where other undesignated components, integers, and steps are excluded. In the context of the present invention, the term “comprises” includes the term “consists”. The term “comprising” thus refers to the term “comprising” as well as the term “consisting”, for example, a composition containing X may consist solely of X, or may include some additional element, for example, X +Y.

The articles "a", "an" and "the" and similar designations used in this writing (especially in the context of the claims) refer to both the singular and plural unless specifically stated otherwise or otherwise. does not appear from the context of the invention. The description of a range of values in this document is intended to act as a simplified method for referring to each individual value within a given range. Except as otherwise stated herein, each individual value is included in the specification as if it were individually stated herein. No language in this specification should be construed as indicating any unclaimed element that is essential to the practice of this invention.

The phrase “substantially” does not exclude the term “completely,” that is, a composition that is “substantially completely” free of Compound Y may be completely free of Compound Y. Where necessary, the phrase “substantially” may be excluded from the specification.

The term "about" when used in relation to the numerical value x means x±10%.

For clarity and ease of reading, definitions are provided below in the description.

Any technical characteristics mentioned in these definitions can be considered in the context of almost every embodiment of the invention. The spirit of the present invention may be readily understood by reference to the following detailed description, the preferred embodiments of the invention, and the examples included therein. Additional definitions are provided in the description.

DETAILED DESCRIPTION OF THE INVENTION

Although the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methodologies, protocols and reagents described herein, as they may vary. Moreover, it should be understood that any terminology used is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise specified, technical and scientific terms used herein have the same meanings as would be understood by one skilled in the art.

The following is a description of the elements of the present invention. These elements are listed in terms of specific embodiments of the invention, but it should be understood that they can be combined with each other in any manner and in any quantities to obtain additional embodiments of the invention. The various examples and preferred embodiments of the invention described below should not be construed as limiting the scope of the present invention to those directly described in the embodiments of the invention. It should be understood that the description provides and covers embodiments of the invention that combine the embodiments specifically set forth with any number of disclosed and/or preferred elements. In addition, any permutations and combinations of all elements of the invention described herein should be considered to be within the scope of the present invention and disclosed herein unless further stated otherwise.

The present inventors have identified a set of antigenic peptides that can be used to stimulate a specific immune response against tumor cells. Such antigenic peptides differ from (fragments of) human tumor antigens presented in Tables 1A and 1B, but have a similar amino acid sequence.

More specifically, the antigenic peptides claimed in accordance with the present invention are contained in polypeptides and proteins produced by commensal bacteria from the human intestine. Accordingly, the antigenic peptides claimed in accordance with the present invention are not human sequences, but are bacterial sequences. Without wishing to be bound by theory, the inventors believe that the human immune repertoire includes clones of T cells that are reactive to bacterial peptides (contained in proteins produced by commensal gut bacteria) that have amino acid identity with fragments of tumor antigens person.

More specifically, the antigenic peptides of the present invention can induce a stronger immune response than the corresponding human peptides because T cells, which have the ability to recognize only human peptides, have been depleted in recognizing self-antigens during maturation, and this is not the case for antigenic peptides claimed in accordance with the present invention. This may explain why the antigenic peptides described herein are capable of inducing an immune response, especially a T cell response, when administered to a human subject.

Accordingly, the present inventors believe that proteins produced by commensal gut bacteria have the ability to “mimic” tumor antigens and can be used to stimulate a specific immune response against tumor cells. These data provide further evidence that commensal bacteria may help kill tumor cells.

The antigenic peptides described herein can be prepared using well-known techniques. For example, peptides can be produced synthetically, using recombinant DNA technologies, or using chemical synthesis. The peptides disclosed in the present invention can be synthesized individually or in the form of longer polypeptides containing two or more peptides (eg, two or more peptides or a peptide and a non-peptide). Antigenic peptides can be isolated, that is, substantially completely purified from other natural proteins and fragments of host cells, for example, at least 70%, 80% or 90%. Preferably, the antigenic peptides claimed in accordance with the present invention are isolated antigenic peptides.

Antigenic peptides claimed in accordance with the present invention

According to a first aspect, the present invention provides an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 1-580 and 861-887. Preferably, the antigenic peptide consists of or includes an amino acid sequence as defined in any of SEQ ID Nos 1-580. Also preferably, the antigenic peptide consists of or includes an amino acid sequence as set forth in any of SEQ ID NOs 861,887.

Accordingly, the present invention relates to antigenic peptides similar in amino acid composition to a tumor antigen. The expression "similar in amino acid composition to a tumor antigen" as used herein refers specifically to a sequence variant of fragments of the original (reference) human tumor antigen, such as IL13RA2 or other human tumor antigens in accordance with the examples herein presented in Tables 1A and 1B. A "sequence variant" generally has, in particular, over the entire length of the sequence, at least 50% identity with a reference sequence, namely with a fragment of a (reference) tumor antigen. Preferably, the sequence variant is at least 60%, preferably at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, more preferably at least is at least 90%, most preferably at least 95% identical to the reference sequence, namely, a fragment of the (reference) tumor antigen. Sequence identities can be calculated using methods known in the art, in particular as described below. Preferably, the sequence variants retain the specific function of the reference sequence, for example, the function of a tumor epitope and/or its ability to induce or maintain an immune response. Specifically, the amino acid sequence variant has an altered sequence in which one or more amino acids of the reference sequence are subject to mutation, such as deletion or substitution, or one or more amino acids are inserted into the reference sequence. For example, a sequence variant that is at least 90% identical to a reference sequence includes no more than 10 changes, that is, deletions, insertions, or substitutions in any combination, per 100 amino acids of the sequence.

Methods for determining the identity (similarity) of two or more sequences are well known in the art. The percentage identity of two sequences can be determined using a mathematical algorithm. A preferred, but non-limiting example of a suitable mathematical algorithm that can be used for this purpose is that of Karlin et al. (1993), PNAS USA, 90:5873-5877. Such an algorithm is integrated into the BLAST software package, for example, the BLAST or NBLAST program (see also Altschul et at, 1990, J. Mol. Biol. 215, 403-410 or Altschul et al. (1997), Nucleic Acids Res, 25:3389 -3402), which are available on the NCBI home page on the World Wide Web at ncbi.nlm.nih.gov) and FASTA (Pearson (1990), Methods Enzymol. 183, 63-98; Pearson and Lipman (1988), Proc. Natl. Acad. Sci. U.S. A 85, 2444-2448). Sequences that are identical to other sequences over a certain length can be identified using these programs. In addition, programs available in the Wisconsin sequence analysis package, version 9.1 (Devereux et al., 1984, Nucleic Acids Res., 387-395) can be used to determine the % identity between two polynucleotides and the % identity between two (poly)peptide sequences. , for example, the BESTFIT and GAP programs. BESTFIT uses the "local homology" algorithm of Smith and Waterman (1981), J. Mol. Biol. 147, 195-197 and finds the single region with the best similarity between the two sequences.

The "fragment" of the (reference) tumor antigen, which typically functions as the parent sequence, preferably contains at least seven, more preferably at least eight, and more preferably at least nine or ten amino acids. It is clear that a “fragment” of a (reference) tumor antigen (protein) is not a full-length tumor antigen (protein). Accordingly, the (reference) tumor antigen "fragment" may have a maximum length that is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8% , 7%, 6%, 5%, 4%, 3%, 2% or 1% of the length of the full-length (reference) tumor antigen. In some embodiments, the length of the (reference) tumor antigen fragment does not exceed 50% of the length of the (full-length) (reference) tumor antigen. According to other embodiments of the invention, the length of the (reference) tumor antigen fragment does not exceed 20% or 10% of the length of the (full-length) (reference) tumor antigen.

In general, the antigenic peptide claimed in accordance with the present invention can be of any length. Preferably, the length of the antigenic peptide claimed in accordance with the present invention does not exceed 350 amino acids. For example, the maximum length of the antigenic peptide claimed in accordance with the present invention may be from 300 to 250 amino acids. More preferably, the maximum length of the antigenic peptide claimed in accordance with the present invention does not exceed 200 amino acids, for example, does not exceed 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14 or 13 amino acids. More specifically, the length of the antigenic peptides provided in accordance with the present invention is preferably a maximum of 30 or 25 amino acids, more preferably a maximum of 20 or 15 amino acids, with the smallest molecules of 10 or 9 amino acids in length being most preferred. More specifically, antigenic peptides are not full-length proteins produced by the commensal gut bacteria from which they are derived.

In general, the present invention relates to an antigenic peptide that consists of or includes a microbiotic sequence variant of a human tumor antigen fragment. The human tumor antigen may be selected from the group consisting of ACPP, ANKRD30A, AREG, ASCL1, ASCL2, BIRC5, CA9, CCNA1, CCND1, CDH17, CDH6, CDKN2A, SEACAM5, CHI3L1, CHI3L2, COL11A1, CT83, CTCFL, DCT, DMRTA2, EGFR, ERBB2, ERG, ESR1, EZH2, FAP, FLT1, FOXM1, FSIP1, GAL3ST1, GPR143, HES6, FL13RA2, KISS1R, KLHDC8A, KLHL14, KLK4, KRT81, LEMD1, LRRC15, MAGEA1, MAGEA10, MAGEA11, MAGEA12, M AGEA4, MLANA, NKX2-1, NPTX2, PAGE3, PAX2, PCDHB16, PIWFL1, PMEL, PRAME, PTHLH, SEMG1, SERHL2, SLC45A3, SLC6A3, SNX31, SOX11, SPINK1, STEAP1, TBL1Y, TDRD1, TOP2A, TPTE, TRPM8, TYMS, TYR, UPK2, VCAM1, WFDC2, WT1, ZEB1, ZNF165 and ZNF280A.

More specifically, the present invention relates to an antigenic peptide that is a microbiotic sequence variant of a human tumor antigen fragment, which tumor antigen fragment may include or consist of any sequence of SEQ ID NOs 580-858 and 888-895. Table 1A below provides an overview of the antigenic peptides claimed in accordance with the present invention and their amino acid sequences and SEQ ID Nos, as well as the corresponding human tumor antigen fragment/epitope (also referred to herein as “human reference peptide”). Table 1A also provides information about which tumor antigen each antigenic peptide of the present invention relates to. SEQ ID NOs 1 to 580 and 861 to 887 refer to the antigenic peptides claimed in accordance with the present invention.

As can be seen from Table 1A, the antigenic peptides claimed in accordance with the present invention can be classified according to the corresponding "human reference protein" as well as according to the corresponding tumor antigen.

According to one embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a fragment of a tumor antigen ACPP (human reference peptide), such as "FLFLLFFWL" (SEQ ID NO: 581), "SLSLGFLFL" (SEQ ID NO: 582) or " LSLGFLFLL" (SEQ ID NO: 583). According to a preferred embodiment of the invention, the antigenic peptide of the present invention is a sequence variant of an ACPP tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 1-4. More preferably, the antigenic peptide of the present invention is a sequence variant of the ACPP (human reference peptide) fragment "FLFLFFWL" (SEQ ID NO: 581), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO 1. Moreover, more preferably, the antigenic peptide of the present invention is a sequence variant of the ACPP (human reference peptide) fragment "SLSLGFLFL" (SEQ ID NO: 582), for example, an antigenic peptide consisting of or including the amino acid sequence as indicated in any of SEQ ID NO: 2 or 3. Moreover, more preferably, the antigenic peptide of the present invention is a sequence variant of the ACPP (human reference peptide) fragment "LSLGFLFLL" (SEQ ID NO: 583), for example, an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 4.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment ANKRD30A (human reference peptide), such as "YTSNDSYIV" (SEQ ID NO: 584), "ILIDSGADI" (SEQ ID NO: 585), " SLFESSAKI" (SEQ ID NO: 586) or "SLTPLLSI" (SEQ ID NO: 587). According to another preferred embodiment of the invention, the antigenic peptide of the present invention is a sequence variant of a tumor antigen fragment ANKRD30A, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 5-15. More preferably, the antigenic peptide of the present invention is a sequence variant of the ANKRD30A (human reference peptide) fragment "YTSNDSYIV" (SEQ ID NO: 584), for example, an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO : 5. Moreover, more preferably, the antigenic peptide of the present invention is a sequence variant of the ANKRD30A (human reference peptide) fragment "ILIDSGADI" (SEQ ID NO: 585), for example, an antigenic peptide consisting of or including the amino acid sequence as specified in any of SEQ ID NO: 6, 7 or 8. Moreover, more preferably, the antigenic peptide of the present invention is a sequence variant of the ANKRD30A (human reference peptide) fragment "SLFESSAKI" (SEQ ID NO: 586), e.g. , consisting of or including an amino acid sequence as specified in any of SEQ ID NO: 9 or 10. Moreover, more preferably, the antigenic peptide of the present invention is a sequence variant of the ANKRD30A (human reference peptide) fragment "SLTPLLSI" (SEQ ID NO: 587), for example, an antigenic peptide consisting of or including the amino acid sequence as defined in any of SEQ ID NO: 11, 12, 13, 14 or 15.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a tumor antigen fragment AREG (human reference peptide), such as "MSAVILTAV" (SEQ ID NO: 588) or "ALAAIAAFM" (SEQ ID NO: 589). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a variant of an AREG tumor antigen sequence, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 16-24. More preferably, the antigenic peptide of the present invention is a sequence variant of the AREG (human reference peptide) fragment "MSAVILTAV" (SEQ ID NO: 588), for example, an antigenic peptide consisting of or including the amino acid sequence as specified in any of SEQ ID NO: 16 or 17. Moreover, more preferably, the antigenic peptide of the present invention is a sequence variant of the AREG (human reference peptide) fragment "ALAAIAAAFM" (SEQ ID NO: 589), for example, an antigenic peptide consisting of or including amino acid sequence as specified in any of SEQ ID NO: 18, 19, 20, 21, 22, 23 or 24.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a tumor antigen fragment ASCL1 (human reference peptide), such as "VSAAFQAGV" (SEQ ID NO: 590). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of an ASCL1 tumor antigen fragment, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 25. More specifically, the antigenic peptide of the present of the invention, which consists of or includes the amino acid sequence as indicated in SEQ ID NO: 25 is a sequence variant of the ASCL1 (human reference peptide) fragment "VSAAFQAGV" (SEQ ID NO: 590).

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a tumor antigen fragment ASCL2 (human reference peptide), such as "KLVNLGFQA" (SEQ ID NO: 591) or "ELLDFSSWL" (SEQ ID NO: 592). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of an ASCL2 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 26-29. More preferably, the antigenic peptide of the present invention is a sequence variant of the ASCL2 (human reference peptide) fragment "KLVNLGFQA" (SEQ ID NO: 591), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 26 or 27. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ASCL2 (human reference peptide) fragment "ELLDFSSWL" (SEQ ID NO: 592), such as an antigenic peptide consisting of or comprising itself amino acid sequence as specified in either SEQ ID Nos 28 or 29.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment BIRC5 (human reference peptide), such as "LTLGEFLKL" (SEQ ID NO: 593). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a variant sequence of a BIRC5 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 30-32. More preferably, the antigenic peptide of the present invention is a sequence variant of the BIRC5 (human reference peptide) fragment "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or including the amino acid sequence as specified in any of SEQ ID NO: 30, 31 or 32. Even more preferably, the antigenic peptide consists of or includes the sequence of SEQ ID NO: 32.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a fragment of a tumor antigen CA9 (human reference peptide), such as "AAGDILALV" (SEQ ID NO: 594), "ALVFGLLFA" (SEQ ID NO: 595), "FQYEGSLTT" (SEQ ID NO: 596), "HLSTAFARV" (SEQ ID NO: 597), "LSLLLLVPV" (SEQ ID NO: 598), "QLLLSLLLL" (SEQ ID NO: 599) or "VQLLLSLLL" (SEQ ID NO: 600). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a CA9 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 33-50. More preferably, the antigenic peptide of the present invention is a sequence variant of the CA9 (human reference peptide) fragment "AAGDILALV" (SEQ ID NO: 594), such as an antigenic peptide consisting of or including an amino acid sequence as specified in any of the SEQ IDs NO: 33 or 34. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CA9 (human reference peptide) fragment "ALVFGLLFA" (SEQ ID NO: 595), such as an antigenic peptide consisting of or comprising the amino acid sequence as defined in any of SEQ ID NO: 35, 36 or 37. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CA9 (human reference peptide) fragment "FQYEGSLTT" (SEQ ID NO: 596), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 38. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a CA9 fragment (reference human peptide) "HLSTAFARV" (SEQ ID NO: 597), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 39, 40 or 41. Also more preferably, an antigenic peptide as claimed in accordance with with the present invention, is a sequence variant of the CA9 (human reference peptide) fragment "LSLLLLVPV" (SEQ ID NO: 598), such as an antigenic peptide consisting of or including the amino acid sequence as specified in any of SEQ ID NO: 42 , 43 or 44. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CA9 (human reference peptide) fragment "QLLLSLLLL" (SEQ ID NO: 599), such as an antigenic peptide consisting of or comprising itself amino acid sequence as specified in any of SEQ ID NO: 45, 46 or 47. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a variant sequence of the CA9 (reference human peptide) fragment "VQLLLSLLL" (SEQ ID NO : 600), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 48, 49 or 50.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a tumor antigen fragment CCNA1 (human reference peptide), such as "NLAKYVAEL" (SEQ ID NO: 601) or "LIAAAAFCL" (SEQ ID NO: 602). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a CCNA1 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 51-55. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CCNA1 (human reference peptide) fragment "NLAKYVAEL" (SEQ ID NO: 601), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 51. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CCNA1 (human reference peptide) fragment "LIAAAAFCL" (SEQ ID NO: 602), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 52, 53, 54, or 55.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment CCND1 (human reference peptide), such as "LLNDRVLRA" (SEQ ID NO: 603). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a CCND1 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence set forth in SEQ ID NO: 56. More specifically, the antigenic peptide set forth in SEQ ID NO: 56, is a sequence variant of the CCND1 (human reference peptide) fragment "LLNDRVLRA" (SEQ ID NO: 603).

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a tumor antigen fragment CDH17 (human reference peptide), such as "GILLTTLLV" (SEQ ID NO: 604), "ILAVVFIRI" (SEQ ID NO: 605), "ILLTTLLVI" (SEQ ID NO: 606) or "LVIGIILAV" (SEQ ID NO: 607). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a CDH17 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 57-63. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CDH17 (human reference peptide) fragment "GILLTTLLV" (SEQ ID NO: 604), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 57. According to another preferred embodiment of the invention, the antigenic peptide of the present invention is a sequence variant of the tumor antigen fragment CDH17 (human reference peptide) "ILAVVFIRI" (SEQ ID NO: 605), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 58 or 59. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CDH17 (human reference peptide) fragment "ILLTTLLVI" (SEQ ID NO: 606 ), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 60, 61 or 62. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a fragment of CDH17 (reference human peptide) "LVIGIILAV" (SEQ ID NO: 607), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 63.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a tumor antigen fragment CDH6 (human reference peptide), such as "ALVAILLCI" (SEQ ID NO: 608), "EMSDVGTFV" (SEQ ID NO: 609) , "EMSTYLLPV" (SEQ ID NO: 610), "FLLEEYTGS" (SEQ ID NO: 611), "ILLCIVILL" (SEQ ID NO: 612), or "LLVTVVLFA" (SEQ ID NO: 613). In another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of a CDH6 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 64-81. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CDH6 (human reference peptide) fragment "ALVAILLCI" (SEQ ID NO: 608), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 64, 65, 66, 67, 68, 69 or 70. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CDH6 fragment (human reference peptide) "EMSDVGTFV" (SEQ ID NO: 609), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 71. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a fragment of CDH6 (reference peptide human) "EMSTYLLPV" (SEQ ID NO: 610), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 72. Also more preferably, the antigenic peptide claimed in accordance with the present invention is is a sequence variant of the CDH6 (human reference peptide) fragment "FLLEEYTGS" (SEQ ID NO: 611), such as an antigenic peptide consisting of or including the amino acid sequence as defined in SEQ ID NO: 73. Also more preferably, an antigenic peptide, claimed in accordance with the present invention is a sequence variant of the CDH6 (human reference peptide) fragment "ILLCIVILL" (SEQ ID NO: 612), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 74 or 75. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CDH6 (human reference peptide) fragment "LLVTVVLFA" (SEQ ID NO: 613), such as an antigenic peptide consisting of or including amino acid sequence as specified in SEQ ID NO: 76, 77, 78, 79, 80 or 81.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment CDKN2A (human reference peptide), such as "AVALVLMLL" (SEQ ID NO: 614). According to another preferred embodiment of the invention, the antigenic peptide of the present invention is a sequence variant of a CDKN2A tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NO: 82. More specifically, the antigenic peptide of the present invention , which consists of or includes the amino acid sequence as defined in SEQ ID NO: 82, is a sequence variant of the CDKN2A (human reference peptide) fragment "AVALVLMLL" (SEQ ID NO: 614).

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment CEACAM5 (human reference peptide), such as "LLTFWNPPT" (SEQ ID NO: 615). According to another preferred embodiment of the invention, the antigenic peptide of the present invention is a sequence variant of a fragment of the tumor antigen CEACAM5, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 83. More specifically, the antigenic peptide of the present invention, which consists of or includes the amino acid sequence as indicated in SEQ ID NO: 83, is a sequence variant of the CEACAM5 (human reference peptide) fragment "LLTFWNPPT" (SEQ ID NO: 615).

According to another embodiment, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment CHI3L1 (human reference peptide), such as "KQLLLSAAL" (SEQ ID NO: 616), "LLLSAALSA" (SEQ ID NO: 617), " QLAGAMVWA" (SEQ ID NO: 618), "SQTGFVVLV" (SEQ ID NO: 619) or "TLASSETGV" (SEQ ID NO: 620). In another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of a CHI3L1 tumor antigen fragment, such as consisting of or including the amino acid sequence as set forth in SEQ ID NOs 84-114. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CHI3L1 (human reference peptide) fragment "KQLLLSAAL" (SEQ ID NO: 616), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 84 or 85. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CHI3L1 (human reference peptide) fragment "LLLSAALSA" (SEQ ID NO: 617), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102 , 103, 104, 105, 106, 107, 108, or 109. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CHI3L1 (human reference peptide) fragment "QLAGAMVWA" (SEQ ID NO: 618 ), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 110, 111 or 112. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a fragment of CHI3L1 (reference human peptide) "SQTGFVVLV" (SEQ ID NO: 619), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 113. Also more preferably, the antigenic peptide claimed in accordance with the present invention, is a sequence variant of the CHI3L1 (human reference peptide) fragment "TLASSETGV" (SEQ ID NO: 620), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 114.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment CHI3L2 (human reference peptide), such as "ILLSIGGYL" (SEQ ID NO: 621), "HLIYSFASI" (SEQ ID NO: 622), " VLIHELAEA" (SEQ ID NO: 623), "SLWAGVVVL" (SEQ ID NO: 624). In another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of a CHI3L2 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 115-119. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CHI3L2 (human reference peptide) fragment "ILLSIGGYL" (SEQ ID NO: 621), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 115. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CHI3L2 (human reference peptide) fragment "HLIYSFASI" (SEQ ID NO: 622), such as an antigenic peptide consisting of or comprising the amino acid sequence as set forth in SEQ ID NO: 116. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the CHI3L2 (human reference peptide) fragment "VLIHELAEA" (SEQ ID NO: 623), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 117 or 118. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a fragment of CHI3L2 (human reference peptide)" SLWAGVVVL" (SEQ ID NO: 624), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 119.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment COL11A1 (human reference peptide), such as "WLWDFTVTT" (SEQ ID NO: 625). According to another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of a fragment of a COL11A1 tumor antigen, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 120. More specifically, the antigenic peptide of the present invention , which consists of or includes the amino acid sequence as defined in SEQ ID NO: 120, is a sequence variant of the COL11A1 (human reference peptide) fragment "WLWDFTVTT" (SEQ ID NO: 625).

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a fragment of the CT83 tumor antigen (human reference peptide), such as "LLASSILCA" (SEQ ID NO: 626). In another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of a fragment of the CT83 tumor antigen, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 121-123. More preferably, the antigenic peptide of the present invention is a sequence variant of the CT83 (human reference peptide) fragment "LLASSILCA" (SEQ ID NO: 626), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 121, 122 or 123.

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic sequence variant of a tumor antigen fragment of CTCFL (human reference peptide), such as "KLAVSLAET" (SEQ ID NO: 627). In another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of a fragment of a CTCFL tumor antigen, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 124. More specifically, the antigenic peptide of the present invention , which consists of or includes the amino acid sequence as set forth in SEQ ID NO: 124, is a sequence variant of the CTCFL (human reference peptide) fragment "KLAVSLAET" (SEQ ID NO: 627).

According to another embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment DCT (human reference peptide), such as "ALVGLFVLL" (SEQ ID NO: 628), "GLFVLLAFL" (SEQ ID NO: 629), " SVYDFFVWL" (SEQ ID NO: 630) or "VVMGTLVAL" (SEQ ID NO: 631). In another preferred embodiment, the antigenic peptide of the present invention is a variant sequence of a DCT tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 125-132. More preferably, the antigenic peptide of the invention is a sequence variant of the DCT (human reference peptide) fragment "ALVGLFVLL" (SEQ ID NO: 628), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 125 or 126. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the DCT (human reference peptide) fragment "GLFVLLAFL" (SEQ ID NO: 629), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 127, 128 or 129. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the DCT (human reference peptide) fragment "SVYDFFVWL" (SEQ ID NO: 630), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 130. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the DCT (human reference peptide) fragment "VVMGTLVAL" (SEQ ID NO: 631), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 131 or 132.

According to another preferred embodiment, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment DMRTA2 (human reference peptide), such as "GTAEGLALA" (SEQ ID NO: 632) or "GLAAGLGPA" (SEQ ID NO: 633) . In another preferred embodiment, the antigenic peptide of the present invention is a variant sequence of a tumor antigen fragment DMRTA2, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 133-134. More preferably, the antigenic peptide of the invention is a sequence variant of the DMRTA2 (human reference peptide) fragment "GTAEGLALA" (SEQ ID NO: 632), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 133 According to another preferred embodiment of the invention, the antigenic peptide of the present invention is a sequence variant of the DMRTA2 (human reference peptide) tumor antigen fragment "GLAAGLGPA" (SEQ ID NO: 633), such as an antigenic peptide consisting of or including an amino acid sequence, as set forth in SEQ ID NO: 134.

According to another preferred embodiment of the invention, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment EGFR (human reference peptide), such as "ALESILHRI" (SEQ ID NO: 634), "ALLAALCPA" (SEQ ID NO: 635), "ALLALLAAL" (SEQ ID NO: 636), "ILDEAYVMA" (SEQ ID NO: 637), "LLLLLVVAL" (SEQ ID NO: 638), "MVGALLLLL" (SEQ ID NO: 639), "NLQEILHGA" (SEQ ID NO: 640) or "SLAVVSLNI" (SEQ ID NO: 641. In another preferred embodiment of the invention, the antigenic peptide of the present invention is a sequence variant of an EGFR tumor antigen fragment, such as an antigenic peptide consisting of or including the amino acid sequence such as as set forth in SEQ ID NOs 135 to 150. More preferably, the antigenic peptide of the invention is a sequence variant of the EGFR (human reference peptide) fragment "ALESILHRI" (SEQ ID NO: 634), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 135 or 136. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the EGFR (human reference peptide) fragment "ALLAALCPA" (SEQ ID NO: 635), such as antigenic a peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 137. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the EGFR (human reference peptide) fragment "ALLALLAAL" (SEQ ID NO: 636), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 138, 139, 140, 141, 142, 143 or 144. Also more preferably, an antigenic peptide as claimed in accordance with of the present invention is a sequence variant of the EGFR (human reference peptide) fragment "ILDEAYVMA" (SEQ ID NO: 637), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 145. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the EGFR (human reference peptide) fragment "LLLLLVVAL" (SEQ ID NO: 638), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 146. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the EGFR (human reference peptide) fragment "MVGALLLLL" (SEQ ID NO: 639), such as an antigenic peptide consisting of or including comprising the amino acid sequence as specified in SEQ ID NO: 147. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the EGFR (human reference peptide) fragment "NLQEILHGA" (SEQ ID NO: 640), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 148. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the EGFR (human reference peptide) fragment "SLAVVSLNI" ( SEQ ID NO: 641), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 149 or 150.

According to another preferred embodiment, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen fragment ERBB2 (human reference peptide), such as "AVVGILLVV" (SEQ ID NO: 642), "ILDEAYVMA" (SEQ ID NO: 643), "LLALLPPGA" (SEQ ID NO: 644), "SIISAVVGI" (SEQ ID NO: 645) or "VVLGVVFGI" (SEQ ID NO: 646). In another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of a fragment of the tumor antigen ERBB2, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 151-162. More preferably, the antigenic peptide of the invention is a sequence variant of the ERBB2 (human reference peptide) fragment "AVVGILLVV" (SEQ ID NO: 642), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 151 , 152, 153 or 154. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ERBB2 (human reference peptide) fragment "ILDEAYVMA" (SEQ ID NO: 643), such as an antigenic peptide consisting of or comprising the amino acid sequence as set forth in SEQ ID NO: 155. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ERBB2 (human reference peptide) fragment "LLALLPPGA" (SEQ ID NO: 644), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 156, 157, 158 or 159. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a fragment of ERBB2 (reference human peptide) "SIISAVVGI" (SEQ ID NO: 645), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 160. Also more preferably, the antigenic peptide claimed in accordance with the present invention is is a sequence variant of the ERBB2 (human reference peptide) fragment "VVLGVVFGI" (SEQ ID NO: 646), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 161 or 162, more specifically antigenic a peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 162.

According to another preferred embodiment, the antigenic peptide of the present invention is a microbiotic variant sequence of a tumor antigen ERG (human reference peptide) fragment, such as "FLLELLSDS" (SEQ ID NO: 647) or "QLWQFLLEL" (SEQ ID NO: 857). In another preferred embodiment, the antigenic peptide of the present invention is a sequence variant of an ERG tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 163-164. More preferably, the antigenic peptide of the invention is a sequence variant of the ERG (human reference peptide) fragment "FLELLSDS" (SEQ ID NO: 647), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 163 Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ERG (human reference peptide) fragment "QLWQFLLEL" (SEQ ID NO: 857), such as an antigenic peptide consisting of or including an amino acid sequence, as set forth in SEQ ID NO: 164.

In another preferred embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment ESR1, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NOs 165-192. More preferably, the antigenic peptide of the invention is a sequence variant of the ESR1 (human reference peptide) fragment "ALLDAEPPI" (SEQ ID NO: 648), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 165 Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 (human reference peptide) fragment "KITDTLIHL" (SEQ ID NO: 649), such as an antigenic peptide consisting of or including an amino acid sequence, as set forth in SEQ ID NO: 166 or 167. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 (human reference peptide) fragment "KLLFAPNLL" (SEQ ID NO: 650), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 168 or 169. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 (human reference peptide) fragment "LLDAEPPIL" (SEQ ID NO: 651), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 170. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 fragment (reference human peptide) "LLNSGVYTF" (SEQ ID NO: 652), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 171 or 172. Also more preferably, an antigenic peptide as claimed herein of the invention is a sequence variant of the ESR1 (human reference peptide) fragment "LMIGLVWRS" (SEQ ID NO: 653), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 173. Also more preferably , the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 (human reference peptide) fragment "PLYDLLLEM" (SEQ ID NO: 654), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 174, 175, 176, 177, 178, 179, 180 or 181. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 (human reference peptide) fragment "QLLLILSHI" (SEQ ID NO: 655), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 182, 183, 184, 185, 186, 187 or 188. Also more preferably, an antigenic peptide as claimed in accordance with of the present invention, is a sequence variant of the ESR1 (human reference peptide) fragment "RLAQLLLIL" (SEQ ID NO: 656 such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 189 or 190. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 (human reference peptide) fragment "TLIHLMAKA" (SEQ ID NO: 657), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 191. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ESR1 (human reference peptide) fragment "VLDKITDTL" (SEQ ID NO: 658), such as an antigenic peptide consisting of or including comprising the amino acid sequence as set forth in SEQ ID NO: 192.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of an EZH2 tumor antigen fragment, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NOs 193-194. More preferably, the antigenic peptide of the invention is a sequence variant of the EZH2 (human reference peptide) fragment "FMVEDETVL" (SEQ ID NO: 659), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 193 Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the EZH2 fragment (human reference peptide) "SMFRVLIGT" (SEQ ID NO: 660), such as an antigenic peptide consisting of or including an amino acid sequence, as set forth in SEQ ID NO: 194.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a FAP tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 195-201. More preferably, the antigenic peptide of the invention is a sequence variant of the FAP (human reference peptide) fragment "ATSAVLALL" (SEQ ID NO: 661), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 195 , 196 or 197. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FAP (human reference peptide) fragment "TGWAGGFFV" (SEQ ID NO: 662), such as an antigenic peptide consisting of or comprising itself amino acid sequence as specified in SEQ ID NO: 198. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FAP (human reference peptide) fragment "VLALLVMCI" (SEQ ID NO: 663), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 199, 200, or 201.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant of the FLT1 tumor antigen fragment sequence, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 202-216. More preferably, the antigenic peptide of the invention is a sequence variant of the FLT1 (human reference peptide) fragment "ALLSCLLLT" (SEQ ID NO: 664), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 202 , 203, 204, 205, 206, 207 or 208. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FLT1 (human reference peptide) fragment "CVAATLFWL" (SEQ ID NO: 665), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 209. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FLT1 (human reference peptide) fragment "EMYSEIPEI" (SEQ ID NO: 666), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 210. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a fragment of FLT1 (reference human peptide) "KMASTLVVA" (SEQ ID NO: 667), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 211 or 212. Also more preferably, an antigenic peptide as claimed herein of the invention is a sequence variant of the FLT1 (human reference peptide) fragment "SIFDKIYST" (SEQ ID NO: 668), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 213. Also more preferably the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FLT1 (human reference peptide) fragment "TLFWLLLTL" (SEQ ID NO: 669), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 214. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FLT1 (human reference peptide) fragment "VLLWEIFSL" (SEQ ID NO: 670), such as an antigenic peptide consisting of or comprising itself amino acid sequence as set forth in SEQ ID NO: 215. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FLT1 (human reference peptide) fragment "WLKDGLPAT" (SEQ ID NO: 671), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 216.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a FOXM1 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 217-227 and 861-877, for example, as set forth in any of SEQ ID NOs 217-227. More preferably, the antigenic peptide of the invention is a sequence variant of the FOXM1 (human reference peptide) fragment "ILLDISFPG" (SEQ ID NO: 672), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 217 or 218. Additional examples of antigenic peptides claimed in accordance with the present invention that are sequence variants of the FOXM1 (human reference peptide) fragment "ILLDISFPG" (SEQ ID NO: 672) are antigenic peptides consisting of or including the amino acid sequence, as set forth in SEQ ID NO: 861, 862, 863, 864, 865 or 866. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "LLDISFPGL" (SEQ ID NO : 673), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 219. Another example of an antigenic peptide claimed in accordance with the present invention, which is a sequence variant of a fragment of FOXM1 (human reference peptide ) "LLDISFPGL" (SEQ ID NO: 673), is an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 867. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a variant FOXM1 (human reference peptide) fragment sequence "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 220. Another example of an antigenic peptide claimed according to with the present invention, which is a sequence variant of the FOXM1 (human reference peptide) fragment "LMDLSTTPL" (SEQ ID NO: 674), is an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 868.

Also more preferably, the antigenic peptide claimed in accordance with the present invention is a microbiotic sequence variant of the FOXM1 (human reference peptide) fragment "RVSSYLVPI" (SEQ ID NO: 675), such as an antigenic peptide consisting of or including the amino acid sequence, as set forth in SEQ ID NO: 221, 222 or 223. Additional examples of antigenic peptides claimed in accordance with the present invention that are sequence variants of the FOXM1 (human reference peptide) fragment "RVSSYLVPI" (SEQ ID NO: 675) are antigenic peptides consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 869, 870 or 871. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FOXM1 (human reference peptide) fragment "SLSKILLDI" (SEQ ID NO: 676), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 224. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a FOXM1 fragment sequence variant (human reference peptide) "SQLSYSQEV" (SEQ ID NO: 677), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 225 or 226. Also more preferably, an antigenic peptide as claimed in accordance with with the present invention, is a sequence variant of the FOXM1 (human reference peptide) fragment "WAAELPFPA" (SEQ ID NO: 678), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 227. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FOXM1 (human reference peptide) fragment "NLSLHDMFV" (SEQ ID NO: 888), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 872. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FOXM1 (human reference peptide) fragment "KMKPLLPRV" (SEQ ID NO: 889), such as an antigenic peptide consisting of or comprising the amino acid sequence as set forth in SEQ ID NO: 873 or 874. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FOXM1 (human reference peptide) fragment "YLVPIQFPV" (SEQ ID NO: 890 ), FOXM1 (human reference peptide) "KMKPLLPRV" (SEQ ID NO: 889), such as SEQ ID NO: 875 or 876. Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of a fragment of FOXM1 (reference peptide human) "YMAMIQFAI" (SEQ ID NO: 891), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 877. Even more preferably, the antigenic peptide consists of or includes SEQ ID NO : 32.

In another preferred embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment FSIP1, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 228-231. More preferably, the antigenic peptide of the invention is a sequence variant of the FSIP1 (human reference peptide) fragment "LLNESETKV" (SEQ ID NO: 679), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 228 Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the FSIP1 (human reference peptide) fragment "RLVELLKDL" (SEQ ID NO: 680), such as an antigenic peptide consisting of or including the amino acid sequence as indicated by SEQ ID NO: 229, 230 or 231.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment GAL3ST1 (human reference peptide), such as "GLASTTPEA" (SEQ ID NO: 681) or "RMAREVAAL" (SEQ ID NO: 682). In another preferred embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a GAL3ST1 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 232-234. More preferably, the antigenic peptide of the invention is a sequence variant of the GAL3ST1 (human reference peptide) fragment "GLASTTPEA" (SEQ ID NO: 681), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 232 Also more preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the GAL3ST1 (human reference peptide) fragment "RMAREVAAL" (SEQ ID NO: 682), such as an antigenic peptide consisting of or including the amino acid sequence, as set forth in SEQ ID NO: 233 or 234.

In another embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment GPR143 (human reference peptide), such as "FLLSLAFYG" (SEQ ID NO: 683), "ILNPAQGFL" (SEQ ID NO: 684), "MAWGLATLL" " (SEQ ID NO: 685) or "RLALGLLQL" (SEQ ID NO: 686). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a GPR143 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 235-247. More preferably, the antigenic peptide of the invention is a GPR143 (human reference peptide) tumor antigen fragment sequence variant "FLLSLAFYG" (SEQ ID NO: 683), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in any of SEQ ID NO: 235, 236 or 237. Also more preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen fragment GPR143 (human reference peptide) "ILNPAQGFL" (SEQ ID NO: 684), such as an antigenic peptide consisting of or comprising itself amino acid sequence as set forth in SEQ ID NO: 238. Also more preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen fragment GPR143 (human reference peptide) "MAWGLATLL" (SEQ ID NO: 685), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 239. Also more preferably, the antigenic peptide of the invention is a variant sequence of the tumor antigen GPR143 (human reference peptide) fragment "RLALGLLQL" (SEQ ID NO: 686), such as an antigenic peptide consisting of or including the amino acid sequence as defined in any of SEQ ID NO: 240, 241, 242, 243, 245, 246 or 247.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment HES6 (human reference peptide), such as "RLLLAGAEV" (SEQ ID NO: 687). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a fragment of a HES6 tumor antigen, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 248. More specifically, the antigenic peptide claimed according to with the present invention, consisting of or including the amino acid sequence as indicated in SEQ ID NO: 248, is a sequence variant of the HES6 (human reference peptide) fragment "RLLLAGAEV" (SEQ ID NO: 687).

In a preferred embodiment, the antigenic peptide of the invention is a variant sequence of the IL13RA2 tumor antigen, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 249-255. More preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen fragment IL13RA2 (human reference peptide) "CLYTFLIST" (SEQ ID NO: 688), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO : 249, 250 or 251. Also more preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen fragment IL13RA2 (human reference peptide) "FLISTTFGC" (SEQ ID NO: 689), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 252. More preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen IL13RA2 (human reference peptide) fragment "VLLDTNYNL" (SEQ ID NO: 690), such as an antigenic peptide consisting of or comprising comprising the amino acid sequence as set forth in SEQ ID NO: 253. Also more preferably, the antigenic peptide of the invention is a sequence variant of the IL13RA2 tumor antigen fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 254 or 255, more specifically an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 255. Additional examples of antigenic peptides of the present invention that are sequence variants of the IL13RA2 (human reference peptide) fragment "WLPFGFILIL" (SEQ ID NO: 692) include antigenic peptides consisting of or including the amino acid sequence as indicated in SEQ ID NO: 878 or 879. Also more preferably, the antigenic peptide of the invention is a sequence variant of the IL13RA2 (human reference peptide) tumor antigen fragment "FLISTTFGCT" (SEQ ID NO: 892), such as an antigenic peptide consisting of or comprising itself amino acid sequence as specified in SEQ ID NO: 880, 881 or 882. Also more preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen IL13RA2 (human reference peptide) fragment "YLYLQWQPPL" (SEQ ID NO: 893), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 883. Also more preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen IL13RA2 (human reference peptide) fragment "GVLLDTNYNL" (SEQ ID NO: 894 ), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 884 or 885. Also more preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen fragment IL13RA2 (human reference peptide) "FQLQNIVKPL" (SEQ ID NO: 895), such as an antigenic peptide consisting of or comprising the amino acid sequence as set forth in SEQ ID NO: 886 or 887. Even more preferably, the antigenic peptide includes or consisting of SEQ ID NO: 255.

