阅读说明：本技术 用于癌症免疫疗法的基于迷路蛋白的肽及其用途 (Labyrinth protein-based peptides for cancer immunotherapy and uses thereof ) 是由 J·A·拉多舍维奇 M·巴比奇 于 2019-12-13 设计创作，主要内容包括：本文描述了包含一种或多种迷路蛋白衍生肽的抗原组合物。在一些实施方案中,所述抗原组合物的每种肽包含T细胞表位和/或B细胞表位。在其他方面,本公开文本提供了例如包含本文公开的抗原组合物的疫苗组合物,包括其试剂盒、药物和组合物(如药物组合物和单位剂量)。还提供了使用本文公开的组合物的方法,如所述组合物的治疗方法,以及产生针对所述一种或多种迷路蛋白衍生肽或其部分的抗体及其抗体组合物的方法。(Antigenic compositions comprising one or more labyrinth protein derived peptides are described herein. In some embodiments, each peptide of the antigenic composition comprises a T cell epitope and/or a B cell epitope. In other aspects, the disclosure provides, for example, vaccine compositions, including kits, medicaments, and compositions (e.g., pharmaceutical compositions and unit doses) thereof, comprising the antigen compositions disclosed herein. Also provided are methods of using the compositions disclosed herein, methods of treatment with such compositions, and methods of generating antibodies and antibody compositions thereof against the one or more labyrinth protein derived peptides or portions thereof.)

1. An antigenic composition comprising one or more labyrinth protein-derived peptides, wherein each labyrinth protein-derived peptide comprises one or more of a T cell epitope and a B cell epitope.

2. The antigenic composition of claim 1, wherein each of said one or more labyrinth protein-derived peptides comprises a T cell epitope and a B cell epitope.

3. The antigenic composition of claim 1 or 2, wherein said one or more labyrinth protein derived peptides are between 8 and 25 amino acids in length.

4. The antigenic composition of any one of claims 1-3, wherein said one or more labyrinth protein derived peptides are substantially homologous to a portion of a labyrinth protein.

5. The antigenic composition of any one of claims 1-4, wherein each of said one or more labyrinth protein-derived peptides comprises a non-terminal proline residue.

6. An antigenic composition comprising one or more labyrinth protein derived peptides selected from the group consisting of:

(a) a first peptide comprising SEQ ID NO 25 or a variant thereof;

(b) a second peptide comprising SEQ ID NO 26 or a variant thereof;

(c) a third peptide comprising a variant of SEQ ID NO 27; and

(d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof,

wherein the one or more labyrinth protein derived peptides are between 12 and 25 amino acids in length, and

wherein each peptide comprises a T cell epitope and a B cell epitope.

7. The antigen composition of claim 6, wherein the first peptide comprises SEQ ID NO 25.

8. The antigen composition of claim 6 or 7, wherein the second peptide comprises SEQ ID NO 26.

9. The antigen composition of any one of claims 6-8, wherein the third peptide comprises SEQ ID NO 27.

10. The antigen composition of any one of claims 6-9, wherein the fourth peptide comprises SEQ ID No. 28.

11. The antigenic composition of any one of claims 6-10, wherein said one or more labyrinth protein-derived peptides are between 21 and 24 amino acids in length.

12. The antigenic composition of any one of claims 6-11, wherein said one or more labyrinth protein-derived peptides are 22 or 23 amino acids in length.

13. The antigenic composition of any one of claims 6-12, wherein said one or more labyrinth protein-derived peptides are substantially homologous to a portion of a labyrinth protein.

14. The antigenic composition of any one of claims 6-13, wherein said first peptide is SEQ ID No. 29 or a variant thereof in which 1 or 2 amino acids have been substituted, deleted, inserted and/or added relative to SEQ ID No. 29.

15. The antigen composition of any one of claims 6-14, wherein the first peptide is SEQ ID No. 29.

16. The antigen composition of any one of claims 6 to 15, wherein the second peptide is SEQ ID No. 30 or a variant thereof in which 1 or 2 amino acids are substituted, deleted, inserted and/or added relative to SEQ ID No. 30.

17. The antigen composition of any one of claims 6-16, wherein the second peptide is SEQ ID NO: 30.

18. The antigen composition of any one of claims 6-17, wherein the third peptide is SEQ ID No. 31 or a variant thereof in which 1 or 2 amino acids are substituted, deleted, inserted and/or added relative to SEQ ID No. 31.

19. The antigen composition of any one of claims 6-18, wherein the third peptide is SEQ ID NO 31.

20. The antigenic composition of any of claims 6-19, wherein said fourth peptide is SEQ ID No. 32 or a variant thereof wherein 1 or 2 amino acids have been substituted, deleted, inserted and/or added relative to SEQ ID No. 32.

21. The antigen composition of any one of claims 6-20, wherein the fourth peptide is SEQ ID No. 32.

22. The antigen composition of any one of claims 6-21, wherein at least one of the one or more labyrinth protein-derived peptides is conjugated to a linker.

23. The antigenic composition of any one of claims 6-22, wherein said antigenic composition comprises two or more of said labyrinth protein-derived peptides.

24. The antigenic composition of any one of claims 6-23, wherein said antigenic composition comprises three or more of said labyrinth protein-derived peptides.

25. The antigenic composition of any one of claims 6-24, wherein said antigenic composition comprises four of said labyrinth protein-derived peptides.

26. A nucleic acid composition comprising one or more nucleic acids encoding at least one of the one or more labyrinth protein-derived peptides comprised in the antigenic composition of any of claims 1-25.

27. A vaccine composition comprising:

(a) an effective amount of the antigenic composition of any one of claims 1-25; and

(b) a pharmaceutically acceptable vehicle.

28. The vaccine composition of claim 27, wherein the pharmaceutically acceptable vehicle is selected from the group consisting of an aqueous suspension, an oily suspension, an emulsion, a liposome, a virosome, and a nanoparticle.

29. The vaccine composition of claim 27 or 28, wherein the pharmaceutically acceptable vehicle comprises an excipient.

30. The vaccine composition of any one of claims 27-29, wherein the pharmaceutically acceptable vehicle comprises an adjuvant.

31. The vaccine composition of claim 30, wherein the adjuvant is an immunopotentiating adjuvant.

32. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual a vaccine composition according to any one of claims 27-31.

33. The method of claim 32, further comprising administering an immune checkpoint inhibitor to the individual.

34. A method of producing an antibody in a host animal, the method comprising administering to the host animal the antigen composition of any one of claims 1-25, the nucleic acid composition of claim 26, or the vaccine composition of any one of claims 27-33, thereby producing the antibody.

Technical Field

In some aspects, the present application relates to antigenic compositions comprising one or more labyrinth protein derived peptides. In other aspects, the present application relates to antigenic compositions comprising one or more labyrinth protein derived peptides, wherein each peptide comprises a T cell epitope and/or a B cell epitope. In other aspects, the application relates to antibodies produced by vaccinating a subject with a composition disclosed herein.

Background

For a long time, the characteristics of cancer have been mainly based on the tissue type or organ from which the cancer originates, such as lung, breast and colon cancer. Many cancer treatments are also based on tissue or organ based classification of cancer. It is well known that such tissue or organ based classification of cancer may not provide sufficient guidance for selecting an effective treatment. In part, the reason is to find that cancers derived from a single tissue type or organ can be highly heterogeneous, and such differences may require individualized cancer treatment approaches. For example, in contrast to the tissue type or organ of origin, defining cancer by biomarkers may improve cancer therapy, such as triple negative breast cancer, which lacks the expression of estrogen receptor, progesterone receptor, and HER2/neu, is unresponsive to traditional hormone-based therapies targeting any one or more of the identified receptors, and requires alternative therapy. After identifying cancer subtypes based on biomarkers, a great deal of research is required to develop novel agents that effectively treat such cancer subtypes.

One such identified cancer subtype is cancers that express labyrinthin. The labyrinth protein is a cell surface protein expressed on the extracellular surface of the plasma membrane of some cancers (e.g., adenocarcinomas). Cell surface expression of the labyrinthin is not cell cycle specific. Furthermore, the labyrinth protein is not found in the serum of normal or tumor-bearing patients and is not shed into the culture medium by the labyrinth protein positive cell line. Thus, the labyrinth proteins represent useful markers for defining cancer subtypes, i.e., cancers that express labyrinth proteins.

Cancer vaccines have been disclosed that target labyrin-expressing cancers solely through B-cell mediated adaptive immune system antibody production. See U.S. patent nos. 6,166,176 and 7,635,759, which are hereby incorporated by reference in their entirety.

All references, including patent applications and publications, cited herein are incorporated by reference in their entirety.

Disclosure of Invention

In one aspect, the present application provides antigenic compositions comprising one or more labyrinth protein derived peptides. In some embodiments, the present application provides antigenic compositions comprising one or more labyrinth protein-derived peptides, wherein each labyrinth protein-derived peptide comprises one or more of a T cell epitope and a B cell epitope. In some embodiments, each of the one or more labyrinth protein-derived peptides comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein derived peptides are between 8 and 25 amino acids in length. In some embodiments, the one or more labyrinth protein derived peptides are substantially homologous to a portion of the labyrinth protein. In some embodiments, each of the one or more labyrinth protein derived peptides comprises a non-terminal proline residue.

In another aspect, the present application provides an antigenic composition comprising one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:28 or a variant thereof, wherein the one or more labyrinth protein-derived peptides are between 12 and 25 amino acids in length, and wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the first peptide comprises SEQ ID NO: 25. In some embodiments, the second peptide comprises SEQ ID No. 26. In some embodiments, the third peptide comprises SEQ ID NO 27. In some embodiments, the fourth peptide comprises SEQ ID No. 28.

In some embodiments, the one or more labyrinth protein derived peptides are between 21 and 24 amino acids in length. In some embodiments, the one or more labyrinth protein-derived peptides are 22 or 23 amino acids in length.

In some embodiments, the one or more labyrinth protein derived peptides are substantially homologous to a portion of the labyrinth protein.

In some embodiments, the first peptide is SEQ ID No. 29 or a variant thereof in which 1 or 2 amino acids are substituted, deleted, inserted and/or added relative to SEQ ID No. 29. In some embodiments, the first peptide is SEQ ID NO 29.

In some embodiments, the second peptide is SEQ ID No. 30 or a variant thereof in which 1 or 2 amino acids are substituted, deleted, inserted and/or added relative to SEQ ID No. 30. In some embodiments, the second peptide is SEQ ID NO 30.

In some embodiments, the third peptide is SEQ ID NO. 31 or a variant thereof in which 1 or 2 amino acids are substituted, deleted, inserted and/or added relative to SEQ ID NO. 31. In some embodiments, the third peptide is SEQ ID NO 31.

In some embodiments, the fourth peptide is SEQ ID No. 32 or a variant thereof in which 1 or 2 amino acids are substituted, deleted, inserted and/or added relative to SEQ ID No. 32. In some embodiments, the fourth peptide is SEQ ID NO 32.

In some embodiments, at least one of the one or more labyrinth protein derived peptides is conjugated to a linker.

In some embodiments, the antigenic composition comprises two or more of the labyrinth protein-derived peptides. In some embodiments, the antigenic composition comprises three or more of the labyrinth protein-derived peptides. In some embodiments, the antigenic composition comprises four of the labyrinth protein-derived peptides.

In another aspect, the present application provides nucleic acid compositions comprising one or more nucleic acids encoding at least one of the one or more labyrinth protein-derived peptides comprised in the antigenic compositions described herein.

In another aspect, the present application provides a vaccine composition comprising: (a) an effective amount of an antigenic composition described herein; and (b) a pharmaceutically acceptable vehicle. In some embodiments, the pharmaceutically acceptable vehicle is selected from the group consisting of aqueous suspensions, oily suspensions, emulsions, liposomes, virosomes, and nanoparticles. In some embodiments, the pharmaceutically acceptable vehicle comprises an excipient. In some embodiments, the pharmaceutically acceptable vehicle comprises an adjuvant. In some embodiments, the adjuvant is an immunopotentiating adjuvant.

In another aspect, the present application provides a method of treating cancer in an individual in need thereof, comprising administering to the individual a vaccine composition described herein. In some embodiments, the method further comprises administering an immune checkpoint inhibitor to the individual.

In another aspect, the present application provides a method of producing an antibody in a host animal, the method comprising administering to the host animal an antigen composition described herein, a nucleic acid composition described herein, or a vaccine composition described herein, thereby producing the antibody.

Drawings

FIGS. 1A-1D each show mass spectra of parent ions m/z of labyrinth protein derived peptide candidates.

FIG. 2 shows UPLC traces of four labyrinth-derived peptides (SEQ ID NOS: 29-32) reconstituted in either a spacer electrolyte (pH 7.4) or water.

FIG. 3 shows a plot of tumor weight (mg) versus days after administration of peptide vaccine (LabVax 3(22) -23) or saline control to mice subcutaneously implanted with MC 38 murine colon (adenocarcinoma) tumor cells.

Detailed Description

In some aspects, the present application provides antigenic compositions comprising one or more labyrinth protein derived peptides. In some embodiments, the labyrinth protein-derived peptide comprises a T cell epitope. In some embodiments, the labyrinth protein-derived peptide comprises a B cell epitope. In some embodiments, the labyrinth protein-derived peptides comprise B cell epitopes and T cell epitopes. In some embodiments, the labyrinth protein-derived peptides activate T cell and B cell adaptive immune responses. In some embodiments, the one or more labyrinth protein-derived peptides are between 8 and 25 amino acids in length, such as between 12 and 25 amino acids in length.

The disclosure of the present application is based in part on the following findings: the labyrinth protein-derived peptides can be designed to contain B-cell epitopes and/or T-cell epitopes to trigger B-cell mediated adaptive immune responses and also elicit T-cell mediated adaptive immune responses to more effectively destroy cancer cells. In some aspects, the disclosure of the present application is based in part on the following findings: the labyrinth protein-derived peptides can be designed to elicit an immune response to effectively destroy cancer cells. Vaccines comprising such labyrinth protein derived peptides and combinations comprising one or more of such labyrinth protein derived peptides will allow for improved treatment of cancers expressing labyrinth proteins.

The design of labyrinth derived peptides comprising B-cell epitopes and T-cell epitopes is challenging because the mechanisms of antigen recognition between B-cells and T-cells are very different. B cells target antigens exposed to solvents, including linear and conformational antigens, through antigen receptors comprising immunoglobulins. In contrast, T cells recognize antigens presented on the surface of Antigen Presenting Cells (APCs) through T cell receptors. Such antigens are processed by the APC and then presented to the APC surface by, for example, class I Major Histocompatibility Complex (MHCI) or class II Major Histocompatibility Complex (MHCII). See, e.g., Sanchez-trincad, j.l., et al, J Immunol, 2017.

The recognition of antigens by B cells and T cells in vivo is highly unpredictable. Increasing the length of the peptide antigen increases cross-reactivity with non-target antigens. It is therefore a challenge to create peptides capable of activating B-cell and T-cell immune responses with high target specificity that can be synthesized and stably formulated in pharmaceutically acceptable vehicles, are safe for in vivo use, and enhance sufficient immunogenic response to effectively treat cancer. The present application discloses a labyrinth protein-derived peptide comprising B-cell epitopes and T-cell epitopes and suitable for use in cancer vaccines.

