Compounds, compositions, multimers, and methods for treating disorders in mammals

Abstract

The disclosure provide for fusion proteins, multimeric proteins, and hexamer proteins capable of use for antibody discovery and / or therapeutic vaccination in companion animals, for example, dogs and cats. The disclosure further provides for multimeric and hexameric proteins capable of the treatment of pain, for example, inflammation, neuropathic pain, diabetes-related pain, arthritic pain and autoimmunity pain, as well as dermatological disorders, for example atopic dermatitis or pruritus, in animals. Use of multimeric and hexameric proteins described herein as vaccines or immunogen is further described.

Description

2920951-529977COMPOUNDS, COMPOSITIONS, MULTIMERS, AND METHODS FOR TREATING DISORDERS IN MAMMALS REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0001] A Sequence Listing in XML format, submitted under 37 C.F.R. §§ 1.831-1.835, entitled 292095 l-529977_Sequence_Listing.xml, 222,401 bytes in size, generated on 27 December 2025, and filed via EFS-Web, is provided in lieu of a paper copy. This Sequence Listing is incorporated by reference into the specification for its disclosures.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 740,046, filed December 30, 2024, U.S. Provisional Application No. 63 / 882,012, filed September 15, 2025, U.S. Provisional Application No. 63 / 882,039, filed September 15, 2025, and U.S. Provisional Application No. 63 / 882,075, filed September 15, 2025, the entire content of each of these applications are herein incorporated herein by reference in their entireties.BACKGROUND

[0003] Monoclonal antibodies are typically used as therapeutics for chronic diseases such as inflammation and autoimmunity and have been increasingly used in animal care. While vaccination may allow for an antibody response, the introduction of a vaccine antigen alone is oftentimes ineffective to generate a potent and long-lasting immune response. Therefore, there is a need to identify new effective monoclonal antibodies to treat a wide variety of disorders, such as chronic diseases, in subjects in need thereof.

[0004] The induction of therapeutic antibodies is often challenged by the ability of the antigen to induce an immune response in an animal from which antibody generation is sought. An immunized animal will often not recognize a vaccinated antigen or be tolerant of an antigen that resembles a self-antigen. An animal that is tolerant to the immunogen will not select B cells that can produce antibodies with the most desirable binding properties.

[0005] The conjugation of antigens with virus-like particles (VLPs) has been used to increase immunogenicity. The success of this approach may be antigen specific, and the process of chemical conjugation can result in modifications to the structure / function of the antigen. These modifications can negatively impact the potency and / or duration of the induced immune response. In other embodiments, these VLP fusions result in shielding of critical epitopes, similarly reducing the efficacy of the induced response.

[0006] Induction of immunity requires the processing of antigen (Ag) by the innate immune system and presentation of the Ag to the adaptive immune systems. Cells of the innate immune system engulf Ag. These are antigen presenting cells (APCs). Dendritic cells (DCs), which areprofessional APCs present Ag to T cells in in secondary lymphoid organs such as lymph nodes. Ag that is engulfed by APCs is processed through the endosomal / lysosomal pathway. Processed peptides are bound by MHC class II molecules in the endomembrane system and are then translocated to the cell surface where they are presented to a large and diverse population of naive T cells. This T cell population is composed of individual cells with T cell receptors that are selective for peptide sequences. Those CD4+ T cells with T cell receptors that have the appropriate affinity to the antigenic peptide respond to such peptides and are provided co-stimulatory cytokines by the DC. CD4+ T cells then present the Ag-CD4 receptor complex to quiescent B cells. Those B cells bearing an membrane localized immunoglobulin that binds the peptide are activated. The activated CD4+ T cell induce class switching of the immunoglobulin from IgM to other isotypes of immunoglobulins including IgG.

[0007] There remains a need for improved means of antibody discovery wherein delivering antigens to APCs by Fc receptor-mediated internalization and of inducing strong, protective immunity. In addition, the goal of a vaccine is to induce protective immunity against antigens that resemble self-antigens, which may be only weakly immunogenic.

[0008] Monoclonal antibodies are typically used as therapeutics for chronic diseases such as inflammation, neuropathic pain, diabetes-related pain, arthritic pain and autoimmunity pain and have been more recently used in animal care. Monoclonal antibody treatments generally require numerous infusions over the life of an animal to be treated to be effective. Vaccine immunogens are generally used to treat or prevent diseases from microbial pathogens. Effective microbial immunogens are antigens that are not present in the vaccinated animal. Self-antigens typically do not generate an immune response due to thymic exclusion of T cells reactive to self-antigens.

[0009] To this end, the disclosure provides for methods of using an antigen fusion polypeptide, for example a hexameric fusion polypeptide, for antibody discovery. By simultaneously binding to more than one Fc receptor, the antigen fusion polypeptides described herein acts like an immune complex and can help to facilitate antibody discovery. Compounds, compositions, and methods of using thereof are further provided.SUMMARY

[0010] The disclosure provides for fusion polypeptides comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer.

[0011] The disclosure further provides for fusion polypeptides comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer, andwherein the fusion polypeptide increases a B cell response in an animal relative to an antigen alone.

[0012] In other aspects the disclosure provides for fusion polypeptides comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer, andwherein the fusion polypeptide increases a B cell response in an animal relative to antigen alone.

[0013] The disclosure further provides for fusion proteins comprising polypeptide chains, wherein the polypeptide chains comprise:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide, or antigenic fragment thereof;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

[0014] In other aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide, or antigenic fragment thereof;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence andwherein the polypeptide chains form an oligomer or are capable of forming an oligomer.

[0015] The disclosure provides for fusion proteins comprising polypeptide chains, wherein the polypeptide chains comprise:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide, or antigenic fragment thereof;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains are capable of forming an oligomer and wherein the fusion protein increases a B cell response in an animal relative to an antigen alone and / or the fusion protein increases an immune response in an animal relative to the antigen alone.

[0016] The disclosure further provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence comprising an NGF polypeptide or an IL- 10 polypeptide;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer or are capable of forming an oligomer.

[0017] In other aspects the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide, or antigenic fragment thereof;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) optionally a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer or are capable of forming an oligomer.

[0018] In other aspects the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence comprising an NGF polypeptide or an IL- 10 polypeptide;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) optionally a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer or are capable of forming an oligomer.

[0019] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide, or antigenic fragments thereof; (b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

[0020] The disclosure further provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence comprising an IL-5 polypeptide or an IL- 13 polypeptide;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

[0021] The disclosure also provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence comprising an IL-5 polypeptide or an IL- 13 polypeptide;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer or are capable or forming an oligomer, and optionallywherein the fusion protein increases a B cell response in an animal relative to an antigen alone.

[0022] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide, or antigenic fragments thereof; (b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region; and .wherein the polypeptide chains form an oligomer or are capable or forming an oligomer.

[0023] In other aspects the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide, or antigenic fragment thereof;(b) optionally a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

[0024] In other aspects the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises the following:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide, or antigenic fragment thereof;(b) optionally a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence; andwherein the polypeptide chains form an oligomer or are capable of forming an oligomer.

[0025] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an NGF polypeptide with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 53 or a fragment thereof;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer, optionally form an oligomer, or are capable of forming an oligomer.

[0026] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an IL- 10 polypeptide selected from: i. a canine IL- 10 polypeptide or fragment thereof;ii. a feline IL- 10 polypeptide or fragment thereof; andiii. a feline IL- 10 D 145K polypeptide or fragment thereof;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer, optionally form an oligomer, or are capable of forming an oligomer.

[0027] In other aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an IL- 10 polypeptide selected from:i. a canine IL- 10 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 57 or fragment thereof;ii. a feline IL- 10 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 60 or fragment thereof; andiii. a feline IL- 10 D145K polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 62, or fragment thereof;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer, optionally form an oligomer, or are capable of forming an oligomer.

[0028] In aspects, polypeptide chains described herein comprise an Antigen-CH1-Hinge-CH2-CH3 -Tailpiece wherein the respective sequences for each component are selected for and described in Table 19. In other embodiments, the polypeptide chain comprises, in N-terminus to C-terminus order, an Antigen-CH1-Hinge-CH2-CH3-Tailpiece wherein the respective sequences for each component are selected for and described in Table 19.

[0029] In aspects, fusion proteins described herein treat, alleviate, mediate, or prevent pain in an a mammal or animal, for example, a canine or feline. In aspects, fusion proteins described herein are used for generation of an antibody immune response that neutralize self-antigens that mediate pain. In other aspects, fusion proteins described herein are used for the generation of an immune response in a subject mammal or animal that relieves pain in the animal. In other aspects, fusion proteins described herein comprise 6, 8, 10, or 12 individual polypeptide chains. In aspects, the fusion protein forms a cyclic pentamer comprising 10 individual polypeptide chains, forms a cyclic hexamer comprising 12 individual polypeptide chains, or forms a cyclic heptamer comprising 14 individual polypeptide chains.

[0030] In aspects, polypeptide chains described herein form oligomers or are capable of forming oligomers. In other aspects, two individual polypeptide chains are cross-linked with each other and form a monomer subunit. In aspects, multiple monomer subunits form an oligomeric, pentameric, hexameric, or heptameric protein structure.

[0031] In aspects, fusion proteins described herein increase an immune response in an animal sufficiently to treat pain or pain related disorders. In aspects, fusion proteins described herein may be used to treat arthritic conditions and pain associated with arthritic conditions in animals, such as dogs or cats.

[0032] In aspects, fusion proteins described herein increase a B cell response in an animal relative to an antigen alone and / or the fusion protein increases an immune response in an animal relative to antigen alone. In aspects, animals immunized with fusion proteins described herein increase a B cell response and / or antibody titer to the antigen in an animal relative to an animal relative to an animal immunized with a non-fusion protein antigen sequence.

[0033] In aspects, two individual polypeptide chains described herein are connected to each other by disulfide linkages thereby forming a monomer subunit comprising two individual polypeptide chains. In further aspects, five monomer subunits described herein form a pentameric protein, six monomer subunits described herein form a hexameric protein, or seven monomer subunits described herein form a heptameric protein. In further aspects the pentameric protein is a cyclic pentamer, the hexameric protein is a cyclic hexamer, or a heptameric protein is a cyclic heptamer. In aspects of the disclosure, the multimeric, pentameric, hexameric, or heptameric protein comprises identical monomeric subunits. In other aspects, the multimeric, pentameric, hexameric, or heptameric proteins comprises monomeric subunits that are not identical. In aspects, the multimeric, pentameric, hexameric, or heptameric proteins described herein comprise disulfide bonds formed between adjacent monomeric subunits at residue 309.

[0034] The disclosure further provides for aspects wherein the immunoglobulin heavy chain constant region comprises a human IgGl immunoglobulin Fc, or optionally a human IgG2 Fc, a human IgG3 Fc, a human IgG4 Fc, a human IgA Fc, a human IgD Fc, a human IgE Fc, a human IgM Fc, a canine IgG-a Fc, a canine IgG-b Fc, a canine IgG-c Fc, a canine IgG-d Fc, a murine IgGl Fc, a murine IgG2 Fc, a murine IgG3 Fc, a murine IgM, or a functional variant thereof.

[0035] In aspects, immunoglobulin heavy chains described herein comprises an amino acid sequence that is substituted relative to the native heavy chain. In other aspects, the substitutions promote the assembly of polypeptide chains into an oligomeric protein structure and optionally into a hexameric protein structure comprising six monomer subunits, each monomeric subunit comprising two individual polypeptide chains.

[0036] In aspects, immunoglobulin heavy chain sequences described herein comprise one or more substitutions at residues selected from 220, 228, 235, 309, 329, 355, and / or 409, wherein residue number corresponds to the EU numbering convention for immunoglobulins. In further aspects, the substitution is selected from a serine at residue 220, a proline at residue 228, aglutamate at residue 235, a cysteine at residue 309, a glycine at residue 329, and / or a cysteine at residue 355. In additional aspects, the substitution is a cysteine at residue 309.

[0037] In aspects, the immunoglobulin sequence comprises domains selected from an optional antigen-CHl linker, hinge, a CHI, a CH2, an optional interdomain linker, a CH3, an optional CH4, and an IgM tailpiece or optionally an IgA tailpiece.

[0038] In aspects, the disclosure provides for an optional antigen-CHl linker polypeptide comprising a sequence comprising a glycine and / or serine rich polypeptide of 2 to 100 amino acids in length. In some embodiments, the optional antigen-CHl linker is a polypeptide having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to SEQ ID NO: 2.

[0039] The disclosure provides for aspects wherein the CHI domain comprises a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence selected from SEQ ID NOs: 3, 4, and 5.

[0040] In other aspects, the disclosure provides for hinge regions comprising sequences having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence selected from SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11.

[0041] The disclosure provides for aspects wherein the CH2 domain comprises a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence selected from SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17.

[0042] In aspects, the disclosure provides for an optional interdomain linker comprising a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to SEQ ID NO: 27. In further aspects, fusion proteins described herein comprise a linker which is optionally a glycine and / or serine rich sequence. Inaspects, the linker is 2 to 20 amino acids, 2 to 10 amino acids, 3 to 15 amino acids, 5 to 15 amino acids, or 5 to 10 amino acids in length.

[0043] In aspects, the disclosure provides for CH3 domains comprising a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence a sequence selected from SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23.

[0044] In aspects, the disclosure provides for an IgM tailpiece comprising a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to SEQ ID NO: 1.

[0045] The disclosure farther provides for aspects wherein at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% of oligomer subunits are present in a hexameric form. In other aspects, more than 90% of the oligomer subunits are in hexameric form whereas the reminder of 10% or less are in sub-hexameric form (lower than hexameric multimers). In further aspects, In other aspects, more than 80% of the oligomer subunits are in hexameric form whereas the reminder of 20% or less are in sub-hexameric form (lower than hexameric multimers).

[0046] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide;(b) a linker connected to the antigen polypeptide comprising a sequence at least 95% to SEQ ID NO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 95% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) optionally a hinge polypeptide sequence, if present, comprises a sequence at least 95% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 95% to SEQ ID NO: 27.

[0047] In further aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide;(b) a linker connected to the antigen polypeptide comprising a sequence at least 99% identical to SEQ ID NO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 99% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) a hinge polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 99% to SEQ ID NO: 27.

[0048] In aspects, the disclosure provides for polypeptide chains comprising (Formula I): A (Antigen) - B (CHI) - C (hinge) - D (CH2) - E (Optional Interdomain Linker) - F (CH3) - G (tailpiece)wherein,A comprises an antigen polypeptide sequence comprising a pain mediating polypeptide; B comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0049] In further aspects, polypeptide chains A - G of Formula I comprise:A comprises a IL- 10 antigen;B comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 11.

[0050] In further aspects, polypeptide chains A - G of Formula I comprise:A comprises a IL- 10 antigen;B comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 95% Identity to SEQ ID NO: 62;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 11.

[0051] In further aspects, polypeptide chains A - G of Formula I comprise:A comprises a IL- 10 antigen;B comprises an amino acid sequence 100% identical to SEQ ID NO: 3;C comprises an amino acid sequence 100% identical to SEQ ID NO: 7;D comprises an amino acid sequence 100% identical to SEQ ID NO: 11;E is optional and if present comprises an amino acid sequence 100% identical to SEQ ID NO: 27;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0052] In further aspects, polypeptide chains A - G of Formula I comprise:A comprises an NGF antigen;B comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0053] In further aspects, polypeptide chains A - G of Formula I comprise:A comprises an NGF antigen;B comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 95% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

[0054] In further aspects, polypeptide chains A - G of Formula I comprise:A comprises an NGF antigen;B comprises an amino acid sequence 100% identical to SEQ ID NO: 3;C comprises an amino acid sequence 100% identical to SEQ ID NO: 7;D comprises an amino acid sequence 100% identical to SEQ ID NO:11;E is optional and if present comprises an amino acid sequence 100% identical to SEQ ID NO: 27;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0055] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell response in an animal relative to an antibody such as bedinvetmab (SEQ ID NO: 70 and SEQ ID NO: 71) for NGF or an IL-10 monoclonal about 0.2 fold or more, about 0.5 fold or more, about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about .2 fold to about 3 fold, about .5 fold to about 5 fold, about 1 fold to about 10 fold, about 2 fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In an aspect, the animal is a canine or feline.

[0056] In aspects, the disclosure provides for methods of inducing an immune response in an animal by administering fusion polypeptide, fusion proteins, oligomers, multimers, hexamers, and compositions described herein to an animal. In aspects, an immune response is induced by administering fusion polypeptide, fusion proteins, oligomers, multimers, hexamers, and compositions described herein to an animal by subcutaneous, intradermal, intratumoral, intranodal, intramedullary, intramuscular, intravenous, or intraperitoneal administration. In other aspects, the method includes administration, one, two, or three or more times to an animal.

[0057] The disclosure further provides for methods of reducing pain by generating an antibody immune response, for example by inducing the selection of the neutralizing antibody variable sequences which bind to the pain mediator polypeptides in the animal, comprising administering fusion proteins, oligomers, multimers, hexamers, or compositions described herein to an animal. In aspects, the administered fusion proteins, oligomers, multimers, hexamers, or compositions described herein increases B cell response relative to an antigen alone. In other aspects, the antibody is identified by isolating an antibody from blood, or by isolating a B cell producing an antibody from a secondary lymphoid organ comprising spleen, lymph node, Peyer’s patch, nasal associated lymphoid tissue, adenoid, tonsil, bronchus associated lymphoid tissue, or isolated lymphoid follicle.

[0058] The disclosure further provides for methods for inducing a neutralizing antibody immune response to pain mediators polypeptides comprising administering a composition comprising fusion proteins, oligomers, multimers, or hexamers described herein and an adjuvant described herein to a subject animal, wherein the composition administered to the animal increases a B cell response to the pain mediators polypeptides in an animal relative to antigen alone and wherein the increased B cell response leads to the reduction of pain in the subject animal.

[0059] In another aspect, the disclosure further provides for methods for generating a neutralizing antibody immune response to pain mediator polypeptides comprising administering a hexamer described herein together with an adjuvant described herein to an animal, wherein the composition comprising the hexamer and adjuvant administered to the animal increase a B cell response to the pain mediator polypeptides in an animal relative to the pain mediator polypeptides alone and wherein the increased B cell response leads to the reduction of pain in the animal.

[0060] In aspects, fusion proteins described herein treat, alleviate, mediate, or prevent a dermatological condition in an a mammal or animal, for example, a canine or feline. In aspects, fusion proteins described herein are used for generation of an antibody immune response that neutralize self-antigens that mediate a dermatological condition including atopic dermatitis or pruritus. In other aspects, fusion proteins described herein are used for the generation of an immune response in a subject mammal or animal that relieves a dermatological condition including atopic dermatitis or pruritus in the animal. In other aspects, fusion proteins described herein comprise 6, 8, 10, or 12 individual polypeptide chains. In aspects, the fusion protein forms a cyclic pentamer comprising 10 individual polypeptide chains, forms a cyclic hexamer comprising 12 individual polypeptide chains, or forms a cyclic heptamer comprising 14 individual polypeptide chains.

[0061] In aspects, fusion proteins described herein increase an immune response in an animal sufficiently to treat a dermatologic condition or dermatologic related disorders. In aspects, fusion proteins described herein may be used to treat dermatologic conditions associated with diseases of the skin in animals, such as dogs or cats.

[0062] In aspects, fusion proteins and compositions described herein are used for the generation of an antibody immune response that alleviates a dermatological condition including atopic dermatitis or pruritus in a subject animal by neutralizing polypeptide mediator of a dermatological condition including atopic dermatitis or pruritus, thus alleviating the dermatological condition. In further aspects, hexameric proteins and compositions thereof described herein are used for generation of a neutralizing antibody immune response to a mediator a dermatological condition including atopic dermatitis or pruritus. In other aspects, fusion proteins and compositions described here are used for therapeutic immunization of companion animals, for example, cats and dogs. In other aspects, hexameric proteins and compositions thereof described herein are used for therapeutic immunization of companion animals, for example, cats and dogs.

[0063] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an IL- 10 polypeptide selected from:i. a canine IL-5 polypeptide or fragment thereof;ii. a feline IL-5 polypeptide or fragment thereof; andiii. a feline IL-5 El 3Q polypeptide or fragment thereof;(b) optionally a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer or are capable of forming an oligomer.

[0064] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an IL-5 polypeptide selected from:a. a feline IL-5 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 95;b. a feline IL-5 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 96,c. a feline IL-5 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 98; ord. a canine IL-5 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 110 or a fragment thereof;(b) optionally a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer or are capable of forming an oligomer..

[0065] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an IL- 13 polypeptide selected from:i. a canine IL- 13 polypeptide or fragment thereof; orii. a feline IL- 13 polypeptide or fragment thereof;(b) optionally a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer or are capable of forming an oligomer.

[0066] In other aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an IL- 13 polypeptide selected from:i. a canine IL- 13 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 91 or fragment thereof; orii. a feline IL- 13 polypeptide comprising a polypeptide sequence with at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% of 100% identity to SEQ ID NO: 93 or fragment thereof; and(b) optionally a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer or are capable of forming an oligomer..

[0067] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide;(b) a linker connected to the antigen polypeptide comprising a sequence at least 95% to SEQ ID NO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 95% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) optionally a hinge polypeptide sequence, if present, comprises a sequence at least 95% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 95% to SEQ ID NO: 27.

[0068] In further aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide(b) a linker connected to the antigen polypeptide comprising a sequence at least 99% identical to SEQ ID NO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 99% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) a hinge polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 99% to SEQ ID NO: 27.

[0069] In aspects, the disclosure provides for polypeptide chains comprising (Formula II): A (Antigen) - B (Optional Linker) - C (CHI) - D (hinge) - E (CH2) - F (CH3) - G (tailpiece) wherein,A comprises an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide, or antigenic fragments thereof;B optional, comprises a glycine and / or serine rich amino acid sequence of 2 to 20 amino acids in length, if present;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0070] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an IL-5 antigen;B optional, comprises an amino acid sequence of at least 90% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0071] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an IL-5 antigen;B optional, comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;E comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

[0072] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises a IL-5 antigen;B optional, comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence 100% identical to SEQ ID NO: 3;D comprises an amino acid sequence 100% identical to SEQ ID NO: 7;E comprises an amino acid sequence 100% identical to SEQ ID NO: 13;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0073] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an IL- 13 antigen;B optional, comprises an amino acid sequence of at least 90% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0074] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an IL- 13 antigen;B optional, comprises an amino acid sequence of at least 95% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11;E comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

[0075] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an IL- 13 antigen;B optional, comprises an amino acid sequence 100% identical to SEQ ID NO: 2, if present;C comprises an amino acid sequence 100% identical to SEQ ID NO: 3;D comprises an amino acid sequence 100% identical to SEQ ID NO: 7;E comprises an amino acid sequence 100% identical to SEQ ID NO: 13;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0076] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell response in an animal relative to a therapeutic monoclonal neutralizing antibody for interleukin 5 (IL-5) or a therapeutic monoclonal neutralizing antibody for interleukin-13 (IL- 13) of about 0.2 fold or more, about 0.5 fold or more, about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about 0.2 fold to about 3 fold, about 0.5 fold to about 5 fold, about 1 fold to about 10 fold, about 2 fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In an aspect, the animal is a canine or feline.