In another embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment KISS1R (human reference peptide), such as "ALYLLPLLA" (SEQ ID NO: 693), "FALYNLLAL" (SEQ ID NO: 694), "QLFLVLQAL " (SEQ ID NO: 695), "RLVAAVVLL" (SEQ ID NO: 696), "VLAERAGAV" (SEQ ID NO: 697), "WLVPLFFAA" (SEQ ID NO: 698) or "YLLPLLATC" (SEQ ID NO: 699). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a KISS1R tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 256-287. More preferably, the antigenic peptide of the invention is a sequence variant of the KISS1R (human reference peptide) tumor antigen fragment "ALYLLPLLA" (SEQ ID NO: 693), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO : 256, 257 or 258. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KISS1R (human reference peptide) tumor antigen fragment "FALYNLLAL" (SEQ ID NO: 694), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 259, 260 or 261. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KISS1R (human reference peptide) tumor antigen fragment "QLFLVLQAL" (SEQ ID NO: 695), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 262. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KISS1R (human reference peptide) tumor antigen fragment "RLVAAVVLL" (SEQ ID NO: 696), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 263. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KISS1R (human reference peptide) tumor antigen fragment "VLAERAGAV" (SEQ ID NO : 697), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 264. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KISS1R (human reference peptide) tumor antigen fragment "WLVPLFFAA" (SEQ ID NO: 698), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 266, 267, 268 or 269. Also more preferably, the antigenic peptide of the invention is a sequence variant of a tumor fragment KISS1R (human reference peptide) antigen "YLLPLLATC" (SEQ ID NO: 699), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 270, 271, 272, 273, 274, 275 , 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286 or 287.

In another embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment KLHDC8A (human reference peptide), such as "GLSDAVEAL" (SEQ ID NO: 700) or "MLREAAMGI" (SEQ ID NO: 701). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a KLHDC8A tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 288-289. More preferably, the antigenic peptide of the invention is a sequence variant of the KLHDC8A (human reference peptide) tumor antigen fragment "GLSDAVEAL" (SEQ ID NO: 700), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO : 288. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KLHDC8A (human reference peptide) tumor antigen fragment "MLREAAMGI" (SEQ ID NO: 701), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 289.

In another embodiment, the antigenic peptide of the invention is a microbiotic sequence variant of a KLHL14 tumor antigen fragment (human reference peptide), such as "ALIPAPELV" (SEQ ID NO: 702), "NLLHGLNLL" (SEQ ID NO: 703) or "YVSSLPQPL " (SEQ ID NO: 704). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a KLHL14 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 290-292. More preferably, the antigenic peptide of the invention is a sequence variant of the tumor antigen KLHL14 (human reference peptide) fragment "ALIPAPELV" (SEQ ID NO: 702), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO : 290. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KLHL14 (human reference peptide) tumor antigen fragment "NLLHGLNLL" (SEQ ID NO: 703), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 291. Also more preferably, the antigenic peptide of the invention is a sequence variant of the KLHL14 tumor antigen (human reference peptide) fragment "YVSSLPQPL" (SEQ ID NO: 704), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 292.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a KLK4 tumor antigen fragment (human reference peptide), such as "YLILGVAGS" (SEQ ID NO: 705). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a KLK4 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 293-296. More preferably, the antigenic peptide of the present invention is a sequence variant of the KLK4 (human reference peptide) fragment, "YLILGVAGS" (SEQ ID NO: 705), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO : 293, 294, 295 or 296.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a KRT81 tumor antigen fragment (human reference peptide), such as "NMDCIAEI" (SEQ ID NO: 706). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a KRT81 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NO: 297. More specifically, the antigenic peptide claimed according to with the present invention, consisting of or including the amino acid sequence as indicated in SEQ ID NO: 297, is a sequence variant of the KRT81 (human reference peptide) fragment "NMDCIAEI" (SEQ ID NO: 706).

In another embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment LEMD1 (human reference peptide), such as "AVLGIFIIV" (SEQ ID NO: 707) or "KLAVLGIFI" (SEQ ID NO: 708). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a tumor antigen fragment LEMD1, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 298-299. More preferably, the antigenic peptide of the present invention is a sequence variant of the LEMD1 (human reference peptide) fragment "AVLGIFIIV" (SEQ ID NO: 707), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 298. Also more preferably, the antigenic peptide of the invention is a sequence variant of the LEMD1 (human reference peptide) tumor antigen fragment "KLAVLGIFI" (SEQ ID NO: 708), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 299.

In another embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment LRRC15 (human reference peptide), such as "AIAAIVIGI" (SEQ ID NO: 709), "ALACSLAAC" (SEQ ID NO: 710), "IVIGIVALA" (SEQ ID NO: 711), "RIVAVPTPL" (SEQ ID NO: 712) or "SLKELSPGI" (SEQ ID NO: 713) In another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a fragment of the tumor antigen LRRC15, such as antigenic peptides consisting of or including an amino acid sequence as set forth in any of SEQ ID NOs 300 to 307. More preferably, the antigenic peptide of the present invention is a sequence variant of the LRRC15 (human reference peptide) fragment, "AIAAIVIGI" (SEQ ID NO: 709), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 300. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the LRRC15 (human reference peptide) fragment, " ALACSLAAC" (SEQ ID NO: 710), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 301. Also more preferably, the antigenic peptide of the present invention is a sequence variant of a fragment of LRRC15 (reference peptide human), "IVIGIVALA" (SEQ ID NO: 711), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 302. Also more preferably, the antigenic peptide of the present invention is a fragment sequence variant LRRC15 (human reference peptide), "RIVAVPTPL" (SEQ ID NO: 712), such as an antigenic peptide consisting of or including the amino acid sequence as defined in SEQ ID NO: 303, 304 or 305. Also more preferably, an antigenic peptide of the present invention is a sequence variant of a fragment of LRRC15 (human reference peptide), "SLKELSPGI" (SEQ ID NO: 713), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 306 or 307 .

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment MAGEA1 (human reference peptide), such as "KVADLVGFL" (SEQ ID NO: 714) or "LVLGTLEEV" (SEQ ID NO: 858). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a MAGEA1 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 308-309. More preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA1 (human reference peptide) fragment "KVADLVGFL" (SEQ ID NO: 714), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 308. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA1 (human reference peptide) fragment "LVLGTLEEV" (SEQ ID NO: 858), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 309.

In another embodiment, the antigenic peptide of the invention is a microbiotic sequence variant of a MAGEA4 tumor antigen fragment (human reference peptide), such as "AVSSSSPLV" (SEQ ID NO: 722), "KVDELAHFL" (SEQ ID NO: 723) or "KVLEHVVRV" " (SEQ ID NO: 724. In another preferred embodiment of the invention, the antigenic peptide of the invention is a variant sequence of a MAGEA4 tumor antigen fragment, such as antigenic peptides consisting of or including an amino acid sequence as set forth in any of SEQ ID NOs 320 -322 More preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA4 (human reference peptide) fragment "AVSSSSPLV" (SEQ ID NO: 722), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 320. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA4 (human reference peptide) fragment "KVDELAHFL" (SEQ ID NO: 723), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 321. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA4 (human reference peptide) fragment "KVLEHVVRV" (SEQ ID NO: 724), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 322.

In another embodiment, the antigenic peptide of the invention is a microbiotic sequence variant of a tumor antigen fragment MAGEA10 (human reference peptide), such as "GMLSDVQSM" (SEQ ID NO: 715) or "ILILILSIV" (SEQ ID NO: 716). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a MAGEA10 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 310-313. More preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA10 (human reference peptide) fragment "GMLSDVQSM" (SEQ ID NO: 715), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 310 or 311. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA10 (human reference peptide) fragment "ILILILSIV" (SEQ ID NO: 716), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 312 or 313.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment MAGEA11 (human reference peptide), such as "AMDAIFGSL" (SEQ ID NO: 717), "GLITKAEML" (SEQ ID NO: 718), "GTLEELPAA " (SEQ ID NO: 719) or "KVLEYIANA" (SEQ ID NO: 720). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a MAGEA11 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 314-318. More preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA11 (human reference peptide) fragment "AMDAIFGSL" (SEQ ID NO: 717), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 314. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA11 (human reference peptide) fragment "GLITKAEML" (SEQ ID NO: 718), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 315. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA11 (human reference peptide) fragment "GTLEELPAA" (SEQ ID NO: 719), such as an antigenic peptide consisting of or including an amino acid sequence such as specified in SEQ ID NO: 316 or 317. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the MAGEA11 (human reference peptide) fragment "KVLEYIANA" (SEQ ID NO: 720), such as an antigenic peptide consisting of or comprising itself amino acid sequence as indicated in SEQ ID NO: 318.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment MAGEA12 (human reference peptide), such as "QLVFGIEVV" (SEQ ID NO: 721). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a MAGEA12 tumor antigen fragment, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 319. More specifically, an antigenic peptide as claimed in accordance with with the present invention, consisting of or including the amino acid sequence as indicated in SEQ ID NO: 319, is a sequence variant of the MAGEA12 (human reference peptide) fragment "QLVFGIEVV" (SEQ ID NO: 721).

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen MLANA (human reference peptide) fragment, such as "VILGVLLEI" (SEQ ID NO: 725). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a tumor antigen MLANA fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 323-334. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the MLANA (human reference peptide) fragment "VILGVLLLI" (SEQ ID NO: 725), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO:323, 324, 325, 326, 327, 328, 329. 330, 331, 332, 333 or 334.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment NKX2-1 (human reference peptide), such as "MTAAGVPQL" (SEQ ID NO: 726) or "SVSDILSPL" (SEQ ID NO: 727). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a tumor antigen fragment of NKX2-1, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 335-340. More preferably, the antigenic peptide of the present invention is a sequence variant of the NKX2-1 (human reference peptide) fragment "MTAAGVPQL" (SEQ ID NO: 726), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 335. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the NKX2-1 (human reference peptide) fragment "SVSDILSPL" (SEQ ID NO: 727), such as an antigenic peptide consisting of or including an amino acid sequence, as indicated by SEQ ID NO: 336, 337, 338, 339 or 340.

According to another embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment NPTX2 (human reference peptide), such as ALLAASVAL" (SEQ ID NO: 728), "LLAASVALA" (SEQ ID NO: 729), "QLLRKVAEL" (SEQ ID NO: 730), "TLPELYAFT" (SEQ ID NO: 731) or "YLYGKIKKT" (SEQ ID NO: 732) In another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a fragment of the tumor antigen NPTX2, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 341 to 351. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the NPTX2 (human reference peptide) fragment "ALLAASVAL" ( SEQ ID NO: 728), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 341, 342, 343 or 344. Also more preferably, the antigenic peptide of the present invention is a variant sequence of a fragment of NPTX2 (human reference peptide) "LLAASVALA" (SEQ ID NO: 729), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 345, 346, 347 or 348. Also more preferably, an antigenic peptide of the present invention is a sequence variant of the NPTX2 (human reference peptide) fragment "QLLRKVAEL" (SEQ ID NO: 730), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 349. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the NPTX2 (human reference peptide) fragment "TLPELYAFT" (SEQ ID NO: 731), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 350 Also more preferably, the antigenic peptide of the present invention is a sequence variant of the NPTX2 (human reference peptide) fragment "YLYGKIKKT" (SEQ ID NO: 732), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 351.

In another embodiment, the antigenic peptide of the invention is a variant sequence of a PAGE3 tumor antigen fragment, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NOs 352-354. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the PAGE3 (human reference peptide) fragment "QVLGLAAYL" (SEQ ID NO: 733), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 352, 353 or 354.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a fragment of a tumor antigen PAX2, such as an antigenic peptide consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 355-358. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the PAX2 (human reference peptide) fragment "GLDEVKSSL" (SEQ ID NO: 734), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 355, 356, 357 or 358.

In another preferred embodiment, the antigenic peptide of the invention is a sequence variant of a fragment of the tumor antigen PCDHB16, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NOs 359-365. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the PCDHB16 (human reference peptide) fragment "FVLLSLSGA" (SEQ ID NO: 735), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 359. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PCDHB16 (human reference peptide) fragment "SLFLFSVLL" (SEQ ID NO: 736), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 360. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PCDHB16 (human reference peptide) fragment "SETVYLVVA" (SEQ ID NO: 737), such as an antigenic peptide consisting of or comprising itself amino acid sequence as specified in SEQ ID NO: 361. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PCDHB16 (human reference peptide) fragment "VLLFVAVRE" (SEQ ID NO: 738), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 362, 363 or 364. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PCDHB16 (human reference peptide) fragment "VSSLFLFSV" (SEQ ID NO: 739), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 365.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment PIWIL1 (human reference peptide), such as "SIAGFVASI" (SEQ ID NO: 740). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment PIWIL1, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 366. More specifically, the antigenic peptide as set forth in in accordance with the present invention, which consists of or includes the amino acid sequence as indicated in SEQ ID NO: 366, is a sequence variant of the PIWIL1 (human reference peptide) fragment "SIAGFVASI" (SEQ ID NO: 740).

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a PMEL (human reference peptide) tumor antigen fragment, such as "ILLVLMAVV" (SEQ ID NO: 741), "LIVGILLVL" (SEQ ID NO: 742), " LMAVVLASL" (SEQ ID NO: 743), "PLLDGTATL" (SEQ ID NO: 744), "SLADTNSLA" (SEQ ID NO: 745) or "VLQAAIPLT" (SEQ ID NO: 746). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant of a PMEL tumor antigen fragment sequence, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 367-379. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the PMEL (human reference peptide) fragment "ILLVLMAVV" (SEQ ID NO: 741), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 367. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PMEL (human reference peptide) fragment "LIVGILLVL" (SEQ ID NO: 742), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 368, 369, 370, 371, 372 or 373. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PMEL (human reference peptide) fragment "LMAVVLASL" (SEQ ID NO: 743), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 374 or 375.

Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PMEL (human reference peptide) fragment "PLLDGTATL" (SEQ ID NO: 744), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO : 376. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PMEL (human reference peptide) fragment "SLADTNSLA" (SEQ ID NO: 745), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 377 or 378. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PMEL (human reference peptide) fragment "VLQAAIPLT" (SEQ ID NO: 746), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 379.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a fragment of a tumor antigen PRAME ((human reference peptide) such as "AVLDGLDVL" (SEQ ID NO: 747), "QLLALLPSL" (SEQ ID NO: 748), " RLRELLCEL" (SEQ ID NO: 749) or "VLYPVPLES" (SEQ ID NO: 750). In another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant of a PRAME tumor antigen fragment sequence, such as antigenic peptides consisting of or comprising comprising the amino acid sequence as set forth in SEQ ID NOs 380 to 387. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the PRAME (human reference peptide) fragment "AVLDGLDVL" (SEQ ID NO: 747), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 380 or 381. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PRAME (human reference peptide) fragment "QLLALLPSL" (SEQ ID NO : 748), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 382, 383, 384 or 385. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the PRAME fragment (reference peptide human) "RLRELLCEL" (SEQ ID NO: 749), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 386. Also more preferably, the antigenic peptide of the present invention is a PRAME fragment sequence variant (human reference peptide) "VLYPVPLES" (SEQ ID NO: 750), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 387.

In another preferred embodiment, the antigenic peptide of the invention is a microbiotic variant of a PTHLH (human reference peptide) tumor antigen fragment sequence, such as "AVFLLSYAV" (SEQ ID NO: 751). In another preferred embodiment, the antigenic peptide of the invention is a microbiotic a sequence variant of a fragment of a tumor antigen PTHLH, such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 388. More specifically, an antigenic peptide of the present invention that consists of or includes an amino acid the sequence as indicated in SEQ ID NO: 388 is a variant of the PTHLH (human reference peptide) sequence "AVFLLSYAV" (SEQ ID NO: 751).

In another preferred embodiment, the antigenic peptide of the invention is a microbiotic sequence variant of a SEMG1 (human reference peptide) tumor antigen fragment, such as "FVLSLLLIL" (SEQ ID NO: 752), "IIFVLSLLL" (SEQ ID NO: 753) or " LILEKQAAV" (SEQ ID NO: 754). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen SEMG1 fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 389-400. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the SEMG1 (human reference peptide) fragment "FVLSLLLIL" (SEQ ID NO: 752), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 389, 390, 391, 392, 393, 394, 395, 396 or 397. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SEMG1 (human reference peptide) fragment "IIFVLSLLL" (SEQ ID NO: 753), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 398 or 399. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SEMG1 (human reference peptide) fragment "LILEKQAAV "(SEQ ID NO: 754), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 400.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a tumor antigen fragment SERHL2 (human reference peptide), such as "LISELKLAV" (SEQ ID NO: 755), "RAIEHVLQV" (SEQ ID NO: 756), " SSFDRLIPL" (SEQ ID NO: 757) or "TLKEQFQFV" (SEQ ID NO: 758). In another preferred embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment of SERHL2, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 401-405. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the SERHL2 (human reference peptide) fragment "LISELKLAV" (SEQ ID NO: 755), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 401. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SERHL2 (human reference peptide) fragment "RAIEHVLQV" (SEQ ID NO: 756), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 402. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SERHL2 (human reference peptide) fragment "SSFDRLIPL" (SEQ ID NO: 757), such as an antigenic peptide consisting of or comprising itself amino acid sequence as specified in SEQ ID NO: 403 or 404. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SERHL2 (human reference peptide) fragment "TLKEQFQFV" (SEQ ID NO: 758), such as an antigenic peptide, consisting of or including the amino acid sequence as set forth in SEQ ID NO: 405.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment SLC45A3 (human reference peptide), such as "AILDSAFLL" (SEQ ID NO: 759), "AISLVFSLV" (SEQ ID NO: 760), " ALQILPYTL" (SEQ ID NO: 761), "ALTGGFFSA" (SEQ ID NO: 762), "AQLLLVNLL" (SEQ ID NO: 763), "CLFGLLTLI" (SEQ ID NO: 764), "GILLSLFLI" (SEQ ID NO : 765), "GLLPPPPAL" (SEQ ID NO: 766), "GLLTLIFLT" (SEQ ID NO: 767), "GLVAIYFAT" (SEQ ID NO: 768), "NLGALLPRL" (SEQ ID NO: 769) or "SVAAFPVAA " (SEQ ID NO: 770). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a tumor antigen fragment of SLC45A3, such as an antigenic peptide consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 406-427. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "AILDSAFLL" (SEQ ID NO: 759), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 406. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "AISLVFSLV" (SEQ ID NO: 760), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 407 or 408. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "ALQILPYTL" (SEQ ID NO: 761), such as an antigenic peptide consisting of or comprising the amino acid sequence as set forth in SEQ ID NO: 409. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "ALTGFTFSA" (SEQ ID NO: 762), such as an antigenic peptide, consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 410. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "AQLLLVNLL" (SEQ ID NO: 763), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 411. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "CLFGLLTLI" (SEQ ID NO: 764 ), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 412, 413, 414 or 415. Also more preferably, the antigenic peptide of the present invention is a sequence variant of a fragment of SLC45A3 (human reference peptide) "GILLSLFLI" (SEQ ID NO: 765), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 416 or 417. Also more preferably, the antigenic peptide of the present invention is a variant sequence of the SLC45A3 fragment (human reference peptide) "GLLPPPPAL" (SEQ ID NO: 766), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 418. Also more preferably, the antigenic peptide of the present invention is a variant SLC45A3 (human reference peptide) fragment sequence "GLLTLIFLT" (SEQ ID NO: 767), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 419, 420, 421, 422 or 423. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "GLVAIYFAT" (SEQ ID NO: 768), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO : 424. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "NLGALLPRL" (SEQ ID NO: 769), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 425 or 426. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC45A3 (human reference peptide) fragment "SVAAFPVAA" (SEQ ID NO: 770), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 427.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a tumor antigen fragment SLC6A3 (human reference peptide), such as "FLLSLFCVT" (SEQ ID NO: 771), "FSLGVGFGV" (SEQ ID NO: 772), " GLIDEFQLL" (SEQ ID NO: 773), "GMESVITGL" (SEQ ID NO: 774), "ILFGVLIEA" (SEQ ID NO: 775), "KIDFLLSVI" (SEQ ID NO: 776), "LLFMVIAGM" (SEQ ID NO : 777), "LVPYLLFMV" (SEQ ID NO: 778) or "QLTACLVLV" (SEQ ID NO: 779). In another preferred embodiment, the antigenic peptide of the invention is a microbiotic sequence variant of a tumor antigen fragment of SLC6A3, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 428-441. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the SLC6A3 (human reference peptide) fragment "FLLSLFCVT" (SEQ ID NO: 771), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 428, 429 or 430. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC6A3 (human reference peptide) fragment "FSLGVGFGV" (SEQ ID NO: 772), such as an antigenic peptide consisting of or including comprising the amino acid sequence as set forth in SEQ ID NO: 431 or 432. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC6A3 (human reference peptide) fragment "GLIDEFQLL" (SEQ ID NO: 773), such as an antigenic peptide, consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 433. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC6A3 (human reference peptide) fragment "GMESVITGL" (SEQ ID NO: 774), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 434. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC6A3 (human reference peptide) fragment "ILFGVLIEA" (SEQ ID NO: 775) , such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 435 or 436. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC6A3 (human reference peptide) fragment "KIDFLLSVI" (SEQ ID NO: 776), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 437. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SLC6A3 (human reference peptide) fragment "LLFMVIAGM " (SEQ ID NO: 777), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 438 or 439. Also more preferably, the antigenic peptide of the present invention is a sequence variant of a fragment of SLC6A3 ( human reference peptide) "LVPYLLFMV" (SEQ ID NO: 778), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 440. Also more preferably, the antigenic peptide of the present invention is a sequence variant fragment of SLC6A3 (human reference peptide) "QLTACLVLV" (SEQ ID NO: 779), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 441.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment SNX31 (human reference peptide), such as "MISEKMVKL" (SEQ ID NO: 780). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a fragment of a tumor antigen SNX31, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 442. More specifically, the antigenic peptide claimed in in accordance with the present invention, which consists of or includes the amino acid sequence as indicated in SEQ ID NO: 442, is a variant of the SNX31 (human reference peptide) sequence "MISEKMVKL" (SEQ ID NO: 780).

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment SOX11 (human reference peptide), such as "LMFDLSLNF" (SEQ ID NO: 781). In another preferred embodiment, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment of SOX11, such as an antigenic peptide consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 443-445. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the SOX11 (human reference peptide) fragment "LMFDLSLNF" (SEQ ID NO: 781); such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 443, 444 or 445.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a fragment of the tumor antigen SOX17 (human reference peptide), such as "ALPAVMAGL" (SEQ ID NO: 782) or "GLAEPQAAA" (SEQ ID NO: 783). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a tumor antigen fragment of SOX17, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 446-449. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the SOX17 (human reference peptide) fragment "ALPAVMAGL" (SEQ ID NO: 782), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 446. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the SOX17 (human reference peptide) fragment "GLAEPQAAA" (SEQ ID NO: 783), such as an antigenic peptide consisting of or including the amino acid sequence , as indicated by SEQ ID NO: 447, 448 or 449.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment SPINK1 (human reference peptide), such as "GIFLLSALA" (SEQ ID NO: 784). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a tumor antigen fragment SPINK1, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 450. More specifically, the antigenic peptide claimed according to with the present invention, which consists of or includes the amino acid sequence as indicated in SEQ ID NO: 450, is a sequence variant of the SPINK1 (human reference peptide) fragment "GIFLLSALA" (SEQ ID NO: 784).

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment STEAP1 (human reference peptide), such as "ASLTFLYTL" (SEQ ID NO: 785), "AVLHAIYSL" (SEQ ID NO: 786), " FFFAVLHAI" (SEQ ID NO: 787), "GVIAAIVQL" (SEQ ID NO: 788), "KIAAIIASL" (SEQ ID NO: 789), "LIFKSILFL" (SEQ ID NO: 790), "LLLGTIHAL" (SEQ ID NO : 791), "LLSFFFAVL" (SEQ ID NO: 792), "MIAVFLPIV" (SEQ ID NO: 793) or "SLLLGTIHA" (SEQ ID NO: 794). In another preferred embodiment, the antigenic peptide of the invention is a sequence variant of a tumor antigen fragment of STEAP1, such as an antigenic peptide consisting of or including an amino acid sequence as set forth in any of SEQ ID NOs 451 to 468. More preferably, the antigenic peptide as claimed in accordance with the present invention, is a sequence variant of the STEAP1 (human reference peptide) fragment "ASLTFLYTL" (SEQ ID NO: 785), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 451 Also more preferably, the antigenic peptide of the present invention is a sequence variant of the STEAP1 (human reference peptide) fragment "AVLHAIYSL" (SEQ ID NO: 786), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 452. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the STEAP1 (human reference peptide) fragment "FFFAVLHAI" (SEQ ID NO: 787), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 453. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the STEAP1 (human reference peptide) fragment "GVIAAIVQL" (SEQ ID NO: 788), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 454, 455, 456 or 457. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the STEAP1 (human reference peptide) fragment "KIAAIIASL" (SEQ ID NO: 789), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 458, 459 or 460. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the STEAP1 (human reference peptide) fragment "LIFKSILFL" (SEQ ID NO: 790), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 461. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the STEAP1 (human reference peptide) fragment "LLLGTIHAL" (SEQ ID NO: 791), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 462. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the STEAP1 (human reference peptide) fragment "LLSFFFAVL " (SEQ ID NO: 792), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 463, 464 or 465. Also more preferably, the antigenic peptide of the present invention is a variant sequence of a STEAP1 fragment (human reference peptide) "MIAVFLPIV" (SEQ ID NO: 793), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 466. Also more preferably, the antigenic peptide of the present invention is a variant STEAP1 (human reference peptide) fragment sequences "SLLLGTIHA" (SEQ ID NO: 794), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 467 or 468.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TBL1Y (human reference peptide), such as "SLSLIVAVI" (SEQ ID NO: 795). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a variant sequence of a TBL1Y tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 469-470. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the TBL1Y (human reference peptide) fragment "SLSLIVAVI" (SEQ ID NO: 795), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 469 or 470.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TDRD1 (human reference peptide), such as "IISPNLFYA" (SEQ ID NO: 796), "LLDHVLIEM" (SEQ ID NO: 797), " VLIDEHLVL" (SEQ ID NO: 798), "YSSEVLEYM" (SEQ ID NO: 799). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a variant sequence of a tumor antigen fragment TDRD1, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 471-474. More preferably, the antigenic peptide of the present invention is a sequence variant of the TDRD1 (human reference peptide) fragment "IISPNLFYA" (SEQ ID NO: 796), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 471. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TDRD1 (human reference peptide) fragment "LLDHVLIEM" (SEQ ID NO: 797), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 472. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the tumor antigen fragment TDRD1 (human reference peptide) "VLIDEHLVL" (SEQ ID NO: 798), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 473. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TDRD1 (human reference peptide) fragment "YSSEVLEYM" (SEQ ID NO: 799), such as an antigenic peptide consisting of or comprising itself amino acid sequence as indicated in SEQ ID NO: 474.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TOP2A (human reference peptide) such as "ILLRPDTYI" (SEQ ID NO: 800), "LMMTIINLA" (SEQ ID NO: 801), "QLAGSVAEM " (SEQ ID NO: 802), "SLMMTIINL" (SEQ ID NO: 803), "TMLSSLARL" (SEQ ID NO: 804) or "YIFTMLSSL" (SEQ ID NO: 805). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a TOP2A tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 475-483. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the TOP2A (human reference peptide) fragment "ILLRPDTYI" (SEQ ID NO: 800), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 475. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TOP2A (human reference peptide) fragment "LMMTIINLA" (SEQ ID NO: 801), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 476, 477 or 478. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TOP2A (human reference peptide) fragment "QLAGSVAEM" (SEQ ID NO: 802), such as an antigenic peptide consisting of or comprising an amino acid sequence as defined in either SEQ ID NO: 479 or 480. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TOP2A (human reference peptide) fragment "SLMMMTINL" (SEQ ID NO: 803) , such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 481. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TOP2A (human reference peptide) fragment "TMLSSLARL" (SEQ ID NO : 804), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 482. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TOP2A (human reference peptide) fragment "YIFTMLSSL" ( SEQ ID NO: 805), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 483.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TPTE (human reference peptide), such as DLAGVIIEL" (SEQ ID NO: 806), "FGLFGVFLV" (SEQ ID NO: 807), "GLFGVFLVL " (SEQ ID NO: 808), "ILDTAIIVI" (SEQ ID NO: 809), "IVSSFAFGL" (SEQ ID NO: 810), "RLLRLIILL" (SEQ ID NO: 811), "SLAIALFFL" (SEQ ID NO: 812) or "YFWLHTSFI" (SEQ ID NO: 813). In another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a fragment of a tumor antigen TPTE, such as antigenic peptides consisting of or including the amino acid sequence as specified in any of SEQ ID NOs 484 to 504. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the TPTE (human reference peptide) fragment "DLAGVIIEL" (SEQ ID NO: 806), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in any of SEQ ID NOs: 484, 485, 486, 487, 488, 489, or 490. Also more preferably, the antigenic peptide of the present invention is a variant sequence of the TPTE fragment "FGLFGVFLV" (SEQ ID NO: 807), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 491, 492, 493 or 494. Also more preferably, the antigenic peptide of the present invention is a sequence variant of a fragment of TPTE (human reference peptide) "GLFGVFLVL" (SEQ ID NO: 808), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 495, 496 or 497. Also more preferably, an antigenic peptide of the present invention is a sequence variant of the TPTE (human reference peptide) fragment "ILDTAIIVI" (SEQ ID NO: 809), such as an antigenic peptide consisting of or including the amino acid sequence as specified in any of SEQ ID NO: 498 or 499. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TPTE (human reference peptide) fragment "IVSSFAFGL" (SEQ ID NO: 810), such as an antigenic peptide consisting of or including an amino acid sequence as specified in any from SEQ ID NO: 500 or 501. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TPTE (human reference peptide) fragment "RLLRLIILL" (SEQ ID NO: 811), such as an antigenic peptide consisting of or including amino acid sequence as set forth in SEQ ID NO: 502. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TPTE (human reference peptide) fragment "SLAIALFFL" (SEQ ID NO: 812), such as an antigenic peptide consisting of or comprising the amino acid sequence as specified in SEQ ID NO: 503. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TPTE (human reference peptide) fragment "YFWLHTSFI" (SEQ ID NO: 813), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 504.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TRPM8 (human reference peptide), such as "AMFGYTVGT" (SEQ ID NO: 814), "FIAGIVFRL" (SEQ ID NO: 815), " FLLLFAYVL" (SEQ ID NO: 816), "LLFAYVLLM" (SEQ ID NO: 817), "LLLFAYVLL" (SEQ ID NO: 818), "LVLYSLVFV" (SEQ ID NO: 819), "NILLVNLLV" (SEQ ID NO : 820), "QIADVIASL" (SEQ ID NO: 821), "VLYSLVFVL" (SEQ ID NO: 822) or "YLVKINTKA" (SEQ ID NO: 823). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a TRPM8 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 505-518. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "AMFGYTVGT" (SEQ ID NO: 814), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 505. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "FIAGIVFRL" (SEQ ID NO: 815), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 506. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "FLLLFAYVL" (SEQ ID NO: 816), such as an antigenic peptide consisting of or comprising itself amino acid sequence as specified in SEQ ID NO: 507. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "LLFAYVLLM" (SEQ ID NO: 817), such as an antigenic peptide consisting of or comprising an amino acid sequence as defined in any of SEQ ID NO: 508 or 509. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "LLLFAYVLL" (SEQ ID NO: 818), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 510. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "LVLYSLVFV" (SEQ ID NO: 819), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 511. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "NILLVNLLV" (SEQ ID NO: 820), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 512. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TRPM8 (human reference peptide) fragment "QIADVIASL " (SEQ ID NO: 821), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 513, 514, 515 or 516. Also more preferably, the antigenic peptide of the present invention is a TRPM8 (human reference peptide) fragment sequence variant "VLYSLVFVL" (SEQ ID NO: 822), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 517. Also more preferably, the antigenic peptide of the present The invention is a sequence variant of the TRPM8 (human reference peptide) fragment "YLVKINTKA" (SEQ ID NO: 823), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 518.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TYMS (human reference peptide), such as "FLDSLGFST" (SEQ ID NO: 824), "SLRDEFPLL" (SEQ ID NO: 825) or " VLEELLWFI" (SEQ ID NO: 826). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a variant sequence of a tumor antigen fragment TYMS, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 519-524. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the TYMS (human reference peptide) fragment "FLDSLGFST" (SEQ ID NO: 824), such as an antigenic peptide consisting of or including the amino acid sequence as specified in any of SEQ ID NO: 519, 520 or 521.

Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYMS (human reference peptide) fragment "SLRDEFPLL" (SEQ ID NO: 825), such as an antigenic peptide consisting of or including an amino acid sequence as specified in any of SEQ ID NO: 522 or 523. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYMS (human reference peptide) fragment "VEEELLWFI" (SEQ ID NO: 826), such as an antigenic peptide consisting of or including amino acid sequence as indicated in SEQ ID NO: 524.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TYR (human reference peptide), such as "ALLAGLVSL" (SEQ ID NO: 827), "AMVGAVLTA" (SEQ ID NO: 828), "ISSDYVIPI" (SEQ ID NO: 829), "LLAGLVSLL" (SEQ ID NO: 830), "LLSPASFFS" (SEQ ID NO: 831), "MVGAVLTAL" (SEQ ID NO: 832) or "VLTALLAGL" (SEQ ID NO: 833). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment TYR, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 525-539. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the TYR (human reference peptide) fragment "ALLAGLVSL" (SEQ ID NO: 827), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in any of SEQ ID NO: 525 or 526. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYR (human reference peptide) fragment "AMVGAVLTA" (SEQ ID NO: 828), such as an antigenic peptide consisting of or including comprising the amino acid sequence as defined in any of SEQ ID NO: 527, 528, 529 or 530.

Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYR (human reference peptide) fragment "ISSDYVIPI" (SEQ ID NO: 829), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO : 531. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYR (human reference peptide) fragment "LLAGLVSLL" (SEQ ID NO: 830), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 532. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYR (human reference peptide) fragment "LLSPASFFS" (SEQ ID NO: 831), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 533. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYR (human reference peptide) fragment "MVGAVLTAL" (SEQ ID NO: 832), such as an antigenic peptide consisting of or including amino acid sequence as set forth in SEQ ID NO: 534. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the TYR (human reference peptide) fragment "VLTALLAGL" (SEQ ID NO: 833), such as an antigenic peptide consisting of or comprising an amino acid sequence as defined in any of SEQ ID NO: 535, 536, 537, 538 or 539.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment UPK2 (human reference peptide), such as "ALTESLLVA" (SEQ ID NO: 834), "LLALLSPGA" (SEQ ID NO: 835), " LVLGFIIAL" (SEQ ID NO: 836), "SLSGLLSPA" (SEQ ID NO: 837), "TLPLILILL" (SEQ ID NO: 838), "VLGFIIALA" (SEQ ID NO: 839) or "VVITVLLSV" (SEQ ID NO : 840). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a tumor antigen fragment of UPK2, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 540-556. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the UPK2 (human reference peptide) fragment "ALTESLLVA" (SEQ ID NO: 834), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in any of SEQ ID NO: 540, 541 or 542. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the UPK2 (human reference peptide) fragment "LLALLSPGA" (SEQ ID NO: 835), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 543. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the UPK2 (human reference peptide) fragment "LVLGFIIAL" (SEQ ID NO: 836), such as an antigenic peptide consisting of or comprising an amino acid sequence as defined in any of SEQ ID NO: 544, 545, 546 or 547. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the UPK2 (human reference peptide) fragment "SLSGLLSPA" ( SEQ ID NO: 837), such as an antigenic peptide consisting of or including an amino acid sequence as defined in either SEQ ID NO: 548 or 549. Also more preferably, the antigenic peptide of the present invention is a sequence variant of a fragment of UPK2 (reference human peptide) "TLPLILILL" (SEQ ID NO: 838), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 550. Also more preferably, the antigenic peptide of the present invention is a variant sequence of the fragment UPK2 (human reference peptide) "VLGFIIALA" (SEQ ID NO: 839), such as an antigenic peptide consisting of or including the amino acid sequence as defined in any of SEQ ID NO: 551, 552, 553 or 554. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the UPK2 (human reference peptide) fragment "VVITVELSV" (SEQ ID NO: 840), such as an antigenic peptide consisting of or including the amino acid sequence as specified in any of SEQ ID NO : 555 or 556.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic sequence variant of a fragment of a tumor antigen VCAM1 (human reference peptide), such as "AQIGDSVML" (SEQ ID NO: 841), "FASSLIIPA" (SEQ ID NO: 842), " KSIDGAYTI" (SEQ ID NO: 843) or "SILEEGSSV" (SEQ ID NO: 844). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a tumor antigen fragment of VCAM1, such as antigenic peptides consisting of or including the amino acid sequence as set forth in SEQ ID NOs 557-560. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the VCAM1 (human reference peptide) fragment "AQIGDSVML" (SEQ ID NO: 841), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in any of SEQ ID NO: 557. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the VCAM1 (human reference peptide) fragment "FASSLIIPA" (SEQ ID NO: 842), such as an antigenic peptide consisting of or including amino acid sequence as set forth in SEQ ID NO: 558. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the VCAM1 (human reference peptide) fragment "KSIDGAYTI" (SEQ ID NO: 843), such as an antigenic peptide consisting of or comprising the amino acid sequence as set forth in SEQ ID NO: 559. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the VCAM1 (human reference peptide) fragment "SILEEGSSV" (SEQ ID NO: 844), such as an antigenic peptide, consisting of or including the amino acid sequence as set forth in SEQ ID NO: 560.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment WFDC2 (human reference peptide), such as "LLFGFTLVS" (SEQ ID NO: 845), "LLLFGFTLV" (SEQ ID NO: 846) or " RLGPLAAAL" (SEQ ID NO: 847). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a WFDC2 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 561-568. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the WFDC2 (human reference peptide) fragment "LLFGFTLVS" (SEQ ID NO: 845), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in any of SEQ ID NO: 561, 562, 563, 564 or 565. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the WFDC2 (human reference peptide) fragment "LLLFGFTLV" (SEQ ID NO: 846), such as antigenic a peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 566. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the WFDC2 (human reference peptide) fragment "RLGPLAAAL" (SEQ ID NO: 847), such as an antigenic peptide consisting of or including an amino acid sequence as defined in either SEQ ID NO: 567 or 568.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment WT1 (human reference peptide), such as "DLNALLPAV" (SEQ ID NO: 848). In another preferred embodiment, the antigenic peptide of the invention is a microbiotic sequence variant of a WT1 tumor antigen fragment, such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 569. More specifically, the antigenic peptide as set forth in in accordance with the present invention, which consists of or includes the amino acid sequence as indicated in SEQ ID NO: 569 is a sequence variant of the WT1 (human reference peptide) fragment "DLNALLPAV" (SEQ ID NO: 848).

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a ZEB1 tumor antigen fragment (human reference peptide), such as "ILIPQVAYT" (SEQ ID NO: 849), "NLSDIQNVL" (SEQ ID NO: 850) or " VQAVVLPTV" (SEQ ID NO: 851). In another preferred embodiment, the antigenic peptide of the invention is a variant sequence of a ZEB1 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 570-574. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ZEB1 (human reference peptide) fragment "ILIPQVAYT" (SEQ ID NO: 849), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in any of SEQ ID NO: 570 or 571. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the ZEB1 (human reference peptide) fragment "NLSDIQNVL" (SEQ ID NO: 850), such as an antigenic peptide consisting of or including comprising an amino acid sequence as defined in either SEQ ID NO: 572 or 573. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the ZEB1 (human reference peptide) fragment "VQAWLPTV" (SEQ ID NO: 851), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 574.

In another preferred embodiment, the antigenic peptide of the invention is a microbiotic sequence variant of a ZNF165 tumor antigen fragment (human reference peptide), such as "LVLEQFLTI" (SEQ ID NO: 852) or "RISGYISEA" (SEQ ID NO: 853). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a ZNF165 tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 575-578. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ZNF165 fragment (human reference peptide) "LVLEQFLTI" (SEQ ID NO: 852), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in any of SEQ ID NO: 575, 576 or 577. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the ZNF165 (human reference peptide) fragment "RISGYISEA" (SEQ ID NO: 853), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 578.

According to another preferred embodiment of the invention, the antigenic peptide of the invention is a microbiotic variant sequence of a tumor antigen fragment ZNF280A (human reference peptide), such as "AMTDISSLA" (SEQ ID NO: 854) or "VLLSNFYYG" (SEQ ID NO: 855). According to another preferred embodiment of the invention, the antigenic peptide of the invention is a sequence variant of a ZNF280A tumor antigen fragment, such as antigenic peptides consisting of or including the amino acid sequence as defined in any of SEQ ID NOs 579-580. More preferably, the antigenic peptide claimed in accordance with the present invention is a sequence variant of the ZNF280A (human reference peptide) fragment "AMTDISSLA" (SEQ ID NO: 854), such as an antigenic peptide consisting of or including the amino acid sequence as indicated in SEQ ID NO: 579. Also more preferably, the antigenic peptide of the present invention is a sequence variant of the ZNF280A (human reference peptide) fragment "VLLSNFYYG" (SEQ ID NO: 855), such as an antigenic peptide consisting of or including the amino acid sequence , as set forth in SEQ ID NO: 580.

Preferably, the antigenic peptide of the present invention consists of or includes an amino acid sequence as defined in any of SEQ ID NOs 1-160, 162-253 and 255-580. More preferably, the antigenic peptide of the present invention consists of or includes an amino acid sequence as set forth in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. Even more preferably, it consists of or includes an amino acid sequence as defined in any one of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524. Even more preferably, it consists of or includes itself an amino acid sequence as specified in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524. More preferably, the antigenic peptide of the present invention consists of or includes an amino acid sequence as specified in any of SEQ ID NOs 30, 32, 87, 97, and 194.