Accordingly, in some aspects, the present disclosure provides antigenic compositions comprising one or more labyrinth protein-derived peptides, wherein each labyrinth protein-derived peptide comprises one or more of a T cell epitope and a B cell epitope. In some embodiments, each of the one or more labyrinth protein-derived peptides comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein derived peptides are between 8 and 25 amino acids in length. In some embodiments, the one or more labyrinth protein derived peptides are substantially homologous to a portion of the labyrinth protein. In some embodiments, each of the one or more labyrinth protein derived peptides comprises a non-terminal proline residue.

In other aspects, the present disclosure provides antigenic compositions comprising one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:28 or a variant thereof, wherein the one or more labyrinth protein-derived peptides are between 12 and 25 amino acids in length, and wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein-derived peptides include two or more labyrinth protein-derived peptides. In some embodiments, the one or more labyrinth protein-derived peptides include three or more labyrinth protein-derived peptides. In some embodiments, the one or more labyrinth protein-derived peptides include four labyrinth protein-derived peptides. Also provided are compositions comprising the antigenic compositions disclosed herein, including kits, medicaments, and compositions (e.g., pharmaceutical compositions and unit doses) thereof.

In other aspects, the present disclosure provides vaccine compositions comprising: (a) an antigenic composition disclosed herein; and (b) a pharmaceutically acceptable vehicle. Also provided are vaccine compositions, including kits, medicaments, and compositions (e.g., pharmaceutical compositions and unit doses) thereof, comprising the antigenic compositions disclosed herein.

In other aspects, the disclosure provides methods of treating cancer in an individual in need thereof, comprising administering to the individual a vaccine composition described herein.

In other aspects, the disclosure provides methods of producing an antibody in a host animal, the method comprising administering to the host animal any of the antigen compositions, nucleic acids, or vaccine compositions described herein, thereby producing the antibody.

It will also be understood by those skilled in the art that changes in form and details may be made to the embodiments described herein without departing from the scope of the disclosure. Moreover, although various advantages, aspects, and objects have been described with reference to various embodiments, the scope of the disclosure should not be limited by reference to such advantages, aspects, and objects.

Definition of

The term "substantial homology," as used herein, refers to sequence similarity of a sequence disclosed herein as compared to a reference sequence, wherein the sequence has at least about 85% similarity (e.g., homology) to the reference sequence or a portion thereof, such as at least any one of about 86% similarity, 87% similarity, 88% similarity, 89% similarity, 90% similarity, 91% similarity, 92% similarity, 93% similarity, 94% similarity, 95% similarity, 96% similarity, 97% similarity, 98% similarity, 99% similarity, or 100% similarity. Methods for determining sequence similarity are known in the art, for example as described in Pearson, w.r., Curr protocol Bioinformatics, 2013.

As used herein, the term "treatment" is a method for obtaining beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by a disease, reducing the extent of a disease, stabilizing a disease (e.g., preventing or delaying the worsening of a disease), preventing or delaying the spread of a disease (e.g., metastasis), preventing or delaying the recurrence of a disease, delaying or slowing the progression of a disease, improving the disease state, providing remission (e.g., partial or total) of a disease, reducing the dosage of one or more other drugs required to treat a disease, delaying the progression of a disease, improving quality of life, and/or prolonging survival. "treating" or "treatment" also encompasses reducing the pathological consequences of cancer. The methods of the present application contemplate any one or more of these therapeutic aspects.

As used herein, the term "combination therapy" or "combination therapy" means that a first agent is administered in combination with at least one other agent. "in conjunction with … …" means that one mode of treatment, such as a vaccine composition, is administered in addition to (but not necessarily simultaneously with) another mode of treatment. Thus, "in conjunction with … …" refers to the administration of one mode of treatment before, during, or after delivery of another mode of treatment to an individual.

As used herein, the term "effective amount" refers to an amount of a compound or composition sufficient to treat a particular disorder, condition, or disease, such as to ameliorate, alleviate, reduce, and/or delay one or more symptoms of the disorder, condition, or disease. With respect to cancer, an effective amount includes an amount sufficient to, for example, cause tumor shrinkage and/or reduce the rate of tumor growth (e.g., inhibit tumor growth) or prevent or delay other undesirable cell proliferation in the cancer. In some embodiments, an effective amount is an amount sufficient to delay the development of cancer. In some embodiments, an effective amount is an amount sufficient to prevent or delay relapse. An effective amount may be administered in one or more administrations. In the case of cancer, an effective amount of the drug or composition may be: (i) reducing the number of cancer cells; (ii) reducing tumor size; (iii) inhibit, delay, slow to some extent and preferably prevent cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably prevent) tumor metastasis; (v) inhibiting tumor growth; (vi) preventing or delaying the occurrence and/or recurrence of a tumor; and/or (vii) relieving to some extent one or more symptoms associated with the cancer.

As used herein, the term "concurrently administering" or an equivalent thereof means that the first and second therapies in a combination therapy are administered at a time interval of no more than about 15 minutes, such as no more than about any of 10 minutes, 5 minutes, or 1 minute. When the first and second therapies are administered simultaneously, the first and second therapies may be included in the same composition (e.g., a composition including both the first and second therapies) or in separate compositions (e.g., the first therapy is in one composition and the second therapy is included in another composition).

As used herein, the term "sequentially administering" or an equivalent thereof means that the first and second therapies in a combination therapy are administered at a time interval of greater than about 15 minutes, such as greater than any of about 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 60 minutes. The methods disclosed herein encompass situations in which the first therapy or the second therapy may be administered first. The first and second therapies will typically be contained in separate compositions, which may be contained in the same or different packages or kits.

As used herein, the term "concurrently administering" or an equivalent thereof means that administration of the first therapy and administration of the second therapy overlap with each other in the combination therapy.

The term "individual" refers to a mammal and includes, but is not limited to, humans, bovines, equines, felines, canines, rodents, or primates.

As used herein, "delaying" the progression of cancer means delaying, impeding, slowing, delaying, stabilizing and/or prognosticating the progression of the disease. This delay may be of varying lengths of time depending on the medical history and/or the individual being treated. It will be clear to one of ordinary skill in the art that a sufficient or significant delay may actually encompass prevention, as the individual will not suffer from the disease. A method of "delaying" the progression of cancer is a method of reducing the probability of disease progression in a given time frame and/or reducing the extent of disease in a given time frame when compared to not using the method. Such comparisons are typically based on clinical studies using statistically significant numbers of subjects. Cancer progression can be detected using standard methods including, but not limited to, computerized axial tomography (CAT scan), Magnetic Resonance Imaging (MRI), abdominal ultrasound, coagulation tests, arteriography, or biopsy. Progression may also refer to cancer progression, which may initially be undetectable and includes occurrence, recurrence and onset.

As used herein, the term "pharmaceutically acceptable" or "pharmaceutically compatible" means a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition for administration to a patient without causing any significant undesirable biological effect or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The pharmaceutically acceptable carrier, excipient or salt preferably meets the required standards for toxicological and manufacturing testing and/or is included according to the guidelines for inactive ingredients as set forth by the U.S. food and drug administration.

As used herein, the term "based on" or "the basis of … …" includes assessing, determining, obtaining, or measuring one or more characteristics of an individual as described herein or cancer therein, and in some embodiments, includes selecting an individual suitable for receiving treatment as described in the methods disclosed herein. For example, where the labyrinthine status of a cancer is used as a basis for selecting an individual for use in a treatment method herein, assessing (or aiding in the assessment), measuring, obtaining or determining the labyrinthine status may be included in a treatment method as described herein, e.g., measuring the labyrinthine status before and/or during and/or after treatment, and the obtained values are used by a clinician to assess any of the following: (a) the reasonable or likely suitability of the individual to initially receive one or more treatments; (b) the reasonable or likely unsuitability of the individual to initially receive one or more treatments; (c) response to treatment; (d) the reasonable or likely suitability of the individual to continue to receive one or more treatments; (e) the reasonable or likely unsuitability of the individual to continue to receive one or more treatments; (f) adjusting the dosage; or (g) predicting the likelihood of clinical benefit.

In some aspects, one or more bases disclosed herein for use with the methods of the present application, i.e., such labyrinthine status, can be based on comparison to a control. In some embodiments, the control is a known standard obtained from the literature (e.g., a known gene sequence, RNA sequence, protein sequence, gene expression level). In some embodiments, the control is a control sample obtained from an individual who is about to, or is being treated using the methods disclosed herein (e.g., a control sample from a non-cancerous tissue). In some embodiments, the control is a control sample obtained from an individual other than the individual to be or being treated using the methods disclosed herein (e.g., a control sample from a healthy volunteer or a volunteer not having cancer). In some embodiments, the control is obtained from a given patient population. For example, with respect to a gene expression level or an enzyme activity level, a control level can be the median expression level of the gene or the median enzyme activity level of the enzyme for a population of patients. And, for example, if an individual patient is determined to have an expression level of a gene of interest that is higher than the median expression level for a population of patients, then the patient is determined to have high expression of the gene of interest. Alternatively, if an individual patient is determined to have an expression level of the gene of interest that is below the median expression level for a population of patients, then the patient is determined to have low expression of the gene of interest. In some embodiments, a single patient has a disease (e.g., cancer) and a population of patients does not have the disease. In some embodiments, the individual patient and the patient population have the same histological type of disease. For the number of individuals measured, the population may be about or alternatively at least about any of the following: 2. 5, 10, 15, 20, 25, 30, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 300, 400, 500. Preferably, a sufficient number of individuals are measured to provide a statistically significant population, which can be determined by methods known in the art. In some embodiments, the population is a group participating in a clinical trial.

As used herein, the terms "comprising," "having," "including," and "comprising," as well as other similar forms and grammatical equivalents thereof, are intended to be equivalent in meaning and be open-ended, i.e., an item or items following any one of these terms is not intended to be an exhaustive list of such items or is intended to be limited to only the listed item or items. For example, an article "comprising" components A, B and C can consist of (i.e., contain only) components A, B and C, or can contain not only components A, B and C, but also one or more other components. As such, it is intended and should be understood that the disclosure of "including" and its analogous forms, and grammatical equivalents, includes embodiments "consisting essentially of … …" or "consisting of … …".

In instances where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where stated ranges include one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

Reference herein to "about" a certain value or parameter includes (and describes) variations that are directed to that value or parameter itself. For example, a description referring to "about X" includes a description of "X".

As used herein, including in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

Antigenic compositions comprising peptides derived from labyrinthin

In some aspects, the present application provides antigenic compositions comprising one or more labyrinth protein derived peptides. The labyrinth protein is a protein having 255 amino acid sequences as listed in SEQ ID NO:1 (as shown in Table 1). Transcriptional variants associated with labyrinth proteins are known, including junctate, humbaug, and human aspartyl beta-hydroxylase (HAAH) (see, e.g., U.S. patent No. 6,166,176, which is hereby incorporated by reference in its entirety).

TABLE 1 amino acid sequence of the labyrinth protein.

Antigenic compositions disclosed herein comprise one or more of the labyrinth protein-derived peptides described herein, which are based in whole or in part on the sequence of the labyrinth protein (SEQ ID NO: 1). In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising T cell epitopes and/or B cell epitopes.

In some embodiments, the antigenic composition comprises at least two labyrinth protein derived peptides, such as at least any one of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 labyrinth protein derived peptides. In some embodiments, the labyrinth protein-derived peptides described herein have one or more of the following properties: as can be readily synthesized on a commercial scale, as soluble in aqueous solution, having a low pI (e.g., less than about 3.6, e.g., less than any of about 3.4 or 3.3), having a desired charge, such as a low charge, binding to a complex, such as MHC, that is processed by the cell for presentation, exhibiting presentation in vivo, and triggering an immune response. Furthermore, in some embodiments, the labyrinth protein-derived peptides and compositions thereof, such as antigenic compositions and/or vaccine compositions, described herein have freeze-thaw stability, e.g., less than 15% of the labyrinth protein-derived peptides are degraded over at least three freeze-thaw cycles. In some embodiments, the labyrinth protein-derived peptides and compositions thereof, such as antigenic compositions and/or vaccine compositions, described herein have room temperature stability, e.g., less than 15% of the labyrinth protein-derived peptides degrade over at least 6 hours of room temperature incubation. In some embodiments, the labyrinth protein-derived peptide is a peptide that shares the following sequence similarity with a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as any of at least about 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity, wherein the labyrinth protein derived peptides do not comprise a terminal proline residue, and wherein the labyrinth protein derived peptides comprise at least one proline residue, such as 2, 3, 4, or 5 proline residues. In some embodiments, the labyrinth protein-derived peptide is a peptide that shares the following sequence similarity with a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as any of at least about 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity, wherein one terminus of the labyrinth protein derived peptide does not comprise a terminal proline residue, and wherein the labyrinth protein derived peptide comprises at least one proline residue, such as 2, 3, 4, or 5 proline residues. In some embodiments, the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, between 7 and 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein derived peptides are 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, or 50 amino acids in length. In some embodiments, the labyrinth protein-derived peptides have the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptides or derivatives thereof have a sequence similarity of at least about 60% similarity to a portion of the labyrinth protein (SEQ ID NO:1), wherein 1, 2, 3, 4, 5 amino acids of the sequence of the labyrinth protein-derived peptide are deleted, substituted, inserted, and/or added to the labyrinth protein-derived peptide, and wherein when there is a substitution, insertion, and/or addition, a portion is substituted, inserted, and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker. In some embodiments, the labyrinth protein derived peptides have a pI between about 3.4 and about 3.1, such as between about 3.3 and about 3.15. In some embodiments, the labyrinth protein-derived peptide has a pI of less than about 3.4.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising a sequence selected from SEQ ID NOs 2-32 (table 2) or variants thereof. In some embodiments, a labyrinth protein-derived peptide comprising a sequence selected from SEQ ID NOs 2-32 (table 2) or variants thereof comprises one or two flanking amino acid sequences added at the end of the core sequence provided in SEQ ID NOs 2-32. In some embodiments, a labyrinth protein-derived peptide comprising one or two flanking amino acid sequences is a peptide having the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the flanking amino acid sequences are based on the sequence of a portion of the labyrinth protein (SEQ ID NO:1) and are the corresponding continuation of the labyrinth protein sequence from each of the core sequences provided in SEQ ID NOS: 2-32, e.g., from one or both ends of the core sequence. For example, for SEQ ID NO. 3, the first flanking amino acid sequence of the two left amino acids of SEQ ID NO. 3 is Pro-Ala and the second flanking amino acid sequence of the two right amino acids of SEQ ID NO. 3 is Glu-Ala.