[0077] The disclosure further provides for methods of reducing a dermatological condition including atopic dermatitis or pruritus by generating an antibody immune response, for example by inducing the selection of the neutralizing antibody variable sequences which bind to the polypeptide mediator of a dermatological condition in the animal, comprising administering fusion proteins, oligomers, multimers, hexamers, or compositions described herein to an animal. In aspects, the administered fusion proteins, oligomers, multimers, hexamers, or compositions described herein increases B cell response relative to an antigen alone. In other aspects, the antibody is identified by isolating an antibody from blood, or by isolating a B cell producing an antibody from a secondary lymphoid organ comprising spleen, lymph node, Peyer’s patch, nasal associated lymphoid tissue, adenoid, tonsil, bronchus associated lymphoid tissue, or isolated lymphoid follicle.

[0078] The disclosure further provides for methods for inducing a neutralizing antibody immune response to polypeptide mediator of a dermatological condition comprising administering a composition comprising fusion proteins, oligomers, multimers, or hexamers described herein and an adjuvant described herein to a subject animal, wherein the composition administered to the animal increases a B cell response to the polypeptide mediator of a dermatological condition in an animal relative to antigen alone and wherein the increased B cell response leads to the reduction of a dermatological condition including atopic dermatitis or pruritus in the subject animal.

[0079] In another aspect, the disclosure further provides for methods for generating a neutralizing antibody immune response to polypeptide mediator of a dermatological condition comprising administering a hexamer described herein together with an adjuvant described herein to an animal, wherein the composition comprising the hexamer and adjuvant administered to the animal increase a B cell response to the polypeptide mediator of a dermatological condition in an animal relative to the polypeptide mediator of a dermatological condition alone and wherein the increased B cell response leads to the reduction of dermatological condition including atopic dermatitis or pruritus in the animal.

[0080] In aspects, fusion proteins described herein treat, alleviate, mediate, or prevent pain in an a mammal or animal, for example, a canine or feline. In aspects, fusion proteins described herein are used for generation of an antibody immune response that neutralize self-antigens that mediate pain. In other aspects, fusion proteins described herein are used for the generation of an immune response in a subject mammal or animal that relieves pain in the animal. In other aspects, fusion proteins described herein comprise 6, 8, 10, or 12 individual polypeptide chains. In aspects, the fusion protein forms a cyclic pentamer comprising 10 individual polypeptide chains, forms a cyclic hexamer comprising 12 individual polypeptide chains, or forms a cyclic heptamer comprising 14 individual polypeptide chains.

[0081] The disclosure farther provides for aspects wherein at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% of oligomer subunits are present in a hexameric form. In other aspects, more than 90% of the oligomer subunits are in hexameric form whereas the reminder of 10% or less are in sub-hexameric form (lower than hexameric multimers). In farther aspects, In other aspects, more than 80% of the oligomer subunits are in hexameric form whereas the reminder of 20% or less are in sub-hexameric form (lower than hexameric multimers).

[0082] In aspects, the disclosure provides for fusion proteins comprising an antigen from a pathogen that can infect a canine or feline, wherein the fusion protein increases an immune response in an animal relative to the antigen alone and / or wherein the fusion protein increases a B cell response in an animal relative to the antigen alone. In aspects, the fusion proteins are used as vaccines for the treatments of animals, canines and felines.

[0083] The disclosure further provides for fusion proteins wherein the immune response inhibits infection by an infectious disease pathogen or reduces infection by an infectious disease pathogen in a subject animal. In aspects, fusion proteins described herein create an immune response wherein the immune response inhibits one or more infections from any of, but not limited to Lyssavirus rabies, canine parvovirus, canine distemper virus, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper virus, felinepanleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocy tophilum, or other canine or feline pathogen.

[0084] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein the polypeptide chain comprises (Formula II):A (Antigen) - B (Optional linker) C(CH1) - D (hinge) - E (CH2) -F (CH3) - G (tailpiece) wherein,A comprises an antigen from an infectious disease pathogen antigen; an infectious disease receptor antigen, or an antigen originating from a canine or feline infectious disease pathogen; orB is optional and if present comprises an amino acid sequence at least 90% identity to SEQ ID NO: 2 or a glycine and / or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO:11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0085] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen from an infectious disease pathogen antigen; an infectious disease receptor antigen, or an antigen originating from a canine or feline infectious disease pathogen; orB is optional and if present comprises an amino acid sequence at least 95% identity to SEQ ID NO: 2 or a glycine and / or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO:6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO:11;E comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

[0086] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen from an infectious disease pathogen antigen; an infectious disease receptor antigen, or an antigen originating from a canine or feline infectious disease pathogen; orB is optional and if present an amino acid sequence 100% identical to SEQ ID NO: 2;C comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence 100% identical to SEQ ID NO:6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO:11;E comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0087] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell mediated antibody titer in an animal relative to a titer from an administered therapeutic monoclonal neutralizing antibody for an antigen originating from a canine or feline infectious disease pathogen by about 0.2 fold or more, about 0.5 fold or more, about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about 0.2 fold to about 3 fold, about 0.5 fold to about 5 fold, about 1 fold to about 10 fold, about 2 fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In aspects, the disclosure provides for fusion proteins, oligomers, multimers, hexamers, or compositions described herein that can increase an immunes response in an animal that prevents, mitigates, or treats an infectious disease in an animal. In an aspect, the animal is a canine or feline.

[0088] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein are used for generation of an antibody immune response that neutralize a canine or feline infectious pathogen. In other aspects, fusion proteins described herein are used for the generation of an immune response in a subject canine or feline that prevent, inhibit, or mediate a block or partially block a canine or feline infectious pathogen in the canine or feline. In other aspects, fusion proteins described herein comprise 6, 8, 10, or 12 individual polypeptide chains. In aspects, the fusion protein forms a cyclic pentamer comprising 10 individual polypeptide chains, forms a cyclichexamer comprising 12 individual polypeptide chains, or forms a cyclic heptamer comprising 14 individual polypeptide chains.

[0089] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein are used for the generation of an antibody immune response that prevent, inhibit, or mediate a block or a partial block of an infection of a canine or feline infectious pathogen in the canine or feline by binding to a virus antigen. In other aspects, fusion proteins and compositions described here are used for therapeutic immunization of a canine or feline, for example, cats and dogs. In other aspects, hexameric proteins and compositions thereof described herein are used for prophylactic immunization of canines or felines, for example, cats and dogs. In other aspects, the immune response in the animal prevents or cures Lyssavirus rabies, canine parvovirus, canine distemper, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, or Anaplasma phagocy tophilum, or other canine or feline pathogen.

[0090] The disclosure provides for methods of preventing, or inhibiting, or Lyssavirus rabies, canine parvovirus, canine distemper, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocy tophilum, or other canine or feline pathogen by administering fusion proteins, oligomers, multimers, hexamers, or compositions to an animal, such as a canine or feline. In aspects, the disclosure provides for methods of preventing, or inhibitingL ssavzru ' rabies, canine parvovirus, canine distemper, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasmaphagocy tophilum, or other canine or feline pathogen by administering fusion proteins, oligomers, multimers, hexamers, or compositions described herein to an animal, such as a canine or feline. In aspects, the above disorders are treated by formulating fusion proteins, oligomers, multimers, hexamers, or compositions described as a vaccine composition and administering to a mammal or animal in need thereof. In aspects, the fusion proteins are hexameric fusion proteins. In other aspects, fusion proteins, oligomers, multimers, hexamers, or compositions comprise one or more polypeptide chains from Table 19.

[0091] The disclosure further provides for methods of preventing, inhibiting a Lyssavirus rabies, canine parvovirus, canine distemper, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species,, feline distemper, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocytophilum or other canine or feline pathogen infection by generating an antibody immune response, for example, by inducing the selection of the neutralizing antibody variable sequences which bind to an antigen in the canine or feline infectious disease pathogen, comprising administering fusion proteins, oligomers, multimers, hexamers, or compositions described herein to a canine or feline. In aspects, the administered fusion proteins, oligomers, multimers, hexamers, or compositions described herein increases B cell response relative to an antigen alone. In other aspects, the antibody is identified by isolating an antibody from blood, or by isolating a B cell producing an antibody from a secondary lymphoid organ comprising spleen, lymph node, Peyer’s patch, nasal associated lymphoid tissue, adenoid, tonsil, bronchus associated lymphoid tissue, or isolated lymphoid follicle.

[0092] The disclosure further provides for methods for inducing a neutralizing antibody immune response to an antigen from Lyssavirus rabies, canine parvovirus, canine distemper, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species,, feline distemper, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocytophilum or other canine or feline pathogen comprising administering a composition comprising fusion proteins, oligomers, multimers, or hexamers described herein and an adjuvant described herein to a subject animal, wherein the composition administered to the animal increases a B cell response to the infectious disease pathogen antigen alone and wherein the increased B cell response leads to the reduction of the pathogen infection in the subject animal.

[0093] The disclosure further provides for methods for inducing a neutralizing antibody immune response to an antigen from a canine or feline pathogen comprising administering a composition comprising fusion proteins, oligomers, multimers, or hexamers described herein and an adjuvant described herein to a subject animal, wherein the composition administered to the animal increases a B cell response to canine or feline pathogen in an animal relative to antigen alone and wherein the increased B cell response leads to the reduction of infection in the subject animal.

[0094] In another aspect, the disclosure further provides for methods for generating a neutralizing antibody immune response to antigen originating from a canine or feline infectiousdisease pathogen comprising administering fusion proteins, oligomers, multimers, or hexamers described herein described herein together with an adjuvant described herein to an animal, wherein the composition comprising the hexamer and adjuvant administered to the animal increase a B cell response to the antigen originating from a canine or feline infectious disease pathogen in an animal relative to the antigen originating from a canine or feline infectious disease pathogen alone and wherein the increased B cell response leads to the reduction of an infection by the canine or feline infectious pathogen.

[0095] In aspects, the disclosure provides for fusion proteins comprising an antigen from an animal, wherein the fusion protein increases an immune response in an animal relative to the antigen alone and / or wherein the fusion protein increases a B cell response in an animal relative to the antigen alone. In aspects, the fusion proteins are used as vaccines for the sterilization or castration of animals.

[0096] The disclosure further provides for fusion proteins wherein the immune response either blocks or partially blocks the sexual maturation or blocks or partially blocks the viability of gametes (sperm or oocytes) in a subject animal. In aspects, fusion proteins described herein create an immune response wherein the immune response blocks or partially blocks the tropic effect of gonadotropin-releasing hormone (GnRH). In aspects, fusion proteins described herein create an immune response wherein the immune response blocks or partially blocks the fertilization of oocytes by inducing an immune response against Zona Pellucida (ZP) proteins.

[0097] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:a. an antigen originating from an animal in need of non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen; b. an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; andc. a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

[0098] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:a. an antigen originating from an animal in need of non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen; b. an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; andc. a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region; andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0099] In aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:a. an antigen originating from an animal in need of non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen; b. an optional linker connected to the antigen polypeptide sequence;c. a CHI polypeptide sequence connected to the linker;d. a hinge polypeptide sequence;e. a CH2 polypeptide sequence;f. a CH3 polypeptide sequence; andg. a tailpiece polypeptide sequence.

[0100] In other aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:a. an antigen originating from an animal in need of non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen; b. an optional linker connected to the antigen polypeptide sequence;c. a CHI polypeptide sequence connected to the linker;d. a hinge polypeptide sequence;e. a CH2 polypeptide sequence;f. a CH3 polypeptide sequence; andg. a tailpiece polypeptide sequence andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0101] In aspects, the antigen originates from an animal in need of non-surgical sterilization or castration. In further aspects, an antigen described herein comprises a polypeptide from any of but not limited to gonadotropin-releasing hormone (GnRH) and zona pellucida proteins ZP1, ZP2, ZP3, or ZP4.

[0102] In other aspects, the disclosure further provides for fusion proteins wherein the antigen comprises gonadotropin-releasing hormone, or zona pellucida protein or a fragment or variant thereof.

[0103] In aspects, fusion proteins described herein comprise polypeptide chains, wherein each polypeptide chain comprises:a. an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;b. an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; andc. a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer, optionally form an oligomer, or are capable of forming an oligomer.

[0104] In embodiments, fusion proteins described herein comprise polypeptide chains, wherein each polypeptide chain comprises:a. an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;b. an optional linker connected to the antigen polypeptide sequence;c. a CHI polypeptide sequence connected to the linker;d. a hinge polypeptide sequence;e. a CH2 polypeptide sequence;f. a CH3 polypeptide sequence; andg. a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer.

[0105] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein the polypeptide chain comprises (Formula II):A (Antigen) - B (optional linker) C(CH1) - D (hinge) - E (CH2) -F (CH3) - G (tailpiece) wherein,A comprises an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or a zona pellucida protein antigen;B is optional and if present comprises an amino acid sequence at least 90% identity to SEQ ID NO: 2 or a glycine and / or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO:6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO:11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0106] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen; B is optional and if present comprises an amino acid sequence at least 95% identity to SEQ ID NO: 2 or a glycine and / or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO:6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO:11;E comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

[0107] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen; B is optional and if present an amino acid sequence 100% identical to SEQ ID NO: 2;C comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence 100% identical to SEQ ID NO:6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO:11;E comprises an amino acid sequence 100% Identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17; F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and G comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0108] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell mediated antibody titer in an animal relative to a titer from an administered therapeutic monoclonal neutralizing antibody for a gonadotropin-releasing hormone antigen, or zona pellucida protein antigen by about 0.2 fold or more, about 0.5 fold or more, about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about 0.2 fold to about 3 fold, about 0.5 fold to about 5 fold, about 1 fold to about 10 fold, about 2fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In aspects, the disclosure provides for fusion proteins, oligomers, multimers, hexamers, or compositions described herein that can increase an immunes response in an animal in need of non-surgical sterilization or castration.

[0109] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein are used for generation of an antibody immune response that causes non-surgical sterilization or castration. In other aspects, fusion proteins described herein are used for the generation of an immune response in a subject animal that mediates a non-surgical sterilization or castration in an animal. In other aspects, fusion proteins described herein comprise 6, 8, 10, or 12 individual polypeptide chains. In aspects, the fusion protein forms a cyclic pentamer comprising 10 individual polypeptide chains, forms a cyclic hexamer comprising 12 individual polypeptide chains, or forms a cyclic heptamer comprising 14 individual polypeptide chains.

[0110] In aspects, the disclosure provides for fusion proteins comprising an antigen including a gonadotropin-releasing hormone antigen, or zona pellucida protein antigen, wherein the fusion protein increases an immune response in an animal relative to the antigen alone and / or wherein the fusion protein increases a B cell response in an animal relative to the antigen alone. In aspects, the fusion proteins are used as non-surgical sterilization or castration in animals.

[0111] The disclosure further provides for fusion proteins wherein the immune response causes non-surgical sterilization or castration in a subject animal. In aspects, fusion proteins described herein create an immune response wherein the immune response inhibits the sexual maturation of an animal by blocking or partially blocking the tropic effects of gonadotropin-releasing hormone wherein the animal fails to attain or maintain sexual maturity or sexual viability, or an immune response to zona pellucida proteins on oocytes thereby preventing fertilization of oocytes.

[0112] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

[0113] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region; andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0114] In aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

[0115] In other aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(d) a tailpiece polypeptide sequence andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0116] In aspects, an antigen originating from an animal for non-surgical sterilization or castration comprising a polypeptide from any of but not limited to a gonadotropin-releasing hormone antigen, or a zona pellucida protein antigen.

[0117] In aspects, polypeptide chains described herein form oligomers or are capable of forming oligomers. In other aspects, two individual polypeptide chains are cross-linked with each other and form a monomer subunit. In aspects, multiple monomer subunits form an oligomeric, pentameric, hexameric, or heptameric protein structure.

[0118] In aspects, animals immunized with fusion proteins described herein increase a B cell response and / or antibody titer to the antigen in an animal relative to an animal immunized with anon-fusion protein antigen sequence. In further aspects, an immunized with hexameric proteins described herein increase a B cell response and / or antibody titer to the antigen in animal relative to an animal immunized with a non-fusion protein antigen sequence.

[0119] In other aspects, the disclosure further provides for fusion proteins wherein the gonadotropin-releasing hormone antigen, or zona pellucida protein antigen comprises an antigen from an animal for non-surgical castration or sterilization.

[0120] In aspects, fusion proteins described herein comprise polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer, optionally form an oligomer, or are capable of forming an oligomer.

[0121] In embodiments, fusion proteins described herein comprise polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer.

[0122] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein the polypeptide chain comprises (Formula II):A (Antigen) - B (optional linker) - C(CH1) - D (hinge) - E (CH2) -F (CH3) - G (tailpiece) wherein,A comprises an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;B is optional and if present comprises an amino acid sequence at least 90% identity to SEQ ID NO: 2 or a glycine and I or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 ;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0123] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;B is optional and if present comprises an amino acid sequence at least 95% identity to SEQ ID NO: 2 or a glycine and I or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11 ;E comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

[0124] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen originating from an animal for non-surgical sterilization or castration, a gonadotropin-releasing hormone, or zona pellucida protein antigen;B is optional and if present an amino acid sequence 100% identical to SEQ ID NO: 2;C comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence 100% Identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0125] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell mediated antibody titer in an animal relative to a titer from an administered therapeutic monoclonal neutralizing antibody for an antigen comprising a gonadotropin-releasing hormone antigen, or zona pellucida protein by about 0.2 fold or more, about 0.5 fold or more, about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about 0.2 fold to about 3 fold, about 0.5 fold to about 5 fold, about 1 fold to about 10 fold, about 2 fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In aspects, the disclosure provides for fusion proteins, oligomers, multimers, hexamers, that cause an immune response that inhibits an animal in need of nonsurgical sterilization or castration from attaining or maintaining sexual maturity or sexual viability, or an immune response to zona pellucida proteins on oocytes thereby preventing fertilization of oocytes.

[0126] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein are used for generation of an antibody immune response that inhibits an animal in need of nonsurgical sterilization or castration from attaining or maintaining sexual maturity or sexual viability, or an immune response to zona pellucida proteins on oocytes thereby preventing fertilization of oocytes. In other aspects, fusion proteins described herein are used for the generation of an immune response that inhibits an animal in need of nonsurgical sterilization or castration from attaining or maintaining sexual maturity or sexual viability, or an immune response to zona pellucida proteins on oocytes thereby preventing fertilization of oocytes. In other aspects, fusion proteins described herein comprise 6, 8, 10, or 12 individual polypeptide chains. In aspects, the fusion protein forms a cyclic pentamer comprising 10 individual polypeptide chains, forms a cyclic hexamer comprising 12 individual polypeptide chains, or forms a cyclic heptamer comprising 14 individual polypeptide chains.

[0127] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from or present in Table A or Table B;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region; andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0128] In aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from or present in Table A or Table B;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

[0129] In other aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from or present in Table A or Table B;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(d) a tailpiece polypeptide sequence andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0130] In aspects, the disclosure provides for fusion proteins comprising polypeptide chains, wherein the polypeptide chain comprises (Formula II):A (Antigen) - B (optional linker) C (CHI) - D (hinge) - E (CH2) -F (CH3) - G (tailpiece) wherein,A an antigen originating from any of those in Table A or Table B;B is optional and if present comprises an amino acid sequence at least 90% identity to SEQ ID NO: 2 or a glycine and I or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

[0131] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen originating from any of those in Table A or Table B;B is optional and if present comprises an amino acid sequence at least 95% identity to SEQ ID NO: 2 or a glycine and I or serine rich linker of 2 to 100 amino acids in length;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

[0132] In further aspects, polypeptide chains A - G of Formula II comprise:A comprises an antigen originating from any of those in Table A or Table B;B is optional and if present an amino acid sequence 100% identical to SEQ ID NO: 2; C comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

[0133] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell mediated antibody titer in an animal relative to a titer from an administered therapeutic monoclonal neutralizing antibody for an antigen originating from an antigen from any of those in Table A or Table B by about 0.2 fold or more, about 0.5 fold or more, about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about 0.2 fold to about 3 fold, about 0.5 fold to about 5 fold, about 1 fold to about 10 fold, about 2 fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In aspects,the disclosure provides for fusion proteins, oligomers, multimers, hexamers, or compositions described herein that can increase an immunes response in an animal that neutralizes the antigen.

[0134] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein are used for generation of an antibody immune response that neutralize an antigen of Table A or Table B. In other aspects, fusion proteins described herein are used for the generation of an immune response in a subject canine or feline that neutralize an antigen. In other aspects, fusion proteins described herein comprise 6, 8, 10, or 12 individual polypeptide chains. In aspects, the fusion protein forms a cyclic pentamer comprising 10 individual polypeptide chains, forms a cyclic hexamer comprising 12 individual polypeptide chains, or forms a cyclic heptamer comprising 14 individual polypeptide chains.

[0135] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein are used for the generation of an antibody immune response that neutralizes an antigen. In other aspects, fusion proteins and compositions described here are used for therapeutic immunization of an animal. In other aspects, hexameric proteins and compositions thereof described herein are used for prophylactic immunization of animals or for therapeutic treatment of an animal.

[0136] The disclosure provides for methods of preventing, or inhibiting, a disease In other aspects, fusion proteins, oligomers, multimers, hexamers, or compositions comprise one or more polypeptide chains from Table C or Table 19.

[0137] The disclosure further provides for methods of neutralizing an antigen by generating an antibody immune response, for example, by inducing the selection of the neutralizing antibody variable sequences which bind to an antigen, comprising administering fusion proteins, oligomers, multimers, hexamers, or compositions described herein to a canine or feline. In aspects, the administered fusion proteins, oligomers, multimers, hexamers, or compositions described herein increases B cell response relative to an antigen alone. In other aspects, the antibody is identified by isolating an antibody from blood, or by isolating a B cell producing an antibody from a secondary lymphoid organ comprising spleen, lymph node, Peyer’s patch, nasal associated lymphoid tissue, adenoid, tonsil, bronchus associated lymphoid tissue, or isolated lymphoid follicle.