Moreover, an antigenic peptide of the present invention consisting of or including an amino acid sequence as indicated in any of SEQ ID NOs 30, 32, 194, 220, 254 or 255 is most preferred. More preferably, the antigenic peptide of the present invention consists of or includes an amino acid sequence as specified in any of SEQ ID NO: 30 or 32. More preferably, the antigenic peptide of the present invention consists of or includes an amino acid sequence as specified in any of SEQ ID NO: 194 or 220. More preferably, the antigenic peptide of the present invention consists of or includes an amino acid sequence as defined in either SEQ ID NO: 254 or 255.

As shown in the examples disclosed herein, the specific antigenic peptides of the present invention allow for the creation of a strong immune response against themselves, and also, most importantly, for the creation of a strong immune response against peptides having amino acid similarity to peptides in the tumor antigen, even in the event that human reference peptides in the tumor antigen induce immune tolerance.

Advantageously, the antigenic peptides of the present invention may be in the form of immunogenic compounds, in particular; intended for use in the prevention and treatment of cancer.

Immunogenic compounds comprising the antigenic peptide of the present invention

According to a further aspect, the present invention also provides an immunogenic compound comprising an antigenic peptide of the present invention as disclosed above. More specifically, preferred variants of the antigenic peptide as disclosed above are also useful as the immunogenic compound of the present invention. For example, the antigenic peptide of the immunogenic compound preferably consists of or includes an amino acid sequence as set forth in any of SEQ ID NOs 1-580 and 861-887, such as an antigenic peptide consisting of and including the amino acid sequence , as set forth in any of SEQ ID NOs 1-580. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 1-160, 162-253 and 255-580 are more preferred.

For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524 , are even more preferable. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524 are even more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524 are even more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 87, 97, and 194 are most preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 194, 220, 254 or 255 are particularly preferred. Also preferred are combinations thereof, more specifically an immunogenic compound comprising the individual antigenic peptides of the present invention.

As used herein, the term "immunogenic compound" refers to a compound that has the ability to induce, enhance, prolong or maintain an immune response, more particularly to induce, enhance, prolong or maintain an immune response when administered to a mammal, particularly when administered to a human.

In general, the term "immunogenic compound" refers to all types of compounds comprising the antigenic peptide of the present invention. For example, an antigenic peptide of the present invention may be associated with a carrier molecule, or an antigenic peptide of the present invention may be included in a polypeptide or protein (and such a polypeptide or protein may exist “free-standing”, that is, not associated with any other compound , or such a polypeptide or protein comprising an antigenic peptide may be linked to a carrier molecule).

Preferably, the immunogenic compound of the present invention comprises an antigenic peptide and a carrier molecule, in particular wherein the antigenic peptide (or a polypeptide or protein comprising an antigenic peptide) is linked to a carrier molecule. A preferred carrier molecule is a carrier protein or a carrier peptide. According to a preferred embodiment of the invention, an antigenic peptide as disclosed above, or a polypeptide/protein comprising said antigenic peptide, is linked to a carrier protein or carrier peptide, for example, by a covalent or non-covalent bond. Alternatively, such a carrier protein or carrier peptide as disclosed herein may be administered (separately) together in the form of an immunostimulant (ie, not as a standalone "immunogenic compound" but as part of a combination therapy as disclosed below).

The carrier molecule may also be a lipid or lipid-like molecule. In this case, the immunogenic compound may be a lipopeptide. As used herein, the term “lipopeptide” refers to a molecule that includes a lipid or lipid-like molecule covalently linked to a peptide molecule. In general, “lipid” is soluble in non-polar solvents; usually “lipid” is insoluble (or poorly soluble) in water. Examples of lipid or lipid-like molecules include, but are not limited to, fatty acids, waxes, sterols, monoglycerides, diglycerides, triglycerides and phospholipids. The lipid may be a fatty acid, glycerolipid, glycerophospholipid, sphingolipid, sterol lipid, prenol lipid, saccharolipid, or polyketide. Preferably, the lipid is a fatty acid or a derivative thereof (including monoglycerides, diglycerides, triglycerides and phospholipids). Fatty acids usually include a carbohydrate chain that ends with a carboxyl group. Fatty acids can be saturated or unsaturated. Fatty acids can be attached to functional groups, for example, including oxygens, halogens, nitrogen or sulfur. Preferred fatty acids are saturated or unsaturated long-chain fatty acids such as 14-carbon myristic acid (CH ₃ (CH ₂ ) ₁₂ COOH) or 16-carbon palmitic acid (CH ₃ (CH ₂ ) ₁₄ COOH), as well as phospholipids such as phosphatidylglycerol (PG).

Preferably, an antigenic peptide as disclosed herein, or a polypeptide/protein comprising an antigenic peptide, may be co-administered or linked, for example by a covalent or non-covalent linkage, to a protein/peptide having immunostimulatory properties, such as providing CD4+ Th1 stimulation cells. Although the antigenic peptide, as disclosed herein, preferably binds to MHC class I, CD4+ helper epitopes can additionally be used to promote an effective immune response. Th1 helper cells have the ability to support efficient dendritic cell (DC) activation and CTL-specific activation through the secretion of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2), and also enhancing the expression of a costimulatory signal on DCs and T cells (Galaine et al., Interest in Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine. Vaccines (Basel). 2015 Jun 30; 3(3):490-502).

For example, the adjuvant peptide/protein may preferably be a non-tumor antigen that promotes immune memory or non-specific assistance, or a specific helper protein of tumor origin. Several helper proteins have been described in the literature to provide nonspecific help to T cells, such as tetanus helper protein, keyhole limpet hemocyanin, or PADRE peptide ( et al., Targeting antitumor CD4 helper T cells with universal tumor-reactive helper peptides derived from telomerase for cancer vaccine. Hum Vaccin Immunother. May 2013; 9(5): 1073-7, Slingluff CL, The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Cancer J. 2011 Sep-Oct; 17(5):343-50). Thus, tetanus helper peptide, keyhole limpet hemocyanin and PADRE peptide are preferred examples of such adjuvant peptides/proteins. In addition, specific tumor-derived helper proteins are preferred. Specific helper proteins of tumor origin are usually presented by MHC class II, in particular by HLA-DR, HLA-DP or HLA-DQ.

Specific helper proteins of tumor origin may be fragments of sequences of related overexpressed tumor antigens, such as HER2, NY-ESO-1, hTERT or IL13RA2. Such fragments are at least 10 amino acids in length, more preferably at least 11 amino acids, even more preferably at least 12 amino acids, and even more preferably at least 13 amino acids. In particular, fragments of related overexpressed tumor antigens such as HER2, NY-ESO-1, hTERT or IL13RA2 having a length of 13 to 24 amino acids are preferred. Preferred fragments bind to MHC class II and can thus be identified using, for example, IEDB (immune epitope database) prediction tools; Supported by a contract from the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health in the Department of Health and Human Services; URL: http://www.iedb.org/; http://tools.iedb.org/mhcii/) for binding to MHC class II. Preferably, the adjuvant peptide/protein may be an HHD-DR3 peptide with the sequence MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh H, Raghava GP (2003) MHCBN: a comprehensive database of MHC binding and non-binding peptides. Bioinformatics 19: 665-666 ). Other examples of preferred adjuvant peptides/proteins, in particular helper peptides, include UCP2 peptide (for example, as disclosed in WO 2013/135553 A1 or Dosset et al. Clin Cancer Res. 2012 Nov 15; 18(22):6284-95) and BIRC5 peptide (eg, as described in EP2119726 A1 or Widenmeyer et al. Int J Cancer. 2012 Jul 1; 131(1):140-9). The most preferred helper peptide is UCP2 peptide (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859, for example, as disclosed in WO 2013/135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15; 18(22):6284 -95).

It is also preferred that the immunogenic compound of the present invention is a polypeptide or protein comprising the antigenic peptide of the present invention. Preferably, such protein or polypeptide is a recombinant protein or polypeptide, for example a fusion protein. The term "recombinant" means that it does not exist in nature.

According to a preferred embodiment of the invention, the immunogenic compound of the present invention consists of or includes a polypeptide of formula (I)

Where:

- "PepNt" consists of a polypeptide having a length of from 0 to 500 amino acid residues, and located at the N-terminus of the polypeptide of formula (I);

-"CORE" consists of the antigenic peptide of the present invention, as defined above; And

-"PepCt" consists of a polypeptide having a length of from 0 to 500 amino acid residues and located at the C-terminus of the polypeptide of formula (I).

For example, an immunogenic compound may consist of or include a polypeptide of formula (1a) or (1b):

or

where "PepNt" and "PepCt" and "CORE" are defined above.

Preferably, the polypeptide of formula (I), (Ia) or (Ib) is a fusion peptide or protein, more particularly a recombinant fusion peptide or protein.

It is also preferred that the polypeptide or immunogenic compound as defined above contains from 9 to 1000 amino acids; which includes 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67? 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 and 1000 amino acids. Accordingly, the length of "PepNt" and "PepCt", if necessary, can be determined accordingly.

Thus, "PepNt" and "PepCt" as defined above may contain from 0 to 500 amino acid residues; which includes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, and 500 amino acid residues.

The types of carrier molecules that are used to create the immunogenic compound of the invention, such as an immunogenic compound consisting of or including a polypeptide of formula (I) linked to a carrier molecule, are well known to one skilled in the art. In particular, the function of the carrier molecule is to provide cytokine assistance (or T cell assistance) in order to enhance the immune response against the tumor antigen.

Preferably, the antigenic peptide is linked to a carrier molecule, more specifically to a carrier protein, preferably through a covalent or non-covalent bond. The carrier molecule to which the peptide is optionally bound may be selected from a wide variety of known carriers. Examples of carrier molecules that can be used to create vaccines include proteins such as human or bovine serum albumin and keyhole limpet hemocyanin (KLH), as well as fatty acids. Other embodiments of carrier molecules to which the antigenic peptide of formula (I) may be covalently linked include bacterial toxins or toxoids, such as diphtheria, cholera toxoids, heat labile E. coli or tetanus toxoids, N. meningitidis outer membrane protein (European Patent Application n ° EP0372501), synthetic peptides (European patent applications no. EP0378881 and no. EP0427347), heat shock proteins (PCT application no. W093/17712), pertussis proteins (PCT application no. W098/58668), protein D from H. influenzae (PCT application no. WO00/56360.) and toxin A or B from C. difficile (International patent application WO00/61761).

More preferably, the carrier protein or carrier peptide is a protein/peptide having immunostimulatory properties, such as providing stimulation of CD4+ Th1 cells, as disclosed herein. A preferred example of such molecules is a non-tumor antigen that induces immune memory or non-specific help, or is a specific helper peptide of tumor origin, such as tetanus helper peptide, limpet homocyanine peptide or PADRE peptide. Another preferred example is a tumor-derived specific peptide that can be presented by MHC II, more specifically HLA-DR, HLA-DP or HLA-DQ, such as fragments of related overexpressed tumor antigens, e.g. HER2, NY-ESO-1 , hTERT or IL13RA2 as described above. In a preferred embodiment, the carrier protein or carrier peptide may be a protein/peptide having immunostimulatory properties, for example, HHD-DR3 peptide carrier MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). In particular, "PepNt" and/or "PepCt" may correspond to a carrier protein or carrier peptide, such as the HHD-DR3 carrier protein MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh N, Raghava GP (2003) MHCBN: a comprehensive database of MHC-binding and non-MHC-binding peptides. Bioinformatics 19: 665-666). Other examples of preferred carrier proteins/peptides, in particular helper peptides, are UCP2 peptide (for example, as disclosed in WO 2013/135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15; 18(22):6284-95 ) and BIRC5 peptide (eg, as disclosed in EP 2119726 A1 or Widenmeyer et al., Int J Cancer. 2012 Jul 1; 131(1):140-9). The most preferred helper peptide is UCP2 peptide (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859).

Moreover, in a polypeptide of formula (I), (Ia) or (Ib), "PepNt" and/or "PepCt" may preferably correspond to such a protein/protein having immunostimulatory properties that provides stimulation of CD4+ Th1 cells, as disclosed herein description.

In addition, the immunogenic compound may consist of or include such a protein/peptide with immunostimulatory properties, such as providing stimulation of CD4+ Th1 cells, as disclosed herein, which is covalently linked to the N-terminus of the antigenic peptide of the present invention or the N-terminus a polypeptide/protein comprising said antigenic peptide.

Preferably, the antigenic peptide of the present invention (or a polypeptide/protein comprising said antigenic peptide) is covalently linked to a carrier molecule via a linker molecule.

Preferred linker agents include linker agents designated GMBS, sulfo-GMBS, SMPB and sulfo-SMPB.

In some embodiments of an immunogenic compound as defined herein, the linker agent is selected from the group consisting of GMBS ester, sulfo-GMBS ester (N-[γ-maleimidobuturyl-oxy]sulfosuccinimide ), SMPB (succinimidyl 4-[p-maleimidophenyl]butyrate) and sulfo-SMPB (sulfosuccinimidyl 4-[p-maleimidophenyl]butyrate).

Methods for conjugating two proteins with a linker agent in general and more specifically with a linker agent selected from the group consisting of GMBS, sulfo-GMBS, SMPB and sulfo-SMPB are well known to one skilled in the art. For example, such protocols are disclosed in leaflets published by Pierce (Illinois, USA). GMBS, sulfo-GMBS, SMPB and sulfo-SMPB are composed of heterobifunctional linker agents that include both an N-hydroxysuccinimide (NHS) ester group and a maleimide group. Conjugation using GMBS, sulfo-GMBS, SMPB or sulfo-SMPB usually occurs in two steps. In the first step, the amine-containing protein reacts with a linker agent, the molar amount of which is several times higher than the amount of protein at pH 7-9, forming amide bonds, followed by removal of the excess unreacted linker agent, usually by desalting or dialysis. In the second step, a molecule containing a sulfhydryl group (eg, a peptide of formula (I)) is added to react with the maleimide group already attached to the first protein at pH 6.5-7.5 to form stable thioester bonds.

The use of SMPB or sulfo-SMPB as linker agents to covalently link an antigenic peptide of the present invention (or a polypeptide/protein comprising said antigenic peptide, such as a polypeptide of formula (I)) to an amine-containing protein carrier results in the formation of a conjugate of formula (II) below :

Where:

-R1 includes one reactive group of the amine-containing carrier protein, wherein the NH group attached thereto is derived from (a) an alpha amino group located at the N-terminus of the amine-containing carrier protein or (b) a lysine amino acid residue (K) of a side chain amino group of the amine-containing carrier protein; And

-R2 comprises an antigenic peptide of the present invention (or a polypeptide/protein comprising said antigenic peptide, such as a polypeptide of formula (I)), wherein the sulfur atom (S) attached thereto is derived from the sulfhydryl group (SH) of the cysteine residue located on N -terminus or C-terminus of the peptide of formula (I). In some embodiments, the sulfhydryl molecule may be part of a non-naturally occurring amino acid, or any other molecule located at the end of the peptide of formula (I).

The use of GMBS or sulfo-GMBS as linker agents for covalently linking an antigenic peptide of the present invention (or a polypeptide/protein comprising said antigenic peptide, such as a polypeptide of formula (I)) to an amine-containing protein carrier, in particular a CRM 197 carrier, leads to the formation of the conjugate of formula (III) below:

Where:

- R1 includes one reactive group of the amino-containing protein of the carrier, and the NH group attached to it comes from (a) an alpha amino group located at the N-terminus of the amino-containing protein of the carrier or (b) a lysine amino acid residue (K) of the side chain amino group of the amino-containing protein of the carrier; And

-R2 comprises an antigenic peptide of the present invention (or a polypeptide/protein comprising said antigenic peptide, such as a polypeptide of formula (I)), wherein the sulfur atom (S) attached thereto is derived from the sulfhydryl group (SH) of the cysteine residue located on N -terminus or C-terminus of the peptide of formula (I).

In some embodiments, the sulfhydryl molecule may be part of a non-naturally occurring amino acid or any other molecule located at the end of the peptide of formula (I).

MHC peptide multimers (pMHC) including an antigenic peptide

In a further aspect, the present invention also provides a peptide-MHC multimer (pMHC) comprising an antigenic peptide of the present invention.

As used herein, the term “peptide-MHC multimer” (pMHC) refers to a stable multimeric complex consisting of protein subunits of the major histocompatibility complex (MHC abbreviation for Major Histocompatibility Complex) “loaded” with the antigenic peptide of the invention. In general, "MHC multimers" are oligomeric forms of MHC molecules. The main function of the MHC molecule is antigen binding. According to the present invention, said antigen is the antigenic peptide of the present invention. Accordingly, an MHC protein complex "loaded" with an antigenic peptide of the invention generally means that the antigenic peptide of the invention is associated with one or more MHC proteins. "Peptide-MHC multimers" (pMHC) of the invention include, but are not limited to, peptide-MHC dimer, trimer, tetramer, pentamer, hexamer, heptamer, or octamer. MHC tetramers and pentamers are preferred. The term "Major Histocompatibility Complex (MHC)" is the common designation for the system of histocompatibility antigens described across species, including human leukocyte antigens (HLA). In humans, there are three major distinct genetic loci that encode MHC class I molecules: HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02, and HLA-A*11 are examples of various MHC class I alleles that can be expressed from these loci.

According to one embodiment of the invention, the pMHC multimer is a MHC class I peptide/molecule multimer. In another specific embodiment, the pMHC is an HLA corresponding to a class I MHC multimer/peptide. Accordingly, the pMHC multimer may be an HLA-peptide multimer selected from the group consisting of an HLA-A peptide multimer, an HLA-B peptide multimer, an HLA-C peptide multimer, an HLA-E peptide multimer, a MICA peptide multimer, and MICB-peptide multimer.

Methods for preparing pMHC multimers are well known in the art and are described, for example, in WO 96/26962 and WO 01/18053, which are incorporated herein by reference.

In addition to the MHC molecule and the antigenic peptide of the invention, the pMHC may include other components such as a multimerization agent and/or a label (eg, for imaging). Examples of labels include, but are not limited to, fluorescent labels, for example, fluorescently labeled proteins such as streptavidin. Fluorescent labels include allophycocyanin (APC), phycoerythrin (PE), R-phycoerythrin (R-PE), and fluorescein isothiocyanate (FITC). The preferred label is biotin.

In one embodiment, said pMHC multimer can be used to visualize a population of T cells that are specific for an MHC class I peptide complex or an HLA corresponding to an MHC class I/peptide complex, as described above. For example, the pMHC multimer may be a multimer in which the MHC heavy chain is biotinylated, allowing for a tetrameric combination with streptavidin. This pMHC tetramer has increased avidity towards the corresponding TCR-bearing T lymphocytes and thus can be used to visualize reactive populations using immunofluorescence. According to another embodiment of the invention, said pMHC multimer can be used to detect and/or isolate in a screen (flow meter or immunomagnetic screen) T cell populations specific for the pMHC complex, as disclosed herein above.

Cells loaded with an antigenic peptide or immunogenic compound

According to a further aspect, the present invention also relates to cells loaded with an antigenic peptide of the present invention or an immunogenic peptide including an antigenic peptide of the present invention, as described above. In particular, preferred embodiments of the antigenic peptide as described above are also applicable to such cells of the present invention. For example, an antigenic peptide loaded into a cell or included in an immunogenic compound loaded into a cell preferably consists of or includes an amino acid sequence as set forth in SEQ ID NOs 1 to 580 and 861 to 887, such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID Nos 1 to 580. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 1 to 160, 162-253 and 255-580 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as set forth in any of SEQ ID Nos. 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524 , are even more preferable. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID Nos. 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524 are more preferred . For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID Nos. 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524 are most preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 87, 97, and 194 are most preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID Nos 30, 32, 194, 220, 254 or 255 are most preferred. Also preferred are their combinations, more specifically, cells loaded with different antigenic peptides of the present invention (or corresponding immunogenic compounds)).

Preferred cells loaded with an antigenic peptide of the present invention or an immunogenic compound of the present invention are antigen presenting cells (APCs), more preferably dendritic cells (DCs).

APCs are of greatest interest because their primary function is to process antigens and present them on their cell surface to T cells of the immune system in a manner that initiates and modulates T cell responses in vivo. In the context of the present invention, it is preferred that the APCs are loaded with the antigenic peptide(s) and/or immunogenic compound(s) of the present invention. This can be accomplished by exposing APCs in vitro to the specified antigenic peptide(s) and/or immunogenic compound(s) (as described in Rizzo MM, Alaniz L, Mazzolini G. Ex vivo loading of autologous dendritic cells with tumor antigens. Methods Mol Biol. 2014;1139:41-4; Rolinski J, Hus I. Breaking immunotolerance of tumors: a new perspective for dendritic cell therapy. J Immunotoxicol. 2014 Oct; 11(4):311-8).

Preferred APCs according to the present invention are dendritic cells (DCs). In fact, it may be advantageous to combine at least one antigenic peptide or immunogenic compound of the present invention with DCs, since they are the most effective APCs and have been reported to be frequently functionally deficient in cancer patients. DCs can be easily isolated by a person skilled in the art, both from healthy matched donors (i.e. DCs are HLA-associated) and from the patient himself, provided that they are functional (i.e. DCs are autologous), for example, either by simple isolation from peripheral blood, or by derivation from peripheral blood cells such as CD14+ monocytes or CD34+ hematopoietic progenitor cells (Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med. 2004 May;10(5):475-80). DCs can indeed be distinguished from other peripheral blood cells by their surface markers such as S100, p55, CD83 and/or OX62, and thus can be isolated and purified with these markers using cell culture techniques well known in the art. areas.

Nucleic acids encoding antigenic peptides and host cells containing nucleic acids

According to a further aspect, the present invention also provides a nucleic acid encoding an antigenic peptide of the present invention, a polypeptide of formula (I) as disclosed above, or an immunogenic compound of the present invention, wherein the immunogenic compound is a peptide or protein. In particular, preferred embodiments of the antigenic peptide as described above are also applicable to the nucleic acids of the present invention. For example, the antigenic peptide encoded by the nucleic acid preferably consists of or includes an amino acid sequence as specified in any of SEQ ID Nos. 1 to 580. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as indicated in any of SEQ ID NOs 1-160, 162-253 and 255-580 are more preferred. For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524 , are even more preferable. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524 are even more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 87, 97, and 194 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 194, 220, 254 or 255 are particularly preferred. Also preferred are combinations, namely combinations of nucleic acids encoding different antigenic peptides according to the invention.

Nucleic acids are preferably single-stranded, double-stranded or partially double-stranded nucleic acids, preferably selected from genomic DNA, cDNA, RNA, antisense DNA, antisense RNA, complementary RNA/DNA sequences, with or without expression elements, mini- genes, gene fragments, regulatory elements, promoters, as well as their combinations.

The possibility of delivering a nucleic acid, for example, ribonucleic acid (RNA) into a cell, both in vitro, in vivo, in situ and ex vivo, for the purpose of subsequent intracellular translation of the nucleic acid and synthesis of the encoded protein of interest, is of great interest in the field of therapy and diagnostics and biological research. The delivery and functioning of the non-integrative polynucleotide are of particular importance. Accordingly, nucleic acids that are not incorporated into host chromosomes, such as mRNA, are preferred. In general, nucleic acids, such as mRNA, can be optimized for expression of an antigenic peptide of the invention, for example, using methods known in the art, such as codon optimization. Additionally, the nucleic acid may be modified, for example, to increase stability, increase durability and/or enhance expression of the antigenic peptide of the invention. Accordingly, an optimized or modified mRNA (mmRNA) that encodes the antigenic peptide of the present invention is preferred. mmRNAs differ from wild-type mRNAs in their functional and/or structural characteristics regarding optimal delivery of the mRNA and/or optimal expression of the antigenic peptide of the invention (for example, as disclosed in WO 2013/151672 A2, WO 2013/101690 A1, WO 2013/052523 A , which are incorporated herein by reference). In general, nucleic acids can be delivered "isolated" or together with a carrier, for example, a cationic carrier. Cationic carriers (positively charged) usually combine readily with nucleic acids, which are negatively charged. The carrier can be of any type, including, for example, polymers, proteins, lipids and nanoparticles. Cationic lipids and nanoparticles (particularly lipid nanoparticles, LNPs) are preferred for the delivery of nucleic acids. Thus, the present invention also relates to nucleic acids, as disclosed herein, associated with a carrier (eg, a lipid, more specifically a cationic lipid or LNP).

In some embodiments, the nucleic acid molecule may be a vector. The term "vector" as used in the context of the present invention refers to a nucleic acid molecule, preferably an artificial nucleic acid molecule, that is, a nucleic acid molecule that does not exist in nature. A vector in the context of the present invention is suitable for inserting and storing a nucleic acid sequence. Such vectors may be storage vectors, expression vectors, cloning vectors, transfer vectors, etc. A storage vector is a vector that provides proper storage of a nucleic acid molecule. Thus, the vector may include a sequence corresponding to, for example, a desired antigenic peptide of the present invention. An expression vector can be used to produce expression products such as RNA, for example mRNA, or peptides, polypeptides or proteins. For example, an expression vector may include sequences necessary for transcription of a portion of the vector sequence, such as a promoter sequence. A cloning vector is typically a vector that includes a cloning site that can be used to insert nucleic acid sequences into the vector. The cloning vector may be, for example, a plasmid vector or a bacteriophage vector. The transfer vector may be a vector suitable for transferring nucleic acid molecules into cells or organisms, such as a viral vector. The vector in the context of the present invention may be, for example, an RNA vector or a DNA vector. Preferably the vector is a DNA molecule. For example, a vector as used herein includes a cloning site, a selection marker such as an antibiotic resistance factor, and a vector propagation sequence such as an origin of replication. Preferably, the vector in the context of the present application is a plasmid vector. A preferred vector is a vector for expression in bacterial cells. More preferably, the vector is useful for expression in so-called "live bacterial vaccine vectors" in which live bacterial cells (such as bacteria or their spores, eg endospores, exospores or microbial cysts) can function as vaccines. Preferred examples of such vectors are described in Silva et al., Live bacterial vaccine vectors: an overview; Braz J Microbiol. 2015 Mar 4;45(4):1117-29.

The nucleic acids encoding the antigenic peptides of the present invention may be in the form of isolated nucleic acids or nucleic acids cloned into plasmids or viral vectors (Tregoning and Kinnear, Using Plasmids as DNA Vaccines for Infectious Diseases. Microbiol Spectr. 2014 Dec; 2(6) doi: 10.1128/microbiolspec.PLAS-0028-2014), the latter are particularly preferred. Examples of suitable viral vectors of the present invention include, but are not limited to, retroviral, adenoviral, adeno-associated viral vectors (AAV), herpes viral and poxviral vectors. It is within the competence of one skilled in the art to clone nucleic acid into a plasmid or viral vector using standard recombinant technologies.

According to a further aspect, the present invention also relates to a host cell comprising a nucleic acid of the present invention. Also preferred are combinations thereof, more particularly host cells comprising various nucleic acids of the present invention, for example encoding various antigenic peptides of the present invention.

Preferably, the nucleic acids contained in the host cell are a vector. Preferably, the host cell is a bacterial cell. Such a host cell may preferably be used to produce an antigenic peptide of the present invention or an immunogenic peptide of the present invention. Moreover, such a host cell can also be an active component of the vaccine.

Preferably the host cell is a bacterial cell, more preferably a bacterial cell of the intestinal microflora. The term "gut microflora bacterial cell" refers to bacteria living in the (human) intestine.

Such a host bacterial cell may serve as a “living bacterial vaccine vector,” with live bacterial cells (such as bacteria or bacterial spores, such as endospores, exospores, or microbial cysts) serving as vaccines. Preferred examples of such cells are described in da Silva et al., Live bacterial vaccine vectors: an overview; Braz J Microbiol. 2015 Mar 4; 45(4):1117-29.

Bacterial cells (such as bacteria or bacterial spores, such as endospores, exospores or microbial cysts), more specifically the bacterial species living in the intestines (in general), have the advantage of being able to induce a stronger immune response than (poly)peptides or the nucleic acids they contain.

Alternatively, the bacterial cells, in particular the intestinal bacterial cells, of the present invention may be in the form of probiotics, that is, in the form of live intestinal bacteria, which can thus be used as a dietary supplement due to their beneficial health effects. They may, for example, be lyophilized into granules, pills or capsules, or mixed directly with dairy products before consumption.

Nanoparticles comprising an antigenic peptide or immunogenic compound

According to a further aspect, the present invention also provides a nanoparticle, including, in particular, a nanoparticle loaded with at least one antigenic peptide of the present invention, or at least one immunogenic compound of the present invention;

and optionally an adjuvant.

In particular, preferred antigenic peptide variants as disclosed herein are also applicable to such nanoparticles of the present invention. For example, the antigenic peptide loaded on the nanoparticle or included in the immunogenic compound loaded on the nanoparticle preferably consists of or includes an amino acid sequence as defined in any of SEQ ID Nos. 1 to 580 and 861 to 887, such as an antigenic peptide , consisting of or including an amino acid sequence, as specified in any of SEQ ID Nos. 1 to 580. For example, antigenic peptides of the present invention, consisting of or including an amino acid sequence, as specified in any of SEQ ID NOs 1- 160, 162-253 and 255-580 are more preferred. For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524 , are even more preferable. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524 are even more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 87, 97, and 194 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 194, 220, 254 or 255 are particularly preferred. Also preferred are combinations thereof, more specifically nanoparticles loaded with various antigenic peptides of the present invention (or corresponding immunogenic compounds).

Nanoparticles, in particular for use as vaccines, are known in the art and are described, for example, in Shao et al., Nanoparticle-based immunotherapy for cancer, ACS Nano 2015, 9(1):16-30; Zhao et al., Nanoparticle vaccines, Vaccine 2014, 32(3):327-37; and Gregory et al., Vaccine delivery using nanoparticles, Front Cell Infect Microbiol. 2013, 3:13, doi: 10.3389/fcimb.2013.00013. eCollection 2013, Review. In particular, the nanoparticle is used to deliver an antigenic peptide (or an immunogenic compound/polypeptide/protein/nucleic acid comprising an antigenic peptide) and may optionally act as an adjuvant. An antigenic peptide (an immunogenic compound/polypeptide/protein/nucleic acid comprising an antigenic peptide) is typically either encapsulated within a nanoparticle or bound/decorated onto the surface of the nanoparticle (“coating”). Compared with traditional approaches, nanoparticles can protect the loaded substance (antigen/adjuvant) from the biological environment, increase lifespan, minimize systemic toxicity, enhance delivery to APCs, or even directly trigger the activation of TAA-specific T cells. Preferably, the nanoparticles have a size (diameter) of no more than 300 nm, more preferably no less than 200 nm, and more preferably no more than 200 nm, and even more preferably no more than 100 nm. Such nanoparticles are adequately protected from uptake by phagocytes, have good structural integrity in the bloodstream and a long circulation time, are able to accumulate at sites of tumor growth, and are able to penetrate deep into tumor tissue.

Examples of nanoparticles are polymeric nanoparticles such as poly(ethylene glycol) (PEG) and poly(D,L-lactide-co-glycolic acid) (PLGA); inorganic nanoparticles such as gold nanoparticles, iron oxide beads, iron oxide and zinc oxide nanoparticles, carbon nanotubes and mesoporous silica nanoparticles; liposomes; such as cationic liposomes; immunostimulating complexes (ISCOM); virus-like particles (VLP); and self-organizing proteins.

Polymer nanoparticles are nanoparticles based on/or containing polymers, such as poly(D,L-lactide-co-glycolide) (PLG), poly(D,L-lactide-co-glycolic acid)(PLGA), poly( γ-glutamic acid) (γ-PGA), poly(ethylene glycol) (PEG), and polystyrene. Polymeric nanoparticles can capture an antigen (eg, an antigenic peptide or a (poly)peptide including it) or bind to or conjugate an antigen (eg, an antigenic peptide or a (poly)peptide including it).

Polymer nanoparticles can be used for delivery, for example, to specific cells or for sustained release of antigen due to their slow biodegradation rate. For example, g-PGA nanoparticles can be used to encapsulate hydrophobic antigens. Polystyrene nanoparticles can form conjugates with a variety of antigens because they can be surface-modified with various functional groups. Polymers such as poly(L-lactic acid)(PLA), PLGA, PEG and natural polymers such as polysaccharides can also be used to synthesize hydrogel nanoparticles, which are a type of hydrophilic three-dimensional polymer nanoparticles. Nanogels have favorable properties including flexible cell size, large surface area for multivalent conjugation, high water content, and also high antigen loading capacity. Accordingly, the preferred nanoparticle is a nanogel such as a chitosan nanogel. Preferred polymer nanoparticles are those based on or containing PEG and PLGA.

Inorganic nanoparticles are nanoparticles based on or including inorganic compounds; Examples of such nanoparticles are gold nanoparticles, iron oxide nanoparticles, iron oxide zinc oxide nanoparticles, carbon nanoparticles (eg, carbon nanotubes) and mesoporous silicon nanoparticles. Inorganic nanoparticles provide rigid structure and controlled synthesis. For example, gold nanoparticles can be synthesized in various shapes such as spheres, rods, cubes. Inorganic nanoparticles can be surface modified, for example, with hydrocarbons. Carbon nanoparticles provide good biocompatibility and can be obtained, for example, in the form of nanotubes or (microsporic) spheres. For example, multiple copies of an antigenic peptide of the present invention (or a poly(peptide) comprising it) can be conjugated to carbon nanoparticles, such as carbon nanotubes. Mesoporous carbon nanoparticles are preferred for oral administration. Silicon-based nanoparticles (SiNPs) are also preferred. SiNPs are biocompatible and show excellent properties for selective tumor targeting and vaccine delivery. A large number of silanol groups on the surface of SiNPs can be added to further modify and impart additional functionality to the particle, such as the ability to recognize cells, absorb specific biomolecules, improve interaction with cells, as well as enhancing cellular uptake. Microsporic nanoparticles are the most preferred.

Liposomes are usually formed by phospholipids such as 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). In general, cationic liposomes are preferred. Liposomes are self-assembled from a phospholipid bilayer shell and an aqueous core. Liposomes can be prepared in the form of unilamellar vesicles (having a single phospholipid bilayer) or in the form of multilamellar vesicles (having several concentric phospholipid layers separated by layers of water). Accordingly, antigens can be encapsulated in the core or sandwiched between different layers/shells. Preferred liposome systems approved for use in humans include the Inflexal® V and Epaxal® systems.

Immunostimulatory complexes (ISCOMs) are basket-like particles, approximately 40 nm in diameter, that are colloidal saponin-containing micelles, for example, formed from the saponin adjuvant Quil-A, cholesterol, phospholipids and (poly)peptide antigen (such as antigen peptide or polypeptide comprising it). Such spherical particles can capture antigens through polar interactions. Two types of ISCOMs have been described, both of which include cholesterol, a phospholipid (usually either phosphatidylethanolamine or phosphatidylcholine) and a saponin (such as Quil-A).

Virus-like particles (VLP abbreviation for Virus-like particles) are self-assembled nanoparticles formed during the self-assembly of biocompatible capsid proteins. Due to this naturally optimized particle size and repeating structural order, virus-like particles can induce a strong immune response. Virus-like particles can be derived from a variety of viruses, the size of which varies from 20 nm to 800 nm and is usually in the range of 20-150 nm. Virus-like particles can be engineered to express additional peptides or proteins, either by fusing these peptides/proteins to the particle or by expressing multiple antigens. Moreover, antigens can be chemically linked to the viral surface to form a bioconjugate of VLPs.

Examples of self-assembling proteins are ferritin and the main vault protein (MVP abbreviation from the English. Main Vault Protein). Ferritin is a protein that can self-assemble into a sphere-like structure measuring 10 nm in size. Ninety-six MVP units can self-assemble into a barrel-shaped, domed nanoparticle measuring approximately 40 nm wide and 70 nm long. Antigens genetically fused to a minimal interaction domain can be packaged into vaulted nanoparticles through a self-assembly process when mixed with MVP. Accordingly, an antigen (such as an antigenic peptide of the present invention or a polypeptide containing it) can be fused to a self-assembling protein or fragment/domain thereof, such as an MVP minimal interaction domain. Accordingly, the present invention relates to a fusion protein comprising a self-assembling protein (or fragment/domain thereof) and an antigenic peptide of the present invention.

In general, preferred examples of nanoparticles (NPs) include iron oxide particles, polystyrene microspheres, poly(γ-glutamic acid) (γ-PGA) nanoparticles, iron oxide-zinc oxide nanoparticles, cationized gelatin nanoparticles, Pluronic-stabilized poly(propylene sulfide) nanoparticles ( PPS), PLGA NPs, (cationic) liposomes, (pH-dependent) polymer micelles, PLGA, cancer cell membrane coated PLGA, lipid calcium phosphate nanoparticles (LCP), protamine hyaluronic acid liposomal nanoparticles (LPN) , polystyrene latex beads, magnetic beads, iron-dextran particles and nanocrystals - quantum dots.

Preferably, the nanoparticles further include an adjuvant, for example a toll-like receptor (TLR) agonist. Thus, an antigenic peptide (or an immunogenic compound/polypeptide/protein/nucleic acid comprising an antigenic peptide) can be delivered to antigen presenting cells (APCs), such as dendritic cells (DCs), along with an adjuvant. The adjuvant may be encapsulated within the nanoparticle or bound/conjugated to its surface, preferably in a similar manner to the antigenic peptide.

The most preferred adjuvants are polynosinic:polycytidylic acid (also referred to as "poly I:C") and/or its derivative poly-ICLC. Poly I:C is an unconjugated double-stranded RNA in which one strand is a polymer of inosinic acid and the other is a polymer of cytidylic acid. Poly I:C is an immunostimulatory agent known to interact with the toll-like receptor (TLR3). Poly I:C is structurally similar to double-stranded RNA, which is a “natural” stimulator of TLR3. Accordingly, poly I:C can be considered a synthetic analogue of double-stranded RNA. Poly-ICLC is a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid and poly-L-lysine double-stranded RNA. Similar to poly I:C, poly:ICLC is a ligand for TLR3. Poly I:C and poly-ICLC typically stimulate the release of cytotoxic cytokines. A preferred example of poly-ICLC is ^Hiltonol® .

Pharmaceutical compositions

According to a further aspect, the present invention also provides a pharmaceutical composition comprising at least one of the following:

- an antigenic peptide of the present invention, as disclosed herein,

- an immunogenic compound of the present invention, as disclosed herein,

- nanoparticles of the present invention, as disclosed in the present description,

- cells according to the present invention, as disclosed in the present description,

- a nucleic acid of the present invention, as disclosed herein, and/or

- a host cell of the present invention, as disclosed herein,

and optionally one or more pharmaceutically available excipient or carrier.

In particular, preferred embodiments of the antigenic peptide as described above are also applicable to such pharmaceutical compositions of the present invention. For example, an antigenic peptide, as part of a pharmaceutical composition, or an antigenic peptide, as part of an immunogenic compound, nanoparticle, or cell, or nucleic acid, or host cell included in a pharmaceutical composition, preferably consists of or includes an amino acid sequence as specified in any of SEQ ID NOs 1 to 580 and 861 to 887, such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID Nos 1 to 580. For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 1-160, 162-253 and 255-580 are more preferred. For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524 , are even more preferable. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524 are even more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 87, 97, and 194 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 194, 220, 254 or 255 are particularly preferred.

In addition, combinations thereof, more particularly pharmaceutical compositions containing various antigenic peptides of the present invention, are preferred. For example, the pharmaceutical composition may contain

(a) at least two different antigenic peptides of the present invention;

(b) at least two different immunogenic compounds of the present invention;

(c) at least two different nanoparticles of the present invention; and/or

(d) at least two different nucleic acids of the present invention.

Accordingly, the present invention relates to a pharmaceutical composition comprising (at least) one antigenic peptide of the present invention, as disclosed herein. In addition, the present invention also relates to a pharmaceutical composition containing (at least) one immunogenic compound of the present invention, as disclosed herein. In addition, the present invention also relates to a pharmaceutical composition containing (at least) one nanoparticle of the present invention, as disclosed herein. In addition, the present invention also relates to a pharmaceutical composition containing (at least) one cell of the present invention, as disclosed herein. In addition, the present invention also relates to a pharmaceutical composition containing (at least) one nucleic acid of the present invention, as disclosed herein. In addition, the present invention also relates to a pharmaceutical composition containing (at least) one host cell of the present invention, as described herein.

Preferably, the pharmaceutical composition contains at least two different antigenic peptides of the present invention.

In particular, the present invention relates to a pharmaceutical composition containing a first antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a human tumor antigen fragment BIRC5; and a second antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of a fragment of the human tumor antigen FOXM1. Preferably, the first antigenic peptide consists of or includes a microbiotic variant sequence of the BIRC5 (human reference peptide) fragment "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 30, 31 or 32, and the second antigenic peptide consists of or includes a microbiotic variant sequence of the FOXM1 (human reference peptide) fragment "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including amino acid sequence as specified in SEQ ID NO: 220 or 868. Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including SEQ ID NO: 32, and an antigenic peptide consisting of or including SEQ ID NO: 220.

In particular, the present invention also relates to a pharmaceutical composition comprising a first antigenic peptide of the present invention that consists of or includes a microbiotic sequence variant of a human tumor antigen fragment BIRC5, and a second antigenic peptide of the present invention that consists of or includes a sequence variant fragment of human tumor antigen IL13RA2. Preferably, the first antigenic peptide of the present invention consists of or includes a microbiotic variant sequence of the BIRC5 (human reference peptide) fragment "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or including an amino acid sequence, as defined in SEQ ID NO: 30, 31 or 32, and the second antigenic peptide consists of or includes a microbiotic variant sequence of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 254, 255, 878 or 879. Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 32, and an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 225.