TABLE 2 amino acid sequences of labyrinth protein derived peptides or parts thereof.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:2 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:2 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:2 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of a labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:2 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:2 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:3 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:3 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:3 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of a labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID No. 3 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID No. 3 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID No. 4 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 4 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:4 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID No. 4 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID No. 4 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:5 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 5 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:5 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID No. 5 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID No. 5 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID No. 7 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO 7 or a variant thereof, wherein the labyrinth protein-derived peptide is between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:7 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID No. 7 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID No. 7 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:8 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:8 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:8 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:8 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:8 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:9 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:9 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:9 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:9 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:9 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:10 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 10 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:10 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:10 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:10 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:11 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:11 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:11 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:11 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:11 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:12 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO 12 or a variant thereof, wherein the labyrinth protein-derived peptide is between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:12 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:12 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:12 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:13 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:13 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 7 and 50 amino acids in length, such as between 7 and 25 amino acids in length, between 7 and 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:13 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:13 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:13 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:14 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 14 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:14 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:14 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:14 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:15 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 15 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 7 and 50 amino acids in length, such as between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:15 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:15 or a variant thereof, wherein 1 or 2 amino acids of the sequence of SEQ ID NO:15 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when substitutions, insertions and/or additions are present, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:16 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 16 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:16 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:16 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:16 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO 17 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 17 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 9 and 50 amino acids in length, such as between 9 and 25 amino acids in length, 9 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:17 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:17 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:17 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:18 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:18 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, 7 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:18 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:18 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:18 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:19 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 19 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 8 and 50 amino acids in length, such as between 10 and 25 amino acids in length, 8 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:19 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:19 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:19 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:20 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:20 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 8 and 50 amino acids in length, such as between 10 and 25 amino acids in length, 8 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:20 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:20 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:20 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:21 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 21 or variants thereof, wherein the labyrinth protein-derived peptides are between 7 and 50 amino acids in length, such as any of between 7 and 25 amino acids in length, between 7 and 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:21 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:21 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:21 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:22 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 22 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 8 and 50 amino acids in length, such as between 10 and 25 amino acids in length, 8 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:22 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:22 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:22 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID No. 23 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 23 or variants thereof, wherein the labyrinth protein-derived peptides are between 8 and 50 amino acids in length, such as any of between 10 and 25 amino acids in length, 8 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:23 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID No. 23 or a variant thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID No. 23 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:24 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:24 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 12 and 50 amino acids in length, such as between 12 and 25 amino acids in length, 12 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:24 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:24 or a variant thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:24 are deleted, substituted, inserted and/or added to the labyrinth protein-derived peptide, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:25 or a variant thereof, wherein the labyrinth protein-derived peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:25 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 11 and 50 amino acids in length, such as between 11 and 25 amino acids in length, 12 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:25 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:25 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:25 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:26 or a variant thereof, wherein the labyrinth protein-derived peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:26 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 11 and 50 amino acids in length, such as between 11 and 25 amino acids in length, 12 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:26 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:26 or a variant thereof, wherein 1, 2, or 3 amino acids of the sequence of SEQ ID NO:26 are deleted, substituted, inserted, and/or added to the labyrinth protein-derived peptide, and wherein when there is a substitution, insertion, and/or addition, a portion is substituted, inserted, and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:27 or a variant thereof, wherein the labyrinth protein-derived peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO 27 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 11 and 50 amino acids in length, such as between 11 and 25 amino acids in length, 11 to 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:27 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:27 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:27 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:28 or a variant thereof, wherein the labyrinth protein-derived peptide comprises T cell epitopes and/or B cell epitopes. In some embodiments, the labyrinth protein-derived peptides comprise SEQ ID NO:28 or variants thereof, wherein the labyrinth protein-derived peptides are any one of between 10 and 50 amino acids in length, such as between 10 and 25 amino acids in length, between 10 and 13 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:28 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:28 or variants thereof, wherein 1, 2 or 3 amino acids of the sequence of SEQ ID NO:28 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptides, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:29 or a variant thereof, wherein the labyrinth protein-derived peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:29 or a variant thereof, wherein the labyrinth protein-derived peptide is between 22 and 50 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:29 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:29 or variants thereof, wherein 1, 2, 3, 4, or 5 amino acids of the sequence of SEQ ID NO:29 are deleted, substituted, inserted, and/or added to the labyrinth protein derived peptides, and wherein when substitutions, insertions, and/or additions are present, a portion is substituted, inserted, and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:30 or a variant thereof, wherein the labyrinth protein-derived peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:30 or a variant thereof, wherein the labyrinth protein-derived peptide is between 22 and 50 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:30 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:30 or variants thereof, wherein 1, 2, 3, 4, or 5 amino acids of the sequence of SEQ ID NO:30 are deleted, substituted, inserted, and/or added to the labyrinth protein derived peptides, and wherein when substitutions, insertions, and/or additions are present, a portion is substituted, inserted, and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:31 or a variant thereof, wherein the labyrinth protein-derived peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:31 or a variant thereof, wherein the labyrinth protein-derived peptide is between 22 and 50 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:31 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptide comprises SEQ ID NO:31 or a variant thereof, wherein 1, 2, 3, 4 or 5 amino acids of the sequence of SEQ ID NO:31 are deleted, substituted, inserted and/or added to the labyrinth protein derived peptide, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises a labyrinth protein-derived peptide comprising SEQ ID NO:32 or a variant thereof, wherein the labyrinth protein-derived peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:32 or a variant thereof, wherein the labyrinth protein-derived peptide is between 23 and 50 amino acids in length. In some embodiments, the labyrinth protein-derived peptide comprises SEQ ID NO:32 or a variant thereof, wherein the labyrinth protein-derived peptide has the following sequence similarity to a portion of labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the labyrinth protein derived peptides comprise SEQ ID NO:32 or variants thereof, wherein 1, 2, 3, 4, or 5 amino acids of the sequence of SEQ ID NO:32 are deleted, substituted, inserted, and/or added to the labyrinth protein derived peptides, and wherein when substitutions, insertions, and/or additions are present, a portion is substituted, inserted, and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the antigenic composition comprises one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the first peptide comprising SEQ ID No. 25 or a variant thereof is any one of between 11 and 50 amino acids in length, such as between 11 and 45 amino acids in length, between 11 and 40 amino acids in length, between 11 and 35 amino acids in length, between 11 and 30 amino acids in length, between 11 and 25 amino acids in length, between 15 and 30 amino acids in length, between 20 and 30 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, a first peptide comprising SEQ ID NO 25 or a variant thereof is at least 11 amino acids in length, such as at least 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, a polypeptide or a polypeptide, Any one of 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length. In some embodiments, a first peptide comprising SEQ ID No. 25 or a variant thereof is NO more than 50 amino acids in length, such as NO more than 49 amino acids in length, 48 amino acids in length, 47 amino acids in length, 46 amino acids in length, 45 amino acids in length, 44 amino acids in length, 43 amino acids in length, 42 amino acids in length, 41 amino acids in length, 40 amino acids in length, 39 amino acids in length, 38 amino acids in length, 37 amino acids in length, 36 amino acids in length, 35 amino acids in length, 34 amino acids in length, 33 amino acids in length, 32 amino acids in length, 31 amino acids in length, 30 amino acids in length, 29 amino acids in length, 28 amino acids in length, 27 amino acids in length, 26 amino acids in length, Any one of 25 amino acids in length, 24 amino acids in length, 23 amino acids in length, 22 amino acids in length, 21 amino acids in length, 20 amino acids in length, 19 amino acids in length, 18 amino acids in length, 17 amino acids in length, 16 amino acids in length, or 15 amino acids in length. In some embodiments, a first peptide comprising SEQ ID NO 25 or a variant thereof is 11 amino acids in length, 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length.

In some embodiments, the first peptide comprises SEQ ID NO: 25. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, the first peptide comprising SEQ ID No. 25 or a variant thereof is a variant of SEQ ID No. 29, wherein at least one amino acid of the sequence of SEQ ID No. 29 is substituted, deleted, inserted and/or added to the first peptide. In some embodiments, the first peptide comprising SEQ ID No. 25 or a variant thereof is a variant of SEQ ID No. 29, wherein 1, 2, 3, 4 or 5 amino acids of the sequence of SEQ ID No. 29 are deleted, substituted, inserted and/or added to the first peptide, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof is substantially homologous to a portion of the labyrinthine protein (SEQ ID NO: 1). In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the variant of SEQ ID NO:29 has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity.

In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof is any one of between 12 and 50 amino acids in length, such as between 12 and 45 amino acids in length, between 12 and 40 amino acids in length, between 12 and 35 amino acids in length, between 12 and 30 amino acids in length, between 12 and 25 amino acids in length, between 15 and 30 amino acids in length, between 20 and 30 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the second peptide comprising SEQ ID NO 26 or a variant thereof is at least 12 amino acids in length, such as at least 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, 36 amino acids in length, a variant thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, or a pharmaceutically acceptable carrier Any one of 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof is NO more than 50 amino acids in length, such as NO more than 49 amino acids in length, 48 amino acids in length, 47 amino acids in length, 46 amino acids in length, 45 amino acids in length, 44 amino acids in length, 43 amino acids in length, 42 amino acids in length, 41 amino acids in length, 40 amino acids in length, 39 amino acids in length, 38 amino acids in length, 37 amino acids in length, 36 amino acids in length, 35 amino acids in length, 34 amino acids in length, 33 amino acids in length, 32 amino acids in length, 31 amino acids in length, 30 amino acids in length, 29 amino acids in length, 28 amino acids in length, 27 amino acids in length, 26 amino acids in length, Any one of 25 amino acids in length, 24 amino acids in length, 23 amino acids in length, 22 amino acids in length, 21 amino acids in length, 20 amino acids in length, 19 amino acids in length, 18 amino acids in length, 17 amino acids in length, 16 amino acids in length, or 15 amino acids in length. In some embodiments, the second peptide comprising SEQ ID NO 26 or a variant thereof is 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length.

In some embodiments, the second peptide comprises SEQ ID No. 26. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof is a variant of SEQ ID No. 30, wherein at least one amino acid of the sequence of SEQ ID No. 26 is substituted, deleted, inserted and/or added to the first peptide. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof is a variant of SEQ ID No. 30, wherein 1, 2, 3, 4 or 5 amino acids of the sequence of SEQ ID No. 30 are deleted, substituted, inserted and/or added to the first peptide, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the second peptide comprising SEQ ID NO:26 or a variant thereof is substantially homologous to a portion of the labyrinthine protein (SEQ ID NO: 1). In some embodiments, the second peptide comprising SEQ ID NO:26 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the variant of SEQ ID NO:30 has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity.

In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is any one of between 11 and 50 amino acids in length, such as between 11 and 45 amino acids in length, between 11 and 40 amino acids in length, between 11 and 35 amino acids in length, between 11 and 30 amino acids in length, between 11 and 25 amino acids in length, between 15 and 30 amino acids in length, between 20 and 30 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is at least 11 amino acids in length, such as at least 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, a variant thereof, and a pharmaceutically acceptable salt thereof, Any one of 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length. In some embodiments, the third peptide comprising SEQ ID No. 27 or a variant thereof is NO more than 50 amino acids in length, such as NO more than 49 amino acids in length, 48 amino acids in length, 47 amino acids in length, 46 amino acids in length, 45 amino acids in length, 44 amino acids in length, 43 amino acids in length, 42 amino acids in length, 41 amino acids in length, 40 amino acids in length, 39 amino acids in length, 38 amino acids in length, 37 amino acids in length, 36 amino acids in length, 35 amino acids in length, 34 amino acids in length, 33 amino acids in length, 32 amino acids in length, 31 amino acids in length, 30 amino acids in length, 29 amino acids in length, 28 amino acids in length, 27 amino acids in length, 26 amino acids in length, Any one of 25 amino acids in length, 24 amino acids in length, 23 amino acids in length, 22 amino acids in length, 21 amino acids in length, 20 amino acids in length, 19 amino acids in length, 18 amino acids in length, 17 amino acids in length, 16 amino acids in length, or 15 amino acids in length. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is 11 amino acids in length, 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length.

In some embodiments, the third peptide comprises SEQ ID NO 27. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID No. 27 or a variant thereof is a variant of SEQ ID No. 31 wherein at least one amino acid of the sequence of SEQ ID No. 27 is substituted, deleted, inserted and/or added to the first peptide. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is a variant of SEQ ID NO 31 wherein 1, 2, 3, 4 or 5 amino acids of the sequence of SEQ ID NO 31 are deleted, substituted, inserted and/or added to the first peptide and wherein when there is a substitution, insertion and/or addition a moiety is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof is substantially homologous to a portion of the labyrinth protein (SEQ ID NO: 1). In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the variant of SEQ ID NO:31 has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity.

In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof is between 10 and 50 amino acids in length, such as any of between 10 and 45 amino acids in length, between 10 and 40 amino acids in length, between 10 and 35 amino acids in length, between 10 and 30 amino acids in length, between 10 and 25 amino acids in length, between 10 and 30 amino acids in length, between 20 and 30 amino acids in length, or between 21 and 25 amino acids in length. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is at least 10 amino acids in length, such as at least 11 amino acids in length, 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, a variant thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, Any one of 35 amino acids in length, 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is NO more than 50 amino acids in length, such as NO more than 49 amino acids in length, 48 amino acids in length, 47 amino acids in length, 46 amino acids in length, 45 amino acids in length, 44 amino acids in length, 43 amino acids in length, 42 amino acids in length, 41 amino acids in length, 40 amino acids in length, 39 amino acids in length, 38 amino acids in length, 37 amino acids in length, 36 amino acids in length, 35 amino acids in length, 34 amino acids in length, 33 amino acids in length, 32 amino acids in length, 31 amino acids in length, 30 amino acids in length, 29 amino acids in length, 28 amino acids in length, 27 amino acids in length, 26 amino acids in length, Any one of 25 amino acids in length, 24 amino acids in length, 23 amino acids in length, 22 amino acids in length, 21 amino acids in length, 20 amino acids in length, 19 amino acids in length, 18 amino acids in length, 17 amino acids in length, 16 amino acids in length, or 15 amino acids in length. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is 10 amino acids in length, 11 amino acids in length, 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, 40 amino acids in length, 41 amino acids in length, 42 amino acids in length, 43 amino acids in length, 44 amino acids in length, 45 amino acids in length, 46 amino acids in length, 47 amino acids in length, 48 amino acids in length, 49 amino acids in length, or 50 amino acids in length.

In some embodiments, the fourth peptide comprises SEQ ID No. 28. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof is a variant of SEQ ID No. 32, wherein at least one amino acid of the sequence of SEQ ID No. 32 is substituted, deleted, inserted and/or added to the first peptide. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof is a variant of SEQ ID No. 32, wherein 1, 2, 3, 4 or 5 amino acids of the sequence of SEQ ID No. 32 are deleted, substituted, inserted and/or added to the first peptide, and wherein when there is a substitution, insertion and/or addition, a portion is substituted, inserted and/or added to the sequence. In some embodiments, the moiety substituted, inserted, or added is a natural amino acid (e.g., an alpha-amino acid or an L-amino acid or a D-amino acid) or an unnatural amino acid. In some embodiments, the moiety substituted, inserted, or added is an amino acid substitution or linker.

In some embodiments, the fourth peptide comprising SEQ ID NO:28 or a variant thereof is substantially homologous to a portion of the labyrinthine protein (SEQ ID NO: 1). In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity. In some embodiments, the variant of SEQ ID NO:32 has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 60% similarity, such as at least about any one of 65% similarity, 70% similarity, 75% similarity, 80% similarity, 85% similarity, 90% similarity, or 95% similarity.

In some embodiments, for any of the antigenic compositions disclosed herein, one or more of the labyrinth protein-derived peptides is soluble in solution. In some embodiments, one or more of the labyrinth protein derived peptides have a solubility in solution of at least about 0.1mg/mL, such as at least about any of 0.5mg/mL, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, or 10 mg/mL. In some embodiments, the solution is a pharmaceutically acceptable vehicle. In some embodiments, the solution comprises one or more of water, a buffer (e.g., PBS), and a salt solution (e.g., sodium chloride solution).