[0138] The disclosure further provides for methods for inducing a neutralizing antibody immune response to an antigen from Table A or Table B comprising administering a composition comprising fusion proteins, oligomers, multimers, or hexamers described herein and an adjuvant described herein to a subject animal, wherein the composition administered to the animal increases a B cell response to an antigen from Table A or Table B relative to antigen alone and wherein the increased B cell response leads to the neutralization of the antigen in the subject animal.

[0139] The disclosure further provides for methods for inducing a neutralizing antibody immune response to an antigen from Table A or Table B comprising administering a composition comprising fusion proteins, oligomers, multimers, or hexamers described herein and an adjuvant described herein to a subject animal, wherein the composition administered to the animal increases a B cell response to an antigen from Table A or Table B in an animal relative to antigen alone and wherein the increased B cell response leads to the neutralization of the antigen in the subject animal.

[0140] In another aspect, the disclosure further provides for methods for generating a neutralizing antibody immune response to an antigen from Table A or Table B comprising administering fusion proteins, oligomers, multimers, or hexamers described herein described herein together with an adjuvant described herein to an animal, wherein the composition comprising the hexamer and adjuvant administered to the animal increase a B cell response to the antigen originating from a canine or feline infectious disease pathogen in an animal relative to the antigen originating from a canine or feline infectious disease pathogen alone and wherein the increased B cell response leads to the neutralization of the antigen in the subject animal.

[0141] The disclosure provides for compositions comprising fusion proteins, fusion polypeptides, oligomers, multimers, and hexamers described herein. In aspects, compositions described herein further comprise at least one adjuvant or combination of adjuvants.

[0142] In aspects, polypeptide chains described herein comprise an Antigen-CH1-Hinge-CH2-CH3 -Tailpiece wherein the respective sequences for each component are selected for and described in Table 19. In other embodiments, the polypeptide chain comprises, in N-terminus to C-terminus order, an Antigen-CH1-Hinge-CH2-CH3-Tailpiece wherein the respective sequences for each component are selected for and described in Table 19.

[0143] In aspects, fusion proteins and compositions described herein are used for the generation of an antibody immune response that alleviates pain in a subject animal by neutralizing pain mediator polypeptides, thus reducing pain. In further aspects, hexameric proteins and compositions thereof described herein are used for generation of a neutralizing antibody immune response to pain mediator polypeptides. In other aspects, fusion proteins and compositions described here are used for therapeutic vaccination or immunization of companion animals, for example, cats and dogs. In other aspects, hexameric proteins and compositions thereof described herein are used for therapeutic vaccination or immunization of companion animals, for example, cats and dogs.

[0144] In an aspect, one or more adjuvants for use with fusion polypeptide, fusion proteins, oligomers, multimers, hexamers, or compositions described herein include, for example, Freund's Complete Adjuvant and Freund's Incomplete Adjuvant, MF59, AS03, aluminum hydroxide, aluminum phosphate, QS-21, Quil A, AS01, AS04, MPLA, CpG ODN 1018, CpG ODN 7909,IC31, hniquimod (R837), Resiquimod, 3M-052, 2’,3’-cGAMP, 3’,3’-cGAMP, c-di-GMP, c-di-AMP, CARBOPOL, CARBOPOL® 934, CARBOPOL® 941 NF, Mn2+, MnJ, MnARK, and / or nanoMn. In aspects, compositions described herein are formulated as vaccine compositions. In aspects, one or more adjuvants for use with fusion proteins, oligomers, multimers, hexamers, or compositions described herein include, for example, consisting of Quil A, CARBOPOL, CARBOPOL® 934, CARBOPOL® 941 NF, aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate, and water and oil-based emulsions.

[0145] In aspects, one or more adjuvants for use with fusion proteins, oligomers, multimers, hexamers, or compositions described herein include, for example, Quil A, CARBOPOL, CARBOPOL® 934, and / or CARBOPOL® 941 NF.

[0146] In aspects, compositions described herein may include an adjuvant in an amount of from about 50 pg to 1000 pg / dose, from about 50 pg to 150 pg / dose from about 100 pg to 500 pg / dose, from about 100 pg to 300 pg / dose, about 100 pg / dose, about 200 pg / dose, about 300 pg / dose, about 500 pg / dose, or more than 600 pg / dose.

[0147] In other aspects, compositions described herein may include fusion proteins, oligomers, multimers, and hexamers described herein in an amount of from about 5 pg per kg per dose to about 10 pg per kg per dose, from about 9 pg per kg per dose to 50 pg per kg per dose, from about 9 pg per kg per dose to about 30 pg per kg per dose, about 9 pg per kg per dose, about 18 pg per kg per dose, about 25 pg per kg per dose, about 45 pg per kg per dose, or more than about 55 pg per kg per dose.

[0148] In further aspects, compositions described herein may include an adjuvant in an amount of from about 50 pg to about 1000 pg / dose, 50 pg to about 150 pg / dose from about 100 pg to about 500 pg / dose, from about 100 pg to about 300 pg / dose, about 100 pg / dose, about 200 pg / dose, about 300 pg / dose, about 500 pg / dose, or more than 600 pg / dose and fusion proteins, oligomers, multimers, and hexamers described herein in an amount of from about 50 pg to 1000 pg / dose, from about 100 pg to 500 pg / dose, from about 100 pg to 300 pg / dose, from about 100 pg to 400 pg / dose, about 100 pg / dose, about 200 pg / dose, about 300 pg / dose, about 500 pg / dose, or more than 600 pg / dose.

[0149] In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell response in an animal relative to an antigen (single antigen; non-hexameric form) alone about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about .2 fold to about 3 fold, about .5 fold to about 5 fold, about 1 fold to about 10 fold, about 2 fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In an aspect, the animal is a canine or feline. In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell response in ananimal relative to an antigen alone about 10 fold to about 50 fold, about 10 fold to about 100 fold, about 10 fold to about 500 fold, about 10 fold to about 1,000 fold, about 50 fold to about 100 fold, about 50 fold to about 500 fold, about 50 fold to about 1,000 fold, about 100 fold to about 500 fold, about 100 fold to about 1,000 fold, or about 500 fold to about 1,000 fold.

[0150] In aspects, polypeptide chains described herein and polypeptide chains of Formula I or Formula II form oligomers or are capable of forming oligomers. In aspects, fusion proteins, oligomers, multimers, hexamers, or compositions described herein increase a B cell response in an animal relative to an antigen (single antigen; non-hexameric form) alone about 1 fold or more, about 1.5 fold or more, about 2 fold or more, about 5 fold or more, about 10 fold or more, about .2 fold to about 3 fold, about .5 fold to about 5 fold, about 1 fold to about 10 fold, about 2 fold to about 10 fold, about 5 fold to about 50 fold, or about 50 fold to about 500 fold. In an aspect, the animal is a canine or feline.

[0151] In aspects, fusion polypeptide, fusion proteins, oligomers, multimers, hexamers, or compositions described herein are administered in an amount of from about 5 pg per kg per dose to about 10 pg per kg per dose, from about 9 pg per kg per dose to about 50 pg per kg per dose, from about 9 pg per kg per dose to about 30 pg per kg per dose, about 9 pg per kg per dose, about 18 pg per kg per dose, about 25 pg per kg per dose, about 45 pg per kg per dose, or more than 53 pg per kg per dose.

[0152] In aspects, the animal is a companion animal. In other aspects, the animal is a mouse, rabbit, rat, Syrian hamster, Armenian hamster, canine, feline, equine, or human. In preferred aspects, the animal is canine or feline.

[0153] In aspects, the disclosure provides for methods of discovering an antibody variable sequence comprising administering fusion proteins, oligomers, multimers, hexamers, or compositions described herein to an animal and wherein the administered fusion proteins, oligomers, multimers, hexamers, or compositions described herein increases the B cell response relative to antigen alone.

[0154] The disclosure provides for compositions comprising fusion proteins, oligomers, multimers, and hexamers described herein. In aspects, compositions described herein are formulated as vaccine compositions. In aspects, compositions described herein further comprise at least one adjuvant or combination of adjuvants. In aspects, compositions described herein exhibit stability for period of time of at least 24 weeks or at least 52 weeks at 2-8°C.

[0155] Nucleic acids encoding fusion proteins, fusion polypeptides, oligomers, multimers, and hexamers described herein are also provided. Cells comprising nucleic acid sequences described herein are further provided.

[0156] Nucleic acid constructs for the expression of fusion proteins, oligomers, multimers, and hexamers described herein are also provided, wherein the nucleic acid construct comprises a DNA or RNA. In aspects, the nucleic acid construct is a self-amplifying RNA. In further aspects, the nucleic acid expression construct encodes a conjugate protein containing a secretion leader sequence. In additional aspects, the protein is expressed under a viral promoter.

[0157] The disclosure further provides for compositions comprising a nucleic acid expression construct is incorporated in a lipid nanoparticle. In aspects, the nucleic acid expression construct is incorporated into a viral particle.

[0158] In aspects, the disclosure provides for methods of discovering an antibody variable sequence comprising administering fusion proteins, oligomers, multimers, hexamers, or compositions described herein to an animal and wherein the administered fusion proteins, oligomers, multimers, hexamers, or compositions described herein increases the B cell response relative to the antigen alone.BRIEF DESCRIPTION OF THE DRAWINGS

[0159] FIG. 1A depicts an exemplary arrangement of the of the IL- 10 Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0160] FIG. IB depicts an exemplary arrangement of the of the NGF Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0161] FIG. 1C depicts an exemplary arrangement of the of the pain related polypeptide Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0162] FIG. ID depicts an exemplary arrangement of the of the TNF or other pro-inflammatory cytokine Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0163] FIG. IE depicts an exemplary arrangement of the of the IL-5 Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0164] FIG. IF depicts an exemplary arrangement of the of the IL- 13 Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0165] FIG. 1G depicts an exemplary arrangement of the of the Polypetide Mediator of a Dermatological Condition Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0166] FIG. 1H depicts an exemplary arrangement of the infectious disease Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0167] FIG. II depicts an exemplary arrangement of the of the gonadotropin releasing hormone or a zona pellucida polypeptide antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0168] FIG. 1 J depicts an exemplary arrangement of the of the polypeptide from Table A or Table B Antigen-IgG fusion protein as a hexamer, wherein the cysteine substitution at residue 309 creates a disulfide bond between monomer subunits. Disulfide links have been simplified so that the links appears as straight solid lines.

[0169] FIG. 2A depicts an exemplary organization of a representative fusion protein including an amino-terminal antigen, a linker region, an immunoglobulin constant homology 1 domain (CHI), a hinge, an immunoglobulin constant homology 2 domain (CH2), a immunoglobulin constant homology 2 domain (CH3), and a carboxy-terminal immunoglobulin M tail piece. In this depiction, the CH2 domain of the human IgG contains a L309C substitution, whereas the canine IgG-b contains a G309C substitution.

[0170] FIG. 2B depicts a representative monomeric subunit containing two fusion proteins. The fusion proteins self-assemble into the monomeric subunit (monomer of two polypeptide chains). The location of residue 309 is indicated. Disulfide links are formed between the individual peptide chains in the hinge region as indicated by the S-S between the peptides.

[0171] FIG. 2C depicts an exemplary arrangement of an the Antigen-IgG fusion protein as a hexamer (six monomer subunits, each monomeric subunit including two polypeptide chains), wherein the cysteine substitution at residue 309 creates a disulfide bond between subunits. A single dimeric subunit is contained within the dashed box. Disulfide links have been simplified so that the links appears as straight solid lines.

[0172] FIG. 2D depicts an exemplary space filling model of a representative hexamer wherein an individual monomeric subunit (monomer comprised of two polypeptide chains) is circled with a dotted line.

[0173] FIG. 3A depicts an exemplary chromatogram from a size exclusion chromatographic separation, wherein a standard IgG is separated. The IgG elutes at a peak of 4.087 minutes corresponding to a size of 150 kDa, and aggregated IgG elutes at a peak of 3.6 minutes.

[0174] FIG. 3B depicts an exemplary chromatogram from an size exclusion chromatographic separation, wherein a purified IgG hexamer mixture is separated. The hexamer elutes at peak of 3.073 minutes whereas oligomers that are less than the full hexamer (subhexamer) elute later at a peak of 3.823 minutes.

[0175] FIG. 4 depicts representative results of immunizations in dogs with a canine IL- 10 hexamer polypeptide, self-amplifying RNA (saRNA) encoding IL- 10, saRNA encoding IL- 10 hexamers. Show on the left is a serum dilution in an Enzyme Linked ImmunoSorbent Assay (ELISA) assay analyzing IC50. Shown on the right is a serum neutralization assay using ELISA.

[0176] FIG. 5 depicts an exemplary organization of the saRNA for expression of the hexamer. The hexamer encoding sequence is located in the region marked “GOI”, wherein GOI indicates a sequence encoding a Neuron Growth Factor (NGF) polypeptide or an Interleukin 10 (IL- 10) polypeptide. The 5’ untranslated region is marked “5’ UTR”. Segments marked “nsPl” through “nsP4” indicate non-structural proteins 1 through 4. The site marked “26S” indicates the 26S ribosome promoter. 3’ UTR indicates the 3’ untranslated region, which contains a terminator and polyadenylation signal sequence.

[0177] FIG. 6A depicts an exemplary dilution ELISA assay results of mice immunized with canine IL- 10 in the first experiment. Mice were immunized with saRNA encoding canine IL- 10 hexamers on day 0, and 14, then with saRNA encoding IL-10 on day 42. A total of four mice were immunized: 1, 2, 3, and 4. Mouse 5 received no canine IL- 10 antigen. Assayed serum was drawn on days 27 and 49 as indicated by “D27’ and “D49” respectively. O.D. represents the optical density of an assay well.

[0178] FIG. 6B depicts an exemplary dilution ELISA assay results of mice immunized with canine IL-10. Mice were immunized with saRNA encoding canine IL- 10 hexamers on day 0, and 14, then with saRNA encoding IL-10 on days 28 and 42. A total of four mice were immunized: 1, 2, 3, and 4. Assayed serum was from draws on day 27 (D27) and day 49 (D49) by dilution ELISA.

[0179] FIG. 6C depicts an exemplary dilution ELISA assay results for mice immunized with canine IL-10. Mice were immunized with saRNA encoding canine IL- 10 hexamers on day 0, and14, then with saRNA encoding IL-10 on days 28 and 42. A total of four mice were immunized:5, 6, 7, and 8. Assayed serum was from draws on day 27 (D27) and day 49 (D49) by dilution ELISA.

[0180] FIG. 7 depicts an exemplary dilution ELISA assay result of cats immunized with saRNA expressing feline IL-10 (D145K) (group 1, cats 1 and 2) , or purified feline IL-10 (D145K) hexamers (Group 2, cats 3 and 4). Assayed serum was drawn on days minus 1 (“-1”, the day prior to vaccination or immunization); and 20, 42, and 63.

[0181] FIG. 8A depicts an exemplary dilution ELISA assay from dogs immunized with saRNA expressing beta-nerve growth factor ( bNGF) hexamers. Four dogs were immunized according to the schedule of Table 11 and the dilution ELISA assay from the day 63 serum draw is shown.

[0182] FIGs. 8B and 8C depict an exemplary neutralization ELISA assays for individual dogs from FIG. 7 A for each of serum draws on the day before vaccination or immunization; 20, 41, and 63 days after first vaccination or immunization. pAb represents the concentration of antibody purified from the subject dog’s serum used in the assay. The figures represent the immunoglobulins to bNGF in the day 63 serum draw.

[0183] FIG. 9A depicts an exemplary dilution ELISA assay from cats immunized with saRNA expressing feline NGF hexamers. Four cats were immunized according to the schedule of Table 12.The assayed serum draw was taken 82 days after the initial immunization.

[0184] FIG. 9B depicts an exemplary neutralization ELISA assays for cats immunized with feline NGF hexamers from FIG. 8A. The assayed serum draw was taken 82 days after the initial immunization. Neg Ctrl is a cat that received no NGF immunogen.

[0185] FIG. 10 depicts an exemplary dilution ELISA assay from mice immunized with canine / feline hexameric NGF. The polypeptide sequence for canine and feline NGF antigen is identical.

[0186] FIG. 11 A depicts an exemplary analytical size exclusion chromatography of protein standards thyroglobulin, immunoglobulin, bovine serum albumin, myoglobin, and uracil.

[0187] FIG. 11B depicts an exemplary analytical size exclusion chromatography of feline IL-10 (D145K) immunogen hexamer (SEQ ID NO: 63).

[0188] FIG. 11C depicts an exemplary analytical size exclusion chromatography of feline IL-10 immunogen hexamer (SEQ ID NO: 61).

[0189] FIG. 11D depicts an exemplary analytical size exclusion chromatography of canine IL-10 hexamer (SEQ ID NO: 59).

[0190] FIG. HE depicts an exemplary analytical size exclusion chromatography of feline IL-5 GG Dimer hlgGl hexamer immunogen (SEQ ID NO: 97).

[0191] FIG. 11F depicts an exemplary analytical size exclusion chromatography of feline IL-5 E13Q GG Dimer hlgGl hexamer immunogen (SEQ ID NO: 98).

[0192] FIG. 11G depicts an exemplary analytical size exclusion chromatography of a feline IL-4 hlgGl hexamer immunogen (SEQ ID NO: 113).

[0193] FIG. 11H depicts an exemplary analytical size exclusion chromatography of canine IL-13 hlgGl hexamer immunogen (SEQ ID NO: 92).

[0194] FIG. Ill depicts an exemplary analytical size exclusion chromatography of feline IL- 13 hlgGl hexamer immunogen (SEQ ID NO: 94)

[0195] FIG. 12A depicts an exemplary immune response in dogs that have been immunized with canine interleukin 13 (cIL-13) hexamers. Four dogs were immunized subcutaneously with purified polypeptide on day 0, and 42 using Quil A adjuvant, and with saRNA encoding canine IL-13 hexamers on day 21. Assayed serum was drawn on days 7, 20, 41, and 63 and assayed by dilution ELISA assay.

[0196] FIGs. 12B and 12C depict an exemplary neutralization ELISA assay of the four dogs immunized with canine IL- 13 from FIG. 12 A. Each dog is plotted individually with the neutralization plot for each serum draw. Assayed serum draws were taken at time points relative to the initial vaccination at days minus 1 (“-1”, the day prior to vaccination); and days 20, 41, and 63 after the vaccination.

[0197] FIG. 13A depicts an exemplary dilution ELISA assay of mice immunized with canine Interleukin- 13 (cIL-13). Mice received saRNA encoding canine IL13 hexamers on days 0 and 14, then saRNA encoding canine IL-13 on day 42. Assayed serum was drawn on day 27, and day 49. A total of four mice were immunized: 1, 2, 3, and 4, while the control mouse received no canine IL-13 antigen.

[0198] FIG. 13B and 13C depict an exemplary neutralization ELISA for the four mice immunized with canine IL- 13 in the same protocol as FIG. 13 A. Each mouse is plotted individually with neutralization curves for each serum draw on day 28 and day 49.

[0199] FIG. 14A depicts an exemplary dilution ELISA assay from cats, where flL-5 is feline Interleukin 5. Cats were immunized with saRNA expressing tandem feline IL5 hexamers (IL5-GG). Four cats were immunized according to the schedule of Table 14. D-7, D20, D41, and D63 refer to days relative to vaccination: 7 days before vaccination; 20, 41, and 63 days after vaccination.

[0200] FIG. 14B depicts an exemplary neutralization ELISA assay for serum draws from individual cats immunized with saRNA expressing tandem IL5 feline 11-5 hexamers (IL5-GG).

[0201] FIG. 15A depicts exemplary dilution assays of serum drawn from cats immunized with either saRNA expressing feline IL5-GG E13Q or feline IL5-GG E13Q hexamer. Serum was drawn on day 63.

[0202] FIG. 15B depicts exemplary neutralization ELISA assays for serum drawn from the four cats immunized with feline IL5-GG-E13Q.

[0203] FIG. 16 depicts an exemplary dilution ELISA assay for serum drawn from four mice immunized with feline IL5-GG E13Q hexamers and a negative control mouse.

[0204] FIG. 17 depicts an exemplary dilution ELISA assay for serum drawn from cats immunized with Feline IL- 13 Hexamer.

[0205] FIG. 18A depicts an exemplary analytical size exclusion chromatography of protein standards thyroglobulin, immunoglobulin, bovine serum albumin, myoglobin, and uracil.

[0206] FIG. 18B depicts an exemplary analytical size exclusion chromatography of feline IL-5 GG Dimer hlgGl hexamer immunogen (SEQ ID NO: 97).

[0207] FIG. 18C depicts an exemplary analytical size exclusion chromatography of feline IL-5 E13Q GG Dimer hlgGl hexamer immunogen (SEQ ID NO: 98).

[0208] FIG. 18D depicts an exemplary analytical size exclusion chromatography of a feline IL-4 hlgGl hexamer immunogen (SEQ ID NO: 113).

[0209] FIG. 18E depicts an exemplary analytical size exclusion chromatography of canine IL- 13 hlgGl hexamer immunogen (SEQ ID NO: 92).

[0210] FIG. 18F depicts an exemplary analytical size exclusion chromatography of feline IL-13 hlgGl hexamer immunogen (SEQ ID NO: 94).

[0211] FIG. 19A shows an exemplary depiction of the linear arrangement of the fusion protein wherein three CD40L domains are covalently linked by peptide linkers, and wherein the linked CD40L domains are covalently linked to an Fc domain polypeptide.

[0212] FIG. 19B shows an exemplary depiction of the arrangement of the dimerized single chain CD40L-Fc fusion protein.

[0213] FIG. 19C shows an exemplary depiction of the options within the fusion protein for the linkers between the CD40L subunits, and optional substitution at position 193 of CD40L.DETAILED DESCRIPTION

[0214] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that the present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are variations and modifications of the present disclosure, which are encompassed within the scope of the present disclosure.

[0215] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Although various features of the disclosure can be described in the context of a single embodiment, the features can also be provided separately orin any suitable combination. Conversely, although the present disclosure can be described herein in the context of separate embodiments for clarity, the present disclosure can also be implemented in a single embodiment.

[0216] The following terms supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0217] Reference to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures.