In particular, the present invention also relates to a pharmaceutical composition containing a first antigenic peptide of the present invention, which consists of or includes a microbiotic sequence variant of a fragment of a human tumor antigen FOXM1, and a second antigenic peptide of the present invention, which consists of or includes itself a microbiotic variant of the sequence of a fragment of the human tumor antigen IL13RA2. Preferably, the first antigenic peptide of the present invention consists of or includes a microbiotic variant sequence of the FOXM1 (human reference peptide) fragment "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including an amino acid sequence, as defined in SEQ ID NO: 220 or 868, and the second antigenic peptide consists of or includes a microbiotic variant sequence of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 254, 255, 878 or 879. Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including an amino acid sequence , as set forth in SEQ ID NO: 32, and an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 255.

Preferably, the pharmaceutical composition includes at least three different antigenic peptides of the present invention.

In particular, the present invention also relates to a pharmaceutical composition containing a first antigenic peptide of the present invention, which consists of or includes a microbiotic sequence variant of a human tumor antigen fragment BIRC5, and a second antigenic peptide of the present invention, which consists of or includes itself a microbiotic variant sequence of a human tumor antigen fragment FOXM1, and a third antigenic peptide of the present invention which consists of or includes a microbiotic variant sequence of a human tumor antigen fragment IL13RA2. Preferably, the first antigenic peptide of the present invention consists of or includes a microbiotic variant sequence of the BIRC5 (human reference peptide) fragment "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or including an amino acid sequence, as indicated by SEQ ID NO: 30, 31 or 32; a second antigenic peptide of the present invention which consists of or includes a microbiotic variant sequence of a human tumor antigen fragment FOXM1 (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including an amino acid sequence as specified in any SEQ ID NO: 220 or 868; and a third antigenic peptide that consists of or includes a microbiotic variant sequence of the human tumor antigen IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in any SEQ ID NO: 254, 255, 878, or 879. Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 30, also an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 220, and also an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 255 .

It should be understood that the pharmaceutical composition may also contain - instead of the above preferred combinations of antigenic peptides - a corresponding combination of immunogenic compounds of the present invention, a corresponding combination of nanoparticles of the present invention, or a corresponding combination of nucleic acids of the invention.

Preferably, the pharmaceutical composition further contains one or more pharmaceutically available excipient or excipient.

The pharmaceutical composition of the invention may be in any form suitable for carrying out the purposes of the present invention. For example, the composition may be in a form suitable for parenteral, enteral or topical administration, such as a liquid suspension, a solid dosage form (granules, pills, capsules or tablets), or a paste or gel. The selection of the appropriate form of the composition depending on the intended field of application is within the competence of one skilled in the art.

The composition claimed in accordance with the present invention may additionally contain other active agents, for example, those that can enhance the effects of the antigenic peptide or immunogenic compound. Alternatively, the composition may not contain other active ingredients (ie, other than an antigenic peptide of the present invention, an immunogenic compound of the present invention, a nanoparticle of the present invention, a cell of the present invention, and/or a host cell of the present invention).

The pharmaceutical composition as defined herein is preferably an immunogenic composition, that is, a composition that is capable of inducing, enhancing, prolonging and maintaining an immune response. This can be achieved by an antigenic peptide of the present invention or by an immunogenic compound of the present invention contained in said composition. Preferably, the pharmaceutical composition further contains one or more immunostimulating compounds. A pharmaceutical composition, specifically an immunogenic composition, may be referred to herein as a "vaccine composition".

Preferably, the pharmaceutical composition also contains at least one immunostimulating agent, more specifically capable of enhancing, potentiating, prolonging and maintaining the immune response mediated by the antigenic peptide. Preferred immunostimulatory agents of the present invention include, but are not limited to, immunostimulatory agents, antigen presenting cells, and combinations thereof. Preferably, the immunostimulating agent is an immune adjuvant or an antigen presenting cell (APC).

Preferably, the immunostimulating agent is an immune adjuvant. Some immune adjuvants have the ability to assist and prolong the interaction between antigen and the immune system, while others are capable of recruiting or activating natural immune cells and thus inducing an adaptive immune response. Adjuvants belonging to the first category include, but are not limited to, mineral compounds such as aluminum, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide; and oil emulsions such as paraffin oil, vegetable oil, Freund's complete/incomplete adjuvant (FCA/FIA), saponins (eg from plants such as Quillaja, soybean, Polygala senega). Adjuvants belonging to the latter category include, but are not limited to, immune stimulating complexes (ISCOMs) such as cytokines (eg, GM-CSF; interleukins such as IL-1, IL-2, IL6, IL8, or IL12; necrosis factor tumors (TNFs), such as TNFα or TNFβ; interferons IFNS, such as IFNα, IFNβ, IFNγ or IFNδ, etc); toll-like receptor (TLRs) ligands such as imiquimod, resicmivod or MPL; exosomes, such as exosomes isolated from dendritic cells (DCs) or from tumor cells; bacterial products such as heat shock proteins (HSPs) such as gp96, hsp90, hsp70, calreticulin, hsp110, hsp170), pathogen-associated molecular patterns (PAMPs), trehalose dimycolate (TDM), muramyl dipeptide (MDP), polysaccharides ( PLS), such as polysaccharide-K.

More preferably, the immune adjuvant is a protein/peptide having immunostimulatory properties, such as providing stimulation of CD4+ Th1 cells, as disclosed herein. A preferred example of such compounds are a non-tumor antigen that induces immune memory or non-specific help, or is a specific helper protein of tumor origin, such as tetanus helper protein, keyhole limpet hemocyanin and PADRE peptide, as disclosed herein. Another preferred example is a specific helper peptide of tumor origin, which may be presented by MHC II, in particular HLA-DR, HLA-DP or HLA-DQ, such as sequence fragments of related overexpressed tumor antigens such as HER2, NY-ESO-1, hTERT or IL13RA2, as disclosed herein above. In particular, the immune adjuvant may be an HHD-DR3 peptide with the sequence MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). This peptide is another example of a helper peptide (having immunostimulatory properties) that is preferred in the context of the present invention. Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh N, Raghava GP (2003) MHCBN: a comprehensive database of peptides that do or do not bind to MHC. Bioinformatics 19: 665- 666). Other examples of preferred adjuvants, in particular helper peptides, are UCP2 peptide (for example, as disclosed in WO 2013/135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15; 18(22):6284-95) and BIRC5 peptide (eg, as disclosed in EP 2119726 A1 or Widenmeyer et al., Int J Cancer. 2012 Jul 1; 131(1):140-9). The most preferred helper peptide is UCP2 (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859).

Preferably, the pharmaceutical composition contains at least two different antigenic peptides of the present invention and a helper peptide, preferably UCP2 peptide (SEQ ID NO: 859).

Preferably, the pharmaceutical composition contains a first antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a fragment of a human tumor antigen BIRC5, a second antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a fragment of a human tumor antigen FOXM1 and a helper peptide, preferably UCP2 (SEQ ID NO: 859). More preferably, the pharmaceutical composition contains a first antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of the human tumor antigen fragment BIRC5 (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or comprising an amino acid sequence as defined in any of SEQ ID NO: 30, 31 or 32; a second antigenic peptide of the present invention which consists of or includes a microbiotic variant sequence of a human tumor antigen fragment FOXM1 (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 220 or 868; and a helper peptide, preferably UCP2 peptide (SEQ ID NO: 859). Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including SEQ ID NO: 32; an antigenic peptide consisting of or including SEQ ID NO: 220; and UCP2 helper peptide (SEQ ID NO: 859).

Also preferably, the pharmaceutical composition contains a first antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of a human tumor antigen fragment BIRC5, a second antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of a human tumor antigen fragment IL13RA2, and a helper peptide, preferably UCP2 peptide (SEQ ID NO: 859). More preferably, the pharmaceutical composition contains a first antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of the human tumor antigen fragment BIRC5 (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or comprising an amino acid sequence as defined in any of SEQ ID NO: 30, 31 or 32; a second antigenic peptide of the present invention which consists of or includes a microbiotic variant sequence of a fragment of a human tumor antigen IL13RA2 (a second antigenic peptide of the present invention which consists of or includes a microbiotic variant sequence of a fragment of a human tumor antigen) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or including the amino acid sequence as defined in any of SEQ ID NO: 254, 255, 878 or 879; and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including SEQ ID NO: 32; an antigenic peptide consisting of or including SEQ ID NO: 225; and UCP2 helper peptide (SEQ ID NO: 859).

Also preferably, the pharmaceutical composition contains a first antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a fragment of human tumor antigen FOXM1; a second antigenic peptide of the present invention, which consists of or includes a microbiotic sequence variant of a fragment of the human tumor antigen IL13RA2; and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859). More preferably, the pharmaceutical composition contains a first antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of the human tumor antigen fragment FOXM1 (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in any of SEQ ID NO: 220 or 868; a second antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a fragment of human tumor antigen IL13RA2 (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 254, 255, 878 or 879; and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including SEQ ID NO: 220; an antigenic peptide consisting of or including SEQ ID NO: 225; and UCP2 helper peptide (SEQ ID NO: 859).

More preferably, the pharmaceutical composition contains at least three different antigenic peptides of the present invention and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859).

In particular, the pharmaceutical composition may contain a first antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of a human tumor antigen fragment BIRC5, a second antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of a tumor antigen fragment human FOXM1, a third antigenic peptide of the present invention, which consists of or includes a microbiotic sequence variant of a fragment of the human tumor antigen IL13RA2 and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Even more preferably, the pharmaceutical composition contains a first antigenic peptide of the present invention that consists of or includes a microbiotic variant sequence of the human tumor antigen fragment BIRC5 (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide, consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 30, 31 or 32; a second antigenic peptide of the present invention which consists of or includes a microbiotic variant sequence of a human tumor antigen fragment FOXM1 (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 220 or 868; and a third antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a human tumor antigen fragment IL13RA2 (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID NO: 254, 255, 878 or 879; and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Even more preferably, the pharmaceutical composition contains an antigenic peptide consisting of or including SEQ ID NO: 30; an antigenic peptide consisting of or including SEQ ID NO: 220; an antigenic peptide consisting of or including SEQ ID NO: 225 and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859).

The most preferred immune adjuvants are polynosinic:polycytidylic acid (also referred to as "poly I:C") and/or its derivative poly-ICLC. Poly I:C is an unconjugated double-stranded RNA in which one strand is a polymer of inosinic acid and the other a polymer of cytidylic acid. Poly I:C is an immunostimulatory agent known to interact with toll-like receptor 3 (TLR3). Poly I:C is structurally similar to double-stranded RNA, which is a “natural” stimulator of TLR3. Accordingly, poly I:C can be considered a synthetic analogue of double-stranded RNA. Poly-ICLC is a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA. Similar to poly I:C, poly:ICLC is a ligand for TLR3. Poly I:C and poly-ICLC typically stimulate the release of cytotoxic cytokines. A preferred example of poly-ICLC is ^Hiltonol® .

More preferably, the adjuvant is a Montanide, such as Montanide ISA VG and/or Montanide ISA 720 VG. Such adjuvants form standard water-in-oil emulsions when mixed with a water-based antigen medium. Montanide ISA 51 VG is based on a mixture of the surfactant mannide monooleate and mineral oil, while Montanide ISA 720 VG uses non-mineral oil (Aucouturier J, Dupuis L, Deville S, Ascarateil S, Ganne V. Montanide ISA 720 and 51: a new generation of water in oil emulsions as adjuvants for human vaccines. Expert Rev Vaccines. 2002 Jun; 1(1):111-8; Ascarateil S, Puget A, Koziol M-E. Safety data of Montanide ISA 51 VG and Montanide ISA 720 VG, two adjuvants dedicated to human therapeutic vaccines. Journal for Immunotherapy of Cancer. 2015; 3(Suppl 2): P428. doi:10.1186/2051-1426-3-S2-P428).

It is also preferred that the immunostimulating agent is an antigen presenting cell (APC). APCs are of particular interest because their primary function is to process antigens and present them on the cell surface of T cells of the immune system to initiate and modulate T cell responses in vivo. In the composition claimed in accordance with the present invention, it is preferable that the APCs are loaded with the antigenic peptide(s) and/or immunogenic compound(s) of the present invention, which can be accomplished by reacting the APCs in vitro with said antigenic peptide(s) and/or or immunogenic compound(s) (Rizzo et al., Methods Mol Biol. 2014; 1139:41-4; Rolinski and Hus, J Immunotoxicol. 2014 Oct; 11(4):311-8).

Preferably, the APC is a dendritic cell (DC). DCs are the most effective APCs and are reported to be frequently functionally deficient in patients with cancer. DCs can be easily isolated by a person skilled in the art, both from healthy matched donors (i.e. DCs are HLA-associated) and from the patient himself, provided that they are functional (i.e. DCs are autologous), for example, either either by simple isolation from peripheral blood or by clearance from peripheral blood cells such as CD14+ monocytes or CD34+ hematopoietic progenitor cells (Emens et al., 2008). DCs can indeed be distinguished from other peripheral blood cells by their surface markers such as S100, p55, CD83 and/or OX62, and thus can be isolated and purified with these markers using cell culture techniques well known in the art. areas.

According to a preferred embodiment of the invention, the pharmaceutical composition may further comprise at least an anti-cancer drug agent. Said drug agent is thus preferably capable of preventing and/or treating the same type of cancer as the antigenic peptide of the present invention. Preferably, the anticancer drug agent is selected from the group consisting of antibodies, tumor cell lysates, chemotherapeutic agents, radiotherapeutic agents, immune checkpoint modulators, and combinations thereof.

Antibodies are particularly preferred for cancer treatment because they can both bind to specific antigens on the surface of cancer cells, thereby targeting therapy directly to the tumor (such antibodies are referred to as antitumor targeted antibodies), and block immune checkpoint regulation which are impaired in cancer (such antibodies are referred to as immunomodulatory antibodies). The purpose of the latter type of antibodies is to suppress immune resistance to cancer cells that can be observed against T cells that are specific for tumor antigens. Indeed, it is well known in the art that, under natural physiological conditions, immune checkpoints play a key role in maintaining autotolerance (ie, preventing autoimmune reactions) and protecting tissues from damage when the immune system fights a pathogenic infection. However, in cancer, the regulation of immune checkpoint expression may be dysregulated, which is an important mechanism in the development of immune resistance. This resistance is observed in melanoma, ovarian cancer, lung cancer, glioblastoma, breast cancer and pancreatic cancer and is associated with the PD-L1 checkpoint (Konishi et al., B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004 Aug 1; 10(15):5094-100; Ghebeh et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006 Mar; 8(3): 190-8; Hino et al., Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010 Apr 1; 116(7): 1757-66). Other examples of immune checkpoints include, but are not limited to, PD-L2, PD-1, CD80, CD86, CTLA-4, B7H3, B7H4, PVR, TIGIT, GAL9, LAG-3, GITR, CD137, TIM3, VISTA, VISTA -R (Pico de et al., Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med. 2015 Aug; 21(8):482-91; Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22; 12(4):252-64).

For the purposes described above, antibodies are used both in the form of isolated monoclonal antibodies (that is, unconjugated) and in the form of antibodies conjugated to other molecules that may be radioactive or toxic.

Examples of well-known monoclonal antitumor targeted antibodies that are used in cancer immunotherapy include, but are not limited to, alemtuzumab (chronic lymphocytic leukemia), bevacizumab (colorectal cancer, glioblastoma multiforme, cervical cancer, lung cancer, kidney cancer), brentuximab/vedotin ( lymphoma), blinatumumab (acute lymphoblastic leukemia), catumaxomab (malignant ascites in EPCAM+ tumors), cetuximab (head and neck cancer, colorectal cancer), denosumab (breast, prostate and bone cancer), Gemtuzumab / ozogamicin (acute myeloid leukemia), ibritumomab/tiuxetan (non-Hodgkin's lymphoma), panitumumab (colorectal cancer), pertuzumab (breast cancer), obinutuzumab (chronic lymphocytic leukemia), ofatumumab (chronic lymphocytic leukemia), opilimumab (melanoma), ramucirumab (stomach and gastroesophageal cancer), rituximab ( chronic lymphocytic leukemia and non-Hodgkin's lymphoma), siltuximab (multifocal Castleman disease), tositumomab (non-Hodgkin's lymphoma) and trastuzumab (breast, stomach and esophageal cancer); while examples of immunomodulatory antibodies include, but are not limited to, ipilimumab (melanoma), which blocks the CTLA4-dependent immune checkpoint, nivolumab (melanoma, lung cancer), and prembrolizubmab (melanoma), which both block the PDCD1-dependent immune checkpoint, and MPDL3280A, MEDI4736, MEDI0680, and MSB0010718C, which all block PD-L1-dependent immune checkpoint therapy (Sharma and Allison, The future of immune checkpoint therapy. Science. 2015 Apr 3; 348(6230):56-61).

Other antibodies for cancer immunotherapy have been described et al., Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications. Oncoimmunology. 2015 Mar 2; 4(4):e1008814. eCollection 2015 Apr; Redman et al., Mechanisms of action of therapeutic antibodies for cancer. Mol Immunol. Oct 2015; 67(2 Pt A):28-45; Simpson and Caballero, Monoclonal antibodies for the therapy of cancer MC Proc. 2014; 8 (Suppl 4), as well as on the website where the entire antibody universe is presented (a list of therapeutic monoclonal antibodies approved or under review in the European Union or the United States is available at http://www.antibodysociety.org/ news/approved_mabs.php).

Tumor cell lysates can also be combined with the antigenic peptide(s) of the present invention. Tumor cells are indeed capable of initiating an immune response through the presentation of endogenous MHC-peptide complexes, as well as through host dendritic cells (DCs), which can process and present the antigen delivered by such lysates. This increases the range of antigens against which an immune response can be induced. Tumor cell lysates can be easily obtained by heat shock/or chemical treatment of tumor cells, and they can also be autologous (that is, isolated from the patient's body) or allogeneic (that is, isolated from the body of another subject).

Standard chemotherapeutic drugs and radiotherapeutic agents do not need further description here as they are described in detail in the literature, namely by Baskar et al. (Baskar et al., Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012; 9(3):193-9), Paci et al., (Paci et al., Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics. Eur J Cancer. 2014 Aug;50(12):2010-9) and Widmer et al. (Widmer et al., Review of therapeutic drug monitoring of anticancer drugs part two-targeted therapies. Eur J Cancer. 2014 Aug; 50(12):2020-36). A list of such drugs and agents is also available at cancer.gov (http://www.cancer.gov/about-cancer/treatment/drugs).

Preferably, the immune checkpoint modulator, which can be used in combination with an antigenic peptide as disclosed herein, is an activator or inhibitor of one or more immune checkpoint molecules selected from the group consisting of CD27, CD28, CD40, CD122, CD137, ОХ40, GITR, ICOS, A2AR, В7-Н3, В7-Н4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1, TIM-3, VISTA, SEACAM1, GARP, PS, CSF1R, CD94/ NKG2A, TDO, GITR, TNFR and/or FasR/DcR3; or an activator or inhibitor of one or more of their ligands.

More preferably, the immune checkpoint modulator is an activator of a (co)stimulatory checkpoint molecule or an inhibitor of an inhibitory checkpoint molecule, or a combination thereof. Accordingly, the immune checkpoint modulator is more preferably (a) an activator of CD27, CD28, CD40, CD122, CD137, OX40, GITR and/or ICOS or (b) an inhibitor of A2AR, B7-H3, B7-H4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1, PDL-1, PD-L2, TIM-3, VISTA, SEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, TNFR and/or FasR/DcR3.

Even more preferably, the immune checkpoint modulator is an inhibitory checkpoint molecule inhibitor (but preferably is not a stimulatory checkpoint molecule inhibitor). Accordingly, the immune checkpoint modulator is more preferably an inhibitor of A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, PDL-1, PD-L2, TIM-3, VISTA , CEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, TNFR and/or DcR3 or one or more ligands thereof.

Also preferably, the immune checkpoint modulator is an activator of a stimulatory or costimulatory checkpoint molecule (but preferably is not an activator of an inhibitory checkpoint molecule). Accordingly, the immune checkpoint modulator is more preferably an activator of CD27, CD28, CD40, CD122, CD137, OX40, GITR and/or ICOS or one or more ligands thereof.

Even more preferably, the immune checkpoint modulator is a modulator of the CD40 cascade, or the IDO cascade, or the LAG3 cascade, or the CTLA-4 cascade and/or the PD-1 cascade. More specifically, the immune checkpoint modulator is a modulator of CD40, LAG3, CTLA-4, PD-L1, PD-L2, PD-1 and/or IDO, more preferably, the immune checkpoint modulator is an inhibitor of CTLA-4, PD-L1 , PD-L2, PD-1, LAG3, and/or IDO or a CD40 activator, even more preferably, the immune checkpoint modulator is an inhibitor of LAG3, CTLA-4 and/or PD-1, and even more preferably, an immune checkpoint modulator dot represents a CTLA-4 and/or PD-1 inhibitor.

Thus, the checkpoint modulator for combination with the antigenic peptide can be selected from known modulators of the CTLA-4 cascade or the PD-1 cascade. Preferably, the checkpoint modulator for combination with an antigenic peptide, as disclosed herein, may be selected from known CTLA-4 cascade or PD-1 cascade modulators. Particularly preferably, the immune checkpoint modulator is a PD-1 inhibitor. Preferred inhibitors of the CTLA-4 cascade or PD-1 cascade include the monoclonal antibodies Yervoy ^® (Ipilimumab; Bristol Myers Squibb) and Tremelimumab (Pfizer/MedImmune) as well as Opdivo ^® (Nivolumab; Bristol Myers Squibb), Keytruda ^® (Pembrolizumab, also known as as Lambrolizumab or MK-3475; Merck), Imfinzi ^® (Durvalumab, also known as MEDI4736; MedImmune/AstraZeneca), Tecentriq ^® (Atezolizumab also known as MPDL3280A; Roche/Genentech), Pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; AstraZeneca), Bavencio ^® (Avelumab; Merck KGaA/Pfizer, also known as MSB-0010718C), MIH1 (Affymetrix), LY3300054 (Eli Lilly), and Spartalizumab (also known as PDR001; Novartis). The more preferred checkpoint inhibitors are CTLA-4 inhibitors such as Yervoy ^® (Ipilimumab; Bristol Myers Squibb) and Tremelimumab (Pfizer/MedImmune), as well as the PD-1 inhibitors Opdivo ^® (Nivolumab; Bristol Myers Squibb), Keytruda ^® (Pembrolizumab ; Merck), Pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; AstraZeneca), AMP-224 (PD-L2 Fc fusion protein; MedImmune).

Also preferably, the checkpoint modulator, for combination with an antigenic peptide as disclosed herein, is selected from the group consisting of Pembrolizumab, Ipilimumab, Nivolumab, Atezolizumab, Durvalumab, Tremelimumab, Avelumab, Spartalizumab, LAG525 (anti-LAG-3 monoclonal antibody), Epacadostat (also known as INCB24360; IDO inhibitor), Varlilumab (anti-CD27 monoclonal antibody), Urelumab (anti-CD137 monoclonal antibody), AMP-224 and CM-24 (anti-CEACAM1 monoclonal antibody).

The selection of a suitable immune anticancer drug agent for the purposes of the present invention is within the competence of one skilled in the art. For example, if the goal is the prevention or treatment of melanoma, it is preferable to use a melanoma cell lysate and/or the antibody ipilimumab together with a suitable antigenic peptide. Suitable antigenic peptides can be selected by (a) selecting a suitable tumor antigen for a particular cancer type, as known in the art and/or as disclosed herein in Table 1B, and (b) selecting a suitable antigenic peptide of the invention for the selected tumor antigen as previously described, for example in Table 1A.

The anticancer drug agent may also be administered in combination with the composition of the present invention, either simultaneously, separately or sequentially. If the composition and drug agent are administered separately or sequentially, they can be administered in different dosage forms.

Thus, according to another aspect, the invention relates to the composition of the invention and at least one anticancer drug agent, as described above, as a combination dosage form for simultaneous, separate or sequential administration. In other words, the invention provides the combined use of a composition according to the invention and at least one anticancer drug agent as described above, for simultaneous, separate or sequential administration.

Set of parts

According to a further aspect, the present invention also provides a set of parts (also referred to herein as a "kit") that contains at least one of the following:

- an antigenic peptide of the present invention, as disclosed herein,

- an immunogenic compound of the present invention, as disclosed herein,

- nanoparticles of the present invention, as disclosed in the present description,

- a cell according to the present invention, as disclosed in the present description,

- a nucleic acid of the present invention, as disclosed herein,

- a host cell of the present invention, as disclosed herein, and/or

- the pharmaceutical composition of the present invention, as disclosed in the present description.

In particular, preferred embodiments of the antigenic peptide as described above are also applicable to such a kit according to the present invention. For example, an antigenic peptide included in the kit, or an antigenic peptide in an immunogenic compound, nanoparticle, or cell, or nucleic acid, or host cell or pharmaceutical composition included in the kit preferably consists of or includes an amino acid sequence as specified in any of SEQ ID NOs 1 to 580 and 861 to 887, such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID Nos 1 to 580. For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 1-160, 162-253 and 255-580 are more preferred. For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524 , are even more preferable. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524 are even more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 87, 97, and 194 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 194, 220, 254 or 255 are particularly preferred.

Also preferred are combinations thereof, namely a set containing various antigenic peptides of the present invention. In particular, a set of parts according to the present invention may contain more than one component described above, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different components. For example, a set of parts of the present invention may contain at least two (for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10) different immunogenic compounds, at least two (for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10) antigenic peptide, at least two (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) different nanoparticles, at least two (for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10) different cells, at least two (for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10) different nucleic acids, at least two (for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10) different host cells, and/or at least two (for example, 2, 3 , 4, 5, 6, 7, 8, 9, or 10) various pharmaceutical compositions. Preferably, such various components within the set of parts as described above differ in the antigenic peptides claimed in accordance with the present invention, for example, one component refers to a first antigenic peptide and another component refers to a second antigenic peptide (different from the first antigenic peptide ). For example, the kit may contain at least two different immunogenic compounds of the present invention. For example, the kit may contain at least two different antigenic peptides of the present invention. For example, the kit may contain at least two different nanoparticles of the present invention. For example, the kit may contain at least two different nucleic acids of the present invention.

Preferred combinations of antigenic peptides of the present invention in a kit correspond to the preferred combinations of antigenic peptides of the present invention in a pharmaceutical composition as described above.

Thus, the present invention relates to a kit containing (at least one) antigenic peptide of the present invention, as disclosed herein. In addition, the present invention also relates to a kit containing (at least one) immunogenic compound of the present invention, as disclosed herein. In addition, the present invention also relates to a kit containing (at least one) nanoparticle of the present invention, as disclosed herein. In addition, the present invention also relates to a kit containing (at least one) cell of the present invention, as disclosed herein. In addition, the present invention also relates to a kit containing (at least one) nucleic acid of the present invention, as disclosed herein. In addition, the present invention also relates to a kit containing (at least one) host cell of the present invention, as disclosed herein.

The various components of a set of parts can be packaged in one or more containers. The components described above may be presented in lyophilized or dry form, or dissolved in a suitable buffer. The kit may also contain additional reagents, including, for example, preservatives, growth media and/or buffers for storage and/or reconstitution of the components described above, wash solutions and the like.

Thus, the present invention relates to a kit containing at least two, preferably three different antigenic peptides of the present invention, as disclosed herein (or immunogenic compounds, nanoparticles, nucleic acids, cells, etc., as described above that differ in antigenic peptide), and optionally a helper peptide such as UCP2 peptide, and/or an adjuvant such as MONTANIDE ISA 51. Various antigenic peptides (or immunogenic compounds, nanoparticles, nucleic acids, cells, etc. , as described above, which differ in antigenic peptide) can be packaged in one or several containers. For example, the kit may include (one) container containing a first antigenic peptide as disclosed herein and a second antigenic peptide as disclosed herein. Said (one) container may also further contain a helper peptide, such as a UCP2 peptide. Optionally, the first and second antigenic peptides (and optionally a helper peptide) in the (single) container may be in the same dosage form, for example, dissolved in water for injection and/or dimethyl sulfoxide (DMSO). Additionally, the kit may contain an additional container (other than the container containing the antigenic peptides) that includes an adjuvant, for example MONTANIDE ISA 51.

Thus, preferably the container contains

(a) a first vial containing one or more antigenic peptides of the present invention (for example, at least 200 or 300 μg of each antigenic peptide) and, optionally, a helper peptide such as UCP2 (for example, at least 200 or 300 μg of each antigenic peptide ) optionally in the composition of water for injection and dimethyl sulfoxide (DMSO); And

(b) a second vial containing MONTANIDE ISA 51 (eg at least 0.4 or 0.5 ml).

In addition, the kit may contain one or more (eg 2 or 3) syringes, for example, syringes that do not contain silicone and latex. The set may also contain a connector, such as a 1-connector.

Non-limiting examples of such connectors are:

I-connector developed by Green Peptide (Japan), control connector DIDRACDLLFT from Didanorm (France),

I-connector (cont.: ODG0015ST) from Promepla (Monaco), and

I-connector (control: MX494) from Smiths medical (US).

Syringes are preferably preferred for administering MONTANIDE, that is, they are latex and rubber free (ie, do not contain a latex cap on the tip of the plunger) and are preferably also latex free. Non-limiting examples of such syringes include:

2 ml INKJET (Ref: 4606701V from B-Braun, Germany),

5 ml INKJET (Ref: 4606710V from B-Braun, Germany),

2 ml Norm-Ject (Ref: 4020.000V0 from Henke Sass Wolf GMBH, Germany), and

5 ml Norm-Ject (Ref: 4050.000V0 from Henke Sass Wolf GMBH, Germany).

For example, the kit may contain (a) a first vial comprising at least 300 μg of an antigenic peptide of the invention (or two or three antigenic peptides of at least 300 μg each) and, optionally, at least 300 μg of UCP2 dissolved in water for injection and dimethyl sulfoxide (DMSO), (b) a second vial containing at least 0.5 ml of MONTANIDE ISA 51, (c) two silicone- and latex-free syringes, and (d) a 1-piece connector.

Optionally, the kit may also include a vial of water for injection and/or an adapter for the vial. A sterile needle may also be included, for example for vaccinating the patient after receiving the emulsion. The volume of the syringes in the kit can be, for example, 2 ml.

According to one particular embodiment of the invention, the kit contains three different antigenic peptides of the present invention, UCP2 peptide, and MONTANIDE ISA 51, wherein the kit includes (i) a first vial containing at least 300 μg of each antigenic peptide of the invention, at least 300 µg UCP2 (SEQ ID NO: 859) dissolved in water for injection and DMSO, (ii) a second vial containing at least 0.5 ml MONTANIDE ISA 51, (ii) two silicone and latex free syringes, and (g ) 1-connector.

The three antigenic peptides of the present invention in the kit are preferably an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 32, an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: : 220 and an antigenic peptide consisting of or including the amino acid sequence as indicated by SEQ ID NO: 255.

In addition, the kit of parts of the present invention may optionally contain instructions for use. Accordingly, preferably the kit contains a package insert or instructions for use for the prevention and treatment of cancer by use of an immunogenic compound of the present invention, an antigenic peptide of the present invention, a nanoparticle of the present invention, a cell of the present invention, a nucleic acid of the present invention, a host cell of the present invention or a pharmaceutical composition of the present invention.

Also preferably, in addition to any of the components described above, the kit contains an anti-cancer drug agent as disclosed herein.

In addition, the present invention also relates to a vaccine kit for the treatment, prevention and/or stabilization of cancer? comprising a pharmaceutical composition or vaccine as disclosed herein, as well as instructions for the use of said pharmaceutical composition or said vaccine for the prevention and/or treatment of cancer.

Medical use and treatment

As disclosed above, the composition of the present invention may be particularly useful for therapeutic purposes, primarily for triggering a specific immune response against a particular tumor antigen/protein, for example, for the prevention or treatment of cancer in a patient in need of such treatment.

With this in mind, the present invention provides:

- an antigenic peptide of the present invention, as disclosed herein,

- an immunogenic compound of the present invention, as disclosed herein,

- a nanoparticle according to the present invention, as disclosed in the present description,

- a cell according to the present invention, as disclosed in the present description,

- a nucleic acid of the present invention, as disclosed herein,

- a host cell of the present invention, as disclosed herein, and/or

- a pharmaceutical composition according to the present invention, as disclosed herein, or

- a kit of the present invention, as disclosed herein, intended for use in the prevention and/or treatment of cancer. In particular, preferred embodiments of the antigenic peptide as described above are also applicable for use in the prevention and/or treatment of cancer according to the present invention. For example, an antigenic peptide used for the prevention and/or treatment of cancer, or an antigenic peptide in an immunogenic compound, nanoparticle, or cell, or nucleic acid, or host cell or pharmaceutical composition used for the prevention and/or treatment of cancer, preferably consists of or includes an amino acid sequence as defined in any of SEQ ID NOs 1 to 580 and 861 to 887, such as an antigenic peptide consisting of or including an amino acid sequence as defined in any of SEQ ID Nos. 1 to 580. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 1-160, 162253 and 255580 are more preferred. For example, the antigenic peptides of the present invention, consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524 , are even more preferable. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524 are even more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 87, 97, and 194 are more preferred. For example, antigenic peptides of the present invention consisting of or including an amino acid sequence as defined in any of SEQ ID NOs 30, 32, 194, 220, 254 or 255 are particularly preferred.

Also preferred are their combinations, namely, the use of various antigenic peptides of the present invention for the prevention and/or treatment of cancer. In particular, more than one of the components described above may be used for the prevention and/or treatment of cancer. For example, at least two different antigenic peptides, at least two different immunogenic compounds, at least two different nanoparticles, at least two different nucleic acids, at least two different host cells and/or two different pharmaceutical compositions may be used for the prevention and/or treatment of cancer. Preferably, such various components used for the prevention and/or treatment of cancer, as disclosed above, differ in the antigenic peptides of the present invention, for example, one component is a first antigenic peptide and the other component is a second antigenic peptide (different from the first antigenic peptide). peptide). For example, at least two different immunogenic compounds of the present invention can be used for the prevention and/or treatment of cancer. For example, at least two different nanoparticles of the present invention can be used for the prevention and/or treatment of cancer. For example, at least two different nucleic acids of the present invention can be used for the prevention and/or treatment of cancer.

Thus, the present invention relates to (at least one) antigenic peptide of the present invention, as disclosed herein, for the prevention and/or treatment of cancer. In addition, the present invention relates to (at least one) immunogenic compound of the present invention, as disclosed herein, for the prevention and/or treatment of cancer. In addition, the present invention relates to (at least one) nanoparticle of the present invention, as disclosed herein, for the prevention and/or treatment of cancer. In addition, the present invention relates to (at least one) cell of the present invention, as disclosed herein, for the prevention and/or treatment of cancer. In addition, the present invention relates to (at least one) nucleic acid of the present invention, as disclosed herein, for the prevention and/or treatment of cancer. In addition, the present invention relates to (at least one) host cell of the present invention, as disclosed herein, for the prevention and/or treatment of cancer. In addition, the present invention relates to (at least one) pharmaceutical composition of the present invention, as disclosed herein, for the prevention and/or treatment of cancer. In addition, the present invention relates to (at least one) kit of the present invention, as disclosed herein, for the prevention and/or treatment of cancer.

Thus, the present invention also relates to a method of preventing and/or treating cancer or a method of inducing, enhancing or prolonging an antitumor response in a subject in need thereof, comprising administering to the subject

- an antigenic peptide of the present invention, - an immunogenic compound of the present invention,

- nanoparticles of the present invention, - cells of the present invention, - nucleic acid of the present invention, - host cells of the present invention, - kit of the present invention; or

- a pharmaceutical composition according to the present invention, or - a combination according to the present invention, as disclosed in the present description.

Preferably, the cancer to be prevented and/or treated is selected from glioma, kidney cancer, skin cancer, more specifically melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial cancer and prostate cancer.

In addition, the present invention provides a method of inducing or improving in a subject an immune response against one or more CD8 ⁺ cytotoxic T cell-dependent epitopes, the method comprising administering to said subject any of the following:

- an antigenic peptide according to the present invention,

- an immunogenic compound of the present invention,

- nanoparticles according to the present invention, - cells according to the present invention,

- a nucleic acid of the present invention, - a host cell of the present invention,

- the pharmaceutical composition of the present invention,

- a kit according to the present invention or

- combinations of the present invention, as disclosed in the present description.

The immune response, which is dependent on the CD8+ response, can be determined by assessing the inflammatory response, pro-inflammatory cytokine response, including an increase in the expression of one or more IFN-γ, TNF-α and IL-2 mRNA or protein relative to the level before administration of the compounds of the present invention. It can also be assessed by measuring the number or absolute number of antigen-specific T cells after administration of the compounds of the present invention, carried out using HLA-peptide multimer staining, ELISPOT analysis and delayed-type hypersensitivity tests.

The present invention also provides a method of inducing or enhancing in a subject an immune response against one or more multiple MHC class I-restricted epitopes, the method comprising administering to the subject any of the following:

- an antigenic peptide according to the present invention,

- an immunogenic compound of the present invention,

- nanoparticles according to the present invention,

- cells according to the present invention,

- a nucleic acid according to the present invention,

- a host cell according to the present invention,

- the pharmaceutical composition of the present invention,

- a kit according to the present invention, or

- combinations of the present invention, as disclosed in the present description.

A method of inducing or improving in a subject an immune response against multiple epitopes, as disclosed herein, that are limited to multiple MHC class I molecules can be assessed by measuring the cytokine response, including increased expression of one or more IFN-γ, TNF-α and IL-2 mRNA or protein compared to the baseline level before administration of the compounds of the present invention after stimulation of T cells in vitro with individual peptides binding to various MHC class I molecules on the surface of antigen presenting cells. Restriction by MHC class I molecules can be confirmed by the use of antigen presenting cells expressing MHC class I molecules or by the use of antibodies that block MHC class I. It can also be measured by the increase in the number or absolute number of antigen-specific T cells after administration of the compounds of the invention, which is measured by HLA peptide multimer staining using multimers combined with MHC class I molecules.

Thus, according to another aspect, the present invention also relates to:

- the antigenic peptide of the present invention,

- the immunogenic compound of the present invention,

- nanoparticle according to the present invention,

- a cell according to the present invention,

- a nucleic acid according to the present invention,

- a host cell according to the present invention,

- the pharmaceutical composition of the present invention,

- a kit according to the present invention, or

- combinations of the present invention, as disclosed herein,

intended for use as a medicine.

The present invention more particularly relates to a composition as disclosed above for use as a vaccine for immunotherapy. Besides,

- antigenic peptide according to the present invention,

- an immunogenic compound of the present invention,

- nanoparticle according to the present invention,

- a cell according to the present invention,

- a nucleic acid according to the present invention,

- a host cell according to the present invention,

- pharmaceutical composition according to the present invention,

- a kit according to the present invention, or

- the combination of the present invention, as disclosed herein, can be used as a vaccine, more specifically for immunotherapy (cancer).

As used in the context of the present invention, the term "vaccine" refers to a (biological) preparation that confers natural and/or adaptive immunity to a specific disease, preferably cancer. Thus, the vaccine specifically supports the natural and/or adaptive immune response of the immune system in the subject being treated. For example, the antigenic peptide of the present invention typically results in or supports an adaptive immune response in the patient being treated.

In the context of the present invention, the vaccine (composition) can induce a specific immune response against a tumor antigen and is thus preferably used for the prevention and treatment of cancer. A vaccine for the prevention and treatment of cancer may also be referred to as a "cancer vaccine".

Thus, according to a preferred embodiment, the present invention provides a composition as disclosed above for use in the prevention and/or treatment of cancer in a subject in need thereof. More preferably, the present invention relates to the use of the composition of the present invention for the manufacture of a medicament intended for the prevention or treatment of cancer in a subject in need thereof. In other words, the present invention relates to a method for preventing and treating cancer in a subject in need thereof, which comprises administering an effective amount of a composition of the invention to said subject.

Preferably the cancer being prevented and/or treated

- an antigenic peptide according to the present invention,

- an immunogenic compound according to the present invention,

- a nanoparticle according to the present invention,

- a cell according to the present invention,

- a nucleic acid according to the present invention,

- a host cell according to the present invention,

- the pharmaceutical composition according to the present invention,

- a kit according to the present invention or

- a combination according to the present invention, as disclosed in the present description,

relates to a (reference) tumor antigen as disclosed herein. Particularly suitable antigenic peptides can be selected (a) by selecting a suitable tumor antigen for a particular cancer type, as known in the art and/or disclosed in Table 1B (below) and (b) selecting a suitable antigenic peptide of the present invention for the selected tumor antigen as described above, for example in Table 1A. One skilled in the art will appreciate that the antigenic peptide of the present invention may be selected based on the nature of the cancer being prevented and/or treated and/or based on a human gene/tumor antigen involved in the pathogenesis of that type of cancer.

Thus, preferred examples of cancer are presented in Table 1B below. In particular, the antigenic peptides of the present invention are sequence variants of human tumor antigen fragments shown in Table 1B and may be used, in particular, for the treatment of diseases listed next to the corresponding tumor antigen in Table 1B.

In general, the antigenic peptides of the present invention can be administered "isolated" or in the form of immunogenic compounds of the present invention, cells loaded with such peptides of the present invention, nanoparticles of the present invention, nucleic acids of the present invention, host cells of the present invention and/ or pharmaceutical compositions of the present invention.

According to a preferred embodiment of the invention, they can also be administered as part of a microorganism, such as a gut microflora bacterium. Complete gut flora bacteria may also have the advantage of being able to initiate a more powerful immune response than the (poly)peptides or nucleic acids they contain. Alternatively, the gut microflora bacteria of the present invention may be in the form of probiotics, that is, live gut microflora bacteria, which can accordingly be used as dietary supplements due to the beneficial health effects they provide. They can, for example, be lyophilized into granules, pills or capsules, or mixed directly with dairy products before consumption.