In some embodiments, for any of the antigen compositions disclosed herein, one or more of the labyrinth protein-derived peptides are each at least about 90% pure, such as any of at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Methods for determining the purity of a peptide are known in the art, such as using high performance liquid chromatography techniques.

In some embodiments, for any of the antigenic compositions disclosed herein, one or more of the labyrinth protein-derived peptides therein activates both a T cell and/or B cell adaptive immune response. In some embodiments, each of the labyrinth protein-derived peptides activates both a T cell and B cell adaptive immune response for any of the antigenic compositions disclosed herein. In some embodiments, activation of the T cell adaptive immune response results in the production of a target-specific receptor, such as an anti-labyrin-derived peptide epitope T cell receptor. In some embodiments, the activation of the T cell adaptive immune response is via class I major histocompatibility complex (MHC I). In some embodiments, the activation of the T cell adaptive immune response is via the major histocompatibility complex class II (MHC II). In some embodiments, the activation of the T cell adaptive immune response is via MHC I and MHC II. In some embodiments, activation of the B cell adaptive immune response results in the production of target-specific immunoglobulins, such as anti-maze-protein-derived peptide epitope antibodies. Methods for assessing the activation of labyrinth-derived peptides of T-and B-cell adaptive immune responses and whether the peptides are T-and/or B-cell epitopes are known in the art. See, e.g., Bercovici, N.et al, Clin Diagn Lab Immunol,2000,7, 859-; and McAllister, E.J. et al, J Immunol,2017,199, 2998-.

In some embodiments, for any of the antigenic compositions disclosed herein, at least one of the one or more labyrinth protein-derived peptides of the antigenic composition is conjugated. In some embodiments, the labyrinth protein-derived peptide is conjugated to a carrier molecule. In some embodiments, the labyrinth derived peptide is conjugated to a protein, such as ovalbumin, albumin, Keyhole Limpet Hemocyanin (KLH), diphtheria toxoid, tetanus toxoid, or CRM 197. In some embodiments, the labyrinth protein-derived peptide is conjugated to a lipid. In some embodiments, the labyrinth protein-derived peptide is conjugated to an adjuvant. In some embodiments, the labyrinth protein-derived peptides are conjugated to an immunologically effective (e.g., immunopotentiating) adjuvant. In some embodiments, the labyrinth protein-derived peptides are conjugated to one or more other labyrinth protein-derived peptides. In some embodiments, the labyrinth protein-derived peptides are conjugated to one or more other labyrinth protein-derived peptides, wherein the resulting peptide sequence is not the labyrinth protein sequence (SEQ ID NO:1) or a portion thereof. For example, in some embodiments, a first labyrinth protein-derived peptide is conjugated to a second labyrinth protein-derived peptide, wherein the resulting sequence of the first and second peptides is not a labyrinth protein sequence (SEQ ID NO:1) or portion thereof. In some embodiments, the labyrinth protein-derived peptides are conjugated via a linker, such as a cross-linker. In some embodiments, the labyrinth protein-derived peptide is conjugated to a linker.

In some embodiments, the antigenic composition comprises one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. For example, in some embodiments, the antigenic composition comprises a first peptide comprising SEQ ID NO:25 or a variant thereof, wherein the first peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a first peptide comprising SEQ ID No. 29 or a variant thereof, wherein said first peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a first peptide, wherein the first peptide is SEQ ID NO:29, and wherein the first peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response.

In some embodiments, the antigenic composition comprises one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:28 or a variant thereof, wherein these are the only four labyrinth protein-derived peptides in the antigenic composition. In some embodiments, the labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, an antigenic composition comprising a peptide comprising SEQ ID No. 25 or a variant thereof comprises SEQ ID No. 29 or a variant thereof. In some embodiments, an antigenic composition comprising a peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, an antigenic composition comprising a peptide comprising SEQ ID No. 27 or a variant thereof comprises SEQ ID No. 31 or a variant thereof. In some embodiments, an antigenic composition comprising a peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein these are the only four labyrinth protein-derived peptides in the antigenic composition. In some embodiments, the labyrinth protein-derived peptides comprise T cell epitopes and/or B cell epitopes.

In some embodiments, the antigenic composition comprises a second peptide comprising SEQ ID NO:26 or a variant thereof, wherein the second peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a second peptide comprising SEQ ID NO:30 or a variant thereof, wherein the second peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a second peptide, wherein the second peptide is SEQ ID NO:30, and wherein the second peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response.

In some embodiments, the antigenic composition comprises a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein the third peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein the third peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a third peptide, wherein the third peptide is SEQ ID NO:31, and wherein the third peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises a fourth peptide comprising SEQ ID NO:28 or a variant thereof, wherein said fourth peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein said fourth peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, and wherein the fourth peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response.

In some embodiments, the antigenic composition comprises two or more labyrinth protein derived peptides. For example, in some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; and (B) a second peptide comprising SEQ ID NO:26 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the two or more labyrinth protein derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; and (B) a second peptide comprising SEQ ID NO:30 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; and (B) a second peptide, wherein the second peptide is SEQ ID NO:30, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response.

In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; and (B) a third peptide, wherein the third peptide is SEQ ID NO:31, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; and (B) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 26 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a second peptide, wherein the second peptide is SEQ ID NO 30; and (B) a third peptide, wherein the third peptide is SEQ ID NO:31, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 25 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a second peptide, wherein the second peptide is SEQ ID NO 30; and (B) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises: (a) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a third peptide, wherein the third peptide is SEQ ID NO 31; and (B) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises three or more labyrinth protein-derived peptides. For example, in some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; and (c) a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (c) a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; and (c) a third peptide, wherein the third peptide is SEQ ID NO:31, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; and (c) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a third peptide comprising SEQ ID NO 26 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a third peptide, wherein the third peptide is SEQ ID NO 31; and (c) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 26 or a variant thereof; (b) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 30 or a variant thereof; (b) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a second peptide, wherein the second peptide is SEQ ID NO 30; (b) a third peptide, wherein the third peptide is SEQ ID NO 31; and (c) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, the antigenic composition comprises four or more labyrinth protein derived peptides. For example, in some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the four or more labyrinth protein derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; (c) a third peptide, wherein the third peptide is SEQ ID NO 31; and (d) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope.

In some embodiments, wherein the antigenic composition comprises more than one labyrinth protein-derived peptide, the ratio between each of the more than one labyrinth protein-derived peptides can be selected to achieve a desired immunotherapeutic response. In some embodiments, more than one labyrinth protein derived peptide, such as 2, 3, or 4 labyrinth protein derived peptides, are all provided in approximately the same amount in the antigenic composition. For example, in some embodiments wherein the antigenic composition comprises more than one labyrinth protein derived peptide, the ratio of the first peptide to the second peptide is about 1:10 to about 10:1, such as any of about 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9: 1. In some embodiments wherein the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; (c) a third peptide, wherein the third peptide is SEQ ID NO 31; and (d) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, the ratio of the first peptide to the second peptide to the third peptide to the fourth peptide is about 1:1:1: 1. In some embodiments wherein the antigenic composition comprises only the following peptides: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; (c) a third peptide, wherein the third peptide is SEQ ID NO 31; and (d) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, the ratio of the first peptide to the second peptide to the third peptide to the fourth peptide is about 1:1:1: 1.

In some embodiments, the antigenic composition comprises one or more labyrinth protein-derived peptides, wherein each of the one or more labyrinth protein-derived peptides has a pI as follows: between about 3.4 and about 3.1, such as about 3.3 to about 3.15. In some embodiments, the antigenic composition comprises one or more labyrinth protein-derived peptides, wherein each of the one or more labyrinth protein-derived peptides has a pI as follows: less than about 3.4, such as less than any of about 3.35, 3.3, 3.25, 3.2, 3.15, 3.1, 3.05, or 3. In some embodiments, the antigenic composition comprises one or more labyrinth protein-derived peptides, wherein each of the one or more labyrinth protein-derived peptides has a pI as follows: any of about 3.4, about 3.35, about 3.3, about 3.25, about 3.2, about 3.15, about 3.1, about 3.05, or about 3.

Nucleic acid compositions comprising labyrinth protein-derived peptides

In some embodiments, nucleic acid compositions are provided that comprise one or more nucleic acids encoding at least one of the one or more labyrinth protein-derived peptides comprised in the antigenic compositions disclosed herein. In some embodiments, the nucleic acid composition comprises a nucleic acid encoding at least two or more labyrinth protein-derived peptides. In some embodiments, the nucleic acid composition comprises a nucleic acid encoding at least three or more labyrinth protein-derived peptides. In some embodiments, the nucleic acid composition comprises nucleic acids encoding four labyrinth protein-derived peptides.

In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a first peptide comprising SEQ ID No. 25 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a first peptide comprising SEQ ID No. 25. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a first peptide comprising SEQ ID No. 29 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a first peptide, wherein the first peptide is SEQ ID No. 29.

In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a second peptide comprising SEQ ID No. 26 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a second peptide comprising SEQ ID No. 26. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a second peptide comprising SEQ ID NO:30 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a second peptide, wherein the second peptide is SEQ ID No. 30.

In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a third peptide comprising SEQ ID NO 27 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a third peptide comprising SEQ ID No. 27. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a third peptide comprising SEQ ID NO 31 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a third peptide, wherein the third peptide is SEQ ID No. 31.

In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a fourth peptide comprising SEQ ID No. 28 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a fourth peptide comprising SEQ ID No. 28. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a fourth peptide comprising SEQ ID No. 32 or a variant thereof. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding a fourth peptide, wherein the fourth peptide is SEQ ID No. 32.

In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding at least one of the one or more labyrinth protein-derived peptides described herein, wherein at least one of the one or more nucleic acids is a non-naturally occurring sequence. In some embodiments, the nucleic acid composition comprises one or more nucleic acids encoding at least one of the one or more labyrinth protein-derived peptides described herein, wherein at least one of the one or more nucleic acids is conjugated, such as to a label.

Vaccine compositions comprising antigenic compositions

In some embodiments, there is provided a vaccine composition comprising: (a) an effective amount of an antigenic composition having any one of the antigenic compositions described herein; and (b) a pharmaceutically acceptable vehicle.

In some embodiments, the pharmaceutically acceptable vehicle is one or more of an aqueous suspension, an oily suspension, an emulsion, a liposome, a virosome, and a nanoparticle. In some embodiments, the pharmaceutically acceptable vehicle is selected from the group consisting of aqueous suspensions, oily suspensions, emulsions (such as oil-in-water emulsions), liposomes, virosomes and nanoparticles. In some embodiments, the pharmaceutically acceptable vehicle or portion thereof stabilizes the antigenic composition or portion thereof. In some embodiments, the pharmaceutically acceptable vehicle, or portion thereof, extends the circulatory half-life of the one or more labyrinth protein-derived peptides as compared to the circulatory half-life of the one or more labyrinth protein-derived peptides administered in the absence of the pharmaceutically acceptable vehicle.

In some embodiments, the pharmaceutically acceptable vehicle comprises an excipient. Excipients are known in the art. See Mehmood, y, et al, Open Science J Pharm Sci,3,2015,19-27, which is hereby incorporated by reference in its entirety. In some embodiments, the excipient is one or more of a solvent, a co-solvent, a solubilizer, a wetting agent, a suspending agent, an emulsifier, a thickener, a chelating agent, an antioxidant, a reducing agent, an antimicrobial preservative, a buffer, a pH adjuster, a filler, a protectant, and a tonicity agent. In some embodiments, the excipient comprises one or more of the following: sugars, sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffinose, amino acids, glycine, histidine, polyvinylpyrrolidone (PVP), sodium citrate, sodium chloride, potassium chloride, phosphate, monopotassium phosphate, disodium phosphate, Tris base-65, Tris acetate, Tris HCl-65, dextrose, dextran, ficoll, gelatin, starch, hydroxyethyl starch, magnesium stearate, polyethylene glycol (PEG), vitamins, and water.

In some embodiments, the pharmaceutically acceptable vehicle comprises less than about 1% saline (NaCl), such as any of less than about 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.2%, 0.3%, 0.2%, or 0.1% saline. In some embodiments, the pharmaceutically acceptable vehicle comprises about 1% saline, 0.9% saline, 0.8% saline, 0.7% saline, 0.6% saline, 0.5% saline, 0.2% saline, 0.3% saline, 0.2% saline, or 0.1% saline. In some embodiments, the vaccine composition comprises an effective amount of an antigen composition described herein, wherein the antigen composition is reconstituted with a pharmaceutically acceptable vehicle comprising less than about 1% saline, such as any of less than about 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.2%, 0.3%, 0.2%, or 0.1% saline. In some embodiments, the vaccine composition comprises an effective amount of an antigen composition described herein, wherein the antigen composition is reconstituted with a pharmaceutically acceptable vehicle comprising about 1% saline, 0.9% saline, 0.8% saline, 0.7% saline, 0.6% saline, 0.5% saline, 0.2% saline, 0.3% saline, 0.2% saline, or 0.1% saline.

In some embodiments, the pharmaceutically acceptable vehicle comprises one or more of: lipids, lipopolysaccharides, monophosphoryl lipids (a), lipopolysaccharides and 3-O-deacyl-4-monophosphoryl lipid a.

In some embodiments, the pharmaceutically acceptable vehicle comprises an adjuvant. In some embodiments, the pharmaceutically acceptable vehicle comprises an immunopotentiating adjuvant. In some embodiments, the pharmaceutically acceptable vehicle comprises an immunopotentiating amount of an adjuvant, such as an immunopotentiating adjuvant. Adjuvants, including immunopotentiating adjuvants, are known in the art. In some embodiments, the adjuvant is granulocyte-macrophage colony stimulating factor (GM-CSF). In some embodiments, the adjuvant is GM-CSF of the organism to which the vaccine is intended to be administered, e.g., human GM-CSF. In some embodiments, the adjuvant comprises a saponin. See U.S. patent nos. 5,583,112, 5,057,540, 7,858,589 and US 7939084; and Alving, C.R. et al, Curr Opin Immunol,2012,24, 310-. In some embodiments, the saponin is QS-21 (Quillaja saponaria Molina), fraction 21). In some embodiments, the adjuvant comprises 3-O-deacyl-4' -monophosphoryl lipid a (mpl). In some embodiments, the adjuvant comprises AS01B comprising QS-21, MPL and liposomes comprising DOPC (dioleoylphosphatidylcholine) and cholesterol in phosphate buffer. In some embodiments, the adjuvant comprises AS 04. In some embodiments, the adjuvant comprises AS 02A. In some embodiments, the adjuvant comprises AS 01E.

In some embodiments, the vaccine composition comprises any one of the antigenic compositions described herein, wherein the labyrinth protein-derived peptides comprised in the composition are in salt form together with a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts are known in the art. See Berge et al, JPharm Sci,66,1977,1-19, which is hereby incorporated by reference in its entirety. In some embodiments, the pharmaceutically acceptable salt is sodium chloride. In some embodiments, the pharmaceutically acceptable salt is an acetate salt. In some embodiments, the pharmaceutically acceptable salt is sodium acetate. In some embodiments, the pharmaceutically acceptable salt is potassium chloride.