[0218] As used in this specification and the claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0219] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art.Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. In another example, the amount “about 10” includes 10 and any amounts from 9 to 11. In yet another example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. Alternatively, particularly with respect to biological systems or processes, the term “about” can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0220] A “therapeutically-effective amount” or “therapeutically-effective dose” refers to an amount or dose effective, for periods of time necessary, to achieve a desired therapeutic result. The amount can vary according to factors such as the disease state, age, sex, and weight of theindividual, and the ability of the inventive nucleic acid sequences to elicit a desired response in the individual.

[0221] “Polynucleotide” or “oligonucleotide” refers to a polymeric form of nucleotides or nucleic acids of any length, either ribonucleotides or deoxyribonucleotides. This term refers only to the primary structure of the molecule. Thus, this term includes double and single stranded deoxyribonucleic acid (DNA), triplex DNA, as well as double and single stranded ribonucleic acid (RNA). It also includes modified, for example, by methylation and / or by capping, and unmodified forms of the polynucleotide. The term is also meant to include molecules that include non-naturally occurring or synthetic nucleotides as well as nucleotide analogs.

[0222] Unless otherwise stated, nucleic acid sequences in the text of this specification are given, when read from left to right, in the 5' to 3' direction.

[0223] The terms “transfection,” “transformation,” “nucleofection,” or “transduction” as used herein refer to the introduction of one or more exogenous polynucleotides into a host cell or organism by using physical, chemical, and / or electrical methods. The nucleic acid sequences and vectors disclosed herein can be introduced into a cell or organism by any such methods, including, for example, by electroporation, calcium phosphate co-precipitation, strontium phosphate DNA coprecipitation, liposome mediated-transfection, lipid nanoparticle mediated transfection, DEAE dextran mediated-transfection, polycationic mediated-transfection, tungsten particle-facilitated microparticle bombardment, viral, and / or non-viral mediated transfection. In some cases, the method of introducing nucleic acids into the cell or organism involves the use of viral, retroviral, lentiviral, or transposon, or transposable element-mediated vectors.

[0224] “Polypeptide,” “peptide,” “protein,” and their grammatical equivalents as used herein refer to a polymer of amino acid residues. The polypeptide can optionally include glycosylation or other modifications typical for a given protein in a given cellular environment. Polypeptides and proteins disclosed herein (including functional fragments and functional variants thereof can comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such synthetic amino acids are known in the art, and include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, P-phenylserine P-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N’-benzyl-N’-methyl-lysine, N’,N’-dibenzyl-lysine, 6-hydroxylysine, ornithine, a-aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a-aminocycloheptane carboxylic acid, a-(2-amino-2-norbomane)-carboxylic acid, a,y-diaminobutyric acid, a,P-diaminopropionic acid,homophenylalanine, and a-tert-butylglycine. The present disclosure further contemplates that expression of polypeptides or proteins described herein in an engineered cell can be associated with post-translational modifications of one or more amino acids of the polypeptide or protein. Nonlimiting examples of post-translational modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N-linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitylation, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, famesylation, geranylation, glypiation, lipoylation and iodination.

[0225] The term “conservative amino acid substitution” or “conservative mutation” refers to the replacement of one amino acid by another amino acid with a common property as described herein. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz, G. E. and Schirmer, R. H., Principles of Protein Structure, Springer- Verlag, New York (1979)), the content of which is incorporated by reference in its entirety. According to such analyses, groups of amino acids can be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure (Schulz, G. E. and Schirmer, R. H., supra). Examples of conservative substitutions include amino acid substitutions of amino acids within the sub-groups below, for example, lysine for arginine and vice versa such that a positive charge can be maintained; glutamic acid for aspartic acid and vice versa such that a negative charge can be maintained; serine for threonine such that a free -OH can be maintained; and glutamine for asparagine such that a free -NH2 can be maintained. An amino acid substitution may include but is not limited to the replacement of an amino acid in a polypeptide, protein, antibody, variable region, or constant region described herein with another amino acid. Exemplary substitutions are shown below. Amino acid substitutions may be introduced into an the polypeptide, fusion protein, protein, monomer unit, dimer unit, hexamer protein unit.Table 1: Exemplary substitutions

[0226] Conservative substitutions may comprise those, which are described by Dayhoff in “The Atlas of Protein Sequence and Structure. Vol. 5”, Natl. Biomedical Research, the contents of which are incorporated by reference in their entirety. Amino acids may be grouped according to common side-chain properties:(1) hydrophobic: Norleucine, Met, Ala, Vai, Leu, He;(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;(3) acidic: Asp, Glu;(4) basic: His, Lys, Arg;(5) residues that influence chain orientation: Gly, Pro;(6) aromatic: Trp, Tyr, Phe.

[0227] Conservative substitutions may entail exchanging a member of one of these classes with a member of the same class. Non-conservative substitutions will entail exchanging a member of one of these classes with another class.

[0228] Conservative substitutions may be made in accordance with the below. Methods for predicting tolerance to protein modification may be found in, for example, Guo et al., Proc. Natl. Acad. Sci., USA, 101(25):9205-9210 (2004), the contents of which are incorporated by reference in their entirety.Table 2: Representative Conservative Amino Acid substitutionConservative Amino Acid SubstitutionsAmino Acid Substitutions (others are known in the art)Ala Ser, Gly, CysArg Lys, Gin, HisAsn Gin, His, Glu, AspAsp Glu, Asn, GinCys Ser, Met, ThrGin Asn, Lys, Glu, Asp, ArgGlu Asp, Asn, GinGly Pro, Ala, SerHis Asn, Gin, LysHe Leu, Vai, Met, AlaLeu He, Vai, Met, AlaLys Arg, Gin, HisMet Leu, He, Vai, Ala, PhePhe Met, Leu, Tyr, Trp, HisSer Thr, Cys, AlaThr Ser, Vai, AlaTrp Tyr, PheTyr Trp, Phe, HisVai He, Leu, Met, Ala, ThrTable 3: Other epresentative Amino Acid substitutions may be identified in the below Original Residue Exemplary SubstitutionsAla (A) Vai; Leu; HeArg(R) Lys; Gin; AsnAsn (N) Gin; His; Asp; Lys; ArgAsp (D) Glu; AsnCys (C) Ser; AlaGln(Q) Asn; GluGlu (E) Asp; GinGly (G) AlaHis (H) Asn; Gin; Lys; ArgHe (I) Leu; Vai; Met; Ala; Phe; NorleucineLeu (L) Norleucine; He; Vai; Met; Ala; PheLys (K) Arg; Gin; AsnMet (M) Leu; Phe; HePhe (F) Trp; Leu; Vai; He; Ala; TyrPro (P) AlaSer (S) ThrThr (T) Vai; SerTrp (W) Tyr; PheTyr (Y) Trp; Phe; Thr; SerVai (V) He; Leu; Met; Phe; Ala; Norleucine

[0229] In some embodiments, the functional variants can comprise the amino acid sequence of the reference protein with at least one non-conservative amino acid substitution. The term “nonconservative mutations” involves amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc. In this case, it is preferable for the nonconservative amino acid substitution to not interfere with, or inhibit the biological activity of, the functional variant. The non-conservative amino acid substitution can enhance the biological activity of the functional variant, such that the biological activity of the functional variant is increased as compared to the homologous parent protein. Amino acid substitutability is discussed in more detail, for example, in L. Y. Yampolsky and A. Stoltzfus, “The Exchangeability of Amino acids in Proteins,” Genetics 2005 Aug.; 170(4): 1459-1472, the content of this reference which is incorporated by reference in its entirety.

[0230] The terms “identical” and its grammatical equivalents as used herein or “sequence identity” in the context of two nucleic acid sequences or amino acid sequences of polypeptides refer to the residues in the two sequences which are the same when aligned for maximum correspondence over a specified comparison window. A “comparison window,” as used herein, refers to a segment of at least about 20 contiguous positions, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence can be compared to a reference sequence of the same number of contiguous positions after the two sequences are aligned optimally. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted by the local homology algorithm of Smith and Waterman, Adv. Appl. Math., 2:482 (1981); by the alignment algorithm of Needleman and Wunsch, J. Mol. Biol., 48:443 (1970); by the search for similarity method of Pearson and Lipman, Proc. Nat. Acad. Sci U.S.A., 85:2444 (1988); by computerized implementations of these algorithms (including, but not limited to CLUSTAL in the PC / Gene program by Intelligentics, Mountain View Calif., GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, Wis., U.S.A.); the CLUSTAL program is well described by Higgins and Sharp, Gene, 73:237-244 (1988) and Higgins and Sharp, CABIOS,5:151-153 (1989); Corpet et al., Nucleic Acids Res., 16:10881-10890 (1988); Huang et al., Computer Applications in the Biosciences, 8:155-165 (1992); and Pearson et al., Methods in Molecular Biology, 24:307-331 (1994). The content of each of these references is hereby incorporated by reference in their entireties. Alignment is also often performed by inspection and manual alignment. In one class of embodiments, the polypeptides herein are at least 80%, 85%, 90%, 98% 99% or 100% identical to a reference polypeptide (i.e., the full length thereof), or a fragment thereof, e.g., as measured by BLASTP (or CLUSTAL, or any other available alignment software) using default parameters. Similarly, nucleic acids can also be described with reference to a starting nucleic acid, e.g., they can be 50%, 60%, 70%, 75%, 80%, 85%, 90%, 98%, 99% or 100% identical to a reference nucleic acid (i.e., the full length thereof) or a fragment thereof, e.g., as measured by BLASTN (or CLUSTAL, or any other available alignment software) using default parameters. When one molecule is said to have certain percentage of sequence identity with a larger molecule, it means that when the two molecules are optimally aligned, the percentage of residues in the smaller molecule finds a match residue in the larger molecule in accordance with the order by which the two molecules are optimally aligned.

[0231] For purposes of this specification and the claims, it is understood that the phrase “having at least 50% sequence identity with” a reference sequence, or referencing any range therein (e.g., “at least 80% sequence identity with”) encompasses the reference sequence itself. Thus, for example, a claim reciting “a nucleic acid having at least 80% sequence identity with SEQ ID NO: 0” encompasses SEQ ID NO: 0 itself.

[0232] The term “substantially identical” and its grammatical equivalents as applied to nucleic acid or amino acid sequences mean that a nucleic acid or amino acid sequence comprises a sequence that has at least 95% sequence identity with a reference sequence using the programs described above, e.g., BLAST, using standard parameters.

[0233] “Homology” is generally inferred from sequence identity between two or more nucleic acids or proteins (or sequences thereof). The precise percentage of identity between sequences that is useful in establishing homology varies with the nucleic acid and protein at issue, but as little as 25% sequence identity is routinely used to establish homology. Higher levels of sequence identity, e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% or more can also be used to establish homology. Methods for determining sequence identity percentages (e.g., BLASTP and BLASTN using default parameters) are described herein and are generally available. Nucleic acids and / or nucleic acid sequences are “homologous” when they are derived, naturally or artificially, from a common ancestral nucleic acid or nucleic acid sequence. Proteins and / or protein sequences are “homologous” when their encoding DNAs are derived, naturally or artificially, from a common ancestral nucleic acid or nucleic acid sequence. The homologous molecules can be termed“homologs.” For example, any naturally occurring proteins can be modified by any available mutagenesis method. When expressed, this mutagenized nucleic acid encodes a polypeptide that is homologous to the protein encoded by the original nucleic acid.

[0234] Also contemplated and included herein are nucleic acid molecules that hybridize to the disclosed sequences. Hybridization conditions may be mild, moderate, or stringent, as is warranted.

[0235] Appropriate stringency conditions which promote DNA hybridization, for example, 6* sodium chloride / sodium citrate (SSC) at about 45° C, followed by a wash of 2*SSC at 50° C, are known or can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.(1989), 6.3.1-6.3.6. “Stringent hybridization conditions” are those that include a salt concentration of 1.0 M NaCl in 50% formamide, at a temperature of 37°C for 4 to 12 hours, followed by a wash in 0.1X SSC at 60-65°C.

[0236] As will be appreciated by the skilled practitioner, slight changes in nucleic acid sequence do not necessarily alter the amino acid sequence of the encoded polypeptide. This disclosure embraces the degeneracy of codon usage as would be understood by one of ordinary skill in the art. For example, as known in the art, different codons will code for the same amino acid as illustrated in the following chart

[0237] As used herein, the phrase “codon degenerate variant” when used with reference to a nucleic acid sequence means a nucleic acid sequence that differs from the referenced sequence, but that encodes a polypeptide having the same amino acid sequence as that encoded by the referenced sequence.

[0238] Additionally, it will be appreciated by persons skilled in the art that partial sequences often work as effectively as full-length versions. The ways in which the nucleotide sequence can be varied or shortened are well known to persons skilled in the art, as are ways of testing the suitability or effectiveness of the altered genes. In some embodiments, suitability and / or effectiveness of the altered gene may easily be tested by, for example, conventional gas chromatography. All such variations of the genes are therefore included as part of the present disclosure.

[0239] In the present application, when an amino acid residue in an Fc region or domain thereof (e.g., a CH2, CH3, or CH4 domain), a CHI domain, a hinge region, or a tailpiece is referred to by its position, the position number given is, in accordance with the conventional practice in the art, the position number of the residue in the heavy chain of a naturally occurring antibody based on the EU convention for immunoglobulins. For example, a C220S substitution in an IgGl hinge region refers to a cysteine to serine substitution occurring at position 220 in the heavy chain of an IgGl antibody and a L309C substitution in an IgGl CH2 region refers to a leucine to cysteine substitution occurring at position 309 of the heavy chain.

[0240] The term “oligomer” refers to a polymer comprising multiple units.

[0241] Natural immunoglobulins are heterotetramers comprised of two heavy chains and two light chains. The immunoglobulins IgM and IgA contain polypeptides that are capable of forming higher order oligomers. The sequences necessary for forming higher ordered oligomers of IgM or IgA are found within the Fc tailpiece region of the heavy chain of these immunoglobulins. The hetereotetramers of IgM or IgA are referred to as “monomers” prior to the formation of oligomeric states of “dimers”, “trimers”, “tetramers”, “heptamers”, or “hexamers” composed of two, three, four, five, or six monomers. IgA are capable of forming dimers and IgM are capable of forming theoligomeric state of hexamers. By fusing the tailpiece from IgM or IgA to an IgG these hetereotetramers also form the same oligomeric states as IgM or IgA.

[0242] The term “B cell” refers to a B cell of the immune system. B cells mature make immunoglobulins or antibodies. The tern “B cell response” refers to the activation of B cells by a specific antigen and to the selection of antibodies specific to the antigen.

[0243] The term “Antibody discovery” refers to the process of immunizing an animal with a compound that generates an immune response, characterized by the selection of antibodies, and subsequent isolation and identification of the sequences of antibodies elicited during this process and / or cells from the immunized animal producing antibodies elicited during this process.

[0244] The term “pain mediator polypeptide” refers to polypeptides that when present in an animal increases the pain perceived by the animal. Examples of a “pain mediator polypetide” include Interleukin- 10 (IL- 10), and nerve growth factor (NGF). In aspects, pain is a result of inflammation.

[0245] The term “neutralization” refers to the effect that an antibody has on a bound polypeptide where the effect is to block or partially block one or more activities associated with the unbound polypeptide.

[0246] The term “avidity” refers to avidity is the total strength of interaction between a multimeric ligand and a multivalent binding protein.

[0247] The term “isolated” and its grammatical equivalents as used herein refer to the removal of a nucleic acid from its natural environment. It is to be understood, however, that nucleic acids and proteins can be formulated with diluents or adjuvants and still for practical purposes be isolated.

[0248] The term “purified” and its grammatical equivalents as used herein refer to a molecule or composition, whether removed from nature (including genomic DNA and mRNA) or synthesized (including cDNA) and / or amplified under laboratory conditions, that has been increased in purity, wherein “purity” is a relative term, not “absolute purity.” For example, nucleic acids typically are mixed with an acceptable carrier or diluent when used for introduction into cells. The term “substantially purified” and its grammatical equivalents as used herein refer to a nucleic acid sequence, polypeptide, protein or other compound that is essentially free, i.e., is more than about 50% free of, more than about 70% free of, more than about 90% free of, the polynucleotides, proteins, polypeptides and other molecules that the nucleic acid, polypeptide, protein or other compound is naturally associated with.

[0249] “Transposon,” “transposable element” or “TE” refers to a DNA sequence that can change its position within the genome, sometimes creating or reversing mutations and altering the cell’s genome size. Transposition often results in duplication of the transposon. Class I transposonsare copied in two stages: first, they are transcribed from DNA to RNA, and the RNA produced is then reverse transcribed to DNA. This copied DNA is then inserted at a new position into the genome. The reverse transcription step is catalyzed by a reverse transcriptase, which can be encoded by the transposon itself. The characteristics of retrotransposons are similar to retroviruses, such as HIV. The cut-and-paste transposition mechanism of class II transposons does not involve an RNA intermediate. The transpositions are catalyzed by several transposase enzymes. Some transposases non-specifically bind to any target site in DNA, whereas others bind to specific DNA sequence targets. The transposase makes a staggered cut at the target site resulting in single-strand 5’ or 3’ DNA overhangs (sticky ends). This step cuts out the DNA transposon, which is then ligated into a new target site; this process involves activity of a DNA polymerase that fills in gaps and of a DNA ligase that closes the sugar-phosphate backbone. This results in duplication of the target site. The insertion sites of DNA transposons can be identified by short direct repeats which can be created by the staggered cut in the target DNA and filling in by DNA polymerase, followed by a series of inverted repeats important for the transposon excision by transposase. Cut-and-paste transposons can be duplicated if their transposition takes place during S phase of the cell cycle when a donor site has already been replicated, but a target site has not yet been replicated.Transposition can be classified as either “autonomous” or “non-autonomous” in both Class I and Class II transposons. Autonomous transposons can move by themselves while non-autonomous transposons require the presence of another transposon to move. This is often because non-autonomous transposons lack transposase (for class II) or reverse transcriptase (for class I).

[0250] “Transposase” refers an enzyme that binds to the end of a transposon and catalyzes the movement of the transposon to another part of the genome by a cut and paste mechanism or a replicative transposition mechanism. In some embodiments, the transposase ’s catalytic activity can be utilized to move gene(s) from a vector to the genome.

[0251] An “expression vector” or “vector” is any genetic element, e.g., a plasmid, a mini-circle, a nanoplasmid, chromosome, virus, transposon, behaving either as an autonomous unit of polynucleotide replication within a cell. (i.e. capable of replication under its own control) or being rendered capable of replication by insertion into a host cell chromosome, having attached to it another polynucleotide segment, so as to bring about the replication and / or expression of the attached segment. Suitable vectors include, but are not limited to, plasmids, transposons, bacteriophages and cosmids. Vectors can contain polynucleotide sequences that are necessary to effect ligation or insertion of the vector into a desired host cell and to effect the expression of the attached segment. Such sequences differ depending on the host organism; they include promoter sequences to effect transcription, enhancer sequences to increase transcription, ribosomal binding site sequences and transcription and translation termination sequences. Alternatively, expressionvectors can be capable of directly expressing nucleic acid sequence products encoded therein without ligation or integration of the vector into host cell DNA sequences. In some embodiments, the vector is an “episomal expression vector” or “episome,” which is able to replicate in a host cell, and persists as an extrachromosomal segment of DNA within the host cell in the presence of appropriate selective pressure (see, e.g., Conese et al., Gene Therapy, 11:1735-1742 (2004)).Representative commercially-available episomal expression vectors include, but are not limited to, episomal plasmids that utilize Epstein Barr Nuclear Antigen 1 (EBNA1) and the Epstein Barr Virus (EBV) origin of replication (oriP). The vectors pREP4, pCEP4, pREP7, and pcDNA3.1 from Invitrogen (Carlsbad, Calif.) and pBK-CMV from Stratagene (La Jolla, Calif.) represent nonlimiting examples of an episomal vector that uses T-antigen and the SV40 origin of replication in lieu of EBNA1 and oriP. A vector also can comprise a selectable marker gene. In some embodiments where nano plasmids are utilized, strains such as R6K that utilizes an antisense RNA selection marker (e.g. sucrose tolerance) can be used.

[0252] The term “selectable marker gene” refers to a nucleic acid sequence that allows cells expressing the nucleic acid sequence to be specifically selected for or against, in the presence of a corresponding selective agent. Suitable selectable marker genes are known in the art and described in, e.g., International Patent Application Publications WO 1992 / 08796 and WO 1994 / 28143;Wigler et al., Proc. Natl. Acad. Sci. USA, 77: 3567 (1980); O’Hare et al., Proc. Natl. Acad. Sci. USA, 78: 1527 (1981); Mulligan & Berg, Proc. Natl. Acad. Sci. USA, 78: 2072 (1981); Colberre-Garapin et al., J. Mol. Biol., 150:1 (1981); Santerre et al., Gene, 30: 147 (1984); Kent et al., Science, 237: 901-903 (1987); Wigler et al., Cell, 11: 223 (1977); Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA, 48: 2026 (1962); Lowy et al., Cell, 22: 817 (1980); and U.S. Pat. Nos.5,122,464 and 5,770,359. The contents of each of these references are herein incorporated by reference in their entireties.

[0253] The term “coding sequence” refers to a segment of a polynucleotide that encodes for protein or polypeptide. The region or sequence is bounded nearer the 5’ end by a start codon and nearer the 3’ end with a stop codon. Coding sequences can also be referred to as open reading frames.

[0254] The term “operably linked” refers to refers to the physical and / or functional linkage of a DNA segment to another DNA segment in such a way as to allow the segments to function in their intended manners. A DNA sequence encoding a gene product is operably linked to a regulatory sequence when it is linked to the regulatory sequence, such as, for example, promoters, enhancers and / or silencers, in a manner, that allows modulation of transcription of the DNA sequence, directly or indirectly. For example, a DNA sequence is operably linked to a promoter when it is ligated to the promoter downstream with respect to the transcription initiation site of the promoterand in the correct reading frame with respect to the transcription initiation site so as to allow transcription elongation to proceed through the DNA sequence. An enhancer or silencer is operably linked to a DNA sequence coding for a gene product when it is ligated to the DNA sequence in such a manner as to, respectively, increase or decrease the transcription of the DNA sequence. Enhancers and silencers can be located upstream or downstream of or embedded within the coding regions of the DNA sequence. A DNA for a signal sequence is operably linked to DNA coding for a polypeptide if the signal sequence is expressed as a pre-protein that participates in the secretion of the polypeptide. Linkage of DNA sequences to regulatory sequences is typically accomplished by ligation at suitable restriction sites or via adapters or linkers inserted in the sequence using restriction endonucleases known to one of skill in the art.