Methods of administration are well known to one skilled in the art. Depending on the type of composition of the present invention, it may be administered directly to the subject, into the affected organ (ie, by local administration) or systemically (ie, by enteral or parenteral administration), or even applied ex vivo on cells obtained from the subject, or a human cell line, which is then reintroduced to the subject, or even used in vitro to select a subpopulation of immune cells isolated from the subject, which are then reintroduced to the subject.

Enteral routes of administration include oral, rectal, gastric, duodenal or gastrostomy tubes, while parenteral routes include subcutaneous, intravenous, intramuscular, intra-arterial, intradermal, intraosseous, intracerebral and intrathecal injections, among others. The route of administration will most often depend on the antigenic peptide(s) and/or immunogenic compound(s) in the composition, as well as the type of cancer being treated, as well as the presence of other active ingredients in the composition. For example, administration is preferably via intramuscular or intradermal injection, where the immunogenic compound is a nucleic acid as disclosed above, oral/nasal administration is most preferred, especially if said nucleic acid is cloned into a viral vector. Alternatively, if the antigenic peptide and/or immunogenic compound is a (poly)peptide, as previously disclosed, or if it is loaded into/on a nanoparticle, as previously disclosed, intramuscular, intradermal or oral administration is preferred. Also alternatively, if the antigenic peptide and/or immunogenic compound is delivered in the form of gut bacteria as disclosed above, especially if the gut bacteria are contained in probiotics, oral administration is preferred.

The antigenic peptides, immunogenic compounds and nucleic acids of the present invention can be further encapsulated to facilitate their administration to a subject in need thereof. For example, they can be encapsulated in peptide nanocarriers (preferably if the immunogenic compound is a nucleic acid or (poly)peptide), virosomes (preferably if the immunogenic compound is a nucleic acid or (poly)peptide), or system a lipid-based carrier such as a liposome-polycationic-DNA complex (preferably the immunogen is a nucleic acid or (poly)peptide) (Trovato M, De Berardinis P. Novel antigen delivery systems. World J Virol. 2015 Aug 12;4 (3): 156-68; Saade F, Petrovsky N. Technologies for enhanced efficacy of DNA vaccines. Expert Rev Vaccines. 2012 Feb; 11(2): 189-209; Li et al., Peptide Vaccine: Progress and Challenges. Vaccines (Basel).2014 Jul 2;2(3):515-36).

The composition may also be administered more than once to achieve the desired effect. According to a preferred embodiment of the invention, said composition is administered repeatedly at least twice, preferably more than twice. Administration may occur over an extended period of time, for example, weekly, every two weeks, every month, every year, or even every few years after the very first administration to ensure proper immunization of the subject.

Combination therapy

Administration of an antigenic peptide of the present invention, an immunogenic compound of the present invention, a nanoparticle of the present invention, a cell of the present invention, a nucleic acid of the present invention, a host cell of the present invention, a pharmaceutical composition of the present invention, particularly according to the methods and uses of the present invention of the invention may be performed alone or in combination with another agent for co-administration useful for the treatment and/or prevention of cancer, such as an anti-cancer drug agent.

Such a drug agent thus preferably has the ability to prevent and/or treat the same type of cancer as the antigenic peptide of the present invention. The most preferred anticancer drug agents of the present invention are, but are not limited to, antibodies, tumor cell lysates, chemotherapeutic agents, radiotherapeutic agents, immune checkpoint modulators, and combinations thereof.

Antibodies are particularly advantageous for cancer therapy because they can bind to specific antigens on the surface of cancer cells, thereby directing therapy directly to the tumor (such antibodies are referred to as antitumor targeted antibodies), or block immune checkpoints that are dysregulated for cancer (such antibodies are referred to as immunomodulating antibodies). The purpose of the latter type of antibodies is to suppress immune resistance to cancer cells that can be observed against T cells that are specific for tumor antigens. Indeed, it is well known in the art that, under natural physiological conditions, immune checkpoints play a key role in maintaining autotolerance (ie, preventing autoimmune reactions) and protecting tissues from damage when the immune system fights a pathogenic infection. However, in cancer, the regulation of immune checkpoint expression may be dysregulated, which is an important mechanism in the development of immune resistance. This resistance is observed in melanoma, ovarian cancer, lung cancer, glioblastoma, breast cancer, and pancreatic cancer and is associated with the PD-L1 checkpoint (Konishi et al., B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004 Aug 1;10(15):5094-100; Ghebeh et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006 Mar; 8(3): 190-8; Hino et al., Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010 Apr 1; 116(7): 1757-66). Other examples of immune checkpoints include, but are not limited to, PD-L2, PD-1, CD80, CD86, CTLA4, B7H3, B7H4, PVR, TIGIT, GAL9, LAG-3, GITR, CD137, TIM3, VISTA, VISTA-R (Pico de et al., Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med. 2015 Aug;21(8):482-91; Pardoll DM1. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22; 12(4):252-64).

For the purposes described above, antibodies are used both in the form of isolated monoclonal antibodies (that is, unconjugated) and in the form of antibodies conjugated to other molecules that may be radioactive or toxic to cells.

Examples of well-known monoclonal antitumor targeted antibodies that are used in cancer immunotherapy include, but are not limited to, alemtuzumab (chronic lymphocytic leukemia), bevacizumab (colorectal cancer, glioblastoma multiforme, cervical cancer, lung cancer, kidney cancer), brentuximab/vedotin ( lymphomas), blinatumumab (acute lymphoblastic leukemia), catumaxomab (malignant ascites in EPCAM + tumors), cetuximab (head and neck cancer, colorectal cancer), denosumab (breast, prostate and bone cancer), Gemtuzumab / ozogamicin (acute myeloid leukemia), ibritumomab/tiuxetan (non-Hodgkin's lymphoma), panitumumab (colorectal cancer), pertuzumab (breast cancer), obinutuzumab (chronic lymphocytic leukemia), ofatumumab (chronic lymphocytic leukemia), opilimumab (melanoma), ramucirumab (stomach and gastroesophageal cancer), rituximab ( chronic lymphocytic leukemia and non-Hodgkin's lymphoma), siltuximab (multifocal Castleman disease), tositumomab (non-Hodgkin's lymphoma) and trastuzumab (breast, stomach and esophageal cancer); while examples of immunomodulatory antibodies include, but are not limited to, ipilimumab (melanoma), which blocks the CTLA4-dependent immune checkpoint, nivolumab (melanoma, lung cancer), and prembrolizubmab (melanoma), which both block the PDCD1-dependent immune checkpoint , as well as MPDL3280A, MEDI4736, MEDI0680, and MSB0010718C, which all block the PD-L1-dependent immune checkpoint (Sharma and Allison, The future of immune checkpoint therapy. Science. 2015 Apr 3; 348(6230):56-61) .

Other antibodies for cancer immunotherapy have been described by Buque et al., Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications. Oncoimmunology. 2015 Mar 2;4(4):el008814. eCollection 2015 Apr; Redman et al., Mechanisms of action of therapeutic antibodies for cancer. Mol Immunol. 2015 Oct;67(2 Pt A):28-45; Simpson and Caballero, Monoclonal antibodies for the therapy of cancer MC Proc. 2014; 8(Suppl 4)About, as well as on the Antibody Society website (a list of therapeutic monoclonal antibodies approved or under review in the European Union or the United States is available at http://www.antibodysociety.org/ news/approved_mabs.php).

Tumor cell lysates can also be combined with the antigenic peptide(s) of the present invention. Tumor cells are indeed capable of initiating an immune response through the presentation of endogenous MHC-peptide complexes, as well as through host dendritic cells (DCs), which can process and present the antigen delivered by such lysates. This increases the range of antigens against which an immune response can be induced. Tumor cell lysates can be easily obtained by heat shock/or chemical treatment of tumor cells, and they can be autologous (ie, isolated from a patient) or allogeneic (ie, isolated from another subject).

Standard chemotherapeutic drugs and radiotherapy agents do not need further description here as they are described in detail in the literature, namely by Baskar et al. (Baskar et al., Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012 ;9(3): 193-9), Paci et al., Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics. Eur J Cancer. 2014 Aug;50(12):2010- 9) and Widmer et al. (Review of therapeutic drug monitoring of anticancer drugs part two-targeted therapies. Eur J Cancer. 2014 Aug;50(12):2020-36). A list of such drugs and agents is also available at cancer.gov (http://www.cancer.gov/about-cancer/treatment/drugs).

Preferably, the immune checkpoint modulator, which can be used in combination with an antigenic peptide as disclosed herein, is an activator or inhibitor of one or more immune checkpoint molecules selected from the group consisting of CD27, CD28, CD40, CD122, CD137, ОХ40, GITR, ICOS, A2AR, В7-Н3, В7-Н4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1, TIM-3, VISTA, SEACAM1, GARP, PS, CSF1R, CD94/ NKG2A, TDO, GITR, TNFR and/or FasR/DcR3; or an activator or inhibitor of one or more of their ligands.

More preferably, the immune checkpoint modulator is an activator of a (co)stimulatory checkpoint molecule or an inhibitor of an inhibitory checkpoint molecule, or a combination thereof. Accordingly, the immune checkpoint modulator is more preferably (i) an activator of CD27, CD28, CD40, CD 122, CD137, OX40, GITR and/or ICOS or (ii) an inhibitor of A2AR, B7-H3, B7-H4, BTLA, CD40 , CTLA-4, IDO, KIR, LAG3, PD-1, PDL-1, PD-L2, TIM-3, VISTA, CEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, TNFR and/or FasR/DcR3 .

Even more preferably, the immune checkpoint modulator is an inhibitory checkpoint molecule inhibitor (but preferably is not a stimulatory checkpoint molecule inhibitor). Accordingly, the immune checkpoint modulator is more preferably an inhibitor of A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, PDL-1, PD-L2, TIM-3, VISTA , SEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, TNFR and/or DcR3 or one or more ligands thereof.

Even more preferably, the immune checkpoint modulator is a modulator of the CD40 cascade or the IDO cascade, or the LAG3 cascade, or the CTLA-4 cascade and/or the PD-1 cascade. More specifically, the immune checkpoint modulator is a modulator of CD40, LAG3, CTLA-4, PD-L1, PD-L2, PD-1 and/or IDO, more preferably the immune checkpoint modulator is an inhibitor of CTLA-4, PD-L1, PD-L2, PD-1, LAG3, and/or IDO or a CD40 activator, even more preferably the immune checkpoint modulator is an inhibitor of LAG3, CTLA-4 and/or PD-1, and even more preferably the immune checkpoint modulator is CTLA-4 and/or PD-1 inhibitor.

Thus, the checkpoint modulator for combination with the antigenic peptide can be selected from known modulators of the CTLA-4 cascade or the PD-1 cascade. Preferably, the checkpoint modulator for combination with an antigenic peptide as disclosed herein may be selected from known CTLA-4 cascade or PD-1 cascade modulators. Particularly preferably, the immune checkpoint modulator is a PD-1 inhibitor. Preferred inhibitors of the CTLA-4 pathway or PD-1 pathway include the monoclonal antibodies Yervoy (Ipilimumab; Bristol Myers Squibb) and Tremelimumab (Pfizer/Medlmmune) as well as Opdivo ^® (Nivolumab; Bristol Myers Squibb), Keytrudaf (Pembrolizumab, also known as Lambrolizumab or MK-3475; Merck), Imfinzi ^® (Durvalumab, also known as MEDI4736; Medlmmune/AstraZeneca), Tecentriq ^® (Atezolizumab also known as MPDL3280A; Roche/Genentech), Pidilizumab (CT-011; CureTech), MEDI0680 ( AMP-514; AstraZeneca), Bavencio ^® (Avelumab; Merck KGaA/Pfizer, also known as MSB-0010718C), MIH1 (Affymetrix), LY3300054 (Eli Lilly), and Spartalizumab (also known as PDR001; Novartis). The more preferred checkpoint inhibitors are CTLA-4 inhibitors such as Yervoy (Ipilimumab; Bristol Myers Squibb) and Tremelimumab (Pfizer/Medlmmune) as well as the PD-1 inhibitors Opdivo ^® (Nivolumab; Bristol Myers Squibb), Keytruda ^® (Pembrolizumab; Merck ), Pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; AstraZeneca), AMP-224 (PD-L2 Fc fusion protein; Medlmmune).

It is also preferred that the checkpoint modulator for combination with an antigenic peptide as defined herein is selected from the group consisting of Pembrolizumab, Ipilimumab, Nivolumab, Atezolizumab, Durvalumab, Tremelimumab, Avelumab, Spartalizumab, LAG525 (anti-AG-3 monoclonal antibody), Epacadostat ( also known as INCB24360; IDO inhibitor), Varlilumab (anti-C027 monoclonal antibody), Yurelumab (anti-CD137 monoclonal antibody), AMP-224 and CM-24 (anti-CEACAM1 monoclonal antibody).

The selection of a suitable immune anticancer drug agent for the purposes of the present invention is within the purview of one skilled in the art. For example, if the goal is the prevention or treatment of melanoma, it is preferable to use a melanoma cell lysate and/or the antibody ipilimumab along with a suitable antigenic peptide as disclosed herein.

The anticancer drug agent can also be administered together with an antigenic peptide of the present invention, an immunogenic compound of the present invention, a nanoparticle of the present invention, a cell of the present invention, a nucleic acid of the present invention, a host cell of the present invention, or a pharmaceutical composition of the present invention, as at the same time, and sequentially, as disclosed herein, and also in the composition of one or more different pharmaceutical forms. Thus, the invention provides the combined use of the claimed composition and at least one anticancer drug agent, as disclosed above, for simultaneous, separate or sequential administration, as disclosed herein.

In addition, the present invention also relates to a combination of at least two different antigenic peptides according to the invention, for example, for use in the prevention and treatment of cancer. In addition, the present invention also relates to a combination of at least two different immunogenic compounds according to the invention, for example, for use in the prevention and treatment of cancer. In addition, the present invention also relates to a combination of at least two different nanoparticles according to the invention, for example, for use in the prevention and treatment of cancer. In addition, the present invention also relates to a combination of at least two different nucleic acids according to the invention, for example, for use in the prevention and treatment of cancer.

Thus, according to a preferred embodiment of the invention, at least two different antigenic peptides according to the invention can be administered in combination, for example, as part of a single pharmaceutical composition. For example, at least 3 antigenic peptides, at least 4 antigenic peptides, at least 5 antigenic peptides, at least 6 antigenic peptides, at least 7 antigenic peptides, at least 8 antigenic peptides, at least 9 antigenic peptides , at least 10 antigenic peptides, at least 11 antigenic peptides, at least 12 antigenic peptides, at least 13 antigenic peptides, at least 14 antigenic peptides, at least 15 antigenic peptides, at least 20 antigenic peptides, at least 25 antigenic peptides, at least 50 antigenic peptides, at least 100 antigenic peptides, at least 500 antigenic peptides, at least 1000 antigenic peptides or at least 1500 antigenic peptides may be administered in combination, e.g. composition of one pharmaceutical composition. It is within the skill of the person skilled in the art to select a combination of antigenic peptides and/or immunogenic compounds that is suitable for the intended purpose. For example, if the goal is the prevention or treatment of melanoma, the pathogenesis of which involves a tumor antigen encoded by the gene according to Table 1B, the specialist can select any combination of antigenic peptides as described in Table 1A.

According to a particularly preferred embodiment of the invention, two different antigenic peptides of the present invention (eg related to the same type of cancer and/or the same reference antigen) are used in combination. For example,

(a) at least two different immunogenic compounds of the present invention;

(b) at least two different antigenic peptides of the present invention;

(c) at least two different nanoparticles of the present invention; or

(d) at least two different nucleic acids of the present invention can be used in combination.

For example, the present invention relates to a combination

(a) a first antigenic peptide of the present invention, and

(b) a second antigenic peptide of the present invention (different from the first), preferably for use in the prevention and/or treatment of cancer.

For example, the present invention relates to a combination

(a) an immunogenic compound of the present invention, comprising a first antigenic peptide of the present invention, and

(b) an immunogenic compound of the present invention, comprising a second antigenic peptide of the present invention (different from the first), preferably for use in the prevention and/or treatment of cancer.

For example, the present invention relates to a combination

(a) nanoparticles of the present invention, including a first antigenic peptide of the present invention, and

(b) nanoparticles of the present invention, comprising a second antigenic peptide of the present invention (different from the first), preferably for use in the prevention and/or treatment of cancer.

For example, the present invention relates to a combination

(a) a nucleic acid of the present invention, including a polynucleotide encoding a first antigenic peptide of the present invention, and

(b) a nucleic acid of the present invention, comprising a polynucleotide encoding a second antigenic peptide of the present invention (different from the first), preferably for use in the prevention and/or treatment of cancer.

In addition, the antigenic peptide of the present invention can also be combined with a corresponding epitope of a (human) tumor antigen (as described above with respect to peptide "families"). In this way, the selection of T cell clones that are highly effective against the tumor is achieved/maintained. More specifically, the antigenic peptide of the present invention and the corresponding epitope of a (human) tumor antigen can be co-administered. Such co-administration can be carried out at the same time (simultaneously) or sequentially, with sequential administration being preferred since the antigenic peptide of the invention is administered first and the corresponding (human) tumor antigen epitope is administered next. In particular, the antigenic peptide of the present invention can be administered first, and then the corresponding (human) tumor epitope is administered as a (re)booster. For example, an antigenic peptide according to the sequence SEQ ID NO: 30, 31 or 32 can be combined with a reference peptide according to the sequence SEQ ID NO: 593. In another example, an antigenic peptide according to the sequence SEQ ID NO: 87 or 97 can be combined with a reference peptide according to the sequence SEQ ID NO: 617. In another example, an antigenic peptide according to the sequence SEQ ID NO: 145 can be combined with a reference peptide according to the sequence SEQ ID NO: 637. In another example, an antigenic peptide according to the sequence SEQ ID NO: 193 can be combined with a reference peptide according to the sequence SEQ ID NO: 659. In another example, an antigenic peptide according to the sequence SEQ ID NO: 194 can be combined with a reference peptide according to the sequence SEQ ID NO: 660. In another example, an antigenic peptide according to the sequence SEQ ID NO: 221 can be combined with a reference peptide according to the sequence SEQ ID NO: 675. In another example, an antigenic peptide according to the sequence SEQ ID NO: 220 can be combined with a reference peptide according to the sequence SEQ ID NO: 674. In another example, an antigenic peptide according to the sequence SEQ ID NO: 225 can be combined with a reference peptide according to the sequence SEQ ID NO: 691. In another example, an antigenic peptide according to the sequence SEQ ID NO: 524 can be combined with a reference peptide according to the sequence SEQ ID NO: 826. In another example, an antigenic peptide according to the sequence SEQ ID NO: 521 can be combined with a reference peptide according to the sequence SEQ ID NO: 824.

Peptides that can be combined with each other, such as (a) an antigenic peptide of the present invention and a corresponding epitope of a (human) tumor antigen or (b) two different antigenic peptides of the present invention, can be administered

- in one immunogenic compound of the present invention or in different immunogenic compounds of the present invention,

- (loaded) on one nanoparticle according to the present invention or on different nanoparticles according to the present invention,

- (loaded) into one cell according to the present invention or into different cells according to the present invention,

- (encoded) in one nucleic acid molecule of the present invention or in different nucleic acid molecules of the present invention,

- (expressed by) a single host cell of the present invention or different host cells of the present invention, or

- (included) in one pharmaceutical composition of the present invention or in different pharmaceutical compositions of the present invention.

In the following description of the invention, this is referred to as "two different components" (or a combination intended for use according to the invention). In general, the term expression of "two different components" in relation to a combination, for example, intended for use according to the present invention (in combination therapy), refers to

(1) a first component, such as an antigenic peptide of the present invention as disclosed herein, a nanoparticle of the present invention as disclosed herein, a cell of the present invention as disclosed herein, a nucleic acid of the present invention as disclosed herein, a host cell of the present invention as disclosed herein, or a pharmaceutical composition of the present invention as disclosed herein; And

(2) a second component (which is different from the first component), such as an anticancer drug agent as disclosed herein, another antigenic peptide of the present invention as disclosed herein, another immunogenic compound of the present invention as disclosed herein, another a nanoparticle of the present invention as disclosed herein, another cell of the present invention as disclosed herein, another nucleic acid molecule of the present invention as disclosed herein, another host cell of the present invention as disclosed herein, another pharmaceutical composition of the present invention as disclosed herein, or one or more (fragment) human tumor antigen in any form (naked, such as an immunogenic compound disclosed herein, a nanoparticle disclosed herein, a cell (host) disclosed herein, a nucleic acid disclosed herein or a pharmaceutical composition disclosed herein).

Thus, the “two different components” in relation to the combination intended for use in the present invention (in combination therapy) are preferably active components for the treatment and/or prevention of cancer. In other words, each of the at least two different components may also be useful for the prevention and/or treatment of the specified type of cancer if administered separately (not in combination with each other, as disclosed in the description) although their combined use (i.e., combined administration) generally enhances the prophylactic and/or therapeutic effect (such as immune response) of each in a synergistic manner.

Thus, the present invention also relates to a combination of (at least) two different antigenic peptides of the invention, as disclosed herein. In this context, (at least) two different antigenic peptides can be in any form, for example, naked form or in immunogenic compounds, nanoparticles and (pharmaceutical) compositions, loaded onto nanoparticles or encoded in nucleic acids (for example, vectors ). Accordingly, (at least) two different antigenic peptides may be included in (at least) two different components (which are then combined). In a preferred embodiment, the at least two different components of the combination of the present invention are at least two different antigenic peptides of the invention (in any form, e.g., immunogenic compounds, nanoparticles, cells, nucleic acid-encoded pharmaceutical compositions, etc.) .d.).

Preferably, at least two different components of the combination for use according to the present invention relate to the same type of cancer, for example the same or different antigens associated with that type of cancer, and/or the same or different (reference) epitopes of an antigen associated with a given type of cancer. More preferably, at least two different components belong to the same tumor antigen.

According to certain embodiments of the invention, at least two different components of the combination intended for use in the present invention are contained in the same or different compositions. In certain embodiments, at least two different components of a combination for use in the present invention are administered by the same or different routes. In certain embodiments, at least two different components of a combination for use in the present invention are administered at approximately the same time (simultaneously) or sequentially.

Preferably, at least two different components of the combination for use in the present invention are administered at approximately the same time. More generally, it is preferred that the first component be administered at approximately the same time as the second component, with at least two different components of the combination for use according to the present invention preferably being administered in the same form (i.e. as part of a composition of one type, for example, as part of nanoparticles, a pharmaceutical composition, etc.).

The phrase "at approximately the same time" as used herein means that the components are administered substantially simultaneously, either that the second component is administered immediately after the administration of the first component, or that the first component is administered immediately after the administration of the second component . One skilled in the art will understand that "immediately thereafter" includes the time required to prepare for the second administration - more specifically, the time required to vacate and disinfect the second administration site, as well as properly prepare the "administration device" (e.g., syringe, pump etc.). Simultaneous administration also includes those situations where the periods of administration of the first component and the second component overlap, and also when, for example, one component is administered over a longer period of time, such as 30 minutes, 1 hour, 2 hours or even more, for example, by infusion, and the other component is administered at a certain point over a specified long period of time. Administration of the first component and the second component at approximately the same time is particularly preferred if different routes and/or sites of administration are used.

It is also preferred that at least two different components of the composition for use according to the present invention are administered sequentially. In general, it is preferred that the first and second components are administered sequentially, with the two different components of the combination for use according to the present invention preferably being administered in the same form (i.e., the same type of composition, e.g. nanoparticles, pharmaceutical composition, etc.).

This means that the first component is introduced before or after the introduction of the second component. When administered sequentially, the time between administration of the first component and administration of the second component preferably does not exceed one week, more preferably does not exceed 3 days, even more preferably does not exceed 2 days, and even more preferably does not exceed 24 days. It is particularly preferred that the first component and the second component are administered on the same day, and the time interval between the administration of the first and second component is preferably not more than 6 hours, more preferably 3 hours, even more preferably 2 hours, and most preferably 1 hour.

Preferably, the first and second components are administered in the same manner. More generally, it is preferred that the first component and the second component are administered in the same manner, but at least two different components of the combination for use according to the present invention are preferably administered in the same form (i.e. composition of one type, for example, in the composition of nanoparticles, pharmaceutical composition, etc.).

It is also preferred that at least two different components of the combination for use according to the present invention are administered by different routes. More generally, it is preferred that the first component and the second component are administered by different routes, but that at least two different components of the combination for use according to the present invention are preferably administered in the same form (i.e., as part of the same composition). type, for example, in the composition of nanoparticles, pharmaceutical compositions, etc.).

Preferably, at least two different components of the combination for use according to the present invention are in the same composition. More generally, it is preferred that the first component and the second component are in the same composition, wherein the at least two different components of the combination for use according to the present invention are preferably administered in the same form (i.e. compositions of one type, for example, in the composition of nanoparticles, pharmaceutical compositions, etc.).

It is also preferred that at least two different components of the combination for use according to the present invention are in different compositions. More generally, it is preferred that the first component and the second component are in the same composition, wherein at least two different components of the combination for use according to the present invention are preferably administered in the same form (i.e., in the composition one type, for example, in the composition of nanoparticles, pharmaceutical compositions, etc.).

In particular, the present invention relates to a combination, for example intended for use in the prevention and/or treatment of cancer, comprising a first antigenic peptide of the present invention, which consists of or includes a microbiotic sequence variant of a fragment of a human tumor antigen BIRC5, and a second antigenic a peptide of the present invention that consists of or includes a microbiotic sequence variant of a fragment of the human tumor antigen FOXM1. Preferably, the first antigenic peptide consists of or includes a microbiotic variant sequence of the BIRC5 (human reference peptide) tumor antigen fragment "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 30, 31 or 32, and the second antigenic peptide consists of or includes a microbiotic variant sequence of the FOXM1 tumor antigen fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 220 or 868. Even more preferably, the combination, for example for use in the prevention and/or treatment of cancer, includes an antigenic peptide consisting of or including the amino acid sequence, as set forth in SEQ ID NO: 32, and an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 220.

In particular, the present invention relates to a combination, for example intended for use in the prevention and/or treatment of cancer, comprising a first antigenic peptide of the present invention, which consists of or includes a microbiotic sequence variant of a fragment of a human tumor antigen BIRC5, and a second antigenic a peptide of the present invention which consists of or includes a microbiotic sequence variant of a fragment of the human tumor antigen IL13RA2. Preferably, the first antigenic peptide consists of or includes a microbiotic variant sequence of the BIRC5 (human reference peptide) tumor antigen fragment "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 30, 31 or 32, and the second antigenic peptide consists of or includes a microbiotic variant sequence of a fragment of the tumor antigen IL13RA2 (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO : 692), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 254, 255, 878 or 879. Even more preferably, a combination intended, for example, for use in prophylaxis and/or treatment cancer, includes an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 32, and an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 255.

In particular, the present invention relates to a combination, for example intended for use in the prevention and/or treatment of cancer, comprising a first antigenic peptide of the present invention, which consists of or includes a microbiotic sequence variant of a fragment of the human tumor antigen FOXM1, and a second antigenic a peptide of the present invention which consists of or includes a microbiotic sequence variant of a fragment of the human tumor antigen IL13RA2. Preferably, the first antigenic peptide consists of or includes a microbiotic variant sequence of the tumor antigen fragment FOXM1 (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 220 or 868, and the second antigenic peptide consists of or includes a microbiotic variant sequence of a fragment of the tumor antigen IL13RA2 (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692 ), such as an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 254, 255, 878 or 879. Even more preferably, a combination intended, for example, for use in the prevention and/or treatment of cancer , includes an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 220, and an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 255.

More preferably, the combination of the present invention (eg, for use in the prevention and/or treatment of cancer) includes at least three different components as described above, more specifically at least three different antigenic peptides of the present invention. The above description regarding the combination of two different components also applies to the combination of three different components.

Thus, the present invention also provides a combination for use in the prevention and/or treatment of cancer, comprising a first antigenic peptide of the present invention that consists of or includes a microbiotic sequence variant of a human tumor antigen fragment BIRC5, a second antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a fragment of the human tumor antigen FOXM1, and a third antigenic peptide of the present invention, which consists of or includes a microbiotic variant sequence of a fragment of the human tumor antigen IL13RA2. Preferably, the first antigenic peptide consists of or includes a microbiotic variant sequence of the BIRC5 (human reference peptide) tumor antigen fragment "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide consisting of or including the amino acid sequence as specified in SEQ ID NO: 30, 31 or 32; the second antigenic peptide consists of or includes a microbiotic variant sequence of the tumor antigen fragment FOXM1 (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide consisting of or including the amino acid sequence as set forth in SEQ ID NO: 220 or 868; and the third antigenic peptide consists of or includes a microbiotic variant sequence of the IL13RA2 tumor antigen fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 254, 255, 878 or 879. Even more preferably, the combination, for example for use in the prevention and/or treatment of cancer, includes an antigenic peptide consisting of or comprising an amino acid sequence as set forth in SEQ ID NO: 30, an antigenic peptide consisting of or including an amino acid sequence as set forth in SEQ ID NO: 220, and an antigenic peptide consisting of or including an amino acid sequence, as set forth in SEQ ID NO: 255.

It is understood that a combination intended for use in the prevention and/or treatment of cancer may also include, instead of the preferred combinations of antigenic peptides described above, a corresponding combination of immunogenic compounds of the invention, a corresponding combination of nanoparticles of the invention, or a corresponding combination of nucleic acids of the invention.

BRIEF DESCRIPTION OF THE FIGURES

The following is a brief description of the figures attached to the application. The figures are intended to illustrate the present invention in more detail. However, they do not limit the essence of the invention in any way.

Figure 1: demonstrates the in vitro affinity for the IL13RA2-B and IL13RA2-L antigenic peptides compared to the corresponding IL13RA2-H epitope derived from human IL13RA2 as described in Example 2.

Figure 2: demonstrates the in vitro affinity for the antigenic peptides BIRC5-B1, BIRC5-B2 and BIRC5-B3 compared to the corresponding BIRC5-H epitope derived from human BIRC5 as described in Example 2.

Figure 3: Shows the in vitro affinity for (A) the EZH2-B antigenic peptide compared to the corresponding EZH2-H epitope derived from human EZH2 and (B) the EZH2-B2 antigenic peptide compared to the corresponding EZH2-H2 epitope derived from EZH2 person, as described in Example 2.

Figure 4: Shows the in vitro affinity for (A) the TYMS-B antigenic peptide compared to the corresponding TYMS-H epitope derived from human TYMS, and (B) the TYMS-B2 antigenic peptide compared to the corresponding TYMS-H2 epitope derived from Human TYMS as described in Example 2.

Figure 5: Shows the in vitro affinity for (A) the FOXM1-B antigenic peptide compared to the corresponding FOXM1-H epitope derived from human FOXM1 and (B) the FOXM1-B2 antigenic peptide compared to the corresponding FOXM1-H2 epitope derived from FOXM1 person, as described in Example 2.

Figure 6: Shows in vitro affinity for the antigenic peptides CHI3L1-B and CHI3L1-B3 compared to the corresponding CHI3L1-H epitope derived from human CHI3L1 as described in Example 2.

Figure 7: Shows the schematic immunization schedule that was used in Example 3. d: day.

Figure 8: shows for Example 3 ELISPOT results in mice vaccinated with antigenic peptides as indicated in the figure (BIRC5-H, BIRC5-B1, BIRC5-B2, BIRC5-B3, FOXM1-H2, FOXM1-B2, EZH2-H2, EZH2 -B2, IL13RA2-H, IL13RA2-B Normalized spot forming cell (SFC) counts are shown for each group, with each dot representing the mean value for each individual animal/mouse.

Figure 9: shows for Example 4 ELISPOT results in HLA-A2 transgenic mice vaccinated with antigenic IL13R2A-L as indicated in the figure, as well as cross-reactivity with the corresponding human IL13RA2-H peptide. The normalized number of spot-forming cells (SFC) is shown for each group.

Figure 10: shows for Example 5 ELISPOT results for HLA-A2 transgenic mice vaccinated with the BIRC5-B1 antigenic peptide as shown in the figure, and cross-reactivity with the corresponding human BIRC5-H peptide. The normalized number of spot-forming cells (SFC) is shown for each group.

Figure 11: Shows for Example 6 ELISPOT results for HLA transgenic mice vaccinated with the FOXM1-B2 antigenic peptide as shown in the figure and cross-reactivity with the corresponding human FOXM1-H2 peptide. The normalized number of spot-forming cells (SFC) is shown for each group.

Figure 12: Shows the in vitro affinity for the IL13RA2-B and IL13RA2-L antigenic peptides compared to the corresponding IL13RA2-H epitope derived from human IL13RA2, the reference peptide 1A9V, and the HIV positive control as described in Example 8.

Figure 13: Shows in vitro affinity for BIRC5-B1 antigenic peptides compared to the corresponding BIRC5-H epitope derived from human BIRC5, reference peptide 2M, and HIV positive control as described in Example 9.

EXAMPLES

The following are practical examples illustrating various embodiments and aspects of the invention. However, the present invention is not limited in its scope to the specific embodiments described below. The following examples and methods are provided to enable one skilled in the art to more accurately understand and implement the invention. The present invention, however, is not limited in its scope to the embodiments disclosed in the examples, which serve only to illustrate certain aspects of the invention, and methods functionally equivalent to those disclosed are also included within the scope of the invention. Indeed, various modifications of the invention, additional to those disclosed herein, will be readily apparent to one skilled in the art from the following description, accompanied by the figures and examples. All such modifications are within the scope of the appended claims.

EXAMPLE 1: Antigenic peptides having superior binding affinity compared to human peptides.

The binding affinities of the exemplary antigenic peptides produced according to the present invention and corresponding fragments of human tumor antigens (human reference peptides) for MHC class I were predicted in silico. This estimated affinity was determined using NetMHC Server 4.0 (http://www.cbs.dtu.dk/services/NetMHC/) as described by Andreatta M, Nielsen M, “Gap-aware sequence alignment with artificial neural networks: application to the system MHC class I. Bioinformatics (2016) Feb 15; 32(4):511-7. This method provides highly accurate predictions of peptide binding to the major histocompatibility complex (MHC), particularly for peptides 8-11 amino acids in length.

Table 2 below shows the results i.e. information about the putative binding of the peptide to MHC class I.

Table 2 - In silico predicted MHC class 1 peptide binding. Comparison of the predicted affinity of each antigenic peptide of the invention and a human reference peptide shows the superior binding affinity of the antigenic peptide of the invention.

Example 2: Antigenic peptides having superior affinity for the HLA-A*0201 allele.

Next, the binding affinity of various selected antigenic peptides and corresponding fragments of human tumor antigens (human reference peptides) towards the HLA-A*0201 allele was confirmed in vitro. Namely, antigenic peptides with the sequence SEQ ID NO:32 ("FMLGEFLKL", also referred to herein as BIRC5-B1); with the sequence SEQ ID NO:32 ("YTLGEFLYI", also referred to herein as BIRC5-B2) and with the sequence SEQ ID NO:31 ("GLLGEFLQI", also referred to herein as BIRC5-B3) were compared with the corresponding human reference peptide derived from BIRC5 ( "LTLGEFLKL", SEQ ID NO:593, also referred to herein as BIRC5-H). Moreover, antigenic peptides with the sequence SEQ ID NO:97 ("LLLSAALSV", also referred to herein as CHI3L1 B) and with the sequence SEQ ID NO:87 ("YLLSAALTI", also referred to herein as CHI3L1 B3) were compared with the corresponding human-derived reference peptide from CHI3L1 ("LLLSAAALSA", SEQ ID NO:617, also referred to herein as CHI3L1 H). In addition, the antigenic peptide with the sequence SEQ ID NO:145 ("ILDEAYVRV", also referred to herein as EGFR-B) was compared with the corresponding human reference peptide derived from EGFR ("ILDEAYVMA", SEQ ID NO:637, also referred to herein as EGFR- H). Moreover, antigenic peptides with the sequence SEQ ID NO:193 ("FLVEDETVI", also referred to herein as EZH2-B) and with the sequence SEQ ID NO:194 ("AVFRVLIPV", also referred to herein as EZH2-B 2) were compared with the corresponding reference peptides humans derived from EZH2 (“FMVEDETVL”, SEQ ID NO:659, also referred to herein as EZH2-H2, and “SMFRVLIGT”, SEQ ID NO:660, also referred to herein as EZH2-H2, respectively). Moreover, antigenic peptides with the sequence SEQ ID NO:221 ("RLSSYLVEI", also referred to herein as FOXM1-B) and with the sequence SEQ ID NO:220 ("LMDLSTTEV", also referred to herein as FOXM1-B2) were compared with the corresponding human reference peptides , derived from FOXM1 ("RVSSYLVPI", SEQ ID NO:675, also referred to herein as FOXM1-H, and "LMDLSTTPL", SEQ ID NO:674, also referred to herein as FOXM1-H2, respectively). Moreover, antigenic peptides with the sequence SEQ ID NO:254 ("FLPFGFILV", also referred to herein as IL13RA2-B) and with the sequence SEQ ID NO:255 ("FLPFGILPV", also referred to herein as IL13RA2-L) were compared with the corresponding human reference peptide , derived from IL13RA2 ("WLPFGFILI", SEQ ID NO:691, also referred to here as IL13RA2-H). In addition, antigenic peptides with the sequence SEQ ID NO:524 ("SMEELLWFV", also referred to herein as TYMS-B) and with the sequence SEQ ID NO:521 ("FLDSLGFSL", also referred to herein as TYMS-B2) were compared with the corresponding human reference peptides derived from TYMS ("VLEELLWFI", SEQ ID NO:826, also referred to herein as TYMS-H, and "FLDSLGFST", SEQ ID NO:824, also referred to herein as TYMS-H2, respectively).

A. Materials and methods

A1. Measurement of peptide affinity with T2 cell line. The experimental protocol is similar to one validated for HLA-A*0201-presented peptides (Tourdot et al., “A master strategy to enhance the immunogenicity of low-affinity HLA-A2.1-associated peptides: application to the identification of critical tumor epitopes " Eur J Immunol 2000 Dec; 30(12):3411-21). Peptide affinity measurements were performed using the human T2 tumor cell line, which expresses HLA-A*0201 molecules but is TAP 1/2 negative and unable to present endogenous peptides.

T2 cells ( ^2x105 cells per well) were incubated with decreasing concentrations of peptides from 100 μM to 1.5625 μM in AIMV medium supplemented with 100 ng/μl human β2m at 37°C for 16 h. Cells were then washed twice and labeled with antibodies to HLA-A2 associated with PE (clone BB7.2, BD Pharmagen).

The measurement was carried out using the FACS method (Guava Easy Cyte).

For each peptide concentration, the geometric labeling value associated with the peptide of interest was subtracted from the background noise value and expressed as a percentage of the geometric labeling value for HLA-A*0201 obtained for the reference peptide HIV po1 589-597 at a concentration of 100 μM. Relative affinity was further calculated as follows:

Relative affinity - the concentration of each peptide inducing 20% HLA-A*0201 expression/concentration of the reference peptide inducing 20% HLA-A*0201 expression.

A2. Peptide solubilization

Each peptide was solubilized taking into account its amino acid composition. For peptides that do not contain cysteine, methionine or tryptophan, it is possible to add DMSO to a concentration of 10% of the total volume. Other peptides were resuspended in water or PBS pH. 7.4.

B. Results

The relative fluorescence intensity values (data normalized to the fluorescence value of the HIV peptide, i.e. a value of 100 is equivalent to the best binding observed for the HIV peptide) of T2 cells, determined for various concentrations of each peptide, are given below in Table 3:

Table 4 below summarizes for each peptide tested the concentrations required to induce 20% HIV HLA-A*0201 expression and the magnitude of in vitro binding activity.

In addition. Figures 1-6 illustrate the results for selected examples, namely the antigenic peptides IL13RA2-B and IL13RA2-L in comparison with the corresponding IL13RA-H fragment derived from human IL13RA (Fig. 1), for the antigenic peptides BIRC5-B1, BIRC5- B2 and BIRC5-B3 compared with the corresponding BIRC5-H fragment derived from human BIRC5 (Figure 2), for the antigenic peptide EZH2-B compared with the corresponding EZH2-H fragment derived from human EZH2 (Figure 3A) and for EZH2-B2 antigenic peptide compared with the corresponding EZH2-H2 fragment derived from human EZH2 (Figure 3B), for TYMS-B antigenic peptide compared with the corresponding TYMS-H fragment derived from human TYMS (Figure 4A) and for the TYMS-B2 antigenic peptide compared with the corresponding TYMS-H2 fragment derived from human TYMS (Figure 4B), for the FOXM1-B antigenic peptide compared with the corresponding FOXM1-H fragment derived from human FOXM1 (Figure 5A) and for the antigenic peptide FOXM1-B2 in comparison with the corresponding FOXM1-H2 fragment obtained from human FOXM1 (Fig. 5B) and for the antigenic peptides CHI3L1-B and CHI3L1-B3 in comparison with the corresponding CHI3L1 fragment obtained from human CHI3L1-H (Fig. 6).

Taken together, the present results indicate that the antigenic peptides produced in accordance with the present invention exhibit at least similar binding affinities for HLA-A*0201 to those of corresponding human tumor antigen fragments. In most cases, the binding affinity found for the antigenic peptides obtained in accordance with the present invention is stronger than that for the corresponding human epitopes. Without being bound by any theory, it is believed that such strong binding affinity of the antigenic peptides produced in accordance with the present invention reflects their ability to enhance the immune response (ie, their immunogenicity).

EXAMPLE 3: Vaccination of mice with antigenic peptides prepared in accordance with the present invention induces an improved T cell effect in the ELISPOT-IFNγ study.