In some embodiments, the pharmaceutically acceptable vehicle comprises a pharmaceutically acceptable acid. In some embodiments, the pharmaceutically acceptable acid is acetic acid. In some embodiments, the concentration of the pharmaceutically acceptable acid in the vaccine composition is less than or about 1%, such as less than or about 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

In some embodiments, wherein the vaccine composition comprises more than one labyrinth protein-derived peptide, the ratio between each of the more than one labyrinth protein-derived peptides may be selected to achieve a desired immunotherapeutic response. In some embodiments, more than one labyrinth protein-derived peptide, such as 2, 3, or 4 labyrinth protein-derived peptides, are all provided in about the same amount in the vaccine composition. For example, in some embodiments wherein the vaccine composition comprises more than one labyrinth protein derived peptide, the ratio of the first peptide to the second peptide is about 1:10 to about 10:1, such as any of about 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9: 1. In some embodiments wherein the vaccine composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; (c) a third peptide, wherein the third peptide is SEQ ID NO 31; and (d) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, the ratio of the first peptide to the second peptide to the third peptide to the fourth peptide is about 1:1:1: 1. In some embodiments wherein the vaccine composition comprises only the following peptides: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; (c) a third peptide, wherein the third peptide is SEQ ID NO 31; and (d) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, the ratio of the first peptide to the second peptide to the third peptide to the fourth peptide is about 1:1:1: 1.

In some embodiments, the vaccine composition comprises an effective amount of an antigen composition having any one of the antigen compositions described herein, wherein the effective amount is between about 1 μ g and about 500 μ g. In some embodiments, the vaccine composition comprises an effective amount of an antigen composition having any one of the antigen compositions described herein, wherein the effective amount is at least about 1 μ g of total peptide, such as at least any one of about 2 μ g, 3 μ g, 4 μ g, 5 μ g, 10 μ g, 15 μ g, 20 μ g, 25 μ g, 30 μ g, 35 μ g, 40 μ g, 45 μ g, 50 μ g, 55 μ g, 60 μ g, 65 μ g, 70 μ g, 75 μ g, 80 μ g, 85 μ g, 90 μ g, 95 μ g, 100 μ g, 110 μ g, 120 μ g, 130 μ g, 140 μ g, 150 μ g, 175 μ g, 200 μ g, 225 μ g, 250 μ g, 275 μ g, 300 μ g, 325 μ g, 350 μ g, 375 μ g, 400 μ g, 425 μ g, 450 μ g, 475 μ g, or 500 μ g.

In some embodiments, the vaccine composition comprises an effective amount of an antigen composition having any one of the antigen compositions described herein, wherein the effective amount is between about 1 μ g and about 1000 μ g. In some embodiments, the vaccine composition comprises an effective amount of an antigen composition having any one of the antigen compositions described herein, wherein the effective amount is at least about 1 μ g of total peptide, such as at least about 2 μ g, 3 μ g, 4 μ g, 5 μ g, 10 μ g, 15 μ g, 20 μ g, 25 μ g, 30 μ g, 35 μ g, 40 μ g, 45 μ g, 50 μ g, 55 μ g, 60 μ g, 65 μ g, 70 μ g, 75 μ g, 80 μ g, 85 μ g, 90 μ g, 95 μ g, 100 μ g, 110 μ g, 120 μ g, 130 μ g, 140 μ g, 150 μ g, 175 μ g, 200 μ g, 225 μ g, 250 μ g, 275 μ g, 300 μ g, 325 μ g, 350 μ g, 375 μ g, 400 μ g, 425 μ g, 450 μ g, 475 μ g, 500 μ g, 550 μ g, 575 μ g, 650 μ g, 60 μ g, 50 μ g, 60 μ g, 80 μ g, 60 μ g, or more, Any one of 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 μ g.

In some embodiments wherein the vaccine composition comprises more than one labyrinth protein-derived peptide, each of the more than one labyrinth protein-derived peptides is present in the vaccine composition in an amount of about 0.1 μ g to about 500 μ g. In some embodiments, wherein the vaccine composition comprises more than one labyrinth protein derived peptides, each of the more than one labyrinth protein derived peptides is present at about 0.1 μ g, 0.5 μ g, 1 μ g, 2 μ g, 3 μ g, 4 μ g, 5 μ g, 6 μ g, 7 μ g, 8 μ g, 9 μ g, 10 μ g, 11 μ g, 12 μ g, 13 μ g, 14 μ g, 15 μ g, 20 μ g, 25 μ g, 30 μ g, 35 μ g, 40 μ g, 45 μ g, 50 μ g, 55 μ g, 60 μ g, 65 μ g, 70 μ g, 75 μ g, 80 μ g, 85 μ g, 90 μ g, 95 μ g, 100 μ g, 110 μ g, 120 μ g, 130 μ g, 140 μ g, 150 μ g, 175 μ g, 200 μ g, 225 μ g, 250 μ g, 275 μ g, 300 μ g, 375 μ g, 325 μ g, 375 μ g, 425 μ g, 475 μ g, 450 μ g, 475 μ g, 15 μ g, 6 μ g, 7 μ g, 8 μ g, 9 μ g, 10 μ g, 12 μ g, 13 μ g, 15 μ g, 25 μ g, 35 μ g, 25 μ g, 35 μ g, 25 μ g, or more, Or 500 μ g of any of the same.

In some embodiments, the vaccine composition has a pH as follows: about 5 to about 8.5, such as any of about 5.5 to about 7, about 6 to about 6.75, about 6.25 to about 6.75, about 6 to about 7, or about 6.5 to about 7.

In some embodiments, the vaccine composition has a pH of about any one of 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, or 8.5.

In some embodiments, the vaccine composition comprises another therapeutic agent, such as an immune checkpoint inhibitor.

In some embodiments, the vaccine composition is pharmaceutically acceptable. In some embodiments, the vaccine composition is pharmaceutically sterile.

In some embodiments, the vaccine composition comprises: (i) an effective amount of an antigenic composition described herein; and (ii) a pharmaceutically acceptable vehicle. In some embodiments, the vaccine composition comprises: (i) an effective amount of an antigenic composition described herein; and (ii) a pharmaceutically acceptable vehicle comprising an adjuvant, such as GM-CSF. In some embodiments, the antigenic composition comprises one or more labyrinth protein-derived peptides, wherein each labyrinth protein-derived peptide comprises one or more of a T cell epitope and a B cell epitope. In some embodiments, each of the one or more labyrinth protein-derived peptides comprises a T cell epitope and a B cell epitope. In some embodiments, the one or more labyrinth protein derived peptides are between 8 and 25 amino acids in length. In some embodiments, the one or more labyrinth protein derived peptides are substantially homologous to a portion of the labyrinth protein. In some embodiments, each of the one or more labyrinth protein derived peptides comprises a non-terminal proline residue.

In some embodiments, the vaccine composition comprises: (i) an effective amount of an antigenic composition, wherein said antigenic composition comprises one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:28 or a variant thereof, and wherein each peptide comprises a T cell epitope and a B cell epitope; and (ii) a pharmaceutically acceptable vehicle. For example, in some embodiments, the antigenic composition of the vaccine composition comprises a first peptide comprising SEQ ID NO:25 or a variant thereof, wherein the first peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the second peptide is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a first peptide comprising SEQ ID No. 29 or a variant thereof, wherein said first peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a first peptide, wherein the first peptide is SEQ ID NO:29, and wherein the first peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises a second peptide comprising SEQ ID NO:26 or a variant thereof, wherein said second peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the second peptide is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a second peptide comprising SEQ ID NO:30 or a variant thereof, wherein the second peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a second peptide, wherein the second peptide is SEQ ID NO:30, and wherein the second peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein said third peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the third peptide is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein the third peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a third peptide, wherein the third peptide is SEQ ID NO:31, and wherein the third peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises a fourth peptide comprising SEQ ID No. 28 or a variant thereof, wherein said fourth peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the fourth peptide is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein said fourth peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, and wherein the fourth peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises two or more labyrinth protein-derived peptides. For example, in some embodiments, the antigenic composition of the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; and (B) a second peptide comprising SEQ ID NO:26 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the two or more labyrinth protein derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; and (B) a second peptide comprising SEQ ID NO:30 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; and (B) a second peptide, wherein the second peptide is SEQ ID NO:30, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each peptide of the antigenic composition activates a T cell and B cell adaptive immune response. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; and (B) a third peptide, wherein the third peptide is SEQ ID NO:31, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; and (B) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a second peptide comprising SEQ ID NO 26 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (B) a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a second peptide, wherein the second peptide is SEQ ID NO 30; and (B) a third peptide, wherein the third peptide is SEQ ID NO:31, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a second peptide comprising SEQ ID NO 26 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a second peptide, wherein the second peptide is SEQ ID NO 30; and (B) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the two or more labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (B) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a third peptide, wherein the third peptide is SEQ ID NO 31; and (B) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises three or more labyrinth protein-derived peptides. For example, in some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; and (c) a third peptide comprising SEQ ID NO:27 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (c) a third peptide comprising SEQ ID NO:31 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; and (c) a third peptide, wherein the third peptide is SEQ ID NO:31, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; and (c) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a third peptide comprising SEQ ID NO 26 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a third peptide, wherein the third peptide is SEQ ID NO 31; and (c) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises: (a) a second peptide comprising SEQ ID NO 26 or a variant thereof; (b) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the three or more labyrinth protein-derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a second peptide comprising SEQ ID NO 30 or a variant thereof; (b) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (c) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a second peptide, wherein the second peptide is SEQ ID NO 30; (b) a third peptide, wherein the third peptide is SEQ ID NO 31; and (c) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF.

In some embodiments, the antigenic composition of the vaccine composition comprises four or more labyrinth protein-derived peptides. For example, in some embodiments, the antigenic composition of the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, each of the four or more labyrinth protein derived peptides is between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, the first peptide comprising SEQ ID No. 25 or variant thereof comprises SEQ ID No. 29 or variant thereof. In some embodiments, the first peptide comprising SEQ ID NO:25 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the first peptide comprising SEQ ID NO 25 is SEQ ID NO 29. In some embodiments, a first peptide comprising SEQ ID NO:25 or a variant thereof is conjugated. In some embodiments, the second peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, the second peptide comprising SEQ ID NO:30 or a variant thereof has the following sequence similarity to a portion of the labyrinthin (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the second peptide comprising SEQ ID NO 26 is SEQ ID NO 30. In some embodiments, a second peptide comprising SEQ ID NO:26 or a variant thereof is conjugated. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, the third peptide comprising SEQ ID NO:27 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the third peptide comprising SEQ ID NO 27 is SEQ ID NO 31. In some embodiments, the third peptide comprising SEQ ID NO 27 or a variant thereof is conjugated. In some embodiments, the fourth peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the fourth peptide comprising SEQ ID NO 28 or a variant thereof has the following sequence similarity to a portion of the labyrinth protein (SEQ ID NO: 1): at least about 90% similarity, such as at least about any of 92% similarity, 95% similarity, or 97% similarity. In some embodiments, the fourth peptide comprising SEQ ID NO 28 is SEQ ID NO 32. In some embodiments, a fourth peptide comprising SEQ ID No. 28 or a variant thereof is conjugated. In some embodiments, the antigenic composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, the antigenic composition comprises: (a) a first peptide, wherein the first peptide is SEQ ID NO 29; (b) a second peptide, wherein the second peptide is SEQ ID NO 30; (c) a third peptide, wherein the third peptide is SEQ ID NO 31; and (d) a fourth peptide, wherein the fourth peptide is SEQ ID NO:32, wherein each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the pharmaceutically acceptable vehicle comprises a saponin. In some embodiments, the vaccine composition comprises GM-CSF. In some embodiments, the vaccine composition is LabVax 3(22) -23.

In some embodiments, the vaccine composition comprises one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof. In some embodiments, the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof. In some embodiments, the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:28 or variants thereof, wherein these are the only four labyrinth protein derived peptides in the vaccine composition. In some embodiments, the labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID No. 25 or a variant thereof comprises SEQ ID No. 29 or a variant thereof. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein these are the only four labyrinth protein-derived peptides in the vaccine composition. In some embodiments, the vaccine composition consists essentially of: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein these are the only four labyrinth protein-derived peptides in the vaccine composition. In some embodiments, the labyrinth protein-derived peptides comprise T cell epitopes and/or B cell epitopes. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the vaccine composition comprises GM-CSF. In some embodiments, the vaccine composition is LabVax 3(22) -23.

In some embodiments, the vaccine composition comprises four labyrinth protein-derived peptides, wherein the four labyrinth protein-derived peptides are SEQ ID NOs 29-32, wherein these are the only four labyrinth protein-derived peptides in the vaccine composition, wherein each peptide is present in an amount of 100 μ g, and wherein the volume of the vaccine is about 0.1 mL. In some embodiments, the vaccine composition is LabVax3(22) -23. In some embodiments, LabVax3(22) -23 further comprises GM-CSF.

Kits, medicaments and compositions thereof

In some aspects, the present disclosure provides compositions comprising the antigenic compositions disclosed herein, including kits, medicaments, and compositions (e.g., pharmaceutical compositions and unit doses) thereof. In some aspects, the disclosure provides vaccine compositions, including kits, medicaments, and compositions (e.g., pharmaceutical compositions and unit doses) thereof, comprising the antigen compositions disclosed herein.

In some embodiments, a kit of the present disclosure may comprise one or more containers comprising an antigenic composition and/or a vaccine composition (or unit doses and/or articles thereof) described herein. In some embodiments, the kit further comprises one or more containers comprising another agent (or unit dose and/or preparation thereof), such as an adjuvant, including an immunologically effective adjuvant, such as GM-CSF. In some embodiments, the kit further comprises instructions for use according to any of the methods disclosed herein. The kit may further comprise a description of criteria for selecting an individual suitable for treatment with any of the methods disclosed herein. The instructions provided in the kits disclosed herein are typically written instructions on a label or package insert (e.g., paper sheets included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disc) are also acceptable.

In some embodiments, a composition, such as a vaccine composition, comprising an antigenic composition described herein may be present in separate containers or in a single container.

In some embodiments, the kits of the present disclosure are in a suitable package. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed mylar or plastic bags), and the like. The kit may optionally provide additional components, such as buffers and explanatory information. The present application thus also provides articles of manufacture including vials (e.g., sealed vials), bottles, jars, flexible packages, and the like.

The present disclosure also provides medicaments and compositions (e.g., unit doses) useful in the methods described herein. For example, in some embodiments, there is provided the use of a composition comprising an antigenic composition, such as a vaccine composition, for the treatment of cancer in an individual in need thereof.

Method of use thereof

In some aspects, the disclosure provides methods of using the vaccine compositions described herein. In some aspects, the present disclosure provides a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a vaccine composition described herein. In other aspects, the disclosure provides methods of preventing cancer in an individual in need thereof, comprising administering to the individual a vaccine composition described herein. In some embodiments, the cancer is a labyrinth positive cancer. In some embodiments, the cancer is an adenocarcinoma, such as a labyrinth-positive adenocarcinoma.