[0255] The terms “induce,” “induction” and their grammatical equivalents as used herein refer to an increase in nucleic acid sequence transcription, promoter activity and / or expression brought about by a transcriptional regulator, relative to some basal level of transcription.

[0256] The term “transcriptional regulator” refers to a biochemical element that acts to prevent or inhibit the transcription of a promoter-driven DNA sequence under certain environmental conditions (e.g., a repressor or nuclear inhibitory protein), or to permit or stimulate the transcription of the promoter-driven DNA sequence under certain environmental conditions (e.g., an inducer or an enhancer).

[0257] The term “enhancer,” as used herein, refers to a DNA sequence that increases transcription of, for example, a nucleic acid sequence to which it is operably linked. Enhancers can be located many kilobases away from the coding region of the nucleic acid sequence and can mediate the binding of regulatory factors, patterns of DNA methylation, or changes in DNA structure. A large number of enhancers from a variety of different sources are well known in the art and are available as or within cloned polynucleotides (from, e.g., depositories such as the ATCC as well as other commercial or individual sources). A number of polynucleotides comprising promoters (such as the commonly-used CMV promoter) also comprise enhancer sequences.Enhancers can be located upstream or downstream of coding sequences or within coding sequences. The term “Ig enhancers” refers to enhancer elements derived from enhancer regions mapped within the immunoglobulin (Ig) locus (such enhancers include for example, the heavy chain (mu) 5’ enhancers, light chain (kappa) 5’ enhancers, kappa and mu intronic enhancers, and 3’ enhancers (see generally Paul W. E. (ed), Fundamental Immunology, 3rd Edition, Raven Press, New York (1993), pages 353-363; and U.S. Pat. No. 5,885,827).

[0258] The term “promoter” refers to a region of a polynucleotide that initiates transcription of a coding sequence. Promoters are located near the transcription start sites of genes, on the same strand and upstream on the DNA (towards the 5’ region of the sense strand). Some promoters areconstitutive as they are active in all circumstances in the cell, while others are regulated becoming active in response to specific stimuli, e.g., an inducible promoter. The term “promoter activity” and its grammatical equivalents as used herein refer to the extent of expression of nucleotide sequence that is operably linked to the promoter whose activity is being measured. Promoter activity can be measured directly by determining the amount of RNA transcript produced, for example by Northern blot analysis or indirectly by determining the amount of product coded for by the linked nucleic acid sequence, such as a reporter nucleic acid sequence linked to the promoter.

[0259] “Inducible promoter” refers to a promoter, that is induced into activity by the presence or absence of transcriptional regulators, e.g., biotic or abiotic factors. Inducible promoters are useful because the expression of genes operably linked to them can be turned on or off at certain stages of development of an organism or in a particular tissue. Non-limiting examples of inducible promoters include alcohol-regulated promoters, tetracycline-regulated promoters, steroid-regulated promoters, metal-regulated promoters, pathogenesis-regulated promoters, temperature-regulated promoters and light-regulated promoters. The inducible promoter can be part of a gene switch or genetic switch.

[0260] As used herein, the phrase “functional fragment” when used with reference to a polypeptide refers to a fragment of such polypeptide that possesses the primary function of the referenced polypeptide. For example, a functional fragment of a polypeptide that serves as a transmembrane domain is a fragment of that polypeptide that also serves as a transmembrane domain. In some embodiments, the functional fragment of a polypeptide is shorter than the referenced polypeptide by at most 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid residues at the N- and / or C-terminus. When used with reference to a nucleic acid, the phrase “functional fragment” refers to a fragment of the referenced nucleic acid that encodes a polypeptide having the same primary function as the polypeptide encoded by the referenced nucleic acid.

[0261] As used herein, the phrase “functional variant” when used with reference to a polypeptide refers to a polypeptide that differs from the referenced polypeptide but possesses the primary function of the referenced polypeptide. For example, a functional variant of a polypeptide that serves as a transmembrane domain is a fragment of that polypeptide that also serves as a transmembrane domain. In some embodiments, the functional variant has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the referenced amino acid sequence and / or is a conservatively-substituted variant of the referenced sequence. When used with reference to a nucleic acid, the phrase “functional variant” refers to a nucleic acid that differs from the referenced nucleic acid but encodes a polypeptide having the same primary function as the polypeptide encoded by the referenced nucleic acid. In some embodiments, the functional variant has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the referenced nucleic acidsequence, hybridizes under stringent hybridization conditions with the complement of the referenced nucleic acid sequence, or is a codon degenerate variant of the nucleic acid sequence.

[0262] The term “antibody,” also known as immunoglobulin (Ig), as used herein can refers to a monoclonal or polyclonal antibody. The term “monoclonal antibodies,” as used herein, refers to antibodies that are produced by a single clone of B-cells and bind to the same epitope. In contrast, “polyclonal antibodies” refer to a population of antibodies that is produced by different B-cells and bind to different epitopes of the same antigen. The antibodies can be from any animal origin. An antibody may, for example, be an IgG-B, IgG (including IgGl, IgG2, IgG3, and IgG4), IgA (including IgAl and IgA2), IgD, IgE, IgM, or IgY antibody. In some embodiments, the antibody can a single-chain whole antibody.

[0263] An antibody typically includes four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH) region and three or four C-terminal constant regions and each light chain contains one N-terminal variable (VL) region and one C-terminal constant (CL) region. The constant regions of a heavy chain are, in N-terminal to C-terminal order, the CHI, CH2, and CH3 domains and, where it exists, the CH4 domain. Each heavy chain may further comprise a hinge region that connects the CHI domain with the CH2 domain. Each heavy chain may also further comprise a tailpiece that is C-terminal to the constant regions.

[0264] The “Fab region” of the antibody refers to the portion consisting of the VL, VH, CL, and CHI domains from both the heavy and light chains. The “Fc region” comprises the CH2 and CH3 domains and, where applicable, the CH4 domain and / or tailpiece of both heavy chains of an antibody. In certain antibodies, the Fab region and the Fc region are connected by way of a hinge region that may be present in the heavy chains.

[0265] As used herein, the terms “CHI domain,” “CH2 domain,” “CH3 domain,” “CH4 domain,” “hinge region,” and “tailpiece” refer respectively to a CHI domain, CH2 domain, CH3 domain, CH4 domain, hinge region, or tailpiece from an antibody (e.g., an IgG-B, IgA, IgD, IgE, IgG, IgM, or IgY antibody) or a functional fragment or variant thereof.

[0266] The term “naturally-occurring,” as used to describe an antibody or a portion thereof (e.g., a CHI domain, a CH2 domain, a CH3 domain, a CH4 domain, a hinge region, a tailpiece, or an Fc region) refers to a naturally-occurring antibody or a portion of a naturally-occurring antibody. The antibody may be from any species, for example human or canine.

[0267] The terms “non-naturally occurring,” “non-natural,” “synthetic,” and “artificial,” as used to describe a polypeptide or a portion thereof refers to a polypeptide or portion thereof comprising an amino acid sequence that does not occur in nature. In some embodiments, the non-naturally occurring polypeptide or portion thereof is a functional variant of a naturally-occurringantibody or portion thereof (e.g., a CHI domain, a CH2 domain, a CH3 domain, a CH4 domain, a hinge region, a tailpiece, or an Fc region). The antibody may be from any species, for example human or canine.

[0268] “Patient” or “subject” refers to a mammalian subject diagnosed with or suspected of having or developing a medical disorder. In some embodiments, the term “patient” refers to a mammalian subject with a higher than average likelihood of developing such a disorder. Exemplary patients can be humans, apes, dogs, pigs, cattle, cats, horses, goats, sheep, rodents and other mammalians that can benefit from the therapies disclosed herein. Exemplary human patients can be male and / or female. “Patient in need thereof’ or “subject in need thereof’ means a patient diagnosed with or suspected of having a disease or disorder.

[0269] “Administering” refers to herein as providing one or more compositions described herein to a patient or a subject. By way of example and not limitation, composition administration, e.g., injection, can be performed by intravenous (i.v.) injection, sub-cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, or intramuscular (i.m.) injection. One or more such routes can be employed. Parenteral administration can be, for example, by bolus injection or by gradual perfusion over time. Alternatively, or concurrently, administration can be by the oral route. Additionally, administration can also be by surgical deposition of a bolus or pellet of cells, or positioning of a medical device. Administration can also include prescribing a treatment or medication to be provided to a patient.

[0270] As used herein, the terms “treatment,” “treating,” and their grammatical equivalents refer to obtaining a desired pharmacologic and / or physiologic effect. In some embodiments, the effect is therapeutic, i.e., the effect partially or completely cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the term “treating” can include “preventing” a disease or a condition.

[0271] As used herein, a “treatment interval” refers to a treatment cycle, for example, a course of administration of a therapeutic agent that can be repeated, e.g., on a regular schedule. In some embodiments, a dosage regimen can have one or more periods of no administration of the therapeutic agent in between treatment intervals.

[0272] The terms “administered in combination,” “co-administration,” “co-administering,” and “co-providing” as used herein, mean that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as"simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0273] In some embodiments, the first treatment and second treatment can be administered simultaneously (e.g., at the same time), in the same or in separate compositions, or sequentially. Sequential administration refers to administration of one treatment before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1, 2, 3, 4, 5, 6, 7, 8 or more weeks before) administration of an additional, e.g., secondary, treatment. The order of administration of the first and secondary treatment can also be reversed.

[0274] The terms “therapeutically effective amount,” therapeutic amount,” “immunogenically effective amount,” and their grammatical equivalents refer to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or immunogenic result. The effective amount can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of a composition described herein to elicit a desired response in one or more subjects. The precise amount of the compositions of the present disclosure to be administered can be determined by a physician or veterinarian with consideration of the age, weight, and condition of the patient (subject).Polypeptide Chains

[0275] In embodiments, the disclosure relates to a polypeptide chain comprising: an antigen; a CH2 domain; and a CH3 domain. In some embodiments, the polypeptide chain further comprises a CHI domain; a hinge region; a CH4 domain; and / or a tailpiece.

[0276] In some embodiments, the polypeptide chain comprises, in order from its N-terminus to its C-terminus: the antigen; the CH2 domain; and the CH3 domain. In some embodiments, the polypeptide chain further comprises a CHI domain that is between the antigen and the CH2 domain. In some embodiments, the polypeptide chain further comprises a hinge region between theantigen and the CH2 domain or between the CHI domain and the CH2 domain. In some embodiments, the polypeptide chain further comprises a CH4 domain that is C-terminal to the CH3 domain. In some embodiments, the polypeptide chain further comprises a tailpiece that is C-terminal to the CH3 domain or the CH4 domain. In some embodiments, the polypeptide chain comprises, in order from its N-terminus to its C-terminus: the antigen; the CHI domain; the hinge region; the CH2 domain; the CH3 domain; and the tailpiece.

[0277] It is understood that each of the aforementioned elements of the polypeptide chain (the antigen, the CHI domain, the hinge region, the CH2 domain, the CH3 domain, the CH4 domain, and the tailpiece) may individually be linked to one other directly by way of a covalent bond between such elements. For example, the antigen and the CHI domain may be linked together by way of a covalent bond between the C-terminal residue of the antigen and the N-terminal residue of the CHI domain, the CHI domain and the hinge region may be linked together by way of a covalent bond between the C-terminal residue of the CHI domain and the N-terminal residue of the hinge region, the hinge region and the CH2 domain may be linked together by way of a covalent bond between the C-terminal residue of the hinge region and the N-terminal residue of the CH2 domain, the CH2 domain and the CH3 domain may be linked together by way of a covalent bond between the C-terminal residue of the CH2 domain and the N-terminal residue of the CH3 domain, the CH3 domain and the CH4 domain may be linked together by way of a covalent bond between the C-terminal residue of the CH3 domain and the N-terminal residue of the CH4 domain, and the CH4 domain and the tailpiece may be linked together by way of a covalent bond between the C-terminal residue of the CH4 domain and the N-terminal residue of the tailpiece.

[0278] Alternatively, any element of the polypeptide chain may be linked to another element by way of a linker peptide. Any linker peptide known in the art for linking two polypeptides may be used

[0279] It is understood that each element of the polypeptide (the antigen, the CHI domain, the hinge region, the CH2 domain, the CH3 domain, the CH4 domain, and the tailpiece) may individually be naturally-occurring or non-natural. It is also understood that, when any two elements of the polypeptide chain are naturally-occurring, they may each be from a different antibody or antibody subclass. For example, a polypeptide chain may comprise a naturally-occurring CHI domain from an IgAl antibody, a naturally-occurring CH2 domain from an IgGl antibody, and a non-natural CH3 domain that has 90% sequence identity with an IgG4 antibody.

[0280] In aspects, a polypeptide chain connected to an antigen is described in FIG. 1A-1 J. In other aspects, two polypeptide chains are combined to form a monomer subunit of two polypeptide chains as described in, for example, FIG.2A-2C.Representative Antigen-IgGlCHl-Hinge-CH2-CH3-Tailpieces

[0281] In embodiments, the polypeptide chain comprises an Antigen-CHl -Hinge-CH2-CH3-Tailpiece wherein the respective sequences for each component are described in Table 19. In other embodiments, the polypeptide chain comprises, in N-terminus to C-terminus order, an Antigen-CH1-Hinge-CH2-CH3-Tailpiece wherein the respective sequences for each component are described in Table 19.

[0282] In some embodiments, the polypeptide chain comprises an Antigen-CH1(SEQ ID NO: 3)-Hinge (SEQ ID NO: 7)-CH2(SEQ ID NO: 13)-CH3(SEQ ID NO: 18)-Tailpiece (SEQ ID NO:1). In other aspect, the polypeptide chain comprises, in N-terminus to C-terminus order, an Antigen-CHl (SEQ ID NO: 3)-Hinge (SEQ ID NO: 7)-CH2 (SEQ ID NO: 13)-CH3 (SEQ ID NO: 18)-Tailpiece (SEQ ID NO: 1).

[0283] In some embodiments, the polypeptide chain comprises an Antigen-CH1(SEQ ID NO: 4)-Hinge(SEQ ID NO: 9)-CH2(SEQ ID NO: 15)-CH3(SEQ ID NO: 21)-Tailpiece(SEQ ID NO: 1). In other aspect, the polypeptide chain comprises, in N-terminus to C-terminus order, an Antigen-CH1 (SEQ ID NO: 4)-Hinge (SEQ ID NO: 9)-CH2 (SEQ ID NO: 15)-CH3 (SEQ ID NO: 21)-Tailpiece (SEQ ID NO: 1).

[0284] In some embodiments, the polypeptide chain comprises an Antigen-CHl (SEQ ID NO: 5)-Hinge (SEQ ID NO: 11)-CH2 (SEQ ID NO: 17)-CH3 (SEQ ID NO: 23)-Tailpiece (SEQ ID NO: 1). In other aspect, the polypeptide chain comprises, in N-terminus to C-terminus order, an Antigen-CHl (SEQ ID NO: 5)-Hinge (SEQ ID NO: 11)-CH2 (SEQ ID NO: 17)-CH3 (SEQ ID NO: 23)-Tailpiece(SEQ ID NO: 1)

[0285] In some embodiments, the polypeptide chain comprises, optionally in N-terminus to C-terminus order:(a) an antigen comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of an antigen, a substituted variant thereof, or a conservatively-substituted variant thereof;(b) a CHI domain comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100%sequence identity with the amino acid sequence of the CHI domain from a human IgGl antibody, a substituted variant thereof, or a conservatively-substituted variant thereof;(c) a hinge region comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the hinge region from a human IgGl antibody, a substituted variant thereof, or a conservatively-substituted variant thereof;(d) a CH2 domain comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH2 domain from a human IgGl antibody, a substituted variant thereof, or a conservatively-substituted variant thereof;(e) a CH3 domain comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH3 domain from a human IgGl antibody, a substituted variant thereof, or a conservatively-substituted variant thereof; and (f) a tailpiece comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the tailpiece from a human IgM antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0286] In some embodiments, the polypeptide chain comprises, optionally in N-terminus to C-terminus order:(a) an antigen comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100%sequence identity with the amino acid sequence of an antigen, a substituted variant thereof, or a conservatively-substituted variant thereof;(b) a CHI domain comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with an amino acid sequence of SEQ ID NO:3, SEQ ID NO: 4, or SEQ ID NO: 5, a substituted variant thereof, or a conservatively-substituted variant thereof;(c) a hinge region comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with an amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, a substituted variant thereof, or a conservatively-substituted variant thereof;(d) a CH2 domain comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with an amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17, a substituted variant thereof, or a conservatively-substituted variant thereof;(e) a CH3 domain comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with an amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22 or SEQ ID NO: 23, a substituted variant thereof, or a conservatively-substituted variant thereof; and(f) a tailpiece comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100%sequence identity with the amino acid sequence of SEQ ID NO: 1, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0287] In some embodiments, the polypeptide chain comprises, optionally in N-terminus to C-terminus order:(a) an antigen comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of an antigen, a substituted variant thereof, or a conservatively-substituted variant thereof;(b) a IgG polypeptide comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 24, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0288] In some embodiments, the polypeptide chain comprises, optionally in N-terminus to C-terminus order:(a) an antigen comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of an antigen, a substituted variant thereof, or a conservatively-substituted variant thereof;(b) a IgG polypeptide comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 25, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0289] In some embodiments, the polypeptide chain comprises, optionally in N-terminus to C-terminus order:(a) an antigen comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of an antigen, a substituted variant thereof, or a conservatively-substituted variant thereof;(b) a IgG polypeptide comprising an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 26, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0290] In aspects, the disclosure provides for polypeptide chains comprising:A (Antigen) - B (CHI) - C (hinge) - D (CH2) - E (Optional Interdomain Linker) - F (CH3) - G (tailpiece)Formula I

[0291] In aspects, Formula I may cover the following representative combinations of Table 4.In further aspects, proteins of Formula I and Table 4 form the basis of monomer units described herein (for example, two polypeptide chains of Formula I and Table 4), which in turn may be combined to form a multimeric fusion protein described herein. In aspects, the fusion protein comprises 2 to 12 monomer units of the description. In certain embodiments, the multimeric fusion protein comprise 6 monomer units. In certain embodiments, the multimeric fusion protein is in the form of a cyclic hexamer. In other aspects, the description provides for a hexamer of dimers. In aspects, polypeptide chains of Formula I and Table 4 form the basis of monomer units which are combined to form a cyclic hexamer such as, for example, in FIG.2A-2D. In further aspects, polypeptide chains of Formula I and Table 4 are utilized in methods described herein, for example, in methods of vaccination or immunization of animals, such as canines or felines.2920951-529e 4- 73 -- 79 -

[0292] In aspects, the disclosure provides for polypeptide chains comprising:A (Antigen) - B (Optional Linker) - C (CHI) - D (hinge) - E (CH2) - F (CH3) - G (tailpiece)Formula II

[0293] In aspects, Formula II may cover the following representative combinations of Table 5. In further aspects, proteins of Formula II and Table 5 form the basis of monomer units described herein (for example, two polypeptide chains of Formula II and Table 5), which in turn may be combined to form a multimeric fusion protein described herein. In aspects, the fusion protein comprises 2 to 12 monomer units of the description. In certain embodiments, the multimeric fusion protein comprise 6 monomer units. In certain embodiments, the multimeric fusion protein is in the form of a cyclic hexamer. In other aspects, the description provides for a hexamer of dimers. In aspects, polypeptide chains of Formula II and Table 5 form the basis of monomer units which are combined to form a cyclic hexamer such as, for example, in FIG.2A-2D. In further aspects, polypeptide chains of Formula II and Table 5 are utilized in methods described herein, for example, in methods of vaccination of animals, such as canines or felines.e 5

[0294] In aspects, the disclosure provides for polypeptide chains comprising:A (Antigen) - B (Optional Linker) - C (CHI) - D (hinge) - E (CH2) - F (CH3) - G (tailpiece)Formula II

[0295] In aspects, Formula II may cover the following representative combinations of Table C. In further aspects, proteins of Formula II and Table C form the basis of monomer units described herein (for example, two polypeptide chains of Formula II and Table C), which in turn may be combined to form a multimeric fusion protein described herein. In aspects, the fusion protein comprises 2 to 12 monomer units of the description. In certain embodiments, the multimeric fusion protein comprise 6 monomer units. In certain embodiments, the multimeric fusion protein is in the form of a cyclic hexamer. In other aspects, the description provides for a hexamer of dimers. In aspects, polypeptide chains of Formula II and Table C form the basis of monomer units which are combined to form a cyclic hexamer such as, for example, in FIG.2A-2D. In further aspects, polypeptide chains of Formula II and Table C are used in methods described herein, for example, in methods of vaccination or immunization of animals, such as canine animals, feline animals, farm animal, or wild animals.e CRepresentative AntigensPain Antigens

[0296] In an aspect, antigens described herein include an antigen polypeptide sequence comprising a pain mediating polypeptide, or antigenic fragment thereof. In other aspects, antigens described herein may comprise an NGF polypeptide, or a fragment or variant thereof that is capable of binding to a receptor for NFG. The antigen may comprise an NGF polypeptide, or a fragment or variant thereof that is capable of binding to or binds to a TrkA receptor. The antigen may comprise an NGF polypeptide, or a fragment or variant thereof that is capable of binding to a p75NTR receptor. The NGF polypeptide may be from any species. In certain embodiments, the NGF polypeptide may be canine or feline. In certain embodiments, the NGF polypeptide is canine. In certain embodiments, the NGF polypeptide is feline.

[0297] In aspects, the antigen may comprise an IL- 10 polypeptide, or a fragment or variant thereof that is capable of binding to a receptor for IL- 10. In other aspects, antigens described herein may comprise an NGF polypeptide, or a fragment or variant thereof that is not capable of binding to a receptor for NFG. The antigen may comprise an IL- 10 polypeptide, or a fragment or variant thereof that is capable of binding to an IL1R1 receptor. The antigen may comprise an IL-10 polypeptide, or a fragment or variant thereof that is capable of binding to a ILlRAcP receptor. The antigen may comprise an IL- 10 polypeptide, or a fragment or variant thereof that is capable of binding to a heterodimeric receptor composed of an IL1R1 receptor and an ILlRAcP receptor. The IL- 10 polypeptide may be from any species. In certain embodiments, the IL- 10 polypeptide may be canine or feline. In certain embodiments, the IL- 10 polypeptide is canine. In certain embodiments, the IL- 10 polypeptide is feline.