A. Materials and methods

A.1. Mouse model

The immunization schedule is shown in Figure 7. Briefly, mice immunized with HLA-A2 (HLA-A2(CB6F1-Tg(HLA-A*0201/H2-K ^b )A*0201) were selectively (based on sex and age) divided into experimental groups, with each group immunized with a specific vaccine peptide (vacc-pAg) combined with a conventional helper peptide (h-pAg T13L; sequence TPPAYRPPNAPIL; SEQ ID NO:860; Bhasin M. Singh N, Raghava GP (2003) MHCBN : "Comprehensive database of MHC binding and non-MHC binding peptides." Biomformatics 19:665-666) (as shown in Table 5 below) Vacc-pAg was compared pairwise (group 1 vs group 2; group 1 vs group 3; group 1 vs Group 4; Group 5 vs. Group 6; Group 7 vs. Group 8; Group 9 vs. Group 10) Thus, both native and optimized versions of a particular peptide were compared on a case-by-case basis.

The peptides were presented as follows:

- vacc-pAg: BIRC5-H, BIRC5-B1, BIRC5-B2, BIRC5-B3, FOXM1-H2, FOXM1-B2, EZH2-H2, EZH2-B2, IL13RA2-H and IL13RA2-B; all peptides were obtained and used at a concentration of 4 mg/ml (4 mM);

- h-pAg: T13L; batch of Eurogentec 1713334 was resuspended in pure distilled water at a concentration of 10 mg/ml.

Animals were immunized on day 0 (d0) with a primary injection and on day 14 (d14) with a booster injection. Each mouse was injected subcutaneously at the base of the tail with 100 μl of an oil emulsion that contained:

- 100 μg vacc-pAg (25 μl stock solution with a concentration of 4 mg/ml per mouse);

- 150 μg h-pAg (15 μl stock solution with a concentration of 10 mg/ml per mouse);

- 10 µl PBS to achieve a total volume of 50 µl (per mouse);

- incomplete Freund's adjuvant (IFA), added at a 1:1 (volume/volume) ratio (50 μl per mouse).

A separate emulsion was prepared for each vacc-pAg as follows:

IFA reagent was added to the vacc-pA/h-pAg/PBS mixture in a 15-ml tube and vortexed in repeated cycles of 1 min to form a thick emulsion.

A.2. Analysis

7 days after the booster injection (i.p. on d21), animals were euthanized and the spleen was harvested. Splenocytes were obtained by mechanical destruction of the organ, followed by filtration through a membrane with a pore size of 70 μm and purification in a Ficoll density gradient.

Splenocytes were immediately used in the ELISPOT-IFNγ assay (Table 6). Experiments were repeated three times using 2x10 ⁵ splenocytes per well, which were cultured in the presence of vacc-pAg (10 μM), ionomycin (0.1 μM) supplemented with PMA (1 μM) or medium alone to achieve IFNγ secretion. A commercial ELISPOT-IFNγ kit (Diaclone Kit Mujrine IFNγ ELISpot) was used according to the manufacturer's instructions and the assay was performed after approximately 19 h of incubation.

Reaction spots were counted on a CTL ELISpot reader. Data plotting and statistical analysis were performed using Prism-5 software (GraphPad Software Inc.).

B. Results

A total of 50 HLA-A2 (CB6F1-rTg(HLA-A*020Vm-K ^b )A*0201) mice were used for this experiment. At the date of the experiment, all mice were between 6 and 9 weeks old. Both males and females were used for the experiment. Animals were divided into groups with a maximum of five animals per cage. At the time of sacrifice, the spleen T cell population was analyzed by flow cytometry, which showed that the majority of these cells belonged to the CD4+ T cell subset.

After seeding into plates and incubation with appropriate stimuli, the number of IFNγ-producing cells was identified and counted. The data were then normalized as the number of specific spots (the average "medium only" count was subtracted) based on the total number of 50 x 10 ³ T cells.

Individual means (obtained by triplicate) were then used to plot group means. Since the functional capacity of T cells may vary from individual to individual, data were also expressed as the percentage of response to PMA + lonomycin per individual (see Figure 8).

Overall, vaccination with antigenic peptides prepared in accordance with the present invention (BIRC5-B1, BIRC5-B2 BIRC5-B, FOXM1-B2, EZH2-B and IL13RA2-B) induces improved T cell responses in the ELISPOT-IFNγ assay compared with the corresponding human reference epitopes (BIRC5-H, FOXM1-H2, EZH2-H2 and IL13RA2-H).

EXAMPLE 4: Immunogenicity of IL13RA2-L in HLA-A2 transgenic mice and cross-reactivity with the corresponding human peptide.

A. Materials and methods

The antigenic peptide IL13RA2-L (SEQ ID NO:255) prepared according to the present invention and the corresponding human reference peptide IL13RA2-H (SEQ ID NO:691) were tested in separate groups of male and female HHD DR3 mice expressing HLA-A2 and HLA -DR3 MHC and those that have lost murine MHC H-2 class I and class II antigens. Animals in groups of five mice (male and female) were injected subcutaneously on days 0 and 14 with 100 μg IL13RA2-L (SEQ ID NO:255) or IL13RA2-H (SEQ ID NO:691), 150 μg helper peptide (DR3), and IFA. On day 21, mice were euthanized, splenocytes were harvested and stimulated in vitro with IL13RA2-L or the corresponding human IL13RA2-H reference peptide to achieve IFN secretion capacity as determined by ELISpot. Concanavalin A (ConA) was used as a positive control.

B. Results

The number of spot forming cells (SFC) (normalized to the number of CDS cells) is presented in Figure 9. The results are shown for mice immunized with IL13RA2-L. These results indicate that immunization of mice with IL13RA2-L provides induction T cells that are capable of a strong response after administration of IL13RA2-L or the corresponding human peptide. Thus, IL13RA2-L is a potent immunogen and is capable of inducing an effective immune response against the corresponding human peptide. As expected, immunization of mice with the corresponding human IL13RA2-H peptide does not induce an immune response after administration of IL13RA2-L or the corresponding human IL13RA2-H peptide ( data not presented).

These results are confirmed in HHD DR1 mice expressing MHC HLA-A2 and HLA-DR1 and lacking murine MHC H-2 class I and class II antigens (groups of 5 mice).

EXAMPLE 5: Immunogenicity of BIRC5-B1 in HLA-A2 transgenic mice and cross-reactivity with the corresponding human peptide.

A. Materials and methods

The antigenic peptide BIRC5-B1 (SEQ ID NO:32) prepared according to the present invention and the corresponding human reference peptide BIRC5-H (SEQ ID NO:593) were tested in separate groups of male and female HHD DR3 mice expressing HLA-A2 and HLA -DR3 MHC and those that have lost murine MHC H-2 class I and class II antigens. Animals in groups of five mice (male and female) were injected subcutaneously on days 0 and 14 with 100 μg of BIRC5-B1 or BIRC5-H, 150 μg of helper peptide (DR3), and IFA. On day 21, mice were euthanized, splenocytes were harvested, and they were stimulated in vitro with BIRC5-B1 or human BIRC5-H peptide to achieve IFN-secreting capacity as determined by ELISpot. Concanavalin A (ConA) was used as a positive control.

B. Results

The number of spot forming cells (SFC) (normalized to the number of CDS cells) is presented in Figure 10. The results are shown for mice immunized with BIRC5-B1. These results indicate that immunization of mice with BIRC5-B1 induces T cells that are capable of robust responses following administration of BIRC5-B1, or the corresponding human BIRC5-H peptide. Thus, BIRC5-B1 is a potent immunogen and is capable of inducing an effective immune response against the corresponding human peptide. Immunization of mice with the corresponding human BIRC5-H peptide did not induce an immune response against BIRC5-B1 or the corresponding human peptide (data not shown).

These results are confirmed in HHD DR1 mice expressing MHC HLA-A2 and HLA-DR1 and lacking murine MHC H-2 class I and class II antigens (groups of 5 mice).

EXAMPLE 6: Immunogenicity of FOXM1-B2 in HLA-A2 transgenic mice and cross-reactivity with the corresponding human peptide.

A. Materials and methods

The antigenic peptide FOXM1-B2 (SEQ ID NO:220) prepared according to the present invention and the corresponding human peptide FOXM1-H2 (SEQ ID NO:674) were tested in separate groups of male and female HHD DR3 mice expressing HLA-A2 and HLA- DR3 MHC and those that have lost murine MHC H-2 class I and class II antigens. Animals in groups of five mice (male and female) were injected subcutaneously on days 0 and 14 with 100 μg FOXM1-B2 or FOXM1-H2, 150 μg helper peptide (DR3), and IFA. On day 21, mice were euthanized, splenocytes were harvested, and they were stimulated in vitro with FOXM1-B2 or the corresponding human FOXM1-H2 peptide to achieve IFN-secreting capacity as determined by ELISpot. Concanavalin A (ConA) was used as a positive control.

B. Results

The number of spot forming cells (SFC) (normalized to the number of CDS cells) is presented in Figure 11. The results are shown for mice immunized with FOXM1-B2. These results indicate that immunization of mice with FOXM1-B2 induces T cells that are capable of robust responses following administration of FOXM1-B2 or the corresponding human peptide. Thus, FOXM1-B2 is a potent immunogen and is capable of inducing an effective immune response against the corresponding human FOXM1-H2 peptide. Immunization of mice with the corresponding human FOXM1-H2 peptide did not induce an immune response against FOXM1-B2 or the corresponding human peptide (data not shown).

These results are confirmed in HHD DR1 mice expressing MHC HLA-A2 and HLA-DR1 and lacking murine MHC H-2 class I and class II antigens (groups of 5 mice).

Taken together, the immunogenicity studies described in Examples 5 and 6, which were performed on HHD DR3 and HHD DR1 mice, show that the three antigenic peptides produced according to the invention, IL13RA2-L, BIRC5-B1 and FOXM1-B2, induce strong immune response. Cross-reactivity of T cells generated against IL13RA2-L, BIRC5-B1 and FOXM1-B2 for the corresponding human peptides has been demonstrated in HHD DR3 and HHD DR1 mice. Accordingly, these results provide experimental evidence that antigen-based immunotherapy is capable of enhancing T cell responses in vivo and the antigenic peptides produced according to the present invention are extremely effective for this purpose.

EXAMPLE 7: IL13RA2-B has superior affinity for the HLA-A*0201 allele.

This example provides evidence that the antigenic peptide produced according to the invention, with the sequence represented by SEQ ID NO:254 (FLPFGFILV, also designated here as IL13RA2-B), has a higher affinity for the HLA-A*0201 allele compared with other sequence variants of the corresponding human reference peptide derived from IL13RA2 (IL13RA2-H, WLPFGFILI, SEQ ID NO:691). In this experiment, the antigenic peptide with the sequence SEQ ID NO:254 (IL13RA2-B) was compared with the following peptides:

- reference peptide "1A9V" (SEQ ID NO:896), described by Eguchi Junichi et al., 2006, "Identification of peptide analogues of the interleukin 13 alpha-2 receptor capable of improving anti-glioma CTL responses." Cancer Research 66(11): 5883-5891 wherein tryptophan at position 1 of SEQ ID NO:691 is replaced by alanine (1A) and isoleucine at position 9 of SEQ ID NO:691 is replaced by valine (9V);

- peptide "1IA9A" (SEQ ID NO:897), in which tryptophan at position 1 of SEQ ID NO:691 is replaced by isoleucine (II) and isoleucine at position 9 of SEQ ID NO:691 is replaced by alanine (9A); And

- peptide "1F9M" (SEQ ID NO:898), in which tryptophan at position 1 of SEQ ID NO:691 is replaced by phenylalanine (IF) and isoleucine at position 9 of SEQ ID NO:691 is replaced by methine (9M).

A. Materials and methods

The experimental protocol, materials and methods are the same as those described in Example 2 above, with the only difference being that the above (poly)peptides are used.

B. Results

The following in vitro binding affinities were determined:

Accordingly, the antigenic peptide prepared according to the present invention (IL13RA2-B; SEQ ID NO:254) has significantly higher binding affinity for HLA-A*0201 than all other peptides tested, the "1A9V" peptide described by Eguchi Junichi et al., 2006, “Identification of peptide analogues of the interleukin 13 alpha-2 receptor capable of improving anti-glioma CTL responses.” Cancer Research 66(11): 5883-5891, shows the lowest affinity of all peptides tested.

EXAMPLE 8: IL13RA2-L has superior affinity for the HLA-A*0201 allele.

This example provides evidence that the antigenic peptide obtained according to the invention with the sequence; shown as SEQ ID NO:255 (also referred to here as IL13RA2-L) has similar high affinity for the HLA-A*0201 allele as the antigenic peptide prepared according to the invention, shown as SEQ ID NO:254 ( FLPFGFILV, also referred to here as IL13RA2-B), and higher affinity compared to the corresponding human reference peptide derived from IL13RA2 (IL13RA2-H, WLPFGFILI, SEQ ID NO:691) and other sequence variants of the specified peptide. In this experiment, the antigenic peptide with the sequence SEQ ID NO:255 (IL13RA2-L) was compared with the following peptides:

- reference peptide "1A9V" (SEQ ID NO:896), described by Eguchi Junichi et al., 2006, "Identification of peptide analogues of the interleukin 13 alpha-2 receptor capable of improving anti-glioma CTL responses. Cancer Research 66(11):5883-5891 wherein tryptophan at position 1 of SEQ ID NO:691 is replaced by alanine (1A) and isoleucine at position 9 of SEQ ID NO:691 is replaced by valine (9V);

- an antigenic peptide obtained in accordance with the invention, with the sequence shown as SEQ ID NO:254 (as IL13RA2-B);

- the corresponding human IL13RA2-H reference peptide (SEQ ID NO:691; and

- positive control (HIV).

A. Materials and methods

The experimental protocol, materials and methods are the same as those described in Example 2 above, with the only difference being that the above (poly)peptides are used.

B. Results

The following in vitro binding affinities were determined:

Accordingly, the antigenic peptides produced according to the present invention (IL13RA2-B; SEQ ID NO:254 and IL13RA2-L; SEQ ID NO:255) have significantly higher binding affinity to HLA-A*0201 than the corresponding human epitope (IL13RA2 -H) and the reference peptide “1A9V” described by Eguchi Junichi et al., 2006, “Identification of interleukin 13 alpha-2 receptor peptide analogues capable of improving anti-glioma CTL responses.” Cancer Research 66(11):5883-5891. In particular, antigenic peptide IL13RA2-L (SEQ ID NO:255) exhibits strong binding affinity for HLA-A*0201, namely 69% of the maximum HIV po1 589-597 binding activity at 100 μM, 96% at 25 μM and 43% at 6.25 µM The results of the studies are also shown in Figure 12.

EXAMPLE 9: BIRC5-B1 has superior affinity for the HLA-A*0201 allele.

This example provides evidence that the antigenic peptide produced according to the invention with the sequence represented by SEQ ID NO:32 (also designated herein as BIRC5-B1) has a higher affinity than the corresponding human reference peptide derived from BIRC5 (BIRC5-H; SEQ ID NO:593), and comparative sequence variants of the specified peptide ("2M"; SEQ ID NO:899). In this experiment, the antigenic peptide with the sequence SEQ ID NO:32 (BIRC5-B1) was compared with the following peptides:

- peptide "2M" (LMLGEFLKL; SEQ ID NO:899), in which threonine in position 2 of SEQ ID NO:593 is replaced by methionine (2M);

- the corresponding human reference peptide BIRC5-H (SEQ ID NO:593); And

- positive control (HIV).

A. Materials and methods

The experimental protocol, materials and methods are the same as those described in Example 2 above, with the only difference being that the above (poly)peptides are used.

B. Results

The following in vitro binding affinities were determined:

Overall, the antigenic peptide produced according to the present invention (BIRC5-B1; SEQ ID NO:32) has in vitro significantly higher binding affinity for HLA-A*0201 than the corresponding human epitope (BIRC5-H) and the comparative peptide "2M". The research results are also shown in Figure 13.

--->

List of Sequences

<110> Enter S.A.

<120> ANTIGENE PEPTIDES FOR CANCER PREVENTION AND TREATMENT

<130>EB01P011WO1

<150>EP18305444

<151> 2018-04-11

<150> PCT/EP2018/077512

<151> 2018-10-09

<160> 899

<170> Patent In version 3.5

<210> 1

<211> 9

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Val Leu Phe Leu Leu Phe Phe Pro Val

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Ser Met Ser Leu Gly Phe Leu Ser Val

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Phe Leu Ser Leu Gly Phe Leu Ala Val

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Leu Leu Leu Gly Phe Leu Phe Leu Ile

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Tyr Leu Ser Asn Asp Ser Tyr Arg Val

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Gly Leu Ile Asp Ser Gly Ala Phe Leu

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Leu Leu Ile Asp Ser Gly Ala Leu Val

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Arg Leu Ile Asp Ser Gly Ala Thr Val

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Lys Leu Phe Glu Ser Ser Ala Ala Leu

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Thr Leu Phe Glu Ser Ser Ala Phe Ala

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<400> 11

Met Leu Thr Pro Leu Leu Leu Gly Leu

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<210> 12

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<400> 12

Tyr Leu Thr Pro Leu Leu Leu Ile Leu

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<400> 13

Ile Met Thr Pro Leu Leu Leu Pro Val

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<400> 14

Phe Met Thr Pro Leu Leu Leu Cys Leu

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<400> 15

Phe Leu Thr Pro Leu Leu Leu Trp Leu

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Trp Met Ala Val Ile Leu Thr Ala Leu

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Val Leu Ala Val Ile Leu Thr Ala Val

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Val Leu Ala Ala Ile Ala Ala Gly Val

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<400> 19

Leu Leu Ala Ala Ile Ala Ala Phe Leu

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<400> 20

Lys Leu Ala Ala Ile Ala Ala Ala Val

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Ile Leu Ala Ala Ile Ala Ala Ala Val

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Gly Met Ala Ala Ile Ala Ala Phe Leu

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Phe Leu Ala Ala Ile Ala Ala Val Leu

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Ala Leu Ala Ala Ile Ala Ala Leu Val

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Ala Leu Ala Ala Phe Gln Ala Gly Leu

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Ser Leu Val Asn Leu Gly Phe Ser Leu

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Gly Leu Val Asn Leu Gly Phe Ala Leu

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Gln Leu Leu Asp Phe Ser Ser Ser Leu

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<400> 29

Ile Leu Leu Asp Phe Ser Ser Val Val

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<400> 30

Tyr Thr Leu Gly Glu Phe Leu Tyr Ile

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<400> 31

Gly Leu Leu Gly Glu Phe Leu Gln Ile

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Phe Met Leu Gly Glu Phe Leu Lys Leu

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<400> 33

Val Leu Gly Asp Ile Leu Ala Leu Leu

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Lys Val Gly Asp Ile Leu Ala Leu Val

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Asn Leu Val Phe Gly Leu Leu Pro Val

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Phe Leu Val Phe Gly Leu Leu Gly Leu

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Ala Leu Val Phe Gly Leu Leu Arg Val