In some embodiments, a method of treating cancer comprises administering to an individual a vaccine composition, wherein the vaccine composition comprises: (i) an effective amount of an antigenic composition comprising one or more labyrinth protein-derived peptides comprising a sequence selected from the group consisting of SEQ ID NOs 2-32 or variants thereof; and (ii) a pharmaceutically acceptable vehicle. In some embodiments, the labyrinth protein-derived peptides comprising a sequence selected from SEQ ID NOs 2-32 (table 2) or variants thereof comprise flanking amino acid sequences on one or more terminal sides of the core sequence provided in SEQ ID NOs 2-32.

In some embodiments, a method of preventing cancer comprises administering to an individual a vaccine composition, wherein the vaccine composition comprises: (i) an effective amount of an antigenic composition comprising one or more labyrinth protein-derived peptides comprising a sequence selected from the group consisting of SEQ ID NOs 2-32 or variants thereof; and (ii) a pharmaceutically acceptable vehicle. In some embodiments, the labyrinth protein-derived peptides comprising a sequence selected from SEQ ID NOs 2-32 (table 2) or variants thereof comprise flanking amino acid sequences on one or more terminal sides of the core sequence provided in SEQ ID NOs 2-32.

In some embodiments, a method of treating cancer in an individual comprises administering to the individual a vaccine composition described herein, wherein the labyrinthine status of the cancer is used as a basis for selecting the individual for treatment. In some embodiments, the labyrinthin status of a cancer is indicative of labyrinthin expression in the cancer (e.g., labyrinthin overexpression compared to a control, e.g., healthy or non-cancerous tissue of an individual). In some embodiments, the labyrinthin status of the cancer is indicative of labyrinthin presentation on the cancer cell surface. In some embodiments, an individual is selected for treatment when a cancer sample from the individual shows cancer cells in about 10% or more of the sample as positive for trillin, e.g., at least about any one of 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90% or 95% of the cancer cells in the sample, e.g., as determined using Immunohistochemistry (IHC) techniques. In some embodiments, an individual is selected for treatment when a cancer sample from the individual shows that a subpopulation of cancer cells, such as tumor-peripheral cells, of any of about 10% or more, such as at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90% or 95% of the cancer cells in the sample are positive for trillin, e.g., as determined using Immunohistochemistry (IHC) techniques.

In some embodiments, disclosed herein is a method of treating a labyrinth-positive cancer in an individual, the method comprising administering to the individual a vaccine composition, wherein the vaccine composition comprises an effective amount of an antigenic composition comprising: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 32 or a variant thereof. In some embodiments, each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the vaccine composition is LabVax 3(22) -23. In some embodiments, the method further comprises selecting the individual for treatment based on a cancer labyrinth protein status indicative of a labyrinth protein-positive cancer. In some embodiments, when about 10% or more of the cancer cells in a sample from an individual are positive for a labyrinth protein, e.g., determined using Immunohistochemistry (IHC) techniques, then the labyrinth protein status of the cancer is indicative of a labyrinth protein-positive cancer. In some embodiments, the labyrinth positive cancer is adenocarcinoma.

The methods disclosed herein can comprise administering to an individual a plurality of doses of the vaccine compositions described herein over a period of time. For example, the vaccine compositions described herein can be repeatedly administered to an individual over a period of time until the individual generates a sufficient immunogenic response to the components of the vaccine composition. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, wherein the individual receives from about 1 to about 10 separate vaccine composition administrations. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, wherein the individual receives 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 separate vaccine composition administrations. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, wherein the individual receives at least 1, such as at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 separate administrations of the vaccine composition. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, wherein the individual receives at least 1 separate administration of the vaccine composition over a period of about 6 months. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, wherein the individual receives at least 4 separate administrations of the vaccine composition over a period of about 6 months. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, wherein the individual receives at least 10 separate vaccine composition administrations over a period of about 6 months. In some embodiments, the individual vaccine compositions are administered about 1 week apart. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, such as via intradermal administration, wherein the individual receives at least 5 separate vaccine composition administrations over a 12 week period. In some embodiments, the method comprises administering the vaccine composition to an individual in need thereof, such as via intradermal administration, wherein the individual receives at least 7 separate vaccine composition administrations over a 36 week period. In some embodiments, one or more additional vaccinations are administered to an individual in need thereof. In some embodiments, the methods comprise administering the vaccine composition to the individual, wherein subsequent administrations of the vaccine composition to the individual are adjusted (e.g., via frequency of administration, time interval between administrations, or dosage amount). In some embodiments, the frequency of administration and/or the dosage amount of the vaccine composition is adjusted over the course of treatment based on the judgment of the administering physician.

The vaccine composition may be administered by a variety of routes of administration. For example, the agents described herein can be administered to an individual (e.g., a human) parenterally, including intravenously, intraarterially, intraperitoneally, intrapulmonary, orally, inhalationally, intravesicularly, intramuscularly, intratracheally, subcutaneously, intraocularly, intrathecally, intradermally, or transdermally. In some embodiments, the agents described herein, such as vaccine compositions, are administered intradermally, such as via intradermal injection. In some embodiments, the vaccine compositions described herein are administered intradermally, wherein each injection in a series of vaccinations is administered at a different site (e.g., at least 3cm from the previous injection). In some embodiments wherein the route of administration is intradermal, the administration needle or syringe is held in place for at least about 3 minutes to about 5 minutes after injection of the vaccine composition.

In some embodiments, the method for treating and/or preventing cancer in an individual further comprises administering to the individual another agent. In some embodiments, the additional agent is an adjuvant. In some embodiments, the adjuvant is granulocyte-macrophage colony stimulating factor (GM-CSF). In some embodiments, the adjuvant is GM-CSF of the organism to which the vaccine is intended to be administered, e.g., human GM-CSF. In some embodiments, the method comprises administering GM-CSF separately from the vaccine composition. In some embodiments, the additional agent is a chemotherapeutic agent. In some embodiments, the vaccine composition is administered separately from GM-CSF, such as from about 45 minutes to about 60 minutes prior to administration of GM-CSF. In some embodiments, the additional agent is an immune checkpoint inhibitor. In some embodiments, the vaccine composition described herein and another agent are administered simultaneously. In some embodiments, the vaccine composition described herein and the other agent are administered sequentially. In some embodiments, the vaccine composition described herein and another agent are administered concurrently.

In some embodiments, a method of treating and/or preventing a labyrinth-positive cancer in an individual comprises administering to the individual: (i) a vaccine composition, wherein the vaccine composition comprises an effective amount of an antigen composition comprising: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 32 or a variant thereof; and (ii) a composition comprising GM-CSF. In some embodiments, the vaccine composition is administered to the individual intradermally and the composition comprising GM-CSF is administered to the individual subcutaneously. In some embodiments, the vaccine composition and the composition comprising GM-CSF are administered to the individual within 60 minutes of each other. In some embodiments, each peptide comprises a T cell epitope and a B cell epitope. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the effective amount of the antigen composition of the vaccine composition is between about 25 μ g and about 75 μ g. In some embodiments, the vaccine composition is LabVax3(22) -23. In some embodiments, the method further comprises selecting the individual for treatment based on a cancer labyrinth protein status indicative of a labyrinth protein-positive cancer. In some embodiments, when about 10% or more of the cancer cells in a sample from an individual are positive for a labyrinth protein, e.g., determined using Immunohistochemistry (IHC) techniques, then the labyrinth protein status of the cancer is indicative of a labyrinth protein-positive cancer. In some embodiments, the labyrinth positive cancer is adenocarcinoma.

In some embodiments, the methods described herein for treating and/or preventing a labyrinth positive cancer in an individual comprise administering to the individual a vaccine composition described herein. In some embodiments, the method further comprises administering an adjuvant, such as GM-CSF. In some embodiments, the vaccine composition comprises one or more labyrinth protein-derived peptides selected from the group consisting of: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof. In some embodiments, the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO 28 or a variant thereof. In some embodiments, the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 25 or a variant thereof; (b) a second peptide comprising SEQ ID NO 26 or a variant thereof; (c) a third peptide comprising SEQ ID NO 27 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:28 or variants thereof, wherein these are the only four labyrinth protein derived peptides in the vaccine composition. In some embodiments, the labyrinth protein derived peptides are between 21 and 24 amino acids in length, such as 22 or 23 amino acids in length. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID No. 25 or a variant thereof comprises SEQ ID No. 29 or a variant thereof. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID No. 26 or a variant thereof comprises SEQ ID No. 30 or a variant thereof. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID NO 27 or a variant thereof comprises SEQ ID NO 31 or a variant thereof. In some embodiments, a vaccine composition comprising a peptide comprising SEQ ID No. 28 or a variant thereof comprises SEQ ID No. 32 or a variant thereof. In some embodiments, the vaccine composition comprises: (a) a first peptide comprising SEQ ID NO 29 or a variant thereof; (b) a second peptide comprising SEQ ID NO 30 or a variant thereof; (c) a third peptide comprising SEQ ID NO 31 or a variant thereof; and (d) a fourth peptide comprising SEQ ID NO:32 or a variant thereof, wherein these are the only four labyrinth protein-derived peptides in the vaccine composition. In some embodiments, the labyrinth protein-derived peptides comprise T cell epitopes and/or B cell epitopes. In some embodiments, an effective amount of the antigen composition in the vaccine composition is between about 0.1 μ g and about 1000 μ g, such as between about 75 μ g and about 150 μ g, such as about 100 μ g. In some embodiments, the vaccine composition comprises GM-CSF. In some embodiments, the vaccine composition is LabVax 3(22) -23.

The methods disclosed herein are useful for treating or preventing a proliferative disease, such as cancer, in an individual. In some embodiments, the cancer is a cancer that expresses a labyrinthin. In some embodiments, the cancer is adenocarcinoma.

In some embodiments, the cancer is an early stage cancer, a non-metastatic cancer, a primary cancer, an advanced cancer, a locally advanced cancer, a metastatic cancer, a cancer in remission, a recurrent cancer, a drug-resistant cancer, or a refractory cancer. In some embodiments, the cancer is a locally resectable cancer (e.g., a tumor confined to a portion of an organ that allows for complete surgical removal), a locally unresectable cancer (e.g., a local tumor that is unresectable because of vital vascular structures), or a non-resectable cancer. In some embodiments, the cancer is a stage I tumor, a stage II tumor, a stage III tumor, a stage IV tumor, an N1 tumor, or an M1 tumor according to the TNM classification.

The methods disclosed herein can be used to treat or prevent cancer, such as cancers that express labyrinthin, in an individual. In some embodiments, the individual has one or more of the following characteristics: (i) the ability to understand and voluntarily sign informed consent; (ii) at least 18 years of age, histologically confirmed adenocarcinoma and/or cancer expressing labyrinth protein; (iii) previously treated with at least 1 prior systemic therapy (chemotherapy and/or biological therapy) and either not responded/progressed during treatment or progressed after completion of systemic therapy or rejected all other treatments; (iv) one or more tumors must overexpress the labyrinin antigen, as determined by a screening immunohistochemical evaluation of paraffin-embedded archival samples exhibiting > 10% staining for antigen and an intensity of at least 2x background, according to a score made by a single reference pathologist; (v) the prior radiotherapy must have been completed at least 3 weeks prior to the 1 st vaccine injection; (vi) any number of previous chemotherapeutic regimens; (vii) delayed-type hypersensitivity (DTH) response to common recall antigens was recorded prior to the 1 st vaccine injection; (viii) the physical fitness status according to the Carnofsky Scale (Karnofsky scale) is more than or equal to 60 percent; (ix) the expected life of the 1 st vaccine injection is more than or equal to 6 months; (x) Measurable or valuable disease; (xi) A pre-treatment Absolute Granulocyte Count (AGC) of 1,000 or more and a pre-treatment platelet count of 75,000 or more obtained within 4 weeks prior to the 1 st vaccine injection; (xii) Less than or equal to 1.5mg/dl of serum creatinine prior to treatment is required. Measurements must be obtained within 4 weeks prior to the 1 st vaccine injection; and (xiii) serum bilirubin < 1.5 and AST < 2.5X mechanism upper normal limit (5X if there is liver metastasis) obtained within 4 weeks prior to the 1 st vaccine injection.

Method for producing antibody

In some aspects, the disclosure provides methods of producing antibodies in vivo, such as in a host animal. In some embodiments, the method comprises administering to a host animal an antigen composition according to the disclosure herein. In some embodiments, the method comprises administering to a host animal a nucleic acid composition according to the disclosure herein. In some embodiments, the method comprises administering to the host animal a vaccine composition according to the disclosure herein.

Methods for producing antibodies in host animals are known. See, e.g., Lee, BS et al, Methods Mol Biol,1474,2016, 25-47.

In some embodiments, the labyrinth protein-derived peptides are conjugated to a carrier, such as a protein. In some embodiments, the labyrinth protein-derived peptides are conjugated to albumin, such as bovine serum albumin. In some embodiments, the labyrinthin-derived peptide is conjugated to Keyhole Limpet Hemocyanin (KLH).

In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a monoclonal antibody.

In some embodiments, the method of producing an antibody further comprises purifying the antibody.

Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present disclosure. The present disclosure is further illustrated by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures described therein.

Examples

Example 1

This example demonstrates the design, synthesis, and formulation of selected labyrinth protein-derived peptides according to the disclosure herein.

Peptide design for B-cell and T-cell immune response

The labyrinth protein-derived peptides are designed to generate both B-cell and T-cell acquired immune system responses. Using the labyrinth protein amino acid sequence (SEQ ID NO:1) as a starting template, 13 labyrinth protein-derived peptides were designed and four labyrinth protein-derived peptide candidates were selected from them for further evaluation and development (SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO: 32). The four selected labyrinth protein-derived peptide candidates comprise amino acid sequences with known immunogenicity of the adaptive immune system via B-cell mediation, and studies were performed to confirm the predicted binding to the mhc ii complex groove to also trigger T-cell mediated adaptive immune system responses.

In silico testing of the solubility of four labyrinth protein derived peptide candidates was performed in order to identify peptide candidates suitable for formulation and administration. For example, the water solubility of the labyrinth protein derived peptide candidates was tested using a peptide characterization calculator (< http:// www.pepcalc.com/>). All labyrinthin-derived peptide candidates were confirmed to have good aqueous solubility.

Synthesis of labyrinthin-derived peptides

Four labyrin-derived peptide candidates (SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32) were synthesized. Each labyrinthin-derived peptide candidate sequence was confirmed using mass spectrometry. Specifically, an electrospray ionization mass spectrometry technique was used to obtain m/z spectra of parent ions for each sample (the spectra of SEQ ID NOS: 29-32 are shown in FIGS. 1A-1D, respectively), followed by a tandem mass technique to collect ion fragmentation data to confirm the peptide sequence of each of the labyrinth protein-derived peptide candidates (data not shown).

The purity of each of the labyrinthin-derived peptide candidates was measured using high performance liquid chromatography techniques to measure absorbance at 220 nm. The measured purity of each of the labyrinth protein-derived peptide candidates is shown in table 3.

Table 3 purity of the labyrinth protein derived peptides.