[0298] In embodiments, the present disclosure relates to a platform for generating a neutralizing antibody immune response to a pain mediator polypeptide antigen, wherein the antigen comprises a pain mediator polypeptide sequence or fragment thereof. In some embodiments an antigen comprises a substituted protein. In some embodiments the antigen is a protein from a human or animal. In some embodiments the antigen is a protein from a plant, fungus, protist, bacteria, or archaebacteria. In some embodiments the antigen is a viral protein.

[0299] In some embodiments the antigen is a sequence is an amino acid sequence fused to the N-terminus of an IgG sequence that makes a subunit of a hexamer. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 24. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 25. Insome embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 26.

[0300] In some embodiments the present disclosure relates in part to an antigen that is a fragment or variant of IL- 10, IL- 10 (D145K), or NGF that is capable of binding to an corresponding receptor or ligand. The antigen may be from any species. In some embodiments, the antigen may be canine or feline. In some embodiments, the antigen does not bind to the corresponding canine or feline receptor or ligand.

[0301] In some embodiments, the antigen comprises a fragment or variant of canine or feline IL- 10, IL- 10 (D145K), or NGF that is capable of binding to the corresponding canine or feline receptor or ligand. In some embodiments, the antigen comprises a fragment of variant of mature canine or feline IL- 10, IL- 10 (D145K), NGF that is capable of binding to the corresponding canine or feline receptor or ligand.

[0302] The antigen may comprise IL-10, or a fragment or variant thereof that is capable of binding to an IL1 receptor. The IL-10 may be from any species. In some embodiments, the IL-10 may be canine. In some embodiments, the IL- 10 may be feline.

[0303] In some embodiments, the antigen comprises a canine IL-10, or a fragment or variant thereof that is capable of binding to canine IL1 receptor. In some embodiments, the antigen comprises a feline IL- 10, or a fragment or variant thereof that is capable of binding to feline IL1 receptor. In some such embodiments, the antigen comprises a mature canine IL- 10, or a fragment or variant thereof that is capable of binding to canine IL1 receptor. In some such embodiments, the antigen comprises a mature feline IL- 10, or a fragment or variant thereof that is capable of binding to canine IL1 receptor.

[0304] In some embodiments, the antigen comprises a fragment or variant of IL- 10 that is capable of binding to an IL-1 receptor protein consisting of IL1R1, ILlRAcP, or a complex consisting of IL1R1 and ILlRAcP, but has reduced signaling as compared with wild-type IL-10. In some embodiments, the antigen comprises a fragment or variant of canine or feline IL- 10 that is capable of binding to a canine or feline IL-1 receptor but has reduced signaling as compared with wild-type feline IL- 10. In some embodiments, the antigen comprises a fragment or variant of mature feline IL- 10 that is capable of binding to feline IL-1 receptor but has reduced signaling as compared with wild-type feline IL- 10.

[0305] In some embodiments, the antigen comprises a fragment or variant of NGF that is capable of binding to a canine or feline p75NTR or canine TrkA receptor. In certain such embodiments, the antigen comprises a mature canine or feline NGF, or a fragment or variantthereof that is capable of binding to a canine p75NTR or canine TrkA receptor. In some embodiments, the antigen is not capable of binding to canine or feline p75NTR or canine TrkA receptor.

[0306] In certain embodiments, the antigen comprises a feline IL- 10, or a fragment or variant thereof that is capable of binding to feline IL1 receptor. In certain such embodiments, the antigen comprises a mature feline IL- 10, or a fragment or variant thereof that is capable of binding to feline IL1 receptor.

[0307] In aspects described herein, antigens described herein bind to or selectively bind to pain mediating polypeptides described herein, such as NGF, IL- 10, TNF-a, and other pain mediating receptors described herein.NGF

[0308] In certain embodiments, the antigen comprises a canine NGF, or a fragment or variant thereof that is capable of binding to a canine NGF receptor. In certain such embodiments, the antigen comprises a mature canine NGF or canine pro-NGF, or a fragment or variant thereof that is capable of binding to a canine NGF receptor.

[0309] In certain embodiments, the antigen comprises a canine NGF, or a fragment or variant thereof that is capable of binding to a canine NGF receptor. In certain such embodiments, the antigen comprises a mature canine NGF or canine pro-NGF, or a fragment or variant thereof that is capable of binding to a canine NGF receptor.

[0310] In certain embodiments, the antigen comprises a feline NGF, or a fragment or variant thereof that is capable of binding to a feline NGF receptor. In certain such embodiments, the antigen comprises a mature feline NGF or feline pro-NGF, or a fragment or variant thereof that is capable of binding to a feline NGF receptor.

[0311] In certain embodiments, the antigen comprises a feline NGF, or a fragment or variant thereof that is capable of binding to a feline NGF receptor. In certain such embodiments, the antigen comprises a mature feline NGF or feline pro-NGF, or a fragment or variant thereof that is capable of binding to a feline NGF receptor.

[0312] In certain embodiments, the antigen comprises a fragment or variant of NGF that is capable of binding to an NGF receptor but has reduced signaling as compared with wild-type NGF. In certain such embodiments, the antigen comprises a fragment or variant of canine NGF that is capable of binding to the canine NGF receptor but has reduced signaling as compared with wildtype canine NGF. In certain such embodiments, the antigen comprises a fragment or variant ofmature canine NGF or canine pro-NGF that is capable of binding to the canine NGF receptor but has reduced signaling as compared with wild-type canine NGF.

[0313] In certain embodiments, the antigen comprises a fragment or variant of NGF that is capable of binding to an NGF receptor but is not capable of inducing a pain sensation. In certain such embodiments, the antigen comprises a fragment or variant of canine NGF that is capable of binding to the canine NGF receptor but is not capable of inducing a pain sensation. In certain such embodiments, the antigen comprises a fragment or variant of mature canine NGF or canine pro-NGF that is capable of binding to canine NGF receptor but is not capable of inducing a pain sensation.

[0314] In certain embodiments, the antigen comprises a fragment or variant of NGF that is capable of binding to an NGF receptor but has reduced signaling as compared with wild-type NGF. In certain such embodiments, the antigen comprises a fragment or variant of feline NGF that is capable of binding to the feline NGF receptor but has reduced signaling as compared with wildtype feline NGF. In certain such embodiments, the antigen comprises a fragment or variant of feline NGF that is capable of binding to the feline NGF receptor but has reduced signaling as compared with wild-type feline NGF.

[0315] In certain embodiments, the antigen comprises a fragment or variant of NGF that is capable of binding to an NGF receptor but is not capable of inducing a pain sensation. In certain such embodiments, the antigen comprises a fragment or variant of feline NGF that is capable of binding to the feline NGF receptor but is not capable of inducing a pain sensation. In certain such embodiments, the antigen comprises a fragment or variant of mature feline NGF or feline pro-NGF that is capable of binding to feline NGF receptor but is not capable of inducing a pain sensation.

[0316] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 53 or is a conservatively-substituted variant thereof, provided that the antigen is capable of binding to an NGF receptor polypeptide comprising or consisting of TrkA, p75NTR, or a complex comprising or consisting of TrkA andp75NTR.IL-10

[0317] In certain embodiments, the antigen comprises a fragment or variant of IL- 10 that is capable of binding to an IL- 10 receptor but has reduced signaling as compared with wild-type IL-10. In certain such embodiments, the antigen comprises a fragment or variant of canineIL-i that is capable of binding to canine IL-i receptor but has reduced signaling as compared with wild-type canine IL-i . In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-i that is capable of binding to canine IL-i receptor but has reduced signaling as compared with wild-type canine IL-i .

[0318] In certain embodiments, the antigen comprises a fragment or variant of IL-i that is capable of binding to an IL-i receptor but is not capable of inducing a pain sensation or inflammation. In certain such embodiments, the antigen comprises a fragment or variant of canine IL-i that is capable of binding to the canine IL-i receptor but is not capable of inducing a pain sensation or inflammation. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-i that is capable of binding to the canine IL-i receptor but is not capable of inducing a pain sensation or inflammation.

[0319] In certain embodiments, the antigen comprises a fragment or variant of IL- 10 that is capable of binding to an IL- 10 receptor but has reduced signaling as compared with wild-type IL-10. In certain such embodiments, the antigen comprises a fragment or variant of feline IL- 10 that is capable of binding to feline IL- 10 receptor but has reduced signaling as compared with wild-type feline IL- 10. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL- 10 that is capable of binding to feline IL- 10 receptor but has reduced signaling as compared with wild-type feline IL- 10.

[0320] In certain embodiments, the antigen comprises a fragment or variant of IL- 10 that is capable of binding to an IL- 10 receptor but is not capable of inducing a pain sensation or inflammation. In certain such embodiments, the antigen comprises a fragment or variant of feline IL- 10 that is capable of binding to the feline IL- 10 receptor but is not capable of inducing a pain sensation or inflammation. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL- 10 that is capable of binding to the feline IL- 10 receptor but is not capable of inducing a pain sensation or inflammation.

[0321] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 57 or SEQ ID NO: 60, or conservatively-substituted variants thereof. In aspects, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, atleast about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 57 or SEQ ID NO: 60, or conservatively-substituted variants thereof and are capable of binding to an IL-ip receptor polypeptide comprising or consisting of IL1R1, ILlRAcP, or a complex comprising or consisting of IL1R1 andlLlRAcP.TNF-a

[0322] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 73 or substituted variants thereof.

[0323] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 75 or is a conservatively-substituted variant thereof.Other Pain Mediators

[0324] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of an inflammatory cytokine or fragment thereof. In some embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with an amino acid sequence of substance P, CCL2 / MCP-1, IL-6, IL- 17, IL- 18, IL-23, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), HMGB1, or a fragment thereof.

[0325] In certain embodiments, the antigen comprises a proinflammatory polypeptide, or a fragment or variant thereof that is capable of binding to a proinflammatory polypeptide receptor. In certain embodiments, the antigen comprises a proinflammatory polypeptide, or a fragment or variant thereof that is not capable of binding to a proinflammatory polypeptide receptor. In certainsuch embodiments, the antigen comprises a mature canine or feline substance P, CCL2 / MCP-1, IL-6, IL- 17, IL- 18, IL-23, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), HMGB1, or a fragment thereof that is capable of binding to canine or feline receptor for substance P, CCL2 I MCP-1, IL-6, IL-17, IL-18, IL-23, IL-33, IL-36, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), HMGB1, ADAMTS-5, MMP-13, Wnt, LRRK2, Glucagon-like peptide receptor, or p75NTR.Dermatology AntigensIL-5

[0326] In an aspect, antigens described herein include an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide, or antigenic fragment thereof. In other aspects, antigens described herein the antigen may comprise an IL-5 polypeptide, or a fragment or variant thereof that is capable of binding to a receptor for IL-5. The antigen may comprise an IL-5 polypeptide, or a fragment or variant thereof that is capable of binding to a IL5Ra receptor subunit. The antigen may comprise an IL-5 polypeptide, or a fragment or variant thereof that is capable of binding to a CSF2RB receptor subunit. The antigen may comprise an IL-5 polypeptide, or a fragment or variant thereof that is capable of binding to a complex of IL5Ra and CSF2RB receptor subunits. The IL-5 polypeptide may be from any species. In certain embodiments, the IL-5 polypeptide may be canine or feline. In certain embodiments, the IL-5 polypeptide is canine. In certain embodiments, the IL-5 polypeptide is feline.

[0327] In embodiments, the antigen comprises a canine IL-5, or a fragment or variant thereof that is capable of binding to a canine IL-5 receptor. In certain such embodiments, the antigen comprises a mature canine IL-5, or a fragment or variant thereof that is capable of binding to a canine IL-5 receptor. In certain such embodiments, the antigen comprises a mature canine IL-5, or a fragment or variant thereof that is not capable of binding to a canine IL-5 receptor.

[0328] In certain embodiments, the antigen comprises a fragment or variant of IL-5 that is capable of binding to an IL-5 receptor but has reduced signaling as compared with wild-type IL-5. In certain such embodiments, the antigen comprises a fragment or variant of canine IL-5 that is capable of binding to the canine IL-5 receptor but has reduced signaling as compared with wildtype canine IL-5. In certain embodiments, the antigen comprises a fragment or variant of mature canine IL-5 that is capable of binding to the canine IL-5 receptor but has reduced signaling as compared with wild-type canine IL-5. In some embodiments, the antigen comprises a fragment or variant of mature canine IL-5 and is not capable of binding to the canine IL-5 receptor and has no signaling as compared with wild-type canine IL-5.

[0329] In certain embodiments, the antigen comprises a fragment or variant of IL-5 that is capable of binding to an IL-5 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of canine IL-5 that is capable of binding to the canine IL-5 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-5 that is capable of binding to canine IL-5 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-5 that is not capable of binding to canine IL-5 receptor and is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.

[0330] In certain embodiments, the antigen comprises a fragment or variant of IL-5 that is capable of binding to an IL-5 receptor but has reduced signaling as compared with wild-type IL-5. In certain such embodiments, the antigen comprises a fragment or variant of canine IL-5 that is capable of binding to canine IL-5 receptor but has reduced signaling as compared with wild-type canine IL-5. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-5 that is capable of binding to canine IL-5 receptor but has reduced signaling as compared with wild-type canine IL-5.

[0331] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 110 or is a conservatively-substituted variant thereof. In other aspects, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 110 or is a conservatively-substituted variant thereof capable of binding to an IL-5 receptor polypeptide consisting of an IL5Ra receptor subunit, an CSF2RB receptor subunit or a complex of IL5Ra and CSF2RB receptor subunits.

[0332] In other aspects, the antigen comprises a feline IL-5, or a fragment or variant thereof that is capable of binding to a feline IL-5 receptor. In certain such embodiments, the antigen comprises a mature feline IL-5, or a fragment or variant thereof that is capable of binding to afeline IL-5 receptor. In certain such embodiments, the antigen comprises a mature feline IL-5, or a fragment or variant thereof that is not capable of binding to a feline IL-5 receptor.

[0333] In certain embodiments, the antigen comprises a fragment or variant of IL-5 that is capable of binding to an IL-5 receptor but has reduced signaling as compared with wild-type IL-5. In certain such embodiments, the antigen comprises a fragment or variant of feline IL-5 that is capable of binding to the feline IL-5 receptor but has reduced signaling as compared with wild-type feline IL-5. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-5 that is capable of binding to the feline IL-5 receptor but has reduced signaling as compared with wild-type feline IL-5. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-5 that is not capable of binding to the feline IL-5 receptor and has no signaling as compared with wild-type feline IL-5.

[0334] In certain embodiments, the antigen comprises a fragment or variant of IL-5 that is capable of binding to an IL-5 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of feline IL-5 that is capable of binding to the feline IL-5 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-5 that is capable of binding to feline IL-5 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-5 that is not capable of binding to feline IL-5 receptor and is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.

[0335] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NOs: 95, 96, 97, or 98 or is a conservatively-substituted variant thereof. In other embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NOs: 95, 96, 97, or 98 or is a conservatively-substituted variant thereof capable of binding to an IL-5 receptor polypeptide comprising or consisting of an IL5Ra receptor subunit, an CSF2RB receptor subunit or a complex of IL5Ra and CSF2RB receptor subunits.

[0336] In embodiments, the present disclosure relates to a platform for generating a neutralizing antibody immune response to a polypeptide mediator of a dermatological condition, wherein the antigen comprises a polypeptide sequence of mediator of a dermatological condition or fragment thereof. In some embodiments an antigen comprises a substituted protein. In some embodiments the antigen is a protein from a human or animal. In some embodiments the antigen is a protein from a plant, fungus, protist, bacteria, or archaebacteria. In some embodiments the antigen is a viral protein.

[0337] In some embodiments the antigen is a sequence is an amino acid sequence fused to the N-terminus of an IgG sequence that makes a subunit of a hexamer. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 1. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 25. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 26.

[0338] In some embodiments the present disclosure relates in part to an antigen that is a fragment or variant of IL-5, IL-5 (E13Q), or IL-13 that is capable of binding to an corresponding receptor or ligand. The antigen may be from any species. In some embodiments, the antigen may be canine or feline.

[0339] In some embodiments, the antigen comprises a fragment or variant of canine or feline IL-5, IL-5 (E13Q), or IL-13 that is capable of binding to the corresponding canine or feline receptor or ligand. In some embodiments, the antigen comprises a fragment of variant of mature canine or feline IL-5, IL-5 (E13Q), or IL-13 that is capable of binding to the corresponding canine or feline receptor or ligand.

[0340] The antigen may comprise IL-13, or a fragment or variant thereof that is capable of binding to an IL-13 receptor. The IL-13 may be from any species. In some embodiments, the IL-13 may be canine. In some embodiments, the IL- 13 may be feline.

[0341] In some embodiments, the antigen comprises a canine IL- 13, or a fragment or variant thereof that is capable of binding to canine receptor consisting of IL4Ral, IL13Ral, IL13Ra2, or a complex consisting of IL4Ral and IL13Ral. In some embodiments, the antigen comprises a feline IL- 13, or a fragment or variant thereof that is capable of binding to feline IL1 receptor. In some such embodiments, the antigen comprises a mature canine IL-13, or a fragment or variant thereof that is capable of binding to canine IL1 receptor. In some such embodiments, the antigen comprises a mature feline IL- 13, or a fragment or variant thereof that is capable of binding to canine IL- 13 receptor.

[0342] In some embodiments, the antigen comprises a fragment or variant of IL- 13 that is capable of binding to an IL-13 receptor protein consisting of IL4Ral, IL13Ral, IL13Ra2, or a complex consisting of IL4Ral and IL13Ral, but has reduced signaling as compared with wild-type IL-13. In some embodiments, the antigen comprises a fragment or variant of canine or feline IL- 13 that is capable of binding to a canine or feline IL- 13 receptor but has reduced signaling as compared with wild-type feline IL-13. In some embodiments, the antigen comprises a fragment or variant of mature feline IL- 13 that is capable of binding to feline IL- 13 receptor but has reduced signaling as compared with wild-type feline IL-13.

[0343] In certain embodiments, the antigen comprises a feline IL-13, or a fragment or variant thereof that is capable of binding to feline IL 13 receptor. In certain such embodiments, the antigen comprises a mature feline IL-13, or a fragment or variant thereof that is capable of binding to feline IL 13 receptor.IL-13

[0344] In aspects, the antigen may comprise an IL- 13 polypeptide, or a fragment or variant thereof that is capable of binding to a receptor for IL-13. The antigen may comprise an IL- 13 polypeptide, or a fragment or variant thereof that is capable of binding to an IL4Ral receptor subunit. The antigen may comprise an IL- 13 polypeptide, or a fragment or variant thereof that is capable of binding to a IL13Ral receptor subunit. The antigen may comprise an IL-13 polypeptide, or a fragment or variant thereof that is capable of binding to a IL13Ra2 receptor subunit. The antigen may comprise an IL- 13 polypeptide, or a fragment or variant thereof that is capable of binding to a heterodimeric receptor complex consisting of IL4Ral and IL13Ral. The IL-13 polypeptide may be from any species. In certain embodiments, the IL- 13 polypeptide may be canine or feline. In certain embodiments, the IL- 13 polypeptide is canine. In embodiments, the IL-13 polypeptide is feline.

[0345] In aspects, the antigen comprises a canine IL-13, or a fragment or variant thereof that is capable of binding to a canine IL- 13 receptor. In certain such embodiments, the antigen comprises a mature canine IL- 13, or a fragment or variant thereof that is capable of binding to a canine IL- 13 receptor. In certain such embodiments, the antigen comprises a mature canine IL- 13, or a fragment or variant thereof that is not capable of binding to a canine IL- 13 receptor.

[0346] In certain embodiments, the antigen comprises a fragment or variant of IL- 13 that is capable of binding to an IL- 13 receptor but has reduced signaling as compared with wild-type IL-13. In certain such embodiments, the antigen comprises a fragment or variant of canine IL- 13 that is capable of binding to canine IL- 13 receptor but has reduced signaling as compared with wild-type canine IL-13. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL- 13 that is capable of binding to canine IL- 13 receptor but has reduced signaling as compared with wild-type canine IL-13.

[0347] In certain embodiments, the antigen comprises a fragment or variant of IL- 13 that is capable of binding to an IL- 13 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of canine IL- 13 that is capable of binding to the canine IL- 13 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL- 13 that is capable of binding to the canine IL- 13 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.

[0348] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity an amino acid sequence of SEQ ID NO: 91 or 93 or a conservatively-substituted variant thereof. In other aspects, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity an amino acid sequence of SEQ ID NO: 91 or 93 or a conservatively-substituted variant thereof or is capable of binding to an IL- 13 receptor polypeptide comprising or consisting of IL4Ral, IL13Ral, IL13Ra2, or a complex comprising or consisting of IL4Ral and IL13Ral.

[0349] In certain embodiments, the antigen comprises a feline IL- 13, or a fragment or variant thereof that is capable of binding to a feline IL- 13 receptor. In certain such embodiments, the antigen comprises a mature feline IL- 13, or a fragment or variant thereof that is capable of binding to a feline IL- 13 receptor. In certain such embodiments, the antigen comprises a mature feline IL-13, or a fragment or variant thereof that is not capable of binding to a feline IL- 13 receptor.

[0350] In certain embodiments, the antigen comprises a fragment or variant of IL- 13 that is capable of binding to an IL- 13 receptor but has reduced signaling as compared with wild-type IL-13. In certain such embodiments, the antigen comprises a fragment or variant of feline IL- 13 that is capable of binding to feline IL- 13 receptor but has reduced signaling as compared with wild-type feline IL-13. In certain such embodiments, the antigen comprises a fragment or variant of maturefeline IL- 13 that is capable of binding to feline IL- 13 receptor but has reduced signaling as compared with wild-type feline IL-13.

[0351] In certain embodiments, the antigen comprises a fragment or variant of IL- 13 that is capable of binding to an IL- 13 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of feline IL- 13 that is capable of binding to the feline IL- 13 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL- 13 that is capable of binding to the feline IL- 13 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.IL-4

[0352] In aspects, the antigen may comprise an IL-4 polypeptide, or a fragment or variant thereof that is capable of binding to a receptor for IL-4. In aspects, the antigen may comprise an IL-4 polypeptide, or a fragment or variant thereof that is not capable of binding to a receptor for IL-4. The antigen may comprise an IL-4 polypeptide, or a fragment or variant thereof that is capable of binding to an IL4Ral receptor subunit. The antigen may comprise an IL-4 polypeptide, or a fragment or variant thereof that is capable of binding to a IL13Ral receptor subunit. The antigen may comprise an IL-4 polypeptide, or a fragment or variant thereof that is capable of binding to a IL13Ra2 receptor subunit. The antigen may comprise an IL-4 polypeptide, or a fragment or variant thereof that is capable of binding to a heterodimeric receptor complex consisting of IL4Ral and IL13Ral. The antigen may comprise an IL-4 polypeptide, or a fragment or variant thereof that is capable of binding to a heterodimeric receptor complex consisting of IL4Ral and yC. The IL-4 polypeptide may be from any species. In certain embodiments, the IL-4 polypeptide may be canine or feline. In certain embodiments, the IL-4 polypeptide is canine. In embodiments, the IL-4 polypeptide is feline.