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<400> 38

Gly Val Tyr Glu Gly Ser Leu Thr Val

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<400> 39

Val Leu Ser Thr Ala Phe Ala Leu Val

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<400> 40

Gly Leu Ser Thr Ala Phe Ala Ala Val

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<400> 41

Ala Leu Ser Thr Ala Phe Ala Val Val

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<400> 42

Met Leu Leu Leu Leu Leu Val Pro Val

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<400> 43

Leu Leu Leu Leu Leu Leu Val Pro Val

15

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<212>PRT

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<400> 44

Ala Ile Leu Leu Leu Leu Val Pro Val

15

<210> 45

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<400> 45

Tyr Leu Leu Leu Ser Leu Leu Arg Leu

15

<210> 46

<211> 9

<212>PRT

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<220>

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<400> 46

Phe Leu Leu Leu Ser Leu Leu Thr Leu

15

<210> 47

<211> 9

<212>PRT

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<400> 47

Ala Leu Leu Leu Ser Leu Leu Pro Leu

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<210> 48

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<400> 48

Arg Leu Leu Leu Leu Ser Leu Leu Val

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<400> 49

Lys Leu Leu Leu Leu Ser Leu Leu Leu

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<210> 50

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<400> 50

Phe Leu Leu Leu Leu Ser Leu Leu Ile

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<210> 51

<211> 9

<212>PRT

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<220>

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<400> 51

Arg Leu Ala Lys Tyr Val Ala Leu Val

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<210> 52

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<220>

<223> peptide

<400> 52

Leu Ile Ala Ala Ala Ala Phe Thr Val

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<211> 9

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<400> 53

Gly Met Ala Ala Ala Ala Phe Cys Leu

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<400> 54

Gly Leu Ala Ala Ala Ala Phe Cys Ile

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<210> 55

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 55

Phe Leu Ala Ala Ala Ala Phe Cys Leu

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<210> 56

<211> 9

<212>PRT

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<220>

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<400> 56

Trp Leu Asn Asp Arg Val Leu Gln Leu

15

<210> 57

<211> 9

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<220>

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<400> 57

Lys Leu Leu Leu Thr Thr Leu Leu Val

15

<210> 58

<211> 9

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<220>

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<400> 58

Gly Met Ala Val Val Phe Ile Asn Val

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<210> 59

<211> 9

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<400> 59

Gly Met Ala Val Val Phe Ile Glu Val

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<210> 60

<211> 9

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<400> 60

Leu Leu Leu Thr Thr Leu Leu Ala Val

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<400> 61

Ala Leu Leu Thr Thr Leu Leu Leu Val

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<210> 62

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<400> 62

Ala Leu Leu Thr Thr Leu Leu Gly Leu

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<210> 63

<211> 9

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<220>

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<400> 63

Lys Ile Ile Gly Ile Ile Leu Ala Val

15

<210> 64

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<400> 64

Tyr Leu Val Ala Ile Leu Leu Leu Val

15

<210> 65

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<400> 65

Thr Leu Val Ala Ile Leu Leu Asn Val

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<210> 66

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<400> 66

Met Leu Val Ala Ile Leu Leu Ala Val

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<210> 67

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<400> 67

Leu Leu Val Ala Ile Leu Leu Ser Val

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<210> 68

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<400> 68

Phe Leu Val Ala Ile Leu Leu Asn Leu

15

<210> 69

<211> 9

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<220>

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<400> 69

Ala Met Val Ala Ile Leu Leu Asn Ile

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<210> 70

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<220>

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<400> 70

Ala Leu Val Ala Ile Leu Leu Ala Ile

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<210> 71

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<220>

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<400> 71

Leu Leu Ser Asp Val Gly Thr Leu Leu

15

<210> 72

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<400> 72

Phe Leu Ser Thr Tyr Leu Leu Pro Met

15

<210> 73

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<400> 73

Ala Leu Leu Glu Glu Tyr Thr Gly Ile

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<210> 74

<211> 9

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<400> 74

Ser Leu Leu Cys Ile Val Ile Gly Leu

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<210> 75

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<400> 75

Ile Leu Leu Cys Ile Val Ile Gly Leu

15

<210> 76

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<400> 76

Met Leu Val Thr Val Val Leu Thr Val

15

<210> 77

<211> 9

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<400> 77

Met Leu Val Thr Val Val Leu Leu Val

15

<210> 78

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<400> 78

Leu Leu Val Thr Val Val Leu Pro Val

15

<210> 79

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<400> 79

Leu Leu Val Thr Val Val Leu Ala Val

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<210> 80

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<400> 80

Lys Leu Val Thr Val Val Leu Ala Val

15

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<400> 81

Ile Leu Val Thr Val Val Leu Gly Ile

15

<210> 82

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<400> 82

Leu Met Ala Leu Val Leu Met Leu Val

15

<210> 83

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<400> 83

Gly Leu Thr Phe Trp Asn Pro Asn Val

15

<210> 84

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<400> 84

Phe Met Leu Leu Leu Ser Ala Ala Ala

15

<210> 85

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<400> 85

Phe Leu Leu Leu Leu Ser Ala Ala Leu

15

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<400> 86

Tyr Leu Leu Ser Ala Ala Leu Thr Leu

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<400> 87

Tyr Leu Leu Ser Ala Ala Leu Thr Ile

15

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<400> 88

Val Leu Leu Ser Ala Ala Leu Leu Leu

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<210> 89

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<220>

<223> peptide

<400> 89

Val Leu Leu Ser Ala Ala Leu Phe Leu

15

<210> 90

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<220>

<223> peptide

<400> 90

Ser Leu Leu Ser Ala Ala Leu Thr Val

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<210> 91

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 91

Arg Leu Leu Ser Ala Ala Leu Ala Leu

15

<210> 92

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<212>PRT

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<223> peptide

<400> 92

Leu Met Leu Ser Ala Ala Leu Leu Leu

15

<210> 93

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 93

Leu Met Leu Ser Ala Ala Leu Cys Val

15

<210> 94

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 94

Leu Met Leu Ser Ala Ala Leu Ala Val

15

<210> 95

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 95

Leu Leu Leu Ser Ala Ala Leu Trp Val

15

<210> 96

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 96

Leu Leu Leu Ser Ala Ala Leu Thr Val

15

<210> 97

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 97

Leu Leu Leu Ser Ala Ala Leu Ser Val

15

<210> 98

<211> 9

<212>PRT

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<220>

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<400> 98

Leu Leu Leu Ser Ala Ala Leu Met Ile

15

<210> 99

<211> 9

<212>PRT

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<220>

<223> peptide

<400> 99

Leu Leu Leu Ser Ala Ala Leu Leu Leu

15

<210> 100

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 100

Leu Leu Leu Ser Ala Ala Leu Cys Val

15

<210> 101

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 101

Leu Leu Leu Ser Ala Ala Leu Ala Leu

15

<210> 102

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 102

Lys Leu Leu Ser Ala Ala Leu Ser Val

15

<210> 103

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 103

Ile Leu Leu Ser Ala Ala Leu Leu Leu

15

<210> 104

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 104

Ile Leu Leu Ser Ala Ala Leu Gly Ile

15

<210> 105

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 105

Phe Leu Leu Ser Ala Ala Leu Val Val

15

<210> 106

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 106

Phe Leu Leu Ser Ala Ala Leu Ile Leu

15

<210> 107

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 107

Ala Leu Leu Ser Ala Ala Leu Met Leu

15

<210> 108

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 108

Ala Leu Leu Ser Ala Ala Leu Leu Val

15

<210> 109

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 109

Ala Leu Leu Ser Ala Ala Leu Leu Leu

15

<210> 110

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 110

Tyr Met Ala Gly Ala Met Val Gln Leu

15

<210> 111

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 111

Arg Met Ala Gly Ala Met Val Pro Val

15

<210> 112

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 112

Arg Leu Ala Gly Ala Met Val Asp Val

15

<210> 113

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 113

Met Met Thr Gly Phe Val Val Leu Met

15

<210> 114

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 114

Tyr Leu Ala Ser Ser Glu Thr His Val

15

<210> 115

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 115

Ser Met Leu Ser Ile Gly Gly Tyr Val

15

<210> 116

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 116

Leu Leu Ile Tyr Ser Phe Ala Arg Val

15

<210> 117

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 117

Lys Leu Ile His Glu Leu Ala Glu Val

15

<210> 118

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 118

Ile Leu Ile His Glu Leu Ala His Ile

15

<210> 119

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 119

His Leu Trp Ala Gly Val Val Leu Val

15

<210> 120

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 120

Arg Leu Trp Asp Phe Thr Val Gly Val

15

<210> 121

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 121

Val Leu Ala Ser Ser Ile Leu Tyr Ile

15

<210> 122

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 122

Ser Leu Ala Ser Ser Ile Leu Gln Leu

15

<210> 123

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 123

Ala Leu Ala Ser Ser Ile Leu Gln Leu

15

<210> 124

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 124

Phe Leu Ala Val Ser Leu Ala Pro Leu

15

<210> 125

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 125

Ile Leu Val Gly Leu Phe Val Pro Val

15

<210> 126

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 126

Ile Leu Val Gly Leu Phe Val Ala Val

15

<210> 127

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 127

Tyr Leu Phe Val Leu Leu Ala Gly Ile

15

<210> 128

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 128

Ser Leu Phe Val Leu Leu Ala Ala Val

15

<210> 129

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 129

Lys Leu Phe Val Leu Leu Ala Leu Val

15

<210> 130

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 130

Gly Ile Tyr Asp Phe Phe Val Lys Val

15

<210> 131

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 131

Thr Ile Met Gly Thr Leu Val Ser Val

15

<210> 132

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 132

Arg Val Met Gly Thr Leu Val Gly Ile

15

<210> 133

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 133

Thr Leu Ala Glu Gly Leu Ala Leu Ala

15

<210> 134

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 134

Phe Leu Ala Ala Gly Leu Gly Gln Val

15

<210> 135

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 135

Val Leu Glu Ser Ile Leu His Pro Val

15

<210> 136

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 136

Arg Met Glu Ser Ile Leu His Glu Val

15

<210> 137

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 137

Ala Leu Leu Ala Ala Leu Cys Tyr Val

15

<210> 138

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 138

Tyr Leu Leu Ala Leu Leu Ala Trp Leu

15

<210> 139

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 139

Val Leu Leu Ala Leu Leu Ala Glu Val

15

<210> 140

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 140

Ser Leu Leu Ala Leu Leu Ala Phe Val

15

<210> 141

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 141

Arg Leu Leu Ala Leu Leu Ala Ser Val

15

<210> 142

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 142

Arg Leu Leu Ala Leu Leu Ala Ala Val

15

<210> 143

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 143

Leu Leu Leu Ala Leu Leu Ala Pro Val

15

<210> 144

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 144

Ala Leu Leu Ala Leu Leu Ala Ser Val

15

<210> 145

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 145

Ile Leu Asp Glu Ala Tyr Val Arg Val

15

<210> 146

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 146

Ala Leu Leu Leu Leu Val Val Gly Val

15

<210> 147

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 147

Gly Leu Gly Ala Leu Leu Leu Leu Val

15

<210> 148

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 148

Tyr Met Gln Glu Ile Leu His Arg Leu

15

<210> 149

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 149

Thr Leu Ala Val Val Ser Leu Ala Val

15

<210> 150

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 150

Leu Leu Ala Val Val Ser Leu Phe Val

15

<210> 151

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 151

Tyr Leu Val Gly Ile Leu Leu Val Leu

15

<210> 152

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 152

Lys Val Val Gly Ile Leu Leu Pro Ile

15

<210> 153

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 153

Ile Leu Val Gly Ile Leu Leu Val Val

15

<210> 154

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 154

Phe Val Val Gly Ile Leu Leu Gln Val

15

<210> 155

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 155

Ile Leu Asp Glu Ala Tyr Val Arg Val

15

<210> 156

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 156

Leu Leu Ala Leu Leu Pro Pro Glu Val

15

<210> 157

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 157

Leu Leu Ala Leu Leu Pro Pro Glu Leu

15

<210> 158

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 158

Ala Met Ala Leu Leu Pro Pro Glu Val

15

<210> 159

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 159

Ala Leu Ala Leu Leu Pro Pro Pro Val

15

<210> 160

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 160

Ile Leu Ile Ser Ala Val Val Gly Leu

15

<210> 161

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 161

Ile Val Leu Gly Val Val Phe Gly Val

15

<210> 162

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 162

Ile Ile Leu Gly Val Val Phe Gly Leu

15

<210> 163

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 163

Tyr Leu Leu Glu Leu Leu Ser Ala Leu

15

<210> 164

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 164

Ile Met Trp Gln Phe Leu Leu Glu Leu

15

<210> 165

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 165

Tyr Leu Leu Asp Ala Glu Pro Gln Leu

15

<210> 166

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 166

Lys Leu Thr Asp Thr Leu Ile Pro Leu

15

<210> 167

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 167

Lys Leu Thr Asp Thr Leu Ile Glu Leu

15

<210> 168

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 168

Tyr Leu Leu Phe Ala Pro Asn Ala Val

15

<210> 169

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 169

Phe Leu Leu Phe Ala Pro Asn Ser Ala

15

<210> 170

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 170

Tyr Leu Asp Ala Glu Pro Pro Ala Val

15

<210> 171

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 171

Thr Leu Asn Ser Gly Val Tyr Leu Ile

15

<210> 172

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 172

Lys Met Asn Ser Gly Val Tyr Val Ile

15

<210> 173

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 173

Leu Leu Ile Gly Leu Val Trp Ser Leu

15

<210> 174

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 174

Tyr Leu Tyr Asp Leu Leu Leu Thr Val

15

<210> 175

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 175

Val Leu Tyr Asp Leu Leu Leu Glu Val

15

<210> 176

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 176

Thr Leu Tyr Asp Leu Leu Leu Ser Leu

15

<210> 177

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 177

Gln Leu Tyr Asp Leu Leu Leu Val Ala

15

<210> 178

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 178

Gln Leu Tyr Asp Leu Leu Leu Ser Leu

15

<210> 179

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 179

Gly Leu Tyr Asp Leu Leu Leu Arg Ile

15

<210> 180

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 180

Ala Val Tyr Asp Leu Leu Leu Glu Val

15

<210> 181

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 181

Ala Leu Tyr Asp Leu Leu Leu Glu Val

15

<210> 182

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 182

Val Leu Leu Leu Ile Leu Ser Gly Val

15

<210> 183

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 183

Val Leu Leu Leu Ile Leu Ser Glu Val

15

<210> 184

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 184

Ser Leu Leu Leu Ile Leu Ser Phe Val

15

<210> 185

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 185

Met Leu Leu Leu Ile Leu Ser Tyr Leu

15

<210> 186

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 186

Ile Leu Leu Leu Ile Leu Ser Gly Ile

15

<210> 187

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 187

Phe Leu Leu Leu Ile Leu Ser Leu Leu

15

<210> 188

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 188

Phe Leu Leu Leu Ile Leu Ser Phe Leu

15

<210> 189

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 189

Ser Leu Ala Gln Leu Leu Leu Ala Ile

15

<210> 190

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 190

Met Leu Ala Gln Leu Leu Leu Thr Val

15

<210> 191

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 191

Lys Leu Ile His Leu Met Ala Ala Val

15

<210> 192

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 192

Phe Leu Asp Lys Ile Thr Asp Leu Val

15

<210> 193

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 193

Phe Leu Val Glu Asp Glu Thr Val Ile

15

<210> 194

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 194

Ala Val Phe Arg Val Leu Ile Pro Val

15

<210> 195

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 195

Leu Leu Ser Ala Val Leu Ala Leu Val

15

<210> 196

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 196

Leu Leu Ser Ala Val Leu Ala Leu Ala

15

<210> 197

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 197

Gly Ile Ser Ala Val Leu Ala Leu Val

15

<210> 198

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 198

Asn Leu Trp Ala Gly Gly Phe Phe Leu

15

<210> 199

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 199

Tyr Leu Ala Leu Leu Val Met Leu Leu

15

<210> 200

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 200

Leu Leu Ala Leu Leu Val Met Ala Val

15

<210> 201

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 201

Ala Leu Ala Leu Leu Val Met Ala Val

15

<210> 202

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 202

Thr Met Leu Ser Cys Leu Leu His Leu

15

<210> 203

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 203

Met Leu Leu Ser Cys Leu Leu Phe Met

15

<210> 204

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 204

Leu Leu Leu Ser Cys Leu Leu Pro Leu

15

<210> 205

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 205

Leu Leu Leu Ser Cys Leu Leu His Leu

15

<210> 206

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 206

Ile Leu Leu Ser Cys Leu Leu Leu Leu

15

<210> 207

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 207

Phe Leu Leu Ser Cys Leu Leu Cys Leu

15

<210> 208

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 208

Ala Leu Leu Ser Cys Leu Leu Met Leu

15

<210> 209

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 209

Tyr Val Ala Ala Thr Leu Phe Ala Leu

15

<210> 210

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 210

Tyr Leu Tyr Ser Glu Ile Pro Asp Ile

15

<210> 211

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 211

Tyr Met Ala Ser Thr Leu Val His Leu

15

<210> 212

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 212

Gln Met Ala Ser Thr Leu Val Tyr Leu

15

<210> 213

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 213

Tyr Gln Phe Asp Lys Ile Tyr Ser Ile

15

<210> 214

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 214

Met Met Phe Trp Leu Leu Leu Val Val

15

<210> 215

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 215

Gly Met Leu Trp Glu Ile Phe Gly Val

15

<210> 216

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 216

Ala Met Lys Asp Gly Leu Pro Glu Val

15

<210> 217

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 217

Thr Leu Leu Asp Ile Ser Phe Ala Ala

15

<210> 218

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 218

Asn Met Leu Asp Ile Ser Phe Tyr Leu

15

<210> 219

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 219

Ile Leu Asp Ile Ser Phe Pro Leu Val

15

<210> 220

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 220

Leu Met Asp Leu Ser Thr Thr Glu Val

15

<210> 221

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 221

Arg Leu Ser Ser Tyr Leu Val Glu Ile

15

<210> 222

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 222

Met Val Ser Ser Tyr Leu Val Glu Val

15

<210> 223

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 223

Lys Val Ser Ser Tyr Leu Val Glu Val

15

<210> 224

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 224

Ile Leu Ser Lys Ile Leu Leu Phe Ala

15

<210> 225

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 225

Tyr Gln Leu Ser Tyr Ser Gln Met Val

15

<210> 226

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 226

Lys Leu Leu Ser Tyr Ser Gln Glu Leu

15

<210> 227

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 227

Lys Ile Ala Glu Leu Pro Phe Pro Leu

15

<210> 228

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 228

Tyr Leu Asn Glu Ser Glu Thr Val Leu

15

<210> 229

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 229

Met Leu Val Glu Leu Leu Lys Lys Val

15

<210> 230

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 230

Lys Leu Val Glu Leu Leu Lys Leu Leu

15

<210> 231

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 231

Ala Leu Val Glu Leu Leu Lys Pro Leu

15

<210> 232

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 232

Phe Leu Ala Ser Thr Thr Pro Thr Ala

15

<210> 233

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 233

Ser Leu Ala Arg Glu Val Ala Ala Val

15

<210> 234

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 234

Gly Met Ala Arg Glu Val Ala Ala Val

15

<210> 235

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 235

Trp Leu Leu Ser Leu Ala Phe Leu Leu

15

<210> 236

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 236

Ser Leu Leu Ser Leu Ala Phe Ser Ala

15

<210> 237

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 237

Leu Leu Leu Ser Leu Ala Phe Ile Leu

15

<210> 238

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 238

Lys Leu Asn Pro Ala Gln Gly Tyr Val

15

<210> 239

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 239

Lys Leu Trp Gly Leu Ala Thr Leu Ile

15

<210> 240

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 240

Val Leu Ala Leu Gly Leu Leu Ala Val

15

<210> 241

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 241

Ser Leu Ala Leu Gly Leu Leu Gln Val

15

<210> 242

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 242

Ser Leu Ala Leu Gly Leu Leu Leu Val

15

<210> 243

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 243

Met Leu Ala Leu Gly Leu Leu Glu Val

15

<210> 244

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 244

Gly Leu Ala Leu Gly Leu Leu Phe Val

15

<210> 245

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 245

Gly Leu Ala Leu Gly Leu Leu Ala Val

15

<210> 246

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 246

Phe Leu Ala Leu Gly Leu Leu Phe Leu

15

<210> 247

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 247

Ala Leu Ala Leu Gly Leu Leu Met Val

15

<210> 248

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 248

Val Leu Leu Leu Ala Gly Ala Tyr Val

15

<210> 249

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 249

Tyr Leu Tyr Thr Phe Leu Ile Val Leu

15

<210> 250

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 250

Gly Met Tyr Thr Phe Leu Ile Pro Met

15

<210> 251

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 251

Gly Leu Tyr Thr Phe Leu Ile Pro Met

15

<210> 252

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 252

Phe Leu Ile Ser Thr Thr Phe Ala Ala

15

<210> 253

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 253

Ile Leu Leu Asp Thr Asn Tyr Glu Ile

15

<210> 254

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 254

Phe Leu Pro Phe Gly Phe Ile Leu Val

15

<210> 255

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 255

Phe Leu Pro Phe Gly Phe Ile Leu Pro Val

1 5 10

<210> 256

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 256

Met Leu Tyr Leu Leu Pro Leu Ser Leu

15

<210> 257

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 257

Met Leu Tyr Leu Leu Pro Leu Ala Leu

15

<210> 258

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 258

Leu Leu Tyr Leu Leu Pro Leu Phe Leu

15

<210> 259

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 259

Ser Met Leu Tyr Asn Leu Leu Ala Leu

15

<210> 260

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 260

Ala Met Leu Tyr Asn Leu Leu Ala Leu

15

<210> 261

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 261

Ala Leu Leu Tyr Asn Leu Leu Ala Leu

15

<210> 262

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 262

Ile Leu Phe Leu Val Leu Gln Arg Val

15

<210> 263

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 263

Tyr Leu Val Ala Ala Val Val Leu Leu

15

<210> 264

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 264

Tyr Leu Ala Glu Arg Ala Gly His Val

15

<210> 265

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 265

Ile Leu Val Pro Leu Phe Phe Thr Leu

15

<210> 266

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 266

Gly Leu Val Pro Leu Phe Phe Ala Leu

15

<210> 267

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 267

Phe Leu Val Pro Leu Phe Phe Val Val

15

<210> 268

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 268

Phe Leu Val Pro Leu Phe Phe Leu Leu

15

<210> 269

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 269

Ala Leu Val Pro Leu Phe Phe Ala Leu

15

<210> 270

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 270

Tyr Met Leu Pro Leu Leu Ala Gly Ala

15

<210> 271

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 271

Tyr Leu Leu Pro Leu Leu Ala Leu Ala

15

<210> 272

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 272

Trp Leu Leu Pro Leu Leu Ala Val Val

15

<210> 273

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 273

Trp Leu Leu Pro Leu Leu Ala Cys Leu

15

<210> 274

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 274

Trp Leu Leu Pro Leu Leu Ala Ala Leu

15

<210> 275

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 275

Thr Leu Leu Pro Leu Leu Ala Ala Val

15

<210> 276

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 276

Thr Leu Leu Pro Leu Leu Ala Ala Ala

15

<210> 277

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 277

Ser Leu Leu Pro Leu Leu Ala Gly Val

15

<210> 278

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 278

Arg Leu Leu Pro Leu Leu Ala Val Leu

15

<210> 279

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 279

Arg Leu Leu Pro Leu Leu Ala Ala Ile

15

<210> 280

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 280

Gln Leu Leu Pro Leu Leu Ala Tyr Val

15

<210> 281

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 281

Leu Leu Leu Pro Leu Leu Ala Gly Leu

15

<210> 282

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 282

Leu Leu Leu Pro Leu Leu Ala Asp Leu

15

<210> 283

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 283

Leu Leu Leu Pro Leu Leu Ala Ala Ala

15

<210> 284

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 284

His Val Leu Pro Leu Leu Ala Thr Val

15

<210> 285

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 285

His Leu Leu Pro Leu Leu Ala Glu Val

15

<210> 286

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 286

Gly Leu Leu Pro Leu Leu Ala Lys Ile

15

<210> 287

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 287

Gly Ile Leu Pro Leu Leu Ala Thr Val

15

<210> 288

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 288

Tyr Leu Ser Asp Ala Val Glu Ala Val

15

<210> 289

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 289

Ile Leu Arg Glu Ala Ala Met Pro Val

15

<210> 290

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 290

Phe Leu Ile Pro Ala Pro Glu Ser Leu

15

<210> 291

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 291

Phe Leu Leu His Gly Leu Asn Leu Met

15

<210> 292

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 292

Tyr Met Ser Ser Leu Pro Gln Gly Leu

15

<210> 293

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 293

Tyr Met Ile Leu Gly Val Ala Met Ile

15

<210> 294

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 294

Val Leu Ile Leu Gly Val Ala Ala Val

15

<210> 295

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 295

Ser Leu Ile Leu Gly Val Ala Ala Val

15

<210> 296

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 296

Ile Leu Ile Leu Gly Val Ala Gly Ile

15

<210> 297

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 297

Leu Leu Asp Cys Ile Ile Ala Phe Leu

15

<210> 298

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 298

Leu Ile Leu Gly Ile Phe Ile Ser Val

15

<210> 299

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 299

Tyr Leu Ala Val Leu Gly Ile Ser Leu

15

<210> 300

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 300

Val Leu Ala Ala Ile Val Ile Gly Val

15

<210> 301

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 301

Leu Leu Ala Cys Ser Leu Ala Met Leu

15

<210> 302

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 302

Phe Val Ile Gly Ile Val Ala Leu Val

15

<210> 303

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 303

Tyr Val Val Ala Val Pro Thr Pro Val

15

<210> 304

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 304

Tyr Ile Val Ala Val Pro Thr Pro Val

15

<210> 305

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 305

Phe Ile Val Ala Val Pro Thr Pro Ile

15

<210> 306

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 306

Met Leu Lys Glu Leu Ser Pro Glu Leu

15

<210> 307

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 307

Phe Leu Lys Glu Leu Ser Pro Gly Leu

15

<210> 308

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 308

Phe Val Ala Asp Leu Val Gly His Val

15

<210> 309

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 309

Ser Leu Leu Gly Thr Leu Glu Glu Leu

15

<210> 310

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 310

Val Met Leu Ser Asp Val Gln Ser Val

15

<210> 311

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 311

Arg Leu Leu Ser Asp Val Gln Gly Leu

15

<210> 312

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 312

Ser Leu Ile Leu Ile Leu Ser Ser Val

15

<210> 313

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 313

Lys Leu Ile Leu Ile Leu Ser Tyr Leu

15

<210> 314

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 314

Ala Leu Asp Ala Ile Phe Gly Gly Val

15

<210> 315

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 315

Phe Leu Ile Thr Lys Ala Glu Glu Leu

15

<210> 316

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 316

Ser Leu Leu Glu Glu Leu Pro Ala Leu

15

<210> 317

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 317

Met Thr Leu Glu Glu Leu Pro Phe Leu

15

<210> 318

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 318

Ile Ile Leu Glu Tyr Ile Ala Leu Leu

15

<210> 319

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 319

Tyr Met Val Phe Gly Ile Glu Gly Ile

15

<210> 320

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 320

Ser Leu Ser Ser Ser Ser Pro Leu Val

15

<210> 321

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 321

Lys Leu Asp Glu Leu Ala His Phe Leu

15

<210> 322

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 322

Phe Val Leu Glu His Val Val Pro Leu

15

<210> 323

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 323

Tyr Leu Leu Gly Val Leu Leu Leu Leu

15

<210> 324

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 324

Tyr Ile Leu Gly Val Leu Leu Thr Ala

15

<210> 325

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 325

Met Leu Leu Gly Val Leu Leu Leu Leu

15

<210> 326

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 326

Met Ile Leu Gly Val Leu Leu Phe Leu

15

<210> 327

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 327

Leu Met Leu Gly Val Leu Leu Leu Ala

15

<210> 328

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 328

Leu Leu Leu Gly Val Leu Leu Leu Leu

15

<210> 329

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 329

Lys Leu Leu Gly Val Leu Leu Leu Val

15

<210> 330

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 330

Ile Ile Leu Gly Val Leu Leu Ala Val

15

<210> 331

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 331

Phe Ile Leu Gly Val Leu Leu Ser Leu

15

<210> 332

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 332

Ala Leu Leu Gly Val Leu Leu Leu Leu

15

<210> 333

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 333

Ala Leu Leu Gly Val Leu Leu Leu Ala

15

<210> 334

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 334

Ala Ile Leu Gly Val Leu Leu Leu Val

15

<210> 335

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 335

Ile Leu Ala Ala Gly Val Pro Glu Leu

15

<210> 336

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 336

Tyr Val Ser Asp Ile Leu Ser Tyr Val

15

<210> 337

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 337

Tyr Ile Ser Asp Ile Leu Ser Tyr Val

15

<210> 338

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 338

Val Ile Ser Asp Ile Leu Ser Phe Leu

15

<210> 339

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 339

Ser Met Ser Asp Ile Leu Ser Arg Leu

15

<210> 340

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 340

Phe Val Ser Asp Ile Leu Ser Ala Ala

15

<210> 341

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 341

Trp Leu Leu Ala Ala Ser Val Thr Val

15

<210> 342

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 342

Ile Leu Leu Ala Ala Ser Val Leu Val

15

<210> 343

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 343

Phe Leu Leu Ala Ala Ser Val Met Met

15

<210> 344

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 344

Ala Leu Leu Ala Ala Ser Val Leu Val

15

<210> 345

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 345

Leu Leu Ala Ala Ser Val Ala Leu Leu

15

<210> 346

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 346

Leu Leu Ala Ala Ser Val Ala Gly Val

15

<210> 347

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 347

Ile Leu Ala Ala Ser Val Ala Ala Val

15

<210> 348

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 348

Gly Leu Ala Ala Ser Val Ala Pro Val

15

<210> 349

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 349

Ala Leu Leu Arg Lys Val Ala Glu Val

15

<210> 350

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 350

Ser Leu Pro Glu Leu Tyr Ala Trp Ile

15

<210> 351

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 351

Ile Leu Tyr Gly Lys Ile Lys Tyr Leu

15

<210> 352

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 352

Met Leu Leu Gly Leu Ala Ala Phe Leu

15

<210> 353

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 353

Gly Leu Leu Gly Leu Ala Ala Phe Leu

15

<210> 354

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 354

Ala Leu Leu Gly Leu Ala Ala Phe Leu

15

<210> 355

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 355

Tyr Leu Asp Glu Val Lys Ser Leu Val

15

<210> 356

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 356

Tyr Leu Asp Glu Val Lys Ser Leu Ile

15

<210> 357

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 357

Tyr Leu Asp Glu Val Lys Ser Ile Leu

15

<210> 358

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 358

Leu Leu Asp Glu Val Lys Ser Leu Val

15

<210> 359

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 359

Phe Ile Leu Leu Ser Leu Ser Pro Val

15

<210> 360

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 360

Arg Leu Phe Leu Phe Ser Val Leu Val

15

<210> 361

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 361

Ala Leu Thr Val Tyr Leu Val Tyr Leu

15

<210> 362

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 362

Arg Leu Leu Phe Val Ala Val Pro Ile

15

<210> 363

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 363

Arg Leu Leu Phe Val Ala Val Gly Leu

15

<210> 364

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 364

Phe Leu Leu Phe Val Ala Val Ser Val

15

<210> 365

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 365

Phe Ile Ser Leu Phe Leu Phe Ser Val

15

<210> 366

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 366

Leu Ile Ala Gly Phe Val Ala Leu Val

15

<210> 367

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 367

Tyr Leu Leu Val Leu Met Ala Ser Ile

15

<210> 368

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 368

Tyr Leu Val Gly Ile Leu Leu Val Leu

15

<210> 369

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 369

Lys Ile Val Gly Ile Leu Leu Gly Ile

15

<210> 370

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 370

Lys Ile Val Gly Ile Leu Leu Ala Val

15

<210> 371

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 371

Ile Leu Val Gly Ile Leu Leu Val Val

15

<210> 372

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 372

Gly Ile Val Gly Ile Leu Leu Asn Val

15

<210> 373

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 373

Gly Ile Val Gly Ile Leu Leu Ala Val

15

<210> 374

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 374

Leu Leu Ala Val Val Leu Ala Phe Val

15

<210> 375

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 375

Leu Leu Ala Val Val Leu Ala Ala Val

15

<210> 376

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 376

Gly Val Leu Asp Gly Thr Ala Thr Val

15

<210> 377

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 377

Ala Leu Ala Asp Thr Asn Ser Tyr Val

15

<210> 378

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 378

Ala Leu Ala Asp Thr Asn Ser Tyr Leu

15

<210> 379

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 379

Ala Met Gln Ala Ala Ile Pro Met Leu

15

<210> 380

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 380

Ile Val Leu Asp Gly Leu Asp Leu Val

15

<210> 381

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 381

Ala Val Leu Asp Gly Leu Asp Pro Val

15

<210> 382

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 382

Tyr Leu Leu Ala Leu Leu Pro Leu Leu

15

<210> 383

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 383

Tyr Leu Leu Ala Leu Leu Pro Ile Leu

15

<210> 384

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 384

Gln Leu Leu Ala Leu Leu Pro Gly Val

15

<210> 385

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 385

Leu Leu Leu Ala Leu Leu Pro Thr Val

15

<210> 386

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 386

Phe Leu Arg Glu Leu Leu Cys Gln Leu

15

<210> 387

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 387

Leu Leu Tyr Pro Val Pro Leu Gly Val

15

<210> 388

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 388

Ala Leu Phe Leu Leu Ser Tyr Thr Val

15

<210> 389

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 389

Tyr Val Leu Ser Leu Leu Leu Thr Leu

15

<210> 390

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 390

Val Leu Leu Ser Leu Leu Leu Ile Val

15

<210> 391

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 391

Ser Leu Leu Ser Leu Leu Leu Ile Leu

15

<210> 392

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 392

Arg Leu Leu Ser Leu Leu Leu Val Leu

15

<210> 393

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 393

Leu Val Leu Ser Leu Leu Leu Leu Val

15

<210> 394

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 394

Lys Leu Leu Ser Leu Leu Leu Val Leu

15

<210> 395

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 395

Ile Leu Leu Ser Leu Leu Leu Val Leu

15

<210> 396

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 396

Phe Thr Leu Ser Leu Leu Leu Thr Leu

15

<210> 397

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 397

Ala Leu Leu Ser Leu Leu Leu Ile Leu

15

<210> 398

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 398

Val Leu Phe Val Leu Ser Leu Phe Leu

15

<210> 399

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 399

Ile Leu Phe Val Leu Ser Leu Gln Leu

15

<210> 400

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 400

Leu Leu Leu Glu Lys Gln Ala Glu Val

15

<210> 401

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 401

Val Leu Ser Glu Leu Lys Leu Ala Val

15

<210> 402

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 402

Arg Met Ile Glu His Val Leu Thr Val

15

<210> 403

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 403

Gln Ile Phe Asp Arg Leu Ile Pro Ile

15

<210> 404

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 404

Gly Val Phe Asp Arg Leu Ile Pro Ile

15

<210> 405

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 405

Tyr Leu Lys Glu Gln Phe Gln Thr Leu

15

<210> 406

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 406

Ser Leu Leu Asp Ser Ala Phe Leu Leu

15

<210> 407

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 407

Met Leu Ser Leu Val Phe Ser Leu Ile

15

<210> 408

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 408

Leu Met Ser Leu Val Phe Ser Leu Val

15

<210> 409

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 409

Trp Met Gln Ile Leu Pro Tyr Gln Val

15

<210> 410

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 410

Met Met Thr Gly Phe Thr Phe Gly Val

15

<210> 411

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 411

Met Leu Leu Leu Leu Val Asn Leu Val

15

<210> 412

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 412

Val Leu Phe Gly Leu Leu Thr Phe Leu

15

<210> 413

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 413

Gln Leu Phe Gly Leu Leu Thr Asp Val

15

<210> 414

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 414

Phe Leu Phe Gly Leu Leu Thr Met Ile

15

<210> 415

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 415

Phe Leu Phe Gly Leu Leu Thr Asp Ala

15

<210> 416

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 416

Thr Leu Leu Leu Ser Leu Phe Leu Leu

15

<210> 417

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 417

Phe Ile Leu Leu Ser Leu Phe Met Leu

15

<210> 418

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 418

Ile Leu Leu Pro Pro Pro Pro Val Val

15

<210> 419

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 419

Val Leu Leu Thr Leu Ile Phe Ala Leu

15

<210> 420

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 420

Arg Leu Leu Thr Leu Ile Phe Thr Leu

15

<210> 421

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 421

Gln Leu Leu Thr Leu Ile Phe Tyr Leu

15

<210> 422

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 422

Leu Leu Leu Thr Leu Ile Phe Pro Ile

15

<210> 423

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 423

Phe Leu Leu Thr Leu Ile Phe Ser Leu

15

<210> 424

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 424

Val Met Val Ala Ile Tyr Phe Thr Leu

15

<210> 425

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 425

Leu Leu Gly Ala Leu Leu Pro Ala Val

15

<210> 426

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 426

Ile Leu Gly Ala Leu Leu Pro Leu Leu

15

<210> 427

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 427

Ser Val Ala Ala Phe Pro Val Thr Val

15

<210> 428

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 428

Leu Leu Leu Ser Leu Phe Cys Leu Ile

15

<210> 429

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 429

Lys Leu Leu Ser Leu Phe Cys Thr Leu

15

<210> 430

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 430

Phe Leu Leu Ser Leu Phe Cys Ile Ala

15

<210> 431

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 431

Ile Leu Leu Gly Val Gly Phe Gly Ile

15

<210> 432

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 432

Ala Leu Leu Gly Val Gly Phe Gly Ile

15

<210> 433

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 433

Arg Leu Ile Asp Glu Phe Gln Ser Val

15

<210> 434

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 434

Phe Leu Glu Ser Val Ile Thr Thr Val

15

<210> 435

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 435

Gly Leu Phe Gly Val Leu Ile Gly Val

15

<210> 436

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 436

Ala Met Phe Gly Val Leu Ile Ser Val

15

<210> 437

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 437

Phe Ile Asp Phe Leu Leu Ser Glu Val

15

<210> 438

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 438

Gly Leu Phe Met Val Ile Ala Gly Val

15

<210> 439

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 439

Phe Leu Phe Met Val Ile Ala Phe Ala

15

<210> 440

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 440

His Leu Pro Tyr Leu Leu Phe Leu Leu

15

<210> 441

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 441

Thr Leu Thr Ala Cys Leu Val Gly Val

15

<210> 442

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 442

Met Leu Ser Glu Lys Met Val Gln Leu

15

<210> 443

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 443

Asn Leu Phe Asp Leu Ser Leu Val Ala

15

<210> 444

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 444

Gly Leu Phe Asp Leu Ser Leu Arg Val

15

<210> 445

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 445

Ala Leu Phe Asp Leu Ser Leu Pro Ile

15

<210> 446

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 446

Thr Leu Pro Ala Val Met Ala Glu Val

15

<210> 447

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 447

Leu Leu Ala Glu Pro Gln Ala Ser Leu

15

<210> 448

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 448

Ile Leu Ala Glu Pro Gln Ala Leu Val

15

<210> 449

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 449

Phe Ile Ala Glu Pro Gln Ala Ala Leu

15

<210> 450

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 450

Leu Leu Phe Leu Leu Ser Ala Leu Leu

15

<210> 451

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 451

Lys Met Leu Thr Phe Leu Tyr Thr Ala

15

<210> 452

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 452

Ala Val Leu His Ala Ile Tyr Gly Val

15

<210> 453

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 453

His Leu Phe Ala Val Leu His Ala Val

15

<210> 454

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 454

Ser Val Ile Ala Ala Ile Val Leu Val

15

<210> 455

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 455

Phe Val Ile Ala Ala Ile Val Cys Val

15

<210> 456

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 456

Phe Ile Ile Ala Ala Ile Val Ala Val

15

<210> 457

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 457

Ala Val Ile Ala Ala Ile Val Gly Val

15

<210> 458

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 458

Tyr Ile Ala Ala Ile Ile Ala Glu Ala

15

<210> 459

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 459

Phe Val Ala Ala Ile Ile Ala Ser Leu

15

<210> 460

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 460

Phe Ile Ala Ala Ile Ile Ala Pro Ile

15

<210> 461

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 461

Gly Leu Phe Lys Ser Ile Leu Phe Leu

15

<210> 462

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 462

Met Leu Leu Gly Thr Ile His Gly Val

15

<210> 463

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 463

Leu Leu Ser Phe Phe Phe Ala Met Leu

15

<210> 464

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 464

Leu Leu Ser Phe Phe Phe Ala Ala Leu

15

<210> 465

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 465

Phe Leu Ser Phe Phe Phe Ala Ala Met

15

<210> 466

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 466

Phe Leu Ala Val Phe Leu Pro Val Leu

15

<210> 467

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 467

Ser Leu Leu Leu Gly Thr Ile Leu Val

15

<210> 468

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 468

Ile Leu Leu Leu Gly Thr Ile Leu Leu

15

<210> 469

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 469

Arg Leu Ser Leu Ile Val Ala Leu Val

15

<210> 470

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 470

Arg Leu Ser Leu Ile Val Ala Phe Val

15

<210> 471

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 471

Met Ile Ser Pro Asn Leu Phe Arg Val

15

<210> 472

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 472

Leu Leu Asp His Val Leu Ile Ala Val

15

<210> 473

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 473

Arg Leu Ile Asp Glu His Leu Val Val

15

<210> 474

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 474

Thr Leu Ser Glu Val Leu Glu Tyr Leu

15

<210> 475

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 475

Phe Leu Leu Arg Pro Asp Thr Phe Leu

15

<210> 476

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 476

Leu Met Met Thr Ile Ile Asn Gln Val

15

<210> 477

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 477

Leu Leu Met Thr Ile Ile Asn Gln Val

15

<210> 478

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 478

Phe Leu Met Thr Ile Ile Asn Gln Val

15

<210> 479

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 479

Arg Leu Ala Gly Ser Val Ala Gly Val

15

<210> 480

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 480

Lys Leu Ala Gly Ser Val Ala Gly Val

15

<210> 481

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 481

Leu Leu Met Met Thr Ile Ile Thr Val

15

<210> 482

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 482

Ala Met Leu Ser Ser Leu Ala Gly Val

15

<210> 483

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 483

Tyr Val Phe Thr Met Leu Ser Ala Val

15

<210> 484

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 484

Tyr Leu Ala Gly Val Ile Ile Leu Ile

15

<210> 485

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 485

Met Leu Ala Gly Val Ile Ile Tyr Ile

15

<210> 486

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 486