	Peptide purity (%)
		SEQ ID NO:29	96.289
SEQ ID NO:30	95.025
		SEQ ID NO:31	95.019
SEQ ID NO:32	96.530

Solubility and formulation of labyrinth protein-derived peptides

The solubility of each of the labyrin-derived peptide candidates was assessed by visual inspection in ultrapure water, 0.1M PBS (PBS; pH 7.4) and dimethylsulfoxide (DMSO; analytical grade). As reported in Table 4, the solubility of less than 0.1mg/mL solvent is defined as "insoluble" while the solubility of greater than or equal to 0.1mg/mL is defined as "soluble". The concentration range of measured solubility is provided under the available "solubility" classification (table 4).

Table 4 solubility of labyrinth protein derived peptides.

As observed, SEQ ID NO 30, SEQ ID NO 31 and SEQ ID NO 32 were not soluble in ultrapure water, which contradicts the predicted in silico solubility assessment described above. Formulation in pH buffer (PBS, pH 7.4) did not increase the solubility of SEQ ID NO:31 and SEQ ID NO: 32.

Additional tests were done in an attempt to overcome the solubility problems identified above. The results of the solubility tests performed on each of the labyrinth protein-derived peptide candidates (SEQ ID NOS: 29-32) are shown in Table 5. In short, all peptides were re-dissolved in DMSO, confirming the ability of these peptides to dissolve in solution. Peptide solubility was then tested in physiological saline (0.154M sodium (NaCl)) and 0.2M sodium (NaCl). Normal saline is often the solvent/diluent of choice because the Food and Drug administration (Food and Drug Association) accepts it for this purpose. SEQ ID NO. 31 and SEQ ID NO. 32 were insoluble in physiological saline solution. Additional solutions were tested to determine alternative diluents to solubilize the candidate peptide, as determined by visual inspection. As shown in table 5, all four candidate peptides were dissolved in 0.2M saline solution.

TABLE 5 solubility of peptides derived from labyrinthin.

	SEQ ID NO:29	SEQ ID NO:30	SEQ ID NO:31	SEQ ID NO:32
					DMSO	Is that	Is that	Is that	Is that
0.154M sodium (NaCl)	Is that	Is that	Whether or not	Whether or not
					0.2M sodium (NaCl)	Is that	Is that	Is that	Is that

In a further solubility test, two tubes of 1.1mg of peptide per each of the four candidate peptide targets were dissolved in 1mL of phosphate buffer (pH 10) with and without 0.9% NaCl. After testing the solubility, the pH was continuously adjusted with 2% acetic acid to reduce the pH to the value shown in table 6. The peptide solution was then stored at 4 ℃ for several hours to completely dissolve the peptide. After centrifugation, the concentration of peptide remaining in the solution was measured. The solubility (mg/mL) of each peptide candidate under each condition is listed in Table 6. The solubility of all four peptide candidates was above 0.3mg/mL at all test conditions in table 6, and for each peptide candidate, the change in solubility was minimal over the pH range tested.

TABLE 6 solubility of peptides derived from labyrinthin.

The combination of each of the four peptides (SEQ ID NOS: 29-32) was diluted in water (pH of about 6.7-7) or a spacer electrolyte (pH 7.4) and analyzed by an ultra high performance liquid chromatography (UPLC) technique developed to analyze the peptides in the vaccination solution. As shown in FIG. 2, the peptides numbered 1-4 correspond to SEQ ID NO:29-32 in order.

Each peptide had a very low pI and the results are presented in fig. 2, showing that buffering to physiological levels resulted in the detection of a doublet in all four peptides. The doublets of peptides #1(SEQ ID NO:29) and #2(SEQ ID NO:30) were particularly evident. As designed for each peptide, the UPLC trace of each peptide resolved to a single peak when the reconstituted peptide in the spacer electrolyte was further diluted with water (data not provided), as observed for the reconstituted peptide in water in fig. 2. This data indicates that (1) the peptide will be charged when it is in an environment of several pH units above its acidic pI, and (2) the peptide structure remains intact, as demonstrated by: each peptide resolved to a single peak after serial dilution with water (returning to a more acidic pH) and returned to the original retention time.

Example 2

This example demonstrates the inhibition of tumor growth by a vaccine (LabVax 3(22) -23) containing four labyrinth protein-derived peptides (SEQ ID NOS: 29-32).

C57BL/6 hPD-1/PD-L1 mice subcutaneously implanted with MC 38 murine colon (adenocarcinoma) tumor cells were administered at days 15, 26 and 40 post tumor implantation: (a)40 μ g LabVax (10 μ g of each peptide, i.d.) in combination with mouse GM-CSF (1 μ g, s.c.) as an adjuvant; or (b) a saline control. Body weight and tumor weight were measured during the study. Statistical analysis of mouse and tumor weights are provided in table 7.

TABLE 7 statistical analysis of mouse body weight and tumor weight.

Body weights over the course of the study were not different between the vaccine and saline control administered groups, and no adverse events were recorded in any of the groups. The results show that the vaccine significantly reduced tumor growth (fig. 3), and therefore LabVax 3(22) -23 had anti-tumor activity and no toxicity in immunocompetent mice.

The results regarding safety are consistent with a formal study conducted in Balb/C mice (comprehensive Biosciences, Inc.; Senneville, Calif.) according to good laboratory specifications, showing that neither the peptide alone nor the combination [ LabVax 3(22) -23] is toxic after 5 injections (50 μ g of each peptide) over a period of 49 days.

Furthermore, studies on seroconverted mice are consistent with findings that use of these peptides is safe. LabVax 3(22) -23 preclinical acute (2 injections within 14 days) and long-term (4 injections within 49 days) tests in mice were performed under an approved GLP animal study. The dose roughly corresponds to about 120 times the expected human dose (400 μ g per injection). No clinically observed adverse events or abnormalities were recorded during the four injections.

Example 3

To test for antibody production after administration of the peptides described herein, 12 Balb/c mice were divided into 4 treatment groups, where each treatment group was assigned to receive an injection of one of SEQ ID NOs 29-32. As shown in table 8, positive clones were identified in each treatment group.

Table 8 number of positive clones identified for each treatment group.

Example 4

This example demonstrates a phase I study of a tetrapeptide labyrin cancer vaccine (LabVax 3(22) -23) against adenocarcinoma patients. The four peptides of the vaccine are SEQ ID NO: 29-32.

Patients (12) selected for phase I studies had inoperable or metastatic solid tumors (adenocarcinomas) and experienced failure for standard of care treatment. Two treatment groups will be established based on: group A: 6 patients, administered (i.d.) LabVax 3(22) -23; and group B: 6 patients, administered (i.d.) LabVax 3(22) -23+ GM-CSF (adjuvant). If this occurs, the phase I extension will include the following: 7 patients with breast cancer; 7 patients with lung adenocarcinoma; 10 patients with other labyrinth positive adenocarcinomas. Adenocarcinomas that were all positive for MCA 44-3A6 (mouse monoclonal anti-labyrin antibody) were included in each cohort in the expanded test section.

The main objective of this study was to demonstrate that synthetic tetrapeptide cancer vaccines do not cause short-term adverse effects on humans.

Secondary objectives of the study were: (i) compare the safety of vaccines with/without GM-CSF (adjuvant); (ii) preliminary assessment of the efficacy of the vaccine with/without GM-CSF (adjuvant); (iii) comparing the safety of the vaccine (with or without GM-CSF) in more specific regions of the maze-positive breast and lung patients and in other cohorts of adenocarcinomas positive for maze; and (iv) obtaining a preliminary assessment of the vaccine (with or without GM-CSF) in more specific regions of the melanine-positive breast and lung patients and other groups of adenocarcinomas positive for the melanine.

Formulation, bottling, QA, QC, sterility testing and labeling were scheduled under cGMP. A further QA/QC stability test was scheduled for implementation in Emery Pharma. The peptides will be reconstituted in the isolation electrolyte S pH 7.4 to a concentration of 400. mu.g/100. mu.l (100. mu.g each of the four peptides) and sterile filtered. The pH of the final product is about 6.5-7. The vaccine was then aliquoted into vials for clinical use and then stored at-80 ℃. Ongoing studies have demonstrated that peptides can be made and reconstituted in this manner without any effect on the structural integrity of the peptide (according to GLP certified UPLC analysis; Emery Pharma, alamidoda, ca).

For example, saffebridge nutrients, inc. (new york city, new york and mountain view, california) performed computer-based analysis of four peptides and obtained a professional health classification: class 2 of class 4. The scores indicated that the peptides were safe and were only ignored in their scores due to the lack of available data in the literature.

For group B, 100mcg of human GM-CSF was administered subcutaneously 45-60 minutes prior to LabVax 3(22) -23 (i.d.). GM-CSF was injected within 3cm of the vaccine injection site using a 28 gauge needle.

Subjects with advanced/metastatic or recurrent adenocarcinoma (with an emphasis on breast cancer and non-small cell lung cancer that is incurable with available therapy) (stage IV) at any primary site will enroll cohort a and cohort B from the davies university, davies, integrated cancer center. Subsequent phase I expansion will open up to early stage adenocarcinoma subjects with labyrinth-positive tumors.

Patients must meet all of the following criteria to be eligible for study: (i) the ability to understand and voluntarily sign informed consent; (ii) at least 18 years of age, histologically confirmed patients with adenocarcinoma; (iii) the patient must have been previously treated with at least 1 prior systemic therapy (chemotherapy and/or biological therapy) and either not responded to/progressed during treatment or progressed after completion of systemic therapy or refused all other treatments; (iv) tumors must overexpress the labyrinthin antigen, as determined by a screening immunohistochemical evaluation of paraffin-embedded archival samples exhibiting > 10% staining for antigen and at least 2x background in intensity, based on a score made by a single reference pathologist; (v) the prior radiation therapy must have been completed at least 3 weeks prior to the 1 st vaccine injection. For measurable lesions, the patient must not receive a plan for concurrent radiation therapy. Measurable lesions may be located in one or more prior radiation fields, provided that the lesion is revealed as progressing or stable by the CT scan; (vi) any number of previous chemotherapy regimens are allowed. The previous chemotherapy must have been completed at least 3 weeks prior to the 1 st vaccine injection, and the patient must have recovered from all toxicities of the previous treatment prior to the 1 st vaccine injection; (vii) patients must record a delayed-type hypersensitivity (DTH) response to common recall antigens prior to the 1 st vaccine injection. As part of the pre-screening evaluation, the patient will receive a DTH test against at least one common recall antigen; the choice will be at the discretion of the physician based on medical history and physical condition (mumps, trichophyton, candida antigens, influenza matrix and/or PPD, etc.). Skin tests will be read at 48 hours or about 48 hours. A skin reaction will be considered positive if any measurable induration is accompanied by erythema of 10mm or greater. Erythema alone would not be considered a positive DTH response; (viii) the physical performance status of all patients according to the carnofsky scale (Karnofsky scale) must be greater than or equal to 60%; (ix) the expected life of all patients at the 1 st vaccine injection is more than or equal to 6 months; (x) All laboratory work and all radiological examinations (e.g. X-ray, CT) must be completed within 4 weeks before the 1 st vaccine injection; (xi) The patient must have measurable or valuable disease (see section 10). All patients had to obtain a pre-treatment Absolute Granulocyte Count (AGC) of ≧ 1,000 and a pre-treatment platelet count of ≧ 75,000 within 4 weeks prior to the 1 st vaccine injection; (xii) Less than or equal to 1.5mg/dl of serum creatinine prior to treatment is required. Measurements must be obtained within 4 weeks prior to the 1 st vaccine injection; (xiii) The serum bilirubin of the patient obtained within 4 weeks prior to the 1 st vaccine injection must be no more than 1.5 and AST no more than 2.5X the upper normal limit of the mechanism (5X if there is liver metastasis); (xiv) Because of the relatively short life expectancy, the activity and toxicity of this vaccine could not be assessed, excluding patients with known brain and/or leptomeningeal metastases; and (xv) pregnant and lactating women are ineligible because the effect of the vaccine on the unborn fetus or lactating infant is unknown. Urine or serum pregnancy tests (HCG) must be negative for women of child bearing age.

Patients who meet any of the following criteria will be excluded from the study: (i) known active immune diseases, autoimmune diseases, genetic or congenital immune deficiencies, potential immune deficiencies or altered immune function (e.g. active graves ' disease, AIDS/HIV, addison's disease, myasthenia gravis, severe atopic dermatitis, rheumatoid arthritis, eczema scleroderma, goodpasture's syndrome, sjogren's syndrome, ankylosing spondylitis, hashimoto's thyroiditis, systemic lupus erythematosus, autoimmune neutropenia/thrombocytopenia, immune-mediated hemolytic anemia or a previous history of anaphylaxis requiring ICU care). Any clarification on this criteria, please contact the primary investigator; (ii) patients who have previously undergone a splenectomy are ineligible due to impaired immune function; (iii) pregnant or lactating women; (iv) any medical condition that would prevent the subject from participating in and following a study-related procedure, including additional malignancies, laboratory abnormalities, or psychiatric illness; (v) uncontrolled concomitant diseases that researchers believe interfere with patient safety or trial compliance; and (vi) severe infections that the investigator believes will interfere with patient safety or trial compliance within 4 weeks prior to enrollment.

Dose-limiting toxicity (DLT) in a given patient is defined as any grade III non-hematological toxicity that is irreversible to grade II or lower within 96 hours, or any grade IV toxicity. DLT is based on a first course of treatment. Toxicity will be graded according to the NCI adverse event general terminology criteria (CTCAE; version 5.0). To be able to assess toxicity, patients must receive at least 1 complete course of treatment and be observed for at least 6 months after the start of the first course of treatment, or have undergone DLT. All patients who could not be evaluated for toxicity were replaced.

The Maximum Tolerated Dose (MTD) was defined as the highest injected volume tested, where less than 33% of patients experienced DLT attributable to study drug (LabVax 3(22) -23 ± adjuvant) when at least 6 patients received treatment at this dose and toxicity was evaluable. The MTD was 1 injection level lower than the lowest dose tested, with 33% or more of patients experiencing DLT attributable to the study drug. At least 6 patients will receive treatment at MTD.

DLT levels are the lowest injection levels tested, with 33% or more of patients experiencing DLT attributable to one or more study drugs; DLT levels were 1 dose level higher than MTD.

Six patients in each vaccine/vaccine + GM-CSF group will receive treatment at the scheduled intervals for up to 5 to 12 weeks. If the first patient of 0/3 in each group experienced a DLT after the first 2 injections, the next 3 patients would be enrolled while the initial group continued to execute the injection schedule. If exactly 1/3 patients experience a DLT attributable to one or more study drugs, then 3 more patients (6 in total) will be treated until the injection series is reached. If no additional DLT is observed in the expanded injection schedule (i.e., no more than 1/6 has a DLT), the injection protocol will continue. Once 2 or more patients experienced any DLT attributable to one or more study drugs at a given frequency of injections, the injections were terminated. The phase I trial will end when 6 patients per group received treatment and a maximum of 1/6 patients experienced DLT. If a patient exceeding 1/6 experiences a DLT, the remaining patients will use the next lower injection volume.

All patients who did not experience any DLT at the interval (just before) will continue with the next injection as needed. If no DLT is observed and a benefit is observed, treatment will continue in the individual patients according to the injection schedule; the patient will stop treatment due to unacceptable toxicity (as determined by the treating physician and/or patient) or toxicity that requires discontinuation of treatment.

Patients with stable disease or tumor regression will be provided with additional vaccination outside the study (e.g., booster, patient seroconversion priming) after the patient has completed a 12 week injection schedule and a 1 month follow-up period, according to the first human clinical trial. The treating physician will determine the frequency of injection.