[0353] In aspects, the antigen comprises a canine IL-4, or a fragment or variant thereof that is capable of binding to a canine IL-4 receptor. In certain such embodiments, the antigen comprises a mature canine IL-4, or a fragment or variant thereof that is capable of binding to a canine IL-4 receptor. In certain such embodiments, the antigen comprises a mature canine IL-4, or a fragment or variant thereof that is not capable of binding to a canine IL-4 receptor.

[0354] In certain embodiments, the antigen comprises a fragment or variant of IL-4 that is capable of binding to an IL-4 receptor but has reduced signaling as compared with wild-type IL-4. In certain such embodiments, the antigen comprises a fragment or variant of canine IL-4 that iscapable of binding to canine IL-4 receptor but has reduced signaling as compared with wild-type canine IL-4. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-4 that is capable of binding to canine IL-4 receptor but has reduced signaling as compared with wild-type canine IL-4.

[0355] In certain embodiments, the antigen comprises a fragment or variant of IL-4 that is capable of binding to an IL-4 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of canine IL-4 that is capable of binding to the canine IL-4 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-4 that is capable of binding to the canine IL-4 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.

[0356] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 112 or SEQ ID NO: 114 or conservatively-substituted variants thereof. In other embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 112 or SEQ ID NO: 114 or conservatively-substituted variants thereof, capable of binding to an IL-4 receptor polypeptide comprising or consisting of IL4Ral, IL13Ral, yC, a complex comprising or consisting of IL4Ral and IL13Ral, or a complex consisting of IL4Ral and yC.

[0357] In certain embodiments, the antigen comprises a feline IL-4, or a fragment or variant thereof that is capable of binding to a feline IL-4 receptor. In certain such embodiments, the antigen comprises a mature feline IL-4, or a fragment or variant thereof that is capable of binding to a feline IL-4 receptor. In certain such embodiments, the antigen comprises a mature feline IL-4, or a fragment or variant thereof that is not capable of binding to a feline IL-4 receptor.

[0358] In certain embodiments, the antigen comprises a fragment or variant of IL-4 that is capable of binding to an IL-4 receptor but has reduced signaling as compared with wild-type IL-4. In certain such embodiments, the antigen comprises a fragment or variant of feline IL-4 that is capable of binding to feline IL-4 receptor but has reduced signaling as compared with wild-typefeline IL-4. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-4 that is capable of binding to feline IL-4 receptor but has reduced signaling as compared with wild-type feline IL-4.

[0359] In certain embodiments, the antigen comprises a fragment or variant of IL-4 that is capable of binding to an IL-4 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of feline IL-4 that is capable of binding to the feline IL-4 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-4 that is capable of binding to the feline IL-4 receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1

[0360] In aspects, the antigen may comprise an IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide, or a fragment or variant thereof that is capable of binding to an appropriate receptor for IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide. The antigen may comprise an IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide polypeptide, or a fragment or variant thereof that is capable of binding to an appropriate receptor. The antigen may comprise an IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide polypeptide, or a fragment or variant thereof that is capable of binding to an appropriate receptor. The antigen may comprise an IL-lra, IL-IRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide polypeptide, or a fragment or variant thereof that is capable of binding to appropriate receptor subunit. The IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide may be from any species. In certain embodiments, the IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide polypeptide may be canine or feline. In certain embodiments, the IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide polypeptide is canine. In embodiments, the IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide polypeptide is feline.

[0361] In aspects, the antigen comprises a canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide, or a fragment or variant thereof that is capable of binding to an appropriate receptor. In certain such embodiments, the antigen comprises a mature canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide, or a fragment or variant thereof that is capable of binding to the appropriate receptor. In certain such embodiments, the antigen comprises a mature canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide, or a fragment or variant thereof that is not capable of binding to the appropriate canine receptor.

[0362] In certain embodiments, the antigen comprises a fragment or variant of IL-lra, IL-IRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to the appropriate receptor but has reduced signaling as compared with wild-type IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide. In certain such embodiments, the antigen comprises a fragment or variant of canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to an appropriate receptor but has reduced signaling as compared with wild-type canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to an appropriate canine receptor but has reduced signaling as compared with wild-type canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide.

[0363] In certain embodiments, the antigen comprises a fragment or variant of IL-lra, IL-IRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to an appropriate receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of canine IL- IllIra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to the appropriate canine receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature canine IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to the appropriate canine receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.

[0364] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of any one of SEQ ID NOs: 115-140 or is a conservatively-substituted variant thereof.

[0365] In certain embodiments, the antigen comprises a feline IL-lra, IL-lRacP, IL- 17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide, or a fragment or variant thereof that is capable of binding to an appropriate feline receptor. In certain such embodiments, the antigen comprises a mature feline IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide, or a fragment or variant thereof that is capable of binding to an appropriate feline receptor. In certain such embodiments, the antigen comprises a mature feline IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide, or a fragment or variant thereof that is not capable of binding to an appropriate feline receptor.

[0366] In certain embodiments, the antigen comprises a fragment or variant of IL-lra, IL-IRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to an appropriate receptor but has reduced signaling as compared with wild-type IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide. In certain such embodiments, the antigen comprises a fragment or variant of feline IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to feline receptor but has reduced signaling as compared with wild-type feline IL-lra, IL-IRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to the appropriate feline receptor but has reduced signaling as compared with wild-type feline IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide.

[0367] In certain embodiments, the antigen comprises a fragment or variant of IL-lra, IL-IRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to an receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of feline IL-lra, IL-lRacP, IL- 17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to the feline receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus. In certain such embodiments, the antigen comprises a fragment or variant of mature feline IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 polypeptide that is capable of binding to the feline receptor but is not capable of inducing a dermatological condition including atopic dermatitis or pruritus.

[0368] In certain embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of any one of SEQ ID NOs: 115-140 or is a conservatively-substituted variant thereof, provided that the antigen is capable of binding to a receptor polypeptide.

[0369] In aspects described herein, antigens described herein bind to or selectively bind to dermatological condition mediating polypeptide or a dermatological related polypeptides described herein, such as IL-4, IL-5, IL- 13, or other dermatological condition mediating polypeptides or a dermatological related polypeptides described herein.Additional Representative Antigens

[0370] In some aspects, representative antigens for use herein are described in Table A or Table B. These antigens may be used as the Antigen “A” in Formula II. The Table A and TableB antigens may also be used as the “Antigen” in conjunction with the multimer described in FIG 1J.Table B& &

[0371] The disclosure further provides for fusion proteins wherein the immune response results in the neutralization of an antigen.Non-Surgical Sterilization Antigens

[0372] In an aspect, antigens described herein include an antigen originating from an animal in need of a non-surgical castration or sterilization, a gonadotropin-releasing hormone, or Zona Pellucida Protein or fragment thereof.

[0373] In an aspect, antigens described here include an antigen polypeptide sequence comprising an antigen originating from a canine or feline infectious disease pathogen or fragmentthereof. In aspects, the antigen may comprise an antigen originating from a canine or feline infectious disease pathogen, or a fragment or variant thereof.

[0374] In embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of an antigen from an animal in need of a non-surgical castration or sterilization, a gonadotropin-releasing hormone, or Zona Pellucida Protein or fragment thereof.

[0375] In embodiments, the antigen comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of an antigen originating from a an animal in need of a non-surgical castration or sterilization, a gonadotropin-releasing hormone, or Zona Pellucida Protein, or is a conservatively-substituted or truncated variant thereof.

[0376] In embodiments, the present disclosure relates to a platform for generating a neutralizing antibody immune response to an antigen that when neutralized results in the castration or sterilization of the animal, wherein the antigen comprises a polypeptide sequence of an antigen required for the animals fertility, and / or fragment thereof. In some embodiments the antigen is a Gonadotropin-Releasing Hormone or Zona Pellucida protein. In some embodiments an antigen comprises a substituted protein. In some embodiments the antigen is a protein from a human or animal. In some embodiments the antigen is a protein from a canine, feline, bovine, porcine, mammal, and / or vertebrate.

[0377] In some embodiments the antigen that when neutralized results in castration or sterilization of the animal is an amino acid sequence fused to the N-terminus of an IgG sequence that makes a subunit of a hexamer. In some embodiments the antigen is a Gonadotropin-Releasing Hormone or Zona Pellucida protein. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 1. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 25. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 26.

[0378] In some embodiments the present disclosure relates in part to an antigen that is a fragment or variant of an antigen that when neutralized results in castration or sterilization of the animal wherein the antigen is capable of binding to an corresponding receptor or ligand. In someembodiments the antigen is a Gonadotropin-Releasing Hormone or Zona Pellucida protein. The antigen may be from any species. In some embodiments, the antigen may be canine, feline, bovine, porcine, or any other vertebrate.

[0379] In some embodiments, the antigen comprises a fragment or variant of an antigen that when neutralized results in castration or sterilization of the animal wherein the antigen is capable of binding to a canine, feline, bovine, porcine, or any other vertebrate receptor or ligand. In some embodiments, the antigen comprises a fragment of variant of a mature antigen that when neutralized results in castration or sterilization of the animal wherein the antigen is capable of binding to the canine, feline, bovine, porcine, or any other vertebrate receptor or ligand. In some embodiments the antigen is a Gonadotropin-Releasing Hormone or Zona Pellucida protein.

[0380] The antigen may comprise an antigen that when neutralized results in castration or sterilization of the animal, or a fragment or variant thereof that is capable of binding to a canine, feline, bovine, porcine, or any other vertebrate receptor or ligand. The antigen that when neutralized results in castration or sterilization of the animal may be from any species. In some embodiments the antigen is a Gonadotropin-Releasing Hormone or Zona Pellucida protein. In some embodiments the antigen is a protein from a human or animal. In some embodiments the antigen is a protein from a plant, fungus, protist, bacteria, or archaebacteria. In some embodiments the antigen is a viral protein.Representative Infectious Disease Antigens

[0381] In embodiments, the present disclosure relates to a platform for generating a neutralizing antibody immune response to an infectious disease antigen, wherein the antigen comprises a polypeptide sequence of an infectious disease antigen, variant of an infectious disease antigen, and / or fragment thereof. In some embodiments an antigen comprises a substituted protein. In some embodiments the antigen is a protein from a human or animal. In some embodiments the antigen is a protein from a plant, fungus, protist, bacteria, or archaebacteria. In some embodiments the antigen is a viral protein.

[0382] In some embodiments the an infectious disease antigen sequence is an amino acid sequence fused to the N-terminus of an IgG sequence that makes a subunit of a hexamer. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 1. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 25. In some embodiments the antigen is an amino acid sequence fused to amino terminus of SEQ ID NO: 26.

[0383] In some embodiments the present disclosure relates in part to an antigen that is a fragment or variant of an infectious disease antigen that is capable of binding to an corresponding receptor or ligand. The antigen may be from any species. In some embodiments, the antigen may be canine, feline, bovine, porcine, or any other vertebrate.

[0384] In some embodiments, the antigen comprises a fragment or variant of an infectious disease antigen that is capable of binding to a canine, feline, bovine, porcine, or any other vertebrate receptor or ligand. In some embodiments, the antigen comprises a fragment of variant of a mature infectious disease antigen that is capable of binding to the canine, feline, bovine, porcine, or any other vertebrate receptor or ligand.

[0385] The antigen may comprise an infectious disease antigen, or a fragment or variant thereof that is capable of binding to a canine, feline, bovine, porcine, or any other vertebrate receptor or ligand. The infectious disease antigen may be from any species. In some embodiments the antigen is a protein from a human or animal. In some embodiments the antigen is a protein from a plant, fungus, protist, bacteria, or archaebacteria. In some embodiments the antigen is a viral protein.

[0386] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an infectious disease related antigen;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

[0387] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an infectious disease pathogen;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

[0388] The disclosure further provides for a fusion proteins comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen originating from an infectious disease pathogen;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region; andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0389] In aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen from an infectious disease pathogen;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

[0390] In aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an infectious disease receptor antigen;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

[0391] In other aspects, the disclosure provides for a fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen from an infectious disease pathogen;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(d) a tailpiece polypeptide sequence andwherein the polypeptide chains form an oligomer or is capable of forming an oligomer.

[0392] In aspects, the antigen originating from or from an infectious disease pathogen originates or is from a canine or feline infectious disease pathogen.

[0393] In aspects, an antigen originating from a canine or feline infectious disease pathogen comprise a polypeptide from any of but not limited to Lyssavirus rabies, canine parvovirus, canine distemper virus, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper virus, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocy tophilum, or other canine or feline pathogen.

[0394] In other aspects, the disclosure further provides for fusion proteins wherein the infectious disease antigen comprises an antigen from a canine or feline infectious disease pathogen consisting of an of any of but not limited to Lyssavirus rabies, canine parvovirus, canine distemper virus, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper virus, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocy tophilum, or other canine or feline pathogen or a fragment or variant thereof.

[0395] In aspects, fusion proteins described herein comprise polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence originating from or related to one or more of:i. Lyssavirus rabies or fragment thereof;ii. canine parvovirus or fragment thereof;iii. canine distemper virus or fragment thereof;iv. pseudorabies virus or fragment thereof;v. canine herpesvirus or fragment thereof;vi. canine coronavirus or fragment thereof;vii. canine influenza or fragment thereof;viii. anaplasma, leptospirosis or fragment thereof;ix. Bordatella bronchiseptica or fragment thereof;x. Borrelia burgdorferi or fragment thereof;xi. Giardia lamblia or fragment thereof;xii. Isospora species or fragment thereof;xiii. feline distemper virus or fragment thereof;xiv. feline panleukopenia or fragment thereof;xv. feline immunodeficiency virus or fragment thereof;xvi. feline coronavirus or fragment thereof;xvii. feline leukemia virus or fragment thereof;xviii. Bartonella henselae or fragment thereof;xix. Rickettsia felis or fragment thereof;xx. Anaplasma phagocytophilum or fragment thereof;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer, optionally form an oligomer, or are capable of forming an oligomer.

[0396] In embodiments, fusion proteins described herein comprise polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising an antigen originating from any one of the following:i. Lyssavirus rabies or fragment thereof;ii. canine parvovirus or fragment thereof;iii. canine distemper virus or fragment thereof;iv. pseudorabies virus or fragment thereof;v. canine herpesvirus or fragment thereof;vi. canine coronavirus or fragment thereof;vii. canine influenza or fragment thereof;viii. anaplasma, leptospirosis or fragment thereof;ix. Bordatella bronchiseptica or fragment thereof;x. Borrelia burgdorferi or fragment thereof;xi. Giardia lamblia or fragment thereof;xii. Isospora species or fragment thereof;xiii. feline distemper virus or fragment thereof;xiv. feline panleukopenia or fragment thereof;xv. feline immunodeficiency virus or fragment thereof;xvi. feline coronavirus or fragment thereof;xvii. feline leukemia virus or fragment thereof;xviii. Bartonella henselae or fragment thereof;xix. Rickettsia felis or fragment thereof;xx. Anaplasma phagocytophilum or fragment thereof;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer.Representative Optional Antigen-CH2 Linker

[0397] In embodiments, the polypeptide chain comprises an optional antigen-CH2 linker. The antigen-CH2 linker may be naturally-occurring or non-natural. The antigen-CH2 linker may from an antibody from any species, for example human, canine for feline. In certain embodiments, the antigen-CH2 linker is a sequence rich in residues selected from any amino acid. In certain embodiments, the antigen-CH2 linker is a sequence rich in residues selected from glycine and serine.

[0398] In certain embodiments, the antigen-CH2 linker comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 27 or is a conservatively-substituted variant thereof.

[0399] In further aspects, fusion proteins described herein comprise a linker which is optionally a glycine and / or serine rich sequence. In aspects, the linker is 2 to 20 amino acids, 2 to 10 amino acids, 3 to 15 amino acids, 5 to 15 amino acids, or 5 to 10 amino acids in length.Representative CH2 Domains

[0400] In embodiments, the polypeptide chain comprises a CH2 domain. The CH2 domain may be naturally-occurring or non-natural. The CH2 domain may from an antibody from any species, for example human or canine, or is a functional fragment or variant of a CH2 domain from such an antibody. In some embodiments, the CH2 domain is from a human antibody, or is a functional fragment or variant of a CH2 domain from a human antibody. Herein the CH2 domain positions correspond to the EU convention of immunoglobulin sequences.

[0401] In some embodiments, the CH2 domain is from an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH2 domain of an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody, or is a conservatively-substituted variant thereof.

[0402] In some embodiments, the CH2 domain is from an IgG-B, IgA, or IgG antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain is from a canine IgG-B antibody or is a functional fragment or variant thereof.

[0403] In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 16 or is a conservatively-substituted variant thereof. In some embodiments, the CH2 domain comprises SEQ ID NO: 16 with an glycine 309 substitution. In some embodiments, the CH2 domain comprises SEQ ID NO: 16 with an G309C substitution. In some embodiments, the CH2 domain comprises SEQ ID NO: 17.

[0404] In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 17 or is a conservatively-substituted variant thereof, provided that the CH2 domain comprises a cysteine at the residue position corresponding to residue position 309 of SEQ ID NO: 17.

[0405] In some embodiments, the CH2 domain is from an IgA antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain is from an IgAl or IgA2 antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH2 domain from an IgAl or IgA2 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0406] In some embodiments, the CH2 domain is from an IgG antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain is from an IgGl, IgG2, IgG3,or IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH2 domain from an IgGl, IgG2, IgG3, or IgG4 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0407] In some embodiments, the CH2 domain is from an IgGl or IgG4 antibody or is a functional fragment or variant thereof.

[0408] In some embodiments, the CH2 domain is from an IgGl antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain is from a human IgGl antibody or is a functional fragment or variant thereof.

[0409] In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 12, a substituted variant thereof, or a conservatively-substituted variant thereof .

[0410] In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 12 or is a conservatively-substituted variant thereof, provided that the CH2 domain comprises a cysteine at the residue position corresponding to residue position 309 of SEQ ID NO: 12. In some embodiments, the CH2 domain comprises the amino acid sequence of SEQ ID NO: 13.

[0411] In some embodiments, the CH2 domain is from an IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the CH2 domain is from a human IgG4 antibody or is a functional fragment or variant thereof.

[0412] In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 14 or is a conservatively-substituted variant thereof. In some embodiments the CH2 domain of SEQ ID NO: 14 is substituted at residue 235. In some embodiments the CH2domain of SEQ ID NO: 14 is substituted at residue 309. In some embodiments the CH2 domain of SEQ ID NO: 14 is substituted at residue 329. In some embodiments the CH2 domain of SEQ ID NO: 14 is substituted at residues 235, 309 and 329. In some embodiments the CH2 domain of SEQ ID NO: 14 comprises an L235E substitution. In some embodiments the CH2 domain of SEQ ID NO: 14 comprises an L309C substitution. In some embodiments the CH2 domain of SEQ ID NO: 14 comprises a P329G. In some embodiments the CH2 domain of SEQ ID NO: 14 comprises a substitution selected from L235E, L309C and P329G. In some embodiments the CH2 domain of SEQ ID NO: 14 comprises an L235E, L309C and P329G substitution.

[0413] In some embodiments, the CH2 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 15 or is a conservatively-substituted variant thereof, provided that the CH2 domain comprises a cysteine at the residue position corresponding to residue position 309 of SEQ ID NO: 15.

[0414] In some embodiments, the CH2 domain is a functional fragment or variant of a naturally-occurring CH2 domain that comprises a substitution such that it is capable of forming additional or fewer cross-links, for example disulfide bonds, with another polypeptide chain (an inter-chain cross-link) or with another portion of the same polypeptide chain (an intra-chain crosslink). For example, the CH2 domain may comprise additional or fewer cysteine residues as compared with the corresponding naturally-occurring CH2 domain. The cysteine residue serves as a position where a disulfide bond may form with other another cysteine in the same polypeptide chain or in a different polypeptide chain.

[0415] In some embodiments, the CH2 domain is a functional fragment or variant of a CH2 domain from a human IgGl or IgG4 antibody or a canine IgG-B antibody and comprises a substitution as compared with the CH2 domain from, respectively, wild-type human IgGl or IgG4 antibody or wild-type canine IgG-B antibody such that it is capable of forming a cross-link, for example a disulfide bond, with another polypeptide chain. In some embodiments, the substitution is the presence of an additional cysteine as compared with the CH2 domain from wild-type human IgGl or IgG4 antibody or wild-type canine IgG-B antibody.Representative Interdomain Linker Between CH2 and CH3 Domains

[0416] In embodiments, the polypeptide chain comprises a CH2 - CH3 interdomain linker. The CH2 - CH3 interdomain linker may be naturally-occurring or non-natural. The CH2 - CH3 interdomain linker may from an antibody from any species, for example human, or is a functional fragment or variant of a CH2 - CH3 interdomain linker from such an antibody. In certain embodiments, the CH2 - CH3 interdomain linker is from a human antibody, or is a functional fragment or variant of a CH2 - CH3 interdomain linker from a human antibody.

[0417] In certain embodiments, the CH2 - CH3 interdomain linker is from an IgA, IgD, IgE, IgG, or IgM antibody or is a functional fragment or variant thereof. In certain such embodiments, the CH2 - CH3 interdomain linker comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH2 - CH3 interdomain linker of an IgA, IgD, IgE, IgG, or IgM antibody, or is a conservatively-substituted variant thereof. In certain such embodiments, the CH2 - CH3 interdomain linker is from an IgG antibody or is a functional fragment or variant thereof.

[0418] In certain embodiments, the CH2 - CH3 interdomain linker comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 27 or is a conservatively-substituted variant thereof.Representative CH3 Domains

[0419] In embodiments, the polypeptide chain comprises a CH3 domain. The CH3 domain may be naturally-occurring or non-natural. The CH3 domain may from an antibody from any species, for example human or canine, or is a functional fragment or variant of a CH3 domain from such an antibody. In some embodiments, the CH3 domain is from a human antibody, or is a functional fragment or variant of a CH3 domain from a human antibody. Herein the CH3 domain positions correspond to the EU convention of immunoglobulin sequences.