Met Leu Ala Gly Val Ile Ile Gly Ile

15

<210> 487

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 487

Leu Leu Ala Gly Val Ile Ile Thr Ile

15

<210> 488

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 488

Leu Leu Ala Gly Val Ile Ile Gly Ile

15

<210> 489

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 489

Gly Leu Ala Gly Val Ile Ile Thr Ile

15

<210> 490

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 490

Gly Leu Ala Gly Val Ile Ile Ala Val

15

<210> 491

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 491

Val Met Leu Phe Gly Val Phe Met Val

15

<210> 492

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 492

Val Leu Leu Phe Gly Val Phe Leu Val

15

<210> 493

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 493

Ile Leu Leu Phe Gly Val Phe Met Val

15

<210> 494

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 494

Phe Ile Leu Phe Gly Val Phe Met Leu

15

<210> 495

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 495

Val Leu Phe Gly Val Phe Leu Gly Val

15

<210> 496

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 496

Gly Met Phe Gly Val Phe Leu Thr Leu

15

<210> 497

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 497

Phe Leu Phe Gly Val Phe Leu Ala Met

15

<210> 498

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 498

Val Leu Asp Thr Ala Ile Ile Tyr Ile

15

<210> 499

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 499

Lys Leu Asp Thr Ala Ile Ile His Val

15

<210> 500

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 500

Leu Ile Ser Ser Phe Ala Phe Leu Val

15

<210> 501

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 501

Leu Ile Ser Ser Phe Ala Phe Leu Leu

15

<210> 502

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 502

Phe Met Leu Arg Leu Ile Ile Asn Leu

15

<210> 503

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 503

Ala Leu Ala Ile Ala Leu Phe Pro Val

15

<210> 504

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 504

Ala Leu Trp Leu His Thr Ser Phe Ala

15

<210> 505

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 505

Thr Met Phe Gly Tyr Thr Val Phe Leu

15

<210> 506

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 506

Tyr Leu Ala Gly Ile Val Phe Thr Leu

15

<210> 507

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 507

Leu Met Leu Leu Phe Ala Tyr Tyr Leu

15

<210> 508

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 508

Tyr Leu Phe Ala Tyr Val Leu Ile Val

15

<210> 509

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 509

Thr Leu Phe Ala Tyr Val Leu Gly Leu

15

<210> 510

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 510

Gly Leu Leu Phe Ala Tyr Val Glu Val

15

<210> 511

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 511

Lys Ile Leu Tyr Ser Leu Val Glu Val

15

<210> 512

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 512

Phe Leu Leu Leu Val Asn Leu Leu Val

15

<210> 513

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 513

Val Ile Ala Asp Val Ile Ala Leu Leu

15

<210> 514

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 514

Gln Ile Ala Asp Val Ile Ala Phe Leu

15

<210> 515

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 515

Leu Val Ala Asp Val Ile Ala Ser Val

15

<210> 516

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 516

Leu Ile Ala Asp Val Ile Ala Leu Leu

15

<210> 517

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 517

Leu Leu Tyr Ser Leu Val Phe Phe Leu

15

<210> 518

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 518

Phe Leu Val Lys Ile Asn Thr Asn Ile

15

<210> 519

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 519

Lys Leu Asp Ser Leu Gly Phe Thr Leu

15

<210> 520

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 520

Lys Leu Asp Ser Leu Gly Phe Ser Leu

15

<210> 521

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 521

Phe Leu Asp Ser Leu Gly Phe Ser Leu

15

<210> 522

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 522

Phe Met Arg Asp Glu Phe Pro Asp Val

15

<210> 523

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 523

Phe Leu Arg Asp Glu Phe Pro Glu Ala

15

<210> 524

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 524

Ser Met Glu Glu Leu Leu Trp Phe Val

15

<210> 525

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 525

Tyr Leu Leu Ala Gly Leu Val Leu Leu

15

<210> 526

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 526

Tyr Leu Leu Ala Gly Leu Val Leu Ile

15

<210> 527

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 527

Trp Leu Val Gly Ala Val Leu Thr Leu

15

<210> 528

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 528

Leu Leu Val Gly Ala Val Leu Thr Val

15

<210> 529

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 529

Ala Leu Val Gly Ala Val Leu Thr Val

15

<210> 530

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 530

Ala Leu Val Gly Ala Val Leu Leu Val

15

<210> 531

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 531

Cys Leu Ser Asp Tyr Val Ile Pro Val

15

<210> 532

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 532

Lys Leu Ala Gly Leu Val Ser Ser Val

15

<210> 533

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 533

Gly Met Ser Pro Ala Ser Phe Phe Ala

15

<210> 534

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 534

Ala Leu Gly Ala Val Leu Thr Ala Val

15

<210> 535

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 535

Tyr Leu Thr Ala Leu Leu Ala Glu Met

15

<210> 536

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 536

Val Leu Thr Ala Leu Leu Ala Ala Val

15

<210> 537

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 537

Arg Leu Thr Ala Leu Leu Ala Ala Val

15

<210> 538

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 538

Gly Leu Thr Ala Leu Leu Ala Pro Val

15

<210> 539

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 539

Phe Leu Thr Ala Leu Leu Ala Thr Val

15

<210> 540

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 540

Thr Leu Thr Glu Ser Leu Leu Tyr Leu

15

<210> 541

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 541

Lys Leu Thr Glu Ser Leu Leu Thr Ile

15

<210> 542

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 542

Ile Leu Thr Glu Ser Leu Leu Phe Leu

15

<210> 543

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 543

Arg Leu Ala Leu Leu Ser Pro Tyr Ile

15

<210> 544

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 544

Ser Ile Leu Gly Phe Ile Ile Ala Ala

15

<210> 545

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 545

Leu Ile Leu Gly Phe Ile Ile Ala Val

15

<210> 546

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 546

Phe Val Leu Gly Phe Ile Ile Thr Ile

15

<210> 547

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 547

Phe Ile Leu Gly Phe Ile Ile Thr Ile

15

<210> 548

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 548

Ser Leu Ser Gly Leu Leu Ser Gly Val

15

<210> 549

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 549

Phe Leu Ser Gly Leu Leu Ser Ala Leu

15

<210> 550

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 550

Ile Leu Pro Leu Ile Leu Ile Thr Val

15

<210> 551

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 551

Met Leu Gly Phe Ile Ile Ala Phe Leu

15

<210> 552

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 552

Leu Leu Gly Phe Ile Ile Ala Glu Val

15

<210> 553

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 553

Ile Leu Gly Phe Ile Ile Ala Ala Val

15

<210> 554

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 554

Phe Leu Gly Phe Ile Ile Ala Asp Val

15

<210> 555

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 555

Met Ile Ile Thr Val Leu Leu Leu Val

15

<210> 556

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 556

Phe Ile Ile Thr Val Leu Leu Gly Leu

15

<210> 557

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 557

Tyr Gln Ile Gly Asp Ser Val Leu Leu

15

<210> 558

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 558

Met Leu Ser Ser Leu Ile Ile Pro Leu

15

<210> 559

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 559

Ile Leu Ile Asp Gly Ala Tyr Thr Val

15

<210> 560

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 560

Tyr Leu Leu Glu Glu Gly Ser Ser Val

15

<210> 561

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 561

Tyr Met Phe Gly Phe Thr Leu Thr Met

15

<210> 562

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 562

Tyr Leu Phe Gly Phe Thr Leu Gly Met

15

<210> 563

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 563

Val Leu Phe Gly Phe Thr Leu Ser Ile

15

<210> 564

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 564

Arg Met Phe Gly Phe Thr Leu Met Leu

15

<210> 565

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 565

Leu Met Phe Gly Phe Thr Leu Arg Thr

15

<210> 566

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 566

Tyr Leu Leu Phe Gly Phe Thr Arg Val

15

<210> 567

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 567

Val Leu Gly Pro Leu Ala Ala Leu Val

15

<210> 568

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 568

Ile Leu Gly Pro Leu Ala Ala Trp Leu

15

<210> 569

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 569

Ser Leu Asn Ala Leu Leu Pro Tyr Val

15

<210> 570

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 570

Met Met Ile Pro Gln Val Ala Thr Leu

15

<210> 571

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 571

Met Met Ile Pro Gln Val Ala Thr Ile

15

<210> 572

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 572

Tyr Leu Ser Asp Ile Gln Asn Ala Ile

15

<210> 573

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 573

Val Met Ser Asp Ile Gln Asn Arg Val

15

<210> 574

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 574

Tyr Gln Ala Val Val Leu Pro Gly Leu

15

<210> 575

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 575

Leu Leu Leu Glu Gln Phe Leu Ser Val

15

<210> 576

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 576

Leu Leu Leu Glu Gln Phe Leu Ala Ile

15

<210> 577

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 577

Ala Leu Leu Glu Gln Phe Leu Thr Ala

15

<210> 578

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 578

Gly Val Ser Gly Tyr Ile Ser Pro Val

15

<210> 579

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 579

Lys Leu Thr Asp Ile Ser Ser Leu Val

15

<210> 580

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 580

Tyr Leu Leu Ser Asn Phe Tyr Thr Val

15

<210> 581

<211> 9

<212>PRT

<213> Homo sapiens

<400> 581

Phe Leu Phe Leu Leu Phe Phe Trp Leu

15

<210> 582

<211> 9

<212>PRT

<213> Homo sapiens

<400> 582

Ser Leu Ser Leu Gly Phe Leu Phe Leu

15

<210> 583

<211> 9

<212>PRT

<213> Homo sapiens

<400> 583

Leu Ser Leu Gly Phe Leu Phe Leu Leu

15

<210> 584

<211> 9

<212>PRT

<213> Homo sapiens

<400> 584

Tyr Thr Ser Asn Asp Ser Tyr Ile Val

15

<210> 585

<211> 9

<212>PRT

<213> Homo sapiens

<400> 585

Ile Leu Ile Asp Ser Gly Ala Asp Ile

15

<210> 586

<211> 9

<212>PRT

<213> Homo sapiens

<400> 586

Ser Leu Phe Glu Ser Ser Ala Lys Ile

15

<210> 587

<211> 9

<212>PRT

<213> Homo sapiens

<400> 587

Ser Leu Thr Pro Leu Leu Leu Ser Ile

15

<210> 588

<211> 9

<212>PRT

<213> Homo sapiens

<400> 588

Met Ser Ala Val Ile Leu Thr Ala Val

15

<210> 589

<211> 9

<212>PRT

<213> Homo sapiens

<400> 589

Ala Leu Ala Ala Ile Ala Ala Phe Met

15

<210> 590

<211> 9

<212>PRT

<213> Homo sapiens

<400> 590

Val Ser Ala Ala Phe Gln Ala Gly Val

15

<210> 591

<211> 9

<212>PRT

<213> Homo sapiens

<400> 591

Lys Leu Val Asn Leu Gly Phe Gln Ala

15

<210> 592

<211> 9

<212>PRT

<213> Homo sapiens

<400> 592

Glu Leu Leu Asp Phe Ser Ser Trp Leu

15

<210> 593

<211> 9

<212>PRT

<213> Homo sapiens

<400> 593

Leu Thr Leu Gly Glu Phe Leu Lys Leu

15

<210> 594

<211> 9

<212>PRT

<213> Homo sapiens

<400> 594

Ala Ala Gly Asp Ile Leu Ala Leu Val

15

<210> 595

<211> 9

<212>PRT

<213> Homo sapiens

<400> 595

Ala Leu Val Phe Gly Leu Leu Phe Ala

15

<210> 596

<211> 9

<212>PRT

<213> Homo sapiens

<400> 596

Phe Gln Tyr Glu Gly Ser Leu Thr Thr

15

<210> 597

<211> 9

<212>PRT

<213> Homo sapiens

<400> 597

His Leu Ser Thr Ala Phe Ala Arg Val

15

<210> 598

<211> 9

<212>PRT

<213> Homo sapiens

<400> 598

Leu Ser Leu Leu Leu Leu Val Pro Val

15

<210> 599

<211> 9

<212>PRT

<213> Homo sapiens

<400> 599

Gln Leu Leu Leu Ser Leu Leu Leu Leu

15

<210> 600

<211> 9

<212>PRT

<213> Homo sapiens

<400> 600

Val Gln Leu Leu Leu Ser Leu Leu Leu

15

<210> 601

<211> 9

<212>PRT

<213> Homo sapiens

<400> 601

Asn Leu Ala Lys Tyr Val Ala Glu Leu

15

<210> 602

<211> 9

<212>PRT

<213> Homo sapiens

<400> 602

Leu Ile Ala Ala Ala Ala Phe Cys Leu

15

<210> 603

<211> 9

<212>PRT

<213> Homo sapiens

<400> 603

Leu Leu Asn Asp Arg Val Leu Arg Ala

15

<210> 604

<211> 9

<212>PRT

<213> Homo sapiens

<400> 604

Gly Ile Leu Leu Thr Thr Leu Leu Val

15

<210> 605

<211> 9

<212>PRT

<213> Homo sapiens

<400> 605

Ile Leu Ala Val Val Phe Ile Arg Ile

15

<210> 606

<211> 9

<212>PRT

<213> Homo sapiens

<400> 606

Ile Leu Leu Thr Thr Leu Leu Val Ile

15

<210> 607

<211> 9

<212>PRT

<213> Homo sapiens

<400> 607

Leu Val Ile Gly Ile Ile Leu Ala Val

15

<210> 608

<211> 9

<212>PRT

<213> Homo sapiens

<400> 608

Ala Leu Val Ala Ile Leu Leu Cys Ile

15

<210> 609

<211> 9

<212>PRT

<213> Homo sapiens

<400> 609

Glu Met Ser Asp Val Gly Thr Phe Val

15

<210> 610

<211> 9

<212>PRT

<213> Homo sapiens

<400> 610

Glu Met Ser Thr Tyr Leu Leu Pro Val

15

<210> 611

<211> 9

<212>PRT

<213> Homo sapiens

<400> 611

Phe Leu Leu Glu Glu Tyr Thr Gly Ser

15

<210> 612

<211> 9

<212>PRT

<213> Homo sapiens

<400> 612

Ile Leu Leu Cys Ile Val Ile Leu Leu

15

<210> 613

<211> 9

<212>PRT

<213> Homo sapiens

<400> 613

Leu Leu Val Thr Val Val Leu Phe Ala

15

<210> 614

<211> 9

<212>PRT

<213> Homo sapiens

<400> 614

Ala Val Ala Leu Val Leu Met Leu Leu

15

<210> 615

<211> 9

<212>PRT

<213> Homo sapiens

<400> 615

Leu Leu Thr Phe Trp Asn Pro Pro Thr

15

<210> 616

<211> 9

<212>PRT

<213> Homo sapiens

<400> 616

Lys Gln Leu Leu Leu Ser Ala Ala Leu

15

<210> 617

<211> 9

<212>PRT

<213> Homo sapiens

<400> 617

Leu Leu Leu Ser Ala Ala Leu Ser Ala

15

<210> 618

<211> 9

<212>PRT

<213> Homo sapiens

<400> 618

Gln Leu Ala Gly Ala Met Val Trp Ala

15

<210> 619

<211> 9

<212>PRT

<213> Homo sapiens

<400> 619

Ser Gln Thr Gly Phe Val Val Leu Val

15

<210> 620

<211> 9

<212>PRT

<213> Homo sapiens

<400> 620

Thr Leu Ala Ser Ser Glu Thr Gly Val

15

<210> 621

<211> 9

<212>PRT

<213> Homo sapiens

<400> 621

Ile Leu Leu Ser Ile Gly Gly Tyr Leu

15

<210> 622

<211> 9

<212>PRT

<213> Homo sapiens

<400> 622

His Leu Ile Tyr Ser Phe Ala Ser Ile

15

<210> 623

<211> 9

<212>PRT

<213> Homo sapiens

<400> 623

Val Leu Ile His Glu Leu Ala Glu Ala

15

<210> 624

<211> 9

<212>PRT

<213> Homo sapiens

<400> 624

Ser Leu Trp Ala Gly Val Val Val Leu

15

<210> 625

<211> 9

<212>PRT

<213> Homo sapiens

<400> 625

Trp Leu Trp Asp Phe Thr Val Thr Thr

15

<210> 626

<211> 9

<212>PRT

<213> Homo sapiens

<400> 626

Leu Leu Ala Ser Ser Ile Leu Cys Ala

15

<210> 627

<211> 9

<212>PRT

<213> Homo sapiens

<400> 627

Lys Leu Ala Val Ser Leu Ala Glu Thr

15

<210> 628

<211> 9

<212>PRT

<213> Homo sapiens

<400> 628

Ala Leu Val Gly Leu Phe Val Leu Leu

15

<210> 629

<211> 9

<212>PRT

<213> Homo sapiens

<400> 629

Gly Leu Phe Val Leu Leu Ala Phe Leu

15

<210> 630

<211> 9

<212>PRT

<213> Homo sapiens

<400> 630

Ser Val Tyr Asp Phe Phe Val Trp Leu

15

<210> 631

<211> 9

<212>PRT

<213> Homo sapiens

<400> 631

Val Val Met Gly Thr Leu Val Ala Leu

15

<210> 632

<211> 9

<212>PRT

<213> Homo sapiens

<400> 632

Gly Thr Ala Glu Gly Leu Ala Leu Ala

15

<210> 633

<211> 9

<212>PRT

<213> Homo sapiens

<400> 633

Gly Leu Ala Ala Gly Leu Gly Pro Ala

15

<210> 634

<211> 9

<212>PRT

<213> Homo sapiens

<400> 634

Ala Leu Glu Ser Ile Leu His Arg Ile

15

<210> 635

<211> 9

<212>PRT

<213> Homo sapiens

<400> 635

Ala Leu Leu Ala Ala Leu Cys Pro Ala

15

<210> 636

<211> 9

<212>PRT

<213> Homo sapiens

<400> 636

Ala Leu Leu Ala Leu Leu Ala Ala Leu

15

<210> 637

<211> 9

<212>PRT

<213> Homo sapiens

<400> 637

Ile Leu Asp Glu Ala Tyr Val Met Ala

15

<210> 638

<211> 9

<212>PRT

<213> Homo sapiens

<400> 638

Leu Leu Leu Leu Leu Val Val Ala Leu

15

<210> 639

<211> 9

<212>PRT

<213> Homo sapiens

<400> 639

Met Val Gly Ala Leu Leu Leu Leu Leu

15

<210> 640

<211> 9

<212>PRT

<213> Homo sapiens

<400> 640

Asn Leu Gln Glu Ile Leu His Gly Ala

15

<210> 641

<211> 9

<212>PRT

<213> Homo sapiens

<400> 641

Ser Leu Ala Val Val Ser Leu Asn Ile

15

<210> 642

<211> 9

<212>PRT

<213> Homo sapiens

<400> 642

Ala Val Val Gly Ile Leu Leu Val Val

15

<210> 643

<211> 9

<212>PRT

<213> Homo sapiens

<400> 643

Ile Leu Asp Glu Ala Tyr Val Met Ala

15

<210> 644

<211> 9

<212>PRT

<213> Homo sapiens

<400> 644

Leu Leu Ala Leu Leu Pro Pro Gly Ala

15

<210> 645

<211> 9

<212>PRT

<213> Homo sapiens

<400> 645

Ser Ile Ile Ser Ala Val Val Gly Ile

15

<210> 646

<211> 9

<212>PRT

<213> Homo sapiens

<400> 646

Val Val Leu Gly Val Val Phe Gly Ile

15

<210> 647

<211> 9

<212>PRT

<213> Homo sapiens

<400> 647

Phe Leu Leu Glu Leu Leu Ser Asp Ser

15

<210> 648

<211> 9

<212>PRT

<213> Homo sapiens

<400> 648

Ala Leu Leu Asp Ala Glu Pro Pro Ile

15

<210> 649

<211> 9

<212>PRT

<213> Homo sapiens

<400> 649

Lys Ile Thr Asp Thr Leu Ile His Leu

15

<210> 650

<211> 9

<212>PRT

<213> Homo sapiens

<400> 650

Lys Leu Leu Phe Ala Pro Asn Leu Leu

15

<210> 651

<211> 9

<212>PRT

<213> Homo sapiens

<400> 651

Leu Leu Asp Ala Glu Pro Pro Ile Leu

15

<210> 652

<211> 9

<212>PRT

<213> Homo sapiens

<400> 652

Leu Leu Asn Ser Gly Val Tyr Thr Phe

15

<210> 653

<211> 9

<212>PRT

<213> Homo sapiens

<400> 653

Leu Met Ile Gly Leu Val Trp Arg Ser

15

<210> 654

<211> 9

<212>PRT

<213> Homo sapiens

<400> 654

Pro Leu Tyr Asp Leu Leu Leu Glu Met

15

<210> 655

<211> 9

<212>PRT

<213> Homo sapiens

<400> 655

Gln Leu Leu Leu Ile Leu Ser His Ile

15

<210> 656

<211> 9

<212>PRT

<213> Homo sapiens

<400> 656

Arg Leu Ala Gln Leu Leu Leu Ile Leu

15

<210> 657

<211> 9

<212>PRT

<213> Homo sapiens

<400> 657

Thr Leu Ile His Leu Met Ala Lys Ala

15

<210> 658

<211> 9

<212>PRT

<213> Homo sapiens

<400> 658

Val Leu Asp Lys Ile Thr Asp Thr Leu

15

<210> 659

<211> 9

<212>PRT

<213> Homo sapiens

<400> 659

Phe Met Val Glu Asp Glu Thr Val Leu

15

<210> 660

<211> 9

<212>PRT

<213> Homo sapiens

<400> 660

Ser Met Phe Arg Val Leu Ile Gly Thr

15

<210> 661

<211> 9

<212>PRT

<213> Homo sapiens

<400> 661

Ala Thr Ser Ala Val Leu Ala Leu Leu

15

<210> 662

<211> 9

<212>PRT

<213> Homo sapiens

<400> 662

Thr Gly Trp Ala Gly Gly Phe Phe Val

15

<210> 663

<211> 9

<212>PRT

<213> Homo sapiens

<400> 663

Val Leu Ala Leu Leu Val Met Cys Ile

15

<210> 664

<211> 9

<212>PRT

<213> Homo sapiens

<400> 664

Ala Leu Leu Ser Cys Leu Leu Leu Thr

15

<210> 665

<211> 9

<212>PRT

<213> Homo sapiens

<400> 665

Cys Val Ala Ala Thr Leu Phe Trp Leu

15

<210> 666

<211> 9

<212>PRT

<213> Homo sapiens

<400> 666

Glu Met Tyr Ser Glu Ile Pro Glu Ile

15

<210> 667

<211> 9

<212>PRT

<213> Homo sapiens

<400> 667

Lys Met Ala Ser Thr Leu Val Val Ala

15

<210> 668

<211> 9

<212>PRT

<213> Homo sapiens

<400> 668

Ser Ile Phe Asp Lys Ile Tyr Ser Thr

15

<210> 669

<211> 9

<212>PRT

<213> Homo sapiens

<400> 669

Thr Leu Phe Trp Leu Leu Leu Thr Leu

15

<210> 670

<211> 9

<212>PRT

<213> Homo sapiens

<400> 670

Val Leu Leu Trp Glu Ile Phe Ser Leu

15

<210> 671

<211> 9

<212>PRT

<213> Homo sapiens

<400> 671

Trp Leu Lys Asp Gly Leu Pro Ala Thr

15

<210> 672

<211> 9

<212>PRT

<213> Homo sapiens

<400> 672

Ile Leu Leu Asp Ile Ser Phe Pro Gly

15

<210> 673

<211> 9

<212>PRT

<213> Homo sapiens

<400> 673

Leu Leu Asp Ile Ser Phe Pro Gly Leu

15

<210> 674

<211> 9

<212>PRT

<213> Homo sapiens

<400> 674

Leu Met Asp Leu Ser Thr Thr Pro Leu

15

<210> 675

<211> 9

<212>PRT

<213> Homo sapiens

<400> 675

Arg Val Ser Ser Tyr Leu Val Pro Ile

15

<210> 676

<211> 9

<212>PRT

<213> Homo sapiens

<400> 676

Ser Leu Ser Lys Ile Leu Leu Asp Ile

15

<210> 677

<211> 9

<212>PRT

<213> Homo sapiens

<400> 677

Ser Gln Leu Ser Tyr Ser Gln Glu Val

15

<210> 678

<211> 9

<212>PRT

<213> Homo sapiens

<400> 678

Trp Ala Ala Glu Leu Pro Phe Pro Ala

15

<210> 679

<211> 9

<212>PRT

<213> Homo sapiens

<400> 679

Leu Leu Asn Glu Ser Glu Thr Lys Val

15

<210> 680

<211> 9

<212>PRT

<213> Homo sapiens

<400> 680

Arg Leu Val Glu Leu Leu Lys Asp Leu

15

<210> 681

<211> 9

<212>PRT

<213> Homo sapiens

<400> 681

Gly Leu Ala Ser Thr Thr Pro Glu Ala

15

<210> 682

<211> 9

<212>PRT

<213> Homo sapiens

<400> 682

Arg Met Ala Arg Glu Val Ala Ala Leu

15

<210> 683

<211> 9

<212>PRT

<213> Homo sapiens

<400> 683

Phe Leu Leu Ser Leu Ala Phe Tyr Gly

15

<210> 684

<211> 9

<212>PRT

<213> Homo sapiens

<400> 684

Ile Leu Asn Pro Ala Gln Gly Phe Leu

15

<210> 685

<211> 9

<212>PRT

<213> Homo sapiens

<400> 685

Met Ala Trp Gly Leu Ala Thr Leu Leu

15

<210> 686

<211> 9

<212>PRT

<213> Homo sapiens

<400> 686

Arg Leu Ala Leu Gly Leu Leu Gln Leu

15

<210> 687

<211> 9

<212>PRT

<213> Homo sapiens

<400> 687

Arg Leu Leu Leu Ala Gly Ala Glu Val

15

<210> 688

<211> 9

<212>PRT

<213> Homo sapiens

<400> 688

Cys Leu Tyr Thr Phe Leu Ile Ser Thr

15

<210> 689

<211> 9

<212>PRT

<213> Homo sapiens

<400> 689

Phe Leu Ile Ser Thr Thr Phe Gly Cys

15

<210> 690

<211> 9

<212>PRT

<213> Homo sapiens

<400> 690

Val Leu Leu Asp Thr Asn Tyr Asn Leu

15

<210> 691

<211> 9

<212>PRT

<213> Homo sapiens

<400> 691

Trp Leu Pro Phe Gly Phe Ile Leu Ile

15

<210> 692

<211> 10

<212>PRT

<213> Homo sapiens

<400> 692

Trp Leu Pro Phe Gly Phe Ile Leu Ile Leu

1 5 10

<210> 693

<211> 9

<212>PRT

<213> Homo sapiens

<400> 693

Ala Leu Tyr Leu Leu Pro Leu Leu Ala

15

<210> 694

<211> 9

<212>PRT

<213> Homo sapiens

<400> 694

Phe Ala Leu Tyr Asn Leu Leu Ala Leu

15

<210> 695

<211> 9

<212>PRT

<213> Homo sapiens

<400> 695

Gln Leu Phe Leu Val Leu Gln Ala Leu

15

<210> 696

<211> 9

<212>PRT

<213> Homo sapiens

<400> 696

Arg Leu Val Ala Ala Val Val Leu Leu

15

<210> 697

<211> 9

<212>PRT

<213> Homo sapiens

<400> 697

Val Leu Ala Glu Arg Ala Gly Ala Val

15

<210> 698

<211> 9

<212>PRT

<213> Homo sapiens

<400> 698

Trp Leu Val Pro Leu Phe Phe Ala Ala

15

<210> 699

<211> 9

<212>PRT

<213> Homo sapiens

<400> 699

Tyr Leu Leu Pro Leu Leu Ala Thr Cys

15

<210> 700

<211> 9

<212>PRT

<213> Homo sapiens

<400> 700

Gly Leu Ser Asp Ala Val Glu Ala Leu

15

<210> 701

<211> 9

<212>PRT

<213> Homo sapiens

<400> 701

Met Leu Arg Glu Ala Ala Met Gly Ile

15

<210> 702

<211> 9

<212>PRT

<213> Homo sapiens

<400> 702

Ala Leu Ile Pro Ala Pro Glu Leu Val

15

<210> 703

<211> 9

<212>PRT

<213> Homo sapiens

<400> 703

Asn Leu Leu His Gly Leu Asn Leu Leu

15

<210> 704

<211> 9

<212>PRT

<213> Homo sapiens

<400> 704

Tyr Val Ser Ser Leu Pro Gln Pro Leu

15

<210> 705

<211> 9

<212>PRT

<213> Homo sapiens

<400> 705

Tyr Leu Ile Leu Gly Val Ala Gly Ser

15

<210> 706

<211> 9

<212>PRT

<213> Homo sapiens

<400> 706

Asn Met Asp Cys Ile Ile Ala Glu Ile

15

<210> 707

<211> 9

<212>PRT

<213> Homo sapiens

<400> 707

Ala Val Leu Gly Ile Phe Ile Ile Val

15

<210> 708

<211> 9

<212>PRT

<213> Homo sapiens

<400> 708

Lys Leu Ala Val Leu Gly Ile Phe Ile

15

<210> 709

<211> 9

<212>PRT

<213> Homo sapiens

<400> 709

Ala Ile Ala Ala Ile Val Ile Gly Ile

15

<210> 710

<211> 9

<212>PRT

<213> Homo sapiens

<400> 710

Ala Leu Ala Cys Ser Leu Ala Ala Cys

15

<210> 711

<211> 9

<212>PRT

<213> Homo sapiens

<400> 711

Ile Val Ile Gly Ile Val Ala Leu Ala

15

<210> 712

<211> 9

<212>PRT

<213> Homo sapiens

<400> 712

Arg Ile Val Ala Val Pro Thr Pro Leu

15

<210> 713

<211> 9

<212>PRT

<213> Homo sapiens

<400> 713

Ser Leu Lys Glu Leu Ser Pro Gly Ile

15

<210> 714

<211> 9

<212>PRT

<213> Homo sapiens

<400> 714

Lys Val Ala Asp Leu Val Gly Phe Leu

15

<210> 715

<211> 9

<212>PRT

<213> Homo sapiens

<400> 715

Gly Met Leu Ser Asp Val Gln Ser Met

15

<210> 716

<211> 9

<212>PRT

<213> Homo sapiens

<400> 716

Ile Leu Ile Leu Ile Leu Ser Ile Val

15

<210> 717

<211> 9

<212>PRT

<213> Homo sapiens

<400> 717

Ala Met Asp Ala Ile Phe Gly Ser Leu

15

<210> 718

<211> 9

<212>PRT

<213> Homo sapiens

<400> 718

Gly Leu Ile Thr Lys Ala Glu Met Leu

15

<210> 719

<211> 9

<212>PRT

<213> Homo sapiens

<400> 719

Gly Thr Leu Glu Glu Leu Pro Ala Ala

15

<210> 720

<211> 9

<212>PRT

<213> Homo sapiens

<400> 720

Lys Val Leu Glu Tyr Ile Ala Asn Ala

15

<210> 721

<211> 9

<212>PRT

<213> Homo sapiens

<400> 721

Gln Leu Val Phe Gly Ile Glu Val Val

15

<210> 722

<211> 9

<212>PRT

<213> Homo sapiens

<400> 722

Ala Val Ser Ser Ser Ser Pro Leu Val

15

<210> 723

<211> 9

<212>PRT

<213> Homo sapiens

<400> 723

Lys Val Asp Glu Leu Ala His Phe Leu

15

<210> 724

<211> 9

<212>PRT

<213> Homo sapiens

<400> 724

Lys Val Leu Glu His Val Val Arg Val

15

<210> 725

<211> 9

<212>PRT

<213> Homo sapiens

<400> 725

Val Ile Leu Gly Val Leu Leu Leu Ile

15

<210> 726

<211> 9

<212>PRT

<213> Homo sapiens

<400> 726

Met Thr Ala Ala Gly Val Pro Gln Leu

15

<210> 727

<211> 9

<212>PRT

<213> Homo sapiens

<400> 727

Ser Val Ser Asp Ile Leu Ser Pro Leu

15

<210> 728

<211> 9

<212>PRT

<213> Homo sapiens

<400> 728

Ala Leu Leu Ala Ala Ser Val Ala Leu

15

<210> 729

<211> 9

<212>PRT

<213> Homo sapiens

<400> 729

Leu Leu Ala Ala Ser Val Ala Leu Ala

15

<210> 730

<211> 9

<212>PRT

<213> Homo sapiens

<400> 730

Gln Leu Leu Arg Lys Val Ala Glu Leu

15

<210> 731

<211> 9

<212>PRT

<213> Homo sapiens

<400> 731

Thr Leu Pro Glu Leu Tyr Ala Phe Thr

15

<210> 732

<211> 9

<212>PRT

<213> Homo sapiens

<400> 732

Tyr Leu Tyr Gly Lys Ile Lys Lys Thr

15

<210> 733

<211> 9

<212>PRT

<213> Homo sapiens

<400> 733

Gln Val Leu Gly Leu Ala Ala Tyr Leu

15

<210> 734

<211> 9

<212>PRT

<213> Homo sapiens

<400> 734

Gly Leu Asp Glu Val Lys Ser Ser Leu

15

<210> 735

<211> 9

<212>PRT

<213> Homo sapiens

<400> 735

Phe Val Leu Leu Ser Leu Ser Gly Ala

15

<210> 736

<211> 9

<212>PRT

<213> Homo sapiens

<400> 736

Ser Leu Phe Leu Phe Ser Val Leu Leu

15

<210> 737

<211> 9

<212>PRT

<213> Homo sapiens

<400> 737

Ser Leu Thr Val Tyr Leu Val Val Ala

15

<210> 738

<211> 9

<212>PRT

<213> Homo sapiens

<400> 738

Val Leu Leu Phe Val Ala Val Arg Leu

15

<210> 739

<211> 9

<212>PRT

<213> Homo sapiens

<400> 739

Val Ser Ser Leu Phe Leu Phe Ser Val

15

<210> 740

<211> 9

<212>PRT

<213> Homo sapiens

<400> 740

Ser Ile Ala Gly Phe Val Ala Ser Ile

15

<210> 741

<211> 9

<212>PRT

<213> Homo sapiens

<400> 741

Ile Leu Leu Val Leu Met Ala Val Val

15

<210> 742

<211> 9

<212>PRT

<213> Homo sapiens

<400> 742

Leu Ile Val Gly Ile Leu Leu Val Leu

15

<210> 743

<211> 9

<212>PRT

<213> Homo sapiens

<400> 743

Leu Met Ala Val Val Leu Ala Ser Leu

15

<210> 744

<211> 9

<212>PRT

<213> Homo sapiens

<400> 744

Pro Leu Leu Asp Gly Thr Ala Thr Leu

15

<210> 745

<211> 9

<212>PRT

<213> Homo sapiens

<400> 745

Ser Leu Ala Asp Thr Asn Ser Leu Ala

15

<210> 746

<211> 9

<212>PRT

<213> Homo sapiens

<400> 746

Val Leu Gln Ala Ala Ile Pro Leu Thr

15

<210> 747

<211> 9

<212>PRT

<213> Homo sapiens

<400> 747

Ala Val Leu Asp Gly Leu Asp Val Leu

15

<210> 748

<211> 9

<212>PRT

<213> Homo sapiens

<400> 748

Gln Leu Leu Ala Leu Leu Pro Ser Leu

15

<210> 749

<211> 9

<212>PRT

<213> Homo sapiens

<400> 749

Arg Leu Arg Glu Leu Leu Cys Glu Leu

15

<210> 750

<211> 9

<212>PRT

<213> Homo sapiens

<400> 750

Val Leu Tyr Pro Val Pro Leu Glu Ser

15

<210> 751

<211> 9

<212>PRT

<213> Homo sapiens

<400> 751

Ala Val Phe Leu Leu Ser Tyr Ala Val

15

<210> 752

<211> 9

<212>PRT

<213> Homo sapiens

<400> 752

Phe Val Leu Ser Leu Leu Leu Ile Leu

15

<210> 753

<211> 9

<212>PRT

<213> Homo sapiens

<400> 753

Ile Ile Phe Val Leu Ser Leu Leu Leu

15

<210> 754

<211> 9

<212>PRT

<213> Homo sapiens

<400> 754

Leu Ile Leu Glu Lys Gln Ala Ala Val

15

<210> 755

<211> 9

<212>PRT

<213> Homo sapiens

<400> 755

Leu Ile Ser Glu Leu Lys Leu Ala Val

15

<210> 756

<211> 9

<212>PRT

<213> Homo sapiens

<400> 756

Arg Ala Ile Glu His Val Leu Gln Val

15

<210> 757

<211> 9

<212>PRT

<213> Homo sapiens

<400> 757

Ser Ser Phe Asp Arg Leu Ile Pro Leu

15

<210> 758

<211> 9

<212>PRT

<213> Homo sapiens

<400> 758

Thr Leu Lys Glu Gln Phe Gln Phe Val

15

<210> 759

<211> 9

<212>PRT

<213> Homo sapiens

<400> 759

Ala Ile Leu Asp Ser Ala Phe Leu Leu

15

<210> 760

<211> 9

<212>PRT

<213> Homo sapiens

<400> 760

Ala Ile Ser Leu Val Phe Ser Leu Val

15

<210> 761

<211> 9

<212>PRT

<213> Homo sapiens

<400> 761

Ala Leu Gln Ile Leu Pro Tyr Thr Leu

15

<210> 762

<211> 9

<212>PRT

<213> Homo sapiens

<400> 762

Ala Leu Thr Gly Phe Thr Phe Ser Ala

15

<210> 763

<211> 9

<212>PRT

<213> Homo sapiens

<400> 763

Ala Gln Leu Leu Leu Val Asn Leu Leu

15

<210> 764

<211> 9

<212>PRT

<213> Homo sapiens

<400> 764

Cys Leu Phe Gly Leu Leu Thr Leu Ile

15

<210> 765

<211> 9

<212>PRT

<213> Homo sapiens

<400> 765

Gly Ile Leu Leu Ser Leu Phe Leu Ile

15

<210> 766

<211> 9

<212>PRT

<213> Homo sapiens

<400> 766

Gly Leu Leu Pro Pro Pro Pro Ala Leu

15

<210> 767

<211> 9

<212>PRT

<213> Homo sapiens

<400> 767

Gly Leu Leu Thr Leu Ile Phe Leu Thr

15

<210> 768

<211> 9

<212>PRT

<213> Homo sapiens

<400> 768

Gly Leu Val Ala Ile Tyr Phe Ala Thr

15

<210> 769

<211> 9

<212>PRT

<213> Homo sapiens

<400> 769

Asn Leu Gly Ala Leu Leu Pro Arg Leu

15

<210> 770

<211> 9

<212>PRT

<213> Homo sapiens

<400> 770

Ser Val Ala Ala Phe Pro Val Ala Ala

15

<210> 771

<211> 9

<212>PRT

<213> Homo sapiens

<400> 771

Phe Leu Leu Ser Leu Phe Cys Val Thr

15

<210> 772

<211> 9

<212>PRT

<213> Homo sapiens

<400> 772

Phe Ser Leu Gly Val Gly Phe Gly Val

15

<210> 773

<211> 9

<212>PRT

<213> Homo sapiens

<400> 773

Gly Leu Ile Asp Glu Phe Gln Leu Leu

15

<210> 774

<211> 9

<212>PRT

<213> Homo sapiens

<400> 774

Gly Met Glu Ser Val Ile Thr Gly Leu

15

<210> 775

<211> 9

<212>PRT

<213> Homo sapiens

<400> 775

Ile Leu Phe Gly Val Leu Ile Glu Ala

15

<210> 776

<211> 9

<212>PRT

<213> Homo sapiens

<400> 776

Lys Ile Asp Phe Leu Leu Ser Val Ile

15

<210> 777

<211> 9

<212>PRT

<213> Homo sapiens

<400> 777

Leu Leu Phe Met Val Ile Ala Gly Met

15

<210> 778

<211> 9

<212>PRT

<213> Homo sapiens

<400> 778

Leu Val Pro Tyr Leu Leu Phe Met Val

15

<210> 779

<211> 9

<212>PRT

<213> Homo sapiens

<400> 779

Gln Leu Thr Ala Cys Leu Val Leu Val

15

<210> 780

<211> 9

<212>PRT

<213> Homo sapiens

<400> 780

Met Ile Ser Glu Lys Met Val Lys Leu

15

<210> 781

<211> 9

<212>PRT

<213> Homo sapiens

<400> 781

Leu Met Phe Asp Leu Ser Leu Asn Phe

15

<210> 782

<211> 9

<212>PRT

<213> Homo sapiens

<400> 782

Ala Leu Pro Ala Val Met Ala Gly Leu

15

<210> 783

<211> 9

<212>PRT

<213> Homo sapiens

<400> 783

Gly Leu Ala Glu Pro Gln Ala Ala Ala

15

<210> 784

<211> 9

<212>PRT

<213> Homo sapiens

<400> 784

Gly Ile Phe Leu Leu Ser Ala Leu Ala

15

<210> 785

<211> 9

<212>PRT

<213> Homo sapiens

<400> 785

Ala Ser Leu Thr Phe Leu Tyr Thr Leu

15

<210> 786

<211> 9

<212>PRT

<213> Homo sapiens

<400> 786

Ala Val Leu His Ala Ile Tyr Ser Leu

15

<210> 787

<211> 9

<212>PRT

<213> Homo sapiens

<400> 787

Phe Phe Phe Ala Val Leu His Ala Ile

15

<210> 788

<211> 9

<212>PRT

<213> Homo sapiens

<400> 788

Gly Val Ile Ala Ala Ile Val Gln Leu

15

<210> 789

<211> 9

<212>PRT

<213> Homo sapiens

<400> 789

Lys Ile Ala Ala Ile Ile Ala Ser Leu

15

<210> 790

<211> 9

<212>PRT

<213> Homo sapiens

<400> 790

Leu Ile Phe Lys Ser Ile Leu Phe Leu

15

<210> 791

<211> 9

<212>PRT

<213> Homo sapiens

<400> 791

Leu Leu Leu Gly Thr Ile His Ala Leu

15

<210> 792

<211> 9

<212>PRT

<213> Homo sapiens

<400> 792

Leu Leu Ser Phe Phe Phe Ala Val Leu

15

<210> 793

<211> 9

<212>PRT

<213> Homo sapiens

<400> 793

Met Ile Ala Val Phe Leu Pro Ile Val

15

<210> 794

<211> 9

<212>PRT

<213> Homo sapiens

<400> 794

Ser Leu Leu Leu Gly Thr Ile His Ala

15

<210> 795

<211> 9

<212>PRT

<213> Homo sapiens

<400> 795

Ser Leu Ser Leu Ile Val Ala Val Ile

15

<210> 796

<211> 9

<212>PRT

<213> Homo sapiens

<400> 796

Ile Ile Ser Pro Asn Leu Phe Tyr Ala

15

<210> 797

<211> 9

<212>PRT

<213> Homo sapiens

<400> 797

Leu Leu Asp His Val Leu Ile Glu Met

15

<210> 798

<211> 9

<212>PRT

<213> Homo sapiens

<400> 798

Val Leu Ile Asp Glu His Leu Val Leu

15

<210> 799

<211> 9

<212>PRT

<213> Homo sapiens

<400> 799

Tyr Ser Ser Glu Val Leu Glu Tyr Met

15

<210> 800

<211> 9

<212>PRT

<213> Homo sapiens

<400> 800

Ile Leu Leu Arg Pro Asp Thr Tyr Ile

15

<210> 801

<211> 9

<212>PRT

<213> Homo sapiens

<400> 801

Leu Met Met Thr Ile Ile Asn Leu Ala

15

<210> 802

<211> 9

<212>PRT

<213> Homo sapiens

<400> 802

Gln Leu Ala Gly Ser Val Ala Glu Met

15

<210> 803

<211> 9

<212>PRT

<213> Homo sapiens

<400> 803

Ser Leu Met Met Thr Ile Ile Asn Leu

15

<210> 804

<211> 9

<212>PRT

<213> Homo sapiens

<400> 804

Thr Met Leu Ser Ser Leu Ala Arg Leu

15

<210> 805

<211> 9

<212>PRT

<213> Homo sapiens

<400> 805

Tyr Ile Phe Thr Met Leu Ser Ser Leu

15

<210> 806

<211> 9

<212>PRT

<213> Homo sapiens

<400> 806

Asp Leu Ala Gly Val Ile Ile Glu Leu

15

<210> 807

<211> 9

<212>PRT

<213> Homo sapiens

<400> 807

Phe Gly Leu Phe Gly Val Phe Leu Val

15

<210> 808

<211> 9

<212>PRT

<213> Homo sapiens

<400> 808

Gly Leu Phe Gly Val Phe Leu Val Leu

15

<210> 809

<211> 9

<212>PRT

<213> Homo sapiens

<400> 809

Ile Leu Asp Thr Ala Ile Ile Val Ile

15

<210> 810

<211> 9

<212>PRT

<213> Homo sapiens

<400> 810

Ile Val Ser Ser Phe Ala Phe Gly Leu

15

<210> 811

<211> 9

<212>PRT

<213> Homo sapiens

<400> 811

Arg Leu Leu Arg Leu Ile Ile Leu Leu

15

<210> 812

<211> 9

<212>PRT

<213> Homo sapiens

<400> 812

Ser Leu Ala Ile Ala Leu Phe Phe Leu

15

<210> 813

<211> 9

<212>PRT

<213> Homo sapiens

<400> 813

Tyr Phe Trp Leu His Thr Ser Phe Ile

15

<210> 814

<211> 9

<212>PRT

<213> Homo sapiens

<400> 814

Ala Met Phe Gly Tyr Thr Val Gly Thr

15

<210> 815

<211> 9

<212>PRT

<213> Homo sapiens

<400> 815

Phe Ile Ala Gly Ile Val Phe Arg Leu

15

<210> 816

<211> 9

<212>PRT

<213> Homo sapiens

<400> 816

Phe Leu Leu Leu Phe Ala Tyr Val Leu

15

<210> 817

<211> 9

<212>PRT

<213> Homo sapiens

<400> 817

Leu Leu Phe Ala Tyr Val Leu Leu Met

15

<210> 818

<211> 9

<212>PRT

<213> Homo sapiens

<400> 818

Leu Leu Leu Phe Ala Tyr Val Leu Leu

15

<210> 819

<211> 9

<212>PRT

<213> Homo sapiens

<400> 819

Leu Val Leu Tyr Ser Leu Val Phe Val

15

<210> 820

<211> 9

<212>PRT

<213> Homo sapiens

<400> 820

Asn Ile Leu Leu Val Asn Leu Leu Val

15

<210> 821

<211> 9

<212>PRT

<213> Homo sapiens

<400> 821

Gln Ile Ala Asp Val Ile Ala Ser Leu

15

<210> 822

<211> 9

<212>PRT

<213> Homo sapiens

<400> 822

Val Leu Tyr Ser Leu Val Phe Val Leu

15

<210> 823

<211> 9

<212>PRT

<213> Homo sapiens

<400> 823

Tyr Leu Val Lys Ile Asn Thr Lys Ala

15

<210> 824

<211> 9

<212>PRT

<213> Homo sapiens

<400> 824

Phe Leu Asp Ser Leu Gly Phe Ser Thr

15

<210> 825

<211> 9

<212>PRT

<213> Homo sapiens

<400> 825

Ser Leu Arg Asp Glu Phe Pro Leu Leu

15

<210> 826

<211> 9

<212>PRT

<213> Homo sapiens

<400> 826

Val Leu Glu Glu Leu Leu Trp Phe Ile

15

<210> 827

<211> 9

<212>PRT

<213> Homo sapiens

<400> 827

Ala Leu Leu Ala Gly Leu Val Ser Leu

15

<210> 828

<211> 9

<212>PRT

<213> Homo sapiens

<400> 828

Ala Met Val Gly Ala Val Leu Thr Ala

15

<210> 829

<211> 9

<212>PRT

<213> Homo sapiens

<400> 829

Ile Ser Ser Asp Tyr Val Ile Pro Ile

15

<210> 830

<211> 9

<212>PRT

<213> Homo sapiens

<400> 830

Leu Leu Ala Gly Leu Val Ser Leu Leu

15

<210> 831

<211> 9

<212>PRT

<213> Homo sapiens

<400> 831

Leu Leu Ser Pro Ala Ser Phe Phe Ser

15

<210> 832

<211> 9

<212>PRT

<213> Homo sapiens

<400> 832

Met Val Gly Ala Val Leu Thr Ala Leu

15

<210> 833

<211> 9

<212>PRT

<213> Homo sapiens

<400> 833

Val Leu Thr Ala Leu Leu Ala Gly Leu

15

<210> 834

<211> 9

<212>PRT

<213> Homo sapiens

<400> 834

Ala Leu Thr Glu Ser Leu Leu Val Ala

15

<210> 835

<211> 9

<212>PRT

<213> Homo sapiens

<400> 835

Leu Leu Ala Leu Leu Ser Pro Gly Ala

15

<210> 836

<211> 9

<212>PRT

<213> Homo sapiens

<400> 836

Leu Val Leu Gly Phe Ile Ile Ala Leu

15

<210> 837

<211> 9

<212>PRT

<213> Homo sapiens

<400> 837

Ser Leu Ser Gly Leu Leu Ser Pro Ala

15

<210> 838

<211> 9

<212>PRT

<213> Homo sapiens

<400> 838

Thr Leu Pro Leu Ile Leu Ile Leu Leu

15

<210> 839

<211> 9

<212>PRT

<213> Homo sapiens

<400> 839

Val Leu Gly Phe Ile Ile Ala Leu Ala

15

<210> 840

<211> 9

<212>PRT

<213> Homo sapiens

<400> 840

Val Val Ile Thr Val Leu Leu Ser Val

15

<210> 841

<211> 9

<212>PRT

<213> Homo sapiens

<400> 841

Ala Gln Ile Gly Asp Ser Val Met Leu

15

<210> 842

<211> 9

<212>PRT

<213> Homo sapiens

<400> 842

Phe Ala Ser Ser Leu Ile Ile Pro Ala

15

<210> 843

<211> 9

<212>PRT

<213> Homo sapiens

<400> 843

Lys Ser Ile Asp Gly Ala Tyr Thr Ile

15

<210> 844

<211> 9

<212>PRT

<213> Homo sapiens

<400> 844

Ser Ile Leu Glu Glu Gly Ser Ser Val

15

<210> 845

<211> 9

<212>PRT

<213> Homo sapiens

<400> 845

Leu Leu Phe Gly Phe Thr Leu Val Ser

15

<210> 846

<211> 9

<212>PRT

<213> Homo sapiens

<400> 846

Leu Leu Leu Phe Gly Phe Thr Leu Val

15

<210> 847

<211> 9

<212>PRT

<213> Homo sapiens

<400> 847

Arg Leu Gly Pro Leu Ala Ala Ala Leu

15

<210> 848

<211> 9

<212>PRT

<213> Homo sapiens

<400> 848

Asp Leu Asn Ala Leu Leu Pro Ala Val

15

<210> 849

<211> 9

<212>PRT

<213> Homo sapiens

<400> 849

Ile Leu Ile Pro Gln Val Ala Tyr Thr

15

<210> 850

<211> 9

<212>PRT

<213> Homo sapiens

<400> 850

Asn Leu Ser Asp Ile Gln Asn Val Leu

15

<210> 851

<211> 9

<212>PRT

<213> Homo sapiens

<400> 851

Val Gln Ala Val Val Leu Pro Thr Val

15

<210> 852

<211> 9

<212>PRT

<213> Homo sapiens

<400> 852

Leu Val Leu Glu Gln Phe Leu Thr Ile

15

<210> 853

<211> 9

<212>PRT

<213> Homo sapiens

<400> 853

Arg Ile Ser Gly Tyr Ile Ser Glu Ala

15

<210> 854

<211> 9

<212>PRT

<213> Homo sapiens

<400> 854

Ala Met Thr Asp Ile Ser Ser Leu Ala

15

<210> 855

<211> 9

<212>PRT

<213> Homo sapiens

<400> 855

Val Leu Leu Ser Asn Phe Tyr Tyr Gly

15

<210> 856

<211> 20

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 856

Met Ala Lys Thr Ile Ala Tyr Asp Glu Glu Ala Arg Arg Gly Leu Glu

1 5 10 15

Arg Gly Leu Asn

20

<210> 857

<211> 9

<212>PRT

<213> Homo sapiens

<400> 857

Gln Leu Trp Gln Phe Leu Leu Glu Leu

15

<210> 858

<211> 9

<212>PRT

<213> Homo sapiens

<400> 858

Leu Val Leu Gly Thr Leu Glu Glu Val

15

<210> 859

<211> 15

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 859

Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His

1 5 10 15

<210> 860

<211> 13

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 860

Thr Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu

1 5 10

<210> 861

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 861

Trp Leu Leu Asp Ile Ser Phe Pro Leu

15

<210> 862

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 862

His Leu Leu Asp Ile Ser Phe Pro Ala

15

<210> 863

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 863

Glu Leu Leu Asp Ile Ser Phe Pro Ala

15

<210> 864

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 864

Val Leu Leu Asp Ile Ser Phe Glu Leu

15

<210> 865

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 865

Val Leu Leu Asp Ile Ser Phe Lys Val

15

<210> 866

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 866

Ile Met Leu Asp Ile Ser Phe Leu Leu

15

<210> 867

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 867

Leu Leu Asp Ile Ser Phe Pro Ser Leu

15

<210> 868

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 868

Leu Met Asp Leu Ser Thr Thr Asn Val

15

<210> 869

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 869

Met Leu Ser Ser Tyr Leu Val Pro Ile

15

<210> 870

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 870

Leu Leu Ser Ser Tyr Leu Val Pro Ile

15

<210> 871

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 871

Phe Val Ser Ser Tyr Leu Val Pro Thr

15

<210> 872

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 872

Ser Leu Ser Leu His Asp Met Phe Leu

15

<210> 873

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 873

Lys Leu Lys Pro Leu Leu Pro Trp Ile

15

<210> 874

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 874

Lys Leu Lys Pro Leu Leu Pro Phe Leu

15

<210> 875

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 875

Lys Val Val Pro Ile Gln Phe Pro Val

15

<210> 876

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 876

Lys Ile Val Pro Ile Gln Phe Pro Ile

15

<210> 877

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 877

Tyr Gln Ala Met Ile Gln Phe Leu Ile

15

<210> 878

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 878

Phe Met Pro Phe Gly Phe Ile Leu Pro Ile

1 5 10

<210> 879

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 879

Phe Met Pro Phe Gly Phe Ile Leu Gly Val

1 5 10

<210> 880

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 880

Phe Leu Ile Ser Thr Thr Phe Thr Ile Asn

1 5 10

<210> 881

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 881

Phe Met Ile Ser Thr Thr Phe Met Arg Leu

1 5 10

<210> 882

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 882

Gln Met Ile Ser Thr Thr Phe Gly Asn Val

1 5 10

<210> 883

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 883

Trp Leu Tyr Leu Gln Trp Gln Pro Ser Val

1 5 10

<210> 884

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 884

Phe Val Leu Leu Asp Thr Asn Tyr Glu Ile

1 5 10

<210> 885

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 885

Phe Ile Leu Leu Asp Thr Asn Tyr Glu Ile

1 5 10

<210> 886

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 886

Tyr Glu Leu Gln Asn Ile Val Leu Pro Ile

1 5 10

<210> 887

<211> 10

<212>PRT

<213> Artificial Sequence

<220>

<223> peptide

<400> 887

Phe Met Leu Gln Asn Ile Val Lys Asn Leu

1 5 10

<210> 888

<211> 9

<212>PRT

<213> Homo sapiens

<400> 888

Asn Leu Ser Leu His Asp Met Phe Val

15

<210> 889

<211> 9

<212>PRT

<213> Homo sapiens

<400> 889

Lys Met Lys Pro Leu Leu Pro Arg Val

15

<210> 890

<211> 9

<212>PRT

<213> Homo sapiens

<400> 890

Tyr Leu Val Pro Ile Gln Phe Pro Val

15

<210> 891

<211> 9

<212>PRT

<213> Homo sapiens

<400> 891

Tyr Met Ala Met Ile Gln Phe Ala Ile

15

<210> 892

<211> 10

<212>PRT

<213> Homo sapiens

<400> 892

Phe Leu Ile Ser Thr Thr Phe Gly Cys Thr

1 5 10

<210> 893

<211> 10

<212>PRT

<213> Homo sapiens

<400> 893

Tyr Leu Tyr Leu Gln Trp Gln Pro Pro Leu

1 5 10

<210> 894

<211> 10

<212>PRT

<213> Homo sapiens

<400> 894

Gly Val Leu Leu Asp Thr Asn Tyr Asn Leu

1 5 10

<210> 895

<211> 10

<212>PRT

<213> Homo sapiens

<400> 895

Phe Gln Leu Gln Asn Ile Val Lys Pro Leu

1 5 10

<210> 896

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> comparative peptide

<400> 896

Ala Leu Pro Phe Gly Phe Ile Leu Val

15

<210> 897

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> comparative peptide

<400> 897

Ile Leu Pro Phe Gly Phe Ile Leu Ala

15

<210> 898

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> comparative peptide

<400> 898

Phe Leu Pro Phe Gly Phe Ile Leu Met

15

<210> 899

<211> 9

<212>PRT

<213> Artificial Sequence

<220>

<223> comparative peptide

<400> 899

Leu Met Leu Gly Glu Phe Leu Lys Leu

15

<---

Claims (75)

1. An antigenic peptide for the treatment of cancer, which consists of or includes an amino acid sequence as defined in any of SEQ ID NO: 32, 220, 1 - 31, 33 - 219, 221 - 580 and 861 - 887. 2. The antigenic peptide of claim 1, wherein the antigenic peptide consists of or includes an amino acid sequence as set forth in SEQ ID NO: 32. 3. The antigenic peptide of claim 1, wherein the antigenic peptide consists of or includes an amino acid sequence as set forth in SEQ ID NO: 220. 4. The antigenic peptide of claim 1, wherein the antigenic peptide consists of or includes an amino acid sequence as set forth in SEQ ID NO: 255. 5. Antigenic peptide according to any one of paragraphs. 1-4, and the length of the antigenic peptide does not exceed 30 amino acids. 6. Antigenic peptide according to any one of paragraphs. 1-4, and the length of the antigenic peptide does not exceed 25 amino acids. 7. Antigenic peptide according to any one of paragraphs. 1-4, and the length of the antigenic peptide does not exceed 20 amino acids. 8. Antigenic peptide according to any one of paragraphs. 1-4, and the length of the antigenic peptide does not exceed 15 amino acids. 9. Antigenic peptide according to any one of paragraphs. 1-8, and the antigenic peptide is not a full-length (microbiotic) protein. 10. An immunogenic compound for the treatment of cancer, which includes an antigenic peptide according to any one of paragraphs. 1-9. 11. An immunogenic compound according to claim 10, wherein the antigenic peptide is linked to a carrier molecule. 12. The immunogenic compound according to claim 11, wherein the carrier molecule is a carrier protein or a carrier peptide. 13. Immunogenic compound according to any one of paragraphs. 10-12, consisting of or including a polypeptide of formula (I) PepNt-CORE-PepCt (I) Where: - "PepNt" consists of a polypeptide having a length of from 0 to 500 amino acid residues and located at the N-terminus of the polypeptide of formula (I); -"CORE" consists of an antigenic peptide of the present invention, as defined in any one of paragraphs. 1-9; And -"PepCt" consists of a polypeptide having a length of from 0 to 500 amino acid residues and located at the C-terminus of the polypeptide of formula (I). 14. An antigen-presenting cell for the treatment of cancer, which is loaded with an antigenic peptide according to any one of claims. 1-9 or an immunogenic compound according to any one of paragraphs. 10-13. 15. The antigen presenting cell according to claim 14, wherein said cell is a dendritic cell. 16. Nucleic acid for the treatment of cancer, encoding an antigenic peptide according to any one of paragraphs. 1-9 or an immunogenic compound according to any one of paragraphs. 10-13, wherein said immunogenic compound is a peptide or protein. 17. Nucleic acid according to claim 16, wherein the nucleic acid is a DNA molecule or an RNA molecule; preferably selected from genomic DNA; cDNA; mRNA; antisense DNA; antisense RNA; complementary RNA and/or DNA sequences; as well as their combinations. 18. A pharmaceutical composition for the treatment of cancer, which includes an effective amount - an antigenic peptide according to any one of paragraphs. 1-9, - an immunogenic compound according to any one of claims. 10-13, - antigen-presenting cell according to claim 14 or 15, and/or - nucleic acid according to claim 16 or 17. 19. The pharmaceutical composition according to claim 18, further comprising one or more immunostimulating agents. 20. The pharmaceutical composition according to claim 19, wherein the immunostimulating agent is selected from the group consisting of immunoadjuvants and antigen-presenting cells. 21. The pharmaceutical composition according to claim 20, wherein the antigen presenting cell is a dendritic cell. 22. Pharmaceutical composition according to any one of paragraphs. 18-21, wherein said pharmaceutical composition includes (a) at least two different antigenic peptides according to any one of claims. 1-9; (b) at least two different immunogenic compounds according to any one of paragraphs. 10-13; and/or (c) at least two different nucleic acids according to claim 16 or 17. 23. Use of an antigenic peptide according to any one of paragraphs. 1-9, immunogenic compound according to any one of paragraphs. 10-13, antigen presenting cell according to claim 14 or 15, nucleic acid according to claim 16 or 17, or pharmaceutical composition according to any one of paragraphs. 18-22, in cancer treatment. 24. Use according to claim 23, wherein the cancer is selected from glioma, kidney cancer, skin cancer, preferably melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial cancer and prostate cancer. 25. A combination for the treatment of cancer, which contains at least two different antigenic peptides according to any one of paragraphs. 1-9. 26. A combination for the treatment of cancer, which contains at least two different nucleic acids according to claim 16 or 17. 27. The combination according to claim 25 or 26, wherein at least two different components are in different compositions. 28. The combination according to claim 25 or 26, wherein at least two different components are part of one composition. 29. Use of the combination according to claim 25 or 26 in the treatment of cancer. 30. Use according to claim 29, wherein at least two different components are administered by different routes of administration. 31. Use according to claim 29, wherein at least two different components are administered by the same route of administration. 32. Application according to any one of paragraphs. 29-31, wherein at least two different components are introduced sequentially. 33. Application according to any one of paragraphs. 29-31, wherein at least two different components are introduced at approximately the same time. 34. A method of treating cancer in a subject in need thereof, comprising administering to the subject - an antigenic peptide according to any one of paragraphs. 1-9, - an immunogenic compound according to any one of claims. 10-13, - an antigen-presenting cell according to claim 14 or 15, -nucleic acid according to claim 16 or 17, - pharmaceutical composition according to any one of paragraphs. 18-22, and/or - combinations as defined in any of paragraphs. 25-26. 35. The method according to claim 34, where the cancer is selected from glioma, kidney cancer, skin cancer, in particular melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial cancer and prostate cancer. 36. A method of enhancing an antitumor response in a subject in need thereof, comprising administering to the subject - an antigenic peptide according to any one of paragraphs. 1-9, - an immunogenic compound according to any one of claims. 10-13, - an antigen-presenting cell according to claim 14 or 15, - nucleic acid according to claim 16 or 17, - pharmaceutical composition according to any one of paragraphs. 18-22, and/or - combinations according to any one of paragraphs. 25-26. 37. The method according to claim 36, where the cancer is selected from glioma, kidney cancer, skin cancer, in particular melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial cancer and prostate cancer. 38. A method of prolonging an antitumor response in a subject in need thereof, comprising administering to the subject - an antigenic peptide according to any one of paragraphs. 1-9, - an immunogenic compound according to any one of claims. 10-13, - an antigen-presenting cell according to claim 14 or 15, - nucleic acid according to claim 16 or 17, - pharmaceutical composition according to any one of paragraphs. 18-22, and/or - combinations according to any one of paragraphs. 25-26. 39. The method according to claim 38, wherein the cancer is selected from glioma, kidney cancer, skin cancer, in particular melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial cancer and prostate cancer. 40. A peptide-MHC multimer (pMHC) for detecting antigen-specific T cells, comprising an antigenic peptide according to any one of paragraphs. 1-9.