All patients considered to participate in this trial will be pre-screened prior to the therapy regimen to determine that the tumor overexpresses the labyrinin antigen, as determined by screening immunohistochemical evaluations on paraffin-embedded archival samples, which exhibit > 10% staining of malignant cells against the antigen. A single reference pathologist will do this assessment.

This is a single-site, open-label test of the synthetic peptide cancer vaccine LabVax 3(22) -23, which is intended to generate an immune response against tumor-associated antigens. The design of this study will be to examine the safety of the vaccine (+ -GM-CSF as adjuvant) in the adenocarcinoma patient test group. Preliminary information on efficacy will be obtained and post-study correlations on seroconversion will be performed.

Vials will be provided containing sufficient peptide vaccine to achieve a 400 μ g/100 μ l (100 μ g each of the four peptides) injection diluted in the isolation electrolyte S pH 7.4. GM-CSF (250. mu.g/vial) will be used according to the manufacturer's information. Each injection of LabVax 3(22) -23 should be accompanied by administration of 100. mu.g.

Patients will receive 400 μ g of peptide vaccine contained in a total volume of 0.1ml within the skin at weeks 1, 2, 4, 8 and 12 (additional vaccinations at weeks 24 and 36, waiting for clinical response). The vaccine will be stored at-20 ℃ and warmed to room temperature prior to use. The vaccine should be used within one hour after reaching room temperature.

0.1ml is aspirated from a single vial using a 1ml syringe with a 28 gauge needle or smaller. After 60% of the needle length (about 4mm) has penetrated into the dermis, the total volume will be injected intradermally.

After injection of the liquid, the needle/syringe is held in place for 5 minutes (possibly secured with tape) to prevent reflux. Any bandage over the injection site will be placed so that pressure is not exerted on the injected fluid. The patient is advised to avoid applying pressure to the injection site until the liquid is absorbed. Sterile saline was used for reconstitution to achieve equivalent co-administration of 100 μ g GM-CSF (when used) and was administered within one hour of vaccination. Suitable alternative injection sites are located in the legs or abdomen. The aim was to perform each series of vaccinations at a slightly different site (3 cm from the last injection site if the previous one could be seen) and the relative positions would be recorded. Any inflammation at the site will be recorded (photographed and/or written). Inflammation is defined as the area around the injection site that continues to redden and/or indurated more than 20mm for more than 1 week, or any skin ulcer.

The first 3 patients (± GM-CSF) of each group will be observed 60 minutes after immunization of the first 5 immunizations. The worker will assess body temperature, vital signs and response every fifteen minutes at the end of the post-immunization period. Patients will measure and record their body temperature the same night of day (and at another time if they have fever symptoms) and record any other symptoms they encounter. If the patient reports any skin changes, they will be asked to evaluate. If the first 6 patients did not record a serious adverse reaction from the beginning to the end of the first 5 doses, their remaining injection monitoring time would be dispensed with. Patients 7-12 will receive 60 minutes of monitoring immediately after the first vaccine injection; subsequent injections do not require post-vaccine observation unless clinically indicated.

Serum samples will be collected at weeks 0, 1, 2, 4, 8, 12 and 14 (or within 10-20 days after the last injection, including the case where additional vaccine injections are to assess post-test seroconversion, but will also be useful to determine any systemic toxicity if necessary).

A maximum of 3 patients were enrolled weekly until the first 6 patients received no adverse events in 5 doses (grade > 2).

If the intradermal injection results in a skin ulcer, a subsequent injection may be given subcutaneously for the remainder of the vaccination. Where the vaccination is intradermal (i.d.) administration, if the patient develops a significant immune response, the DTH response will prevent further intradermal administration. Significant DTH response was defined as persistent redness and induration over 20mm for more than 1 week around the injection site, or any skin ulcer.

Subjects will receive an assessment of 31 weeks, including a follow-up examination 4 weeks after the last injection (or the last injection if the injection was stopped prematurely). Thereafter, they will receive an assessment of immunological parameters at month 4 and month 7 after the last injection.

Throughout the study, patients may receive continued supportive care and palliative care (e.g., nutritional support, pain control) as clinically indicated. The patient may not receive any concurrent tumor therapy or therapy directed to cancer (e.g., chemotherapy, biological therapy, etc.). Allowing bisphosphonate therapy as part of supportive care. Patients with emergent complications at previously documented disease sites may receive palliative radiation therapy. If medically appropriate, the decision as to whether to continue the therapy regimen will be made through discussions with the sponsor and investigator.

The patient will exit the treatment regimen if any of the following conditions are met: (i) unacceptable toxicity (as determined by the treating physician and/or patient), or toxicity requiring discontinuation of treatment; (ii) patients may choose to withdraw from the study at any time for any reason; (iii) if the researcher deems it to proceed with the best medical benefit not in compliance with the patient or if the patient is not in compliance with the treatment, the patient may be withdrawn from the regimen at the researcher's discretion; (iv) disease progression characterized by the appearance of new lesions, or if existing disease increases beyond 100% of the baseline or nadir (whichever is smaller) major axis one-dimensional diameter; (v) disease progression according to RECIST (solid tumor response assessment criteria) criteria; (vi) the treatment regimen was completed as follows: (a) 5 scheduled vaccinations were completed; and (b) final dose for the 12 th patient (phase I) or the 30 th patient (phase I extension). For a given cohort, patients who started but did not complete the complete injection schedule do not count the total number of patients required to complete each respective cohort; their data will be included in the study summary.

If the patient does not respond to the treatment regimen and/or withdraws from therapy due to toxic effects or "disease progression," further treatment, if any, is at the discretion of the investigator.

After withdrawal from the treatment regimen, all patients will be followed for late toxicity. Patients will be seen 4 weeks, 12 weeks and 28 weeks after cessation of therapy (last injection). If sustained toxicity does not resolve to grade 1 or less in the first 4 weeks, the patient should be seen monthly until toxicity resolves to grade 1 or less. New toxicities after a 4-week follow-up will not be reported unless the investigator deems to be relevant to the regimen treatment. For all patients, a final report form needs to be submitted after final follow-up or at the time of death.

As outlined above, patients will be included in the study. If at any time during the study there is sufficient evidence to indicate an excessively high grade 3 or grade 4 toxicity rate, the study will be terminated. An excessively high grade 3 toxicity rate would be considered 20% (or 4 patients), while an excessively high grade 4 toxicity rate would be considered 10% (or 2 patients) of the patients enrolled by this date. Evidence of too high a toxicity rate is considered sufficient if the lower limit of the 90% unilateral confidence interval of the toxicity rate estimate exceeds the appropriate limit (20% for class 3 and 10% for class 4).

In operation, this occurs if any of the following occurs: (i) grade 3 toxicity (n ═ 20): 2 of the first 2 patients, 3 of the first 6 patients, 4 of the first 9 patients, 5 of the first 13 patients, 6 of the first 14 patients or 7 of the first 19 patients; or (ii) grade 4 toxicity (n ═ 20): 2 of the first 5 patients, 3 of the first 11 patients, 4 of the first 18 patients or 5 of the first 19 patients.

The toxicity rating, definition and specific criteria for each toxicity level will be those outlined in the guidelines defined in CTCAE version 3.0. If a patient develops any grade 3 or higher hematological or non-hematological toxicity that may, likely or certainly be associated with immunity, no further vaccination will be given to the patient and the patient will be withdrawn from the therapy regimen. Modification of vaccine doses is not allowed. If grade 3 or more toxicity is observed as determined by the investigator to be associated with the resulting immune response, a corticosteroid regimen is employed.

The serum will be subjected to a comprehensive metabolic panel test (including total bilirubin, SGOT and creatinine) and monitored at weeks 0, 1, 2, 4, 8 and 12; and monitored at any additional vaccination weeks (i.e. weeks 24 and 36) if deemed necessary according to the protocol. In addition, patients will receive a physical examination at the time of the first immunization and then at each vaccination. The patient will be observed for the development of autoimmunity in normal tissues that may express basal levels of labyrinth proteins, particularly in the skin and salivary glands.

Unless otherwise stated, baseline assessments will be made within 14 days prior to the 1 st vaccine injection. Scanning and X-ray examination must be performed within 28 days before the 1 st vaccine injection. If the patient's condition worsens, laboratory evaluations should be repeated within 48 hours before the next treatment cycle begins.

TABLE 9 study schedule.

a. Pre-study requirements (within 4 weeks prior to the 1 st vaccine injection, unless otherwise indicated); DTH, pregnancy tests, biopsies for immunohistochemistry are included in the pre-study examination.

b. The first of 3 follow-ups as defined in section 7.4.8. If materials are available, booster vaccinations can be performed at the discretion of the physician and patient.

c. If the patient is therefore withdrawn from the study, it is preferable to use 2 consecutive measurements 4 weeks apart to record disease progression.

d.LabVax 3(22)-23(0.1ml,id.)±GM-CSF。

e. Routine includes vital signs, height (just before study), weight.

f. Tumor assessment (clinical measurements; as indicated: radiographic scans, biopsies for immunohistochemistry, etc.).

g. Comprehensive metabolic panel tests (including serum creatinine, AST, total bilirubin; for pre-study at least CBC with autosterology).

Unless otherwise stated, within 4 weeks prior to the 1 st vaccine injection: (i) medical history and physical examination included: height, weight, physical fitness status, clinical tumor measurements; (ii) hematology: complete blood cell count with autosorting; (iii) and (3) biochemical treatment: serum creatinine, AST, total bilirubin; and (iv) radiology: scanning/X-ray examination was performed as necessary to record disease (within 3 months prior to the 1 st vaccine injection). To ensure comparability, a baseline X-ray/scan and subsequent X-rays/scans must be performed using the same technique to assess the response; that is, a scan is performed immediately after bolus administration of contrast agent using a standard volume of contrast agent, the same contrast agent, and preferably the same scanner.

Other studies will include: (i) baseline serum samples (for antibody titers); (ii) pregnancy tests (for fertile women) were performed within 2 weeks prior to the 1 st vaccine injection; (iii) DTH against common recall antigens within 3 months prior to the 1 st vaccine injection; and (iv) immunohistochemistry should be performed within 3 months prior to the 1 st vaccine injection (tumor tissue must be positive for expression of the labyrinthin to qualify).

Toxicity was evaluable in all patients from the time of the first treatment with LabVax 3(22) -23. Toxicity from peptide injection was evaluable for all patients and patients were monitored for acute toxicity. For the first 3 injections, all patients will be monitored by the neighboring physician within 1 hour after injection.

The study will evaluate response and progression using new international criteria set forth by RECIST (solid tumor response evaluation criteria) committee. Only the change in the maximum diameter of the tumor lesion (one-dimensional measurement) was used in RECIST criteria.

Measurable lesions are defined as lesions that can be measured accurately in at least one dimension (longest diameter to be recorded) to ≥ 20mm using conventional techniques (PE, CT, XR, MRI) or ≥ 10mm using helical CT scanning. All tumor measurements must be recorded in millimeters (or centimeters in decimals).

All other lesions (or disease sites) including small lesions (< 20mm longest diameter using conventional techniques or <10mm longest diameter using spiral CT scanning) were considered unmeasurable diseases. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, cutaneous/pulmonary lymphangitis, inflammatory mastopathy, abdominal masses (not tracked by CT or MRI), and cystic lesions are all unmeasurable. Prostate cancer patients may also have PSA-only disease.

All measurable lesions of a total of 10 lesions up to 5 lesions per organ and representing all affected organs should be identified as target lesions and recorded and measured at baseline. The target disease should be selected according to its size (the lesion with the longest diameter) and its suitability for accurate repeated measurements (by imaging techniques or clinical means). The sum of the Longest Diameters (LDs) of all target lesions will be calculated and reported as the baseline LD sum. The baseline LD sum will be used as a reference to further characterize the objective tumor response of the measurable dimension of the disease. If there are >10 measurable lesions, lesions not selected as target lesions will be considered non-target lesions along with unmeasurable disease.

All unmeasurable lesions (or sites of disease) plus any measurable lesions except the 10 lesions listed as target lesions. No measurement is required, but these lesions should be recorded at baseline and "present" or "absent" should be added later.

The best response categories for all patients to the study are summarized below: complete Reaction (CR): all clinical and radiological evidence (target and non-target) of the tumor disappeared; partial Reaction (PR): the sum of LD of the target lesions is reduced by at least 30% with reference to the baseline sum of LD; and disease Stability (SD): the disease state is stable. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; disease Progression (PD): the sum of the LDs of the measured lesions is increased by at least 20% with reference to the minimum LD recorded since the start of treatment or the appearance of one or more new lesions. The appearance of new lesions will also constitute disease progression. In special cases, unequivocal progression of non-target lesions may be accepted as evidence of disease progression. In special cases, unequivocal progression of non-target lesions may be accepted as evidence of disease progression.

TABLE 10 reaction classifications.

Duration of response will be measured from the time the CR/PR measurement criteria are first met (whichever is first recorded) to the first date the disease recurrence or progression is objectively documented. The duration of disease stability will be measured from the start of therapy to the satisfaction of the progression criterion, with the minimum measurement recorded since the start of treatment as a reference.

Following the course of this study, a clinical serological study will be performed on all patients to assess any production of serum antibodies against the labyrinth protein-based peptide. Antibody responses will be measured and evaluated as total immunoglobulin (IgM, IgG, IgA, IgD and IgE) responses to labyrinth protein-based peptides (all 4 phase combinations). IgM and IgG responses alone will be measured for research purposes and will not be used to guide treatment in this study. IgG subclass responses will also be measured for research purposes and will not be used to guide therapy. These responses will be evaluated at weeks 4, 9, 12, 15, 19, 23 and 27.

As outlined above, a 10ml blood sample will be drawn. Each sample was collected into a non-heparinized evacuated blood collection tube with a 20g or larger needle. The blood sample was immediately cooled on wet ice (approximately 4-8 degrees celsius) and held at this temperature until processed to isolate serum. The serum was spiked with sodium azide (using a saturated sodium azide solution to within 0.05% to 0.1% final concentration) as a preservative and the volume added and total serum volume were recorded. The samples were aliquoted and stored at-80 ℃ in two different refrigerators until analysis.

The serum should not be frozen. The sample (10cc) should be stored in a collection tube (supplied by LabyRx, Inc.; sodium azide non-heparinized red top tube with wax phase separator) in a refrigerator (4 ℃). The serum samples were retained in the facility and transported in batches at a later time during the test. The serum is stored to prevent loss of the sample during transport or at subsequent storage sites.

A patient who has been seroconverted to 1:100,000 will be asked (optionally; only once) to provide 10ml of whole blood for isolation of viable lymphocytes. Whole blood was processed on Ficoll step gradients, cells were washed 3 times with Hanks buffer, and cells were aliquoted and cryopreserved in 10% DMSO/90% fetal calf serum (ca. 5X 10)⁶One/vial). These cells were provided to LabyRx (or third party testing laboratory) for evaluation of cellular immune responses and other study related studies.

Prior to patient treatment, formalin-fixed paraffin-embedded tissues with representative tumor tissue samples must be submitted for immunohistochemical staining and detection/evaluation of the labyrinth proteins.

Sequence listing

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<120> labyrinth protein-based peptides for cancer immunotherapy and uses thereof

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