[0420] In some embodiments, the CH3 domain is from an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH3 domain of an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody, or is a conservatively-substituted variant thereof.

[0421] In some embodiments, the CH3 domain is from an IgG-B, IgA, or IgG antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain is from a canine IgG-B antibody or is a functional fragment or variant thereof.

[0422] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 18 or is a conservatively-substituted variant thereof. In some embodiments a residue corresponding to position 355 in SEQ ID NO: 18 is substituted. In some embodiments the residue corresponding to position 355 in SEQ ID NO: 18 is substituted the with an arginine. In some embodiments the substitution in SEQ ID NO: 18 is a R355C substitution. In some embodiments, the CH3 domain comprises the amino acid sequence of SEQ ID NO: 19.

[0423] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 20 or is a conservatively-substituted variant thereof. In some embodiments a residue corresponding to position 409 in SEQ ID NO: 20 is substituted. In some embodiments the residue corresponding to position 409 in SEQ ID NO: 20 is substituted the with a lysine. In some embodiments the substitution in SEQ ID NO: 20 is a R409K substitution. In some embodiments, the CH3 domain comprises the amino acid sequence of SEQ ID NO: 21.

[0424] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 20 or a conservatively-substituted variant thereof. In some embodiments a residue corresponding to position 355 in SEQ ID NO: 20 is substituted. In some embodiments the residue corresponding to position 355 in SEQID NO: 20 is substituted the with an arginine. In some embodiments the substitution in SEQ ID NO: 20 is a Q355R substitution. In some embodiments, the CH3 domain comprises the amino acid sequence of SEQ ID NO: 22.

[0425] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 23, a substituted variant thereof, or a conservatively-substituted variant thereof .

[0426] In some embodiments, the CH3 domain is from an IgA antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain is from an IgAl or IgA2 antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH3 domain from an IgAl or IgA2 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0427] In some embodiments, the CH3 domain is from an IgG antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain is from an IgGl, IgG2, IgG3, or IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH3 domain from an IgGl, IgG2, IgG3, or IgG4 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof

[0428] In some embodiments, the CH3 domain is from an IgGl or IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain is from an IgGl antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain is from a human IgGl antibody or is a functional fragment or variant thereof.

[0429] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, atleast about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 18 or is a conservatively-substituted variant thereof. In some embodiments, the CH3 domain retains an arginine at the residue position corresponding to residue position 355 of SEQ ID NO: 18. In some embodiments, the CH3 domain comprises a substitution at position 355 of SEQ ID NO: 18. In some embodiments, the CH3 domain comprises an R355C substitution of SEQ ID NO: 18. In some embodiments, the CH3 domain comprises SEQ ID NO 19.

[0430] In some embodiments, the CH3 domain is from an IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain is from a human IgG4 antibody or is a functional fragment or variant thereof.

[0431] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 20, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0432] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 20 or is a conservatively-substituted variant thereof. In some embodiments the substituted SEQ ID NO: 20 comprise a substitution at residue 409. In some embodiments the substituted SEQ ID NO: 20 comprises a lysine at residue 409. In some embodiments the substituted SEQ ID NO: 20 comprises an R409K substitution. In some embodiments the substituted CH3 domain comprises SEQ ID NO: 21 or SEQ ID NO: 22.

[0433] In some embodiments, the CH3 domain is a functional fragment or variant of a naturally-occurring CH3 domain that comprises a substitution such that it is capable of forming additional or fewer cross-links, for example disulfide bonds, with another polypeptide chain (an inter-chain cross-link) or with another portion of the same polypeptide chain (an intra-chain crosslink). For example, the CH3 domain may comprise additional or fewer cysteine residues as compared with the corresponding naturally-occurring CH3 domain. The cysteine residue serves as a position where a disulfide bond may form with other another cysteine in the same polypeptide chain or in a different polypeptide chain.

[0434] In some embodiments, the CH3 domain is a functional fragment or variant of a CH3 domain from a human IgGl antibody and comprises a substitution as compared with the CH3 domain from wild-type human IgGl antibody such that it is capable of forming a cross-link, for example a disulfide bond, with another polypeptide chain. In some embodiments, the substitution is the presence of an additional cysteine as compared with the CH3 domain from wild-type human IgGl antibody.

[0435] In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 18 or is a conservatively-substituted variant thereof, provided that the CH3 domain comprises a cysteine at the residue position corresponding to residue position 355 of SEQ ID NO: 18. In some embodiments the arginine at residue at position 355 of SEQ ID NO: 18 is substituted to cysteine. In some embodiments the CH3 domain has a R355C substitution. In some embodiments the CH3 domain is SEQ ID NO: 19.Representative CH4 Domains

[0436] In embodiments, the polypeptide chain may further comprise a CH4 domain. The CH4 domain may be naturally-occurring or non-natural. The CH4 domain may from an antibody from any species, for example human or canine, or is a functional fragment or variant of a CH4 domain from such an antibody. In some embodiments, the CH4 domain is from a human antibody, or is a functional fragment or variant of a CH4 domain from a human antibody. Herein the CH4 domain positions correspond to the EU convention of immunoglobulin sequences.

[0437] In some embodiments, the CH4 domain is from an IgE or IgM antibody or is a functional fragment or variant thereof. In some embodiments, the CH3 domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CH4 domain of an IgE or IgM antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0438] In some embodiments, the CH4 domain is a functional fragment or variant of a naturally-occurring tailpiece that comprises a substitution such that it is capable of formingadditional or fewer cross-links, for example disulfide bonds, with another polypeptide chain (an inter-chain cross-link) or with another portion of the same polypeptide chain (an intra-chain crosslink). For example, the CH4 domain may comprise additional or fewer cysteine residues as compared with the corresponding naturally-occurring CH4 domain. The cysteine residue serves as a position where a disulfide bond may form with other another cysteine in the same polypeptide chain or in a different polypeptide chain.Representative Tailpieces

[0439] In embodiments, the polypeptide chain may further comprise a tailpiece. The tailpiece is the region of the polypeptide chain that causes the monomer subunits to assemble into a multimeric fusion protein. For example, in some embodiments, the tailpiece is capable of forming a cross-link with a polypeptide chain in another monomer subunit, thus causing such monomer subunits to assemble into a multimeric fusion protein. In some embodiments, both polypeptide chains of a monomer subunit form cross-links with different monomer subunits, thus resulting in a fusion protein comprising at least three monomer subunits.

[0440] The tailpiece may be naturally-occurring or non-natural. The tailpiece may from an antibody from any species, for example human or canine, or is a functional fragment or variant of a tailpiece domain from such an antibody. In some embodiments, the tailpiece is from a human antibody, or is a functional fragment or variant of a tailpiece from a human antibody.

[0441] In some embodiments, the tailpiece is from an IgA or IgM antibody or is a functional fragment or variant thereof. In some embodiments, the tailpiece domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the tailpiece of an IgA or IgM antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0442] In some embodiments, the tailpiece is from an IgM antibody or is a functional fragment or variant thereof. In some embodiments, the tailpiece comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the tailpiece from an IgM antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0443] In some embodiments, the tailpiece comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 1, a substituted variant thereof, or a conservatively-substituted variant thereof .

[0444] In some embodiments, the tailpiece is a functional fragment or variant of a naturally-occurring tailpiece that comprises a substitution such that it is capable of forming additional or fewer cross-links, for example disulfide bonds, with another polypeptide chain (an inter-chain cross-link) or with another portion of the same polypeptide chain (an intra-chain cross-link). For example, the tailpiece may comprise additional or fewer cysteine residues as compared with the corresponding naturally-occurring tailpiece. The cysteine residue serves as a position where a disulfide bond may form with other another cysteine in the same polypeptide chain or in a different polypeptide chain.

[0445] In some embodiments, the Fc region of each polypeptide chain further comprises a tailpiece of an antibody. The tailpiece is the region of the polypeptide chain that causes the monomer subunits to assemble into a multimeric fusion protein. For example, in some embodiments, the tailpiece is capable of forming a linkage with a polypeptide chain in another monomer subunit, thus causing such monomer subunits to assemble into a multimeric fusion protein. In some embodiments, both polypeptide chains of a monomer subunit form linkages with different monomer subunits, thus resulting it a fusion protein comprising at least three monomer subunits.

[0446] In some embodiments, tailpiece is non-natural and is designed to have increased length and / or flexibility as compared to naturally-occurring tailpieces.Representative CHI Domains

[0447] In embodiments, the polypeptide chain may further comprise a CHI domain. The CHI domain may be naturally-occurring or non-natural. The CHI domain may from an antibody from any species, for example human or canine, or is a functional fragment or variant of a CHI domain from such an antibody. In some embodiments, the CHI domain is from a human antibody, or is a functional fragment or variant of a CHI domain from a human antibody. Herein the CHI domain positions correspond to the EU convention of immunoglobulin sequences. In aspects, the CHI domain may be modified without influencing the function of fusion proteins, hexameric proteins, vaccines or immunogens described herein.

[0448] In some embodiments, the CHI domain is from an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody or is a functional fragment or variant thereof. In some embodiments, the CHI domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CHI domain of an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0449] In some embodiments, the CHI domain is from a canine IgG-B antibody or is a functional fragment or variant thereof.

[0450] In some embodiments, the CHI domain is from an IgA or IgG antibody or is a functional fragment or variant thereof.

[0451] In some embodiments, the CHI domain is from an IgA antibody or is a functional fragment or variant thereof. In some embodiments, the CHI domain is from an IgAl or IgA2 antibody or is a functional fragment or variant thereof. In some embodiments, the CHI domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CHI domain from an IgAl or IgA2 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0452] In some embodiments, the CHI domain is from an IgG antibody or is a functional fragment or variant thereof. In some embodiments, the CHI domain is from an IgGl, IgG2, IgG3, or IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the CHI domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the CHI domain from an IgGl, IgG2, IgG3, or IgG4 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0453] In some embodiments, the CHI domain is from an IgGl or IgG4 antibody or is a functional fragment or variant thereof.

[0454] In some embodiments, the CHI domain is from an IgGl antibody or is a functional fragment or variant thereof. In some embodiments, the CHI domain is from a human IgGl antibody or is a functional fragment or variant thereof.

[0455] In some embodiments, the CHI domain is a functional fragment of the CHI domain from antibody, for example an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody or functional fragment or variant thereof.

[0456] In some embodiments, the CHI domain is a functional fragment of the CHI domain from a canine IgG-B antibody. In some embodiments, the CHI domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 5, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0457] In some embodiments, the CHI domain is a functional fragment of the CHI domain from a human IgGl antibody. In some embodiments, the CHI domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 3, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0458] In some embodiments, the CHI domain is a functional fragment of the CHI domain from a human IgG4 antibody. In some embodiments, the CHI domain comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 4, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0459] In some embodiments, the CHI domain is a functional fragment or variant of a naturally-occurring CHI domain that comprises a substitution such that it is capable of forming additional or fewer cross-links, for example disulfide bonds, with another polypeptide chain (an inter-chain cross-link) or with another portion of the same polypeptide chain (an intra-chain crosslink). For example, the CHI domain may comprise additional or fewer cysteine residues as compared with the corresponding naturally-occurring CHI domain. The cysteine residue serves asa position where a disulfide bond may form with other another cysteine in the same polypeptide chain or in a different polypeptide chain.Representative Hinge Regions

[0460] In embodiments, the polypeptide chain may further comprise a hinge region. The hinge region may be naturally-occurring or non-natural. The hinge region may from an antibody from any species, for example human or canine, or is a functional fragment or variant of a hinge region from such an antibody. In some embodiments, the hinge region is from a human antibody, or is a functional fragment or variant of a hinge region from a human antibody. Herein the hinge sequence positions correspond to the EU convention of immunoglobulin sequences. Examples of suitable hinge regions include those disclosed in US 2007 / 0081406, the contents of which are hereby incorporated by reference in their entirety.

[0461] In some embodiments, the hinge region is from an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the hinge region of an IgG-B, IgA, IgD, IgE, IgG, or IgM antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0462] In some embodiments, the hinge region is from an IgG-B antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region is from a human IgGl antibody or is a functional fragment or variant thereof.

[0463] In some embodiments, the hinge region comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 10 or is a conservatively-substituted variant thereof. In some embodiments, SEQ ID NO: 10 is substituted at residue 228 of the EU convention for immunoglobulins. In some embodiments the substitution in SEQ ID NO: 10 is a K228P substitution. In some embodiments the sequence for the hinge region comprises SEQ ID NO: 11.

[0464] In some embodiments, the hinge region is from an IgA or IgG antibody or is a functional fragment or variant thereof.

[0465] In some embodiments, the hinge region is from an IgA antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region is from an IgAl or IgA2 antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the hinge region from an IgAl or IgA2 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0466] In some embodiments, the hinge region is from an IgG antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region is from an IgGl, IgG2, IgG3, or IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of the hinge region from an IgGl, IgG2, IgG3, or IgG4 antibody, a substituted variant thereof, or a conservatively-substituted variant thereof.

[0467] In some embodiments, the hinge region is from an IgGl or IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region is from an IgGl antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region is from a human IgGl antibody or is a functional fragment or variant thereof.

[0468] In some embodiments, the hinge region comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 6 or is a conservatively-substituted variant thereof. In some embodiments, SEQ ID NO: 6 is substituted at residue 220 of the EU convention for immunoglobulins. In some embodiments the substitution in SEQ ID NO: 6 is a C220S substitution. In some embodiments the sequence for the hinge region comprises SEQ ID NO: 7.

[0469] In some embodiments, the hinge region is from an IgG4 antibody or is a functional fragment or variant thereof. In some embodiments, the hinge region is from a human IgG4 antibody or is a functional fragment or variant thereof.

[0470] In some embodiments, the hinge region comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 8 or is a conservatively-substituted variant thereof. In some embodiments, SEQ ID NO: 8 is substituted at residue 228 of the EU convention for immunoglobulins. In some embodiments the substitution in SEQ ID NO: 8 is a S228P substitution. In some embodiments the sequence for the hinge region comprises SEQ ID NO: 9.

[0471] In some embodiments, the hinge region is a functional fragment or variant of a naturally-occurring hinge region that comprises a substitution such that it is capable of forming additional or fewer cross-links, for example disulfide bonds, with another polypeptide chain (an inter-chain cross-link) or with another portion of the same polypeptide chain (an intra-chain crosslink). For example, the hinge region may comprise additional or fewer cysteine residues as compared with the corresponding naturally-occurring hinge region. The cysteine residue serves as a position where a disulfide bond may form with other another cysteine in the same polypeptide chain or in a different polypeptide chain.

[0472] In some embodiments, the hinge region is a functional fragment or variant of a hinge region from a human IgGl antibody and comprises a substitution as compared with the hinge region from wild-type human IgGl antibody such that it is capable of forming at least one fewer cross-link, for example a disulfide bond, with another polypeptide chain or another portion of the same polypeptide chain. In some embodiments, the substitution is the presence of one fewer cysteine as compared with the hinge region from wild-type human IgGl antibody.

[0473] In some embodiments, the hinge region comprises an amino acid sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity with the amino acid sequence of SEQ ID NO: 6 or is a conservatively-substituted variant thereof, provided that the hinge region comprises an arginine at the residue position corresponding to residue position 220 of SEQ ID NO: 6. In some embodiments the substitution in SEQ ID NO: 6 is a C220S substitution. In some embodiments the sequence for the hinge region comprises SEQ ID NO: 7.CD40L

[0474] The disclosure features fusion proteins comprising three CD40 ligand (CD40L) subunits and an Fc polypeptide (CD40L-Fc). In one aspect, the CD40L-Fc fusion protein comprises a single chain fusion of three CD40 ligand (CD40L) subunits and an Fc monomer linked via peptide linkers. It has been found that peptide linkers having a length of 9 amino acids or more between the CD40L subunits retained stability and / or did not cause aggregation of such fusion proteins. This is in contrast to other TNF family ligands, which are prone to aggregation when linked via peptide linkers greater than 8 amino acids in length. Thus, the invention is based at least in part on these discoveries. The present invention also features compositions and methods that are useful for treating cancer comprising a CD40L-Fc fusion protein. In some embodiments, the CD40L-Fc fusion protein is administered in combination with an immune checkpoint inhibitor, including a small molecule immune checkpoint inhibitor or an immune checkpoint inhibitory antibody.

[0475] In one aspect, the disclosure provides a fusion protein (e.g., a CD40L-Fc fusion protein) including a fusion of multiple canine or feline CD40 ligand (CD40L) subunits, or fragments thereof, (scCD40L) linked to one another via linkers; and an Fc polypeptide sequence (an Fc polypeptide), where the scCD40L is linked to the Fc polypeptide via a peptide linker and wherein a dimer is formed via intermolecular interaction of the Fc polypeptides.

[0476] In one aspect, the disclosure provides a fusion protein (e.g., a CD40L-Fc fusion protein) incl...

Claims

CLAIMS1. A fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;optionally wherein the fusion protein increases an immune response in a canine or feline relative to the antigen alone and / or wherein the fusion protein increases a B cell response in the canine or feline relative to the antigen alone.

2. The fusion protein of claim 1 , wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) optionally a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

3. The fusion protein of anyone of claim 1 or 2, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a pain mediating polypeptide;(b) a linker connected to the antigen polypeptide comprising a sequence at least 95% to SEQ IDNO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 95% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) optionally a hinge polypeptide sequence, if present, comprises a sequence at least 95% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 95% to SEQ ID NO: 27.

4. The fusion protein of any one of claims 1 -3, wherein the pain mediating polypeptide comprises an NGF polypeptide, an IL- 10 polypeptide, or a TNF polypeptide.

5. A fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;optionally wherein the fusion protein increases an immune response in a canine or feline relative to the antigen alone and / or wherein the fusion protein increases a B cell response in the canine or feline relative to the antigen alone.

6. The fusion protein of claim 5, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide;(b) an optional linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

7. The fusion protein of any one of claims 5 -6, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide;(b) a linker, if present, connected to the antigen polypeptide comprising a sequence at least 95% to SEQ ID NO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 95% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) a hinge polypeptide sequence comprises a sequence at least 95% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 95% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 95% to SEQ ID NO: 27.

8. The fusion protein of anyone of claims 5 -7, wherein the dermatological condition mediating polypeptide or a dermatological related polypeptide comprises an IL-4 polypeptide, an IL-5 polypeptide or a IL- 13 polypeptide.

9. The fusion protein of any one of claims 1 to 8, wherein the polypeptide chains form an oligomer.

10. The fusion protein of any one of claims 1 to 9, wherein the fusion protein increases an immune response in an animal sufficiently to treat pain or pain related disorders and / or wherein an animal immunized with the fusion protein increases a B cell response and / or antibody titer of the antigen in an animal relative to an animal immunized with a non-fusion protein antigen sequence..

11. The fusion protein of any one of claims 1 to 10, wherein two individual polypeptide chains are cross-linked with each other and form a monomer subunit.

12. The fusion protein of any one of claims 1 to 11, wherein multiple monomer subunits form a pentameric, hexameric, or heptameric protein structure.

13. The fusion protein of any one of claims 1 to 12, wherein the immunoglobulin heavy chain comprises an amino acid sequence that is substituted relative to the native heavy chain.

14. The fusion protein of any one of claims 1 to 13, wherein, the amino acid substitutions promote the assembly of polypeptide chains into an oligomeric protein structure and optionally into a hexameric protein structure comprising six monomer subunits, each monomeric subunit comprising two individual polypeptide chains.

15. The fusion protein of any one of claims 1 to 14, wherein the immunoglobulin heavy chain sequence comprises a substitution at one or more residues selected from 220, 228, 235, 309, 329, 355, and 409, wherein residue number corresponds to the EU numbering convention for immunoglobulins.

16. The fusion protein of any one of claims 1 to 15, wherein the substitution is selected from one or more of a serine at residue 220, a proline at residue 228, a glutamate at residue 235, a cysteine at residue 309, a glycine at residue 329, and / or a cysteine at residue 355.

17. The fusion protein of any one of claims 1 to 16, wherein the substitution is a cysteine at residue 309.

18. The fusion protein of any one of claims 1 - 2, 4 - 6, and 8- 17, wherein the CHI domain comprises a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence selected from SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5.

19. The fusion protein of any one of claims 1 - 2, 4 - 6, and 8 - 18, wherein the CH2 domain comprises a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence selected from SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17.

20. The fusion protein of any one of claims 1 - 2, 4 - 6, and 8- 19, wherein the CH3 domain comprises a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence a sequence selected from SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23.

21. The fusion protein of any one of claims 1 - 2, 4 - 6, and 8 - 20, wherein the hinge comprises a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to a sequence selected from SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11.

22. The fusion protein of any one of claims 1 - 2, 4 - 6, and 8-21, wherein the IgM tailpiece comprises a sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity, or 100% sequence identity to SEQ ID NO: 1.

23. The fusion protein of any one of claims 1 to 22, wherein two individual polypeptide chains are connected to each other by disulfide linkages.

24. The fusion protein of any one of claims 1 to 23, wherein six monomer subunits form a hexameric protein and optionally a cyclic hexameric protein25. The fusion protein of any one of claims 1 to 24, wherein the hexameric protein comprises identical monomeric subunits.

26. The fusion protein of any one of claims 1 to 25, wherein the hexameric protein comprises disulfide bonds formed between adjacent monomeric subunits at residue 309.

27. The fusion protein of any one of claims 1 to 26, wherein at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% of oligomer subunits are present in a hexameric form.

28. The fusion protein of any one of claims 1 or 2, wherein each polypeptide chain comprises: (a) an antigen polypeptide sequence comprising a pain mediating polypeptide;(b) a linker connected to the antigen polypeptide comprising a sequence at least 99% identical to SEQ ID NO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 99% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) a hinge polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 99% to SEQ ID NO: 27.

29. The fusion protein of anyone of claims 5 or 6, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising a dermatological condition mediating polypeptide or a dermatological related polypeptide;(b) a linker connected to the antigen polypeptide comprising a sequence at least 99% identical to SEQ ID NO: 27;(c) a CHI polypeptide sequence connected to the linker, wherein the CHI polypeptide comprises a sequence at least 99% identical to one of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ IDNO:5;(d) a hinge polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8; SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;(e) a CH2 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO:14; SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;(f) a CH3 polypeptide sequence comprising a sequence at least 99% identical to one of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO:20; SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; and(g) a tailpiece polypeptide sequence comprising a sequence at least 99% to SEQ ID NO: 27.

30. A polypeptide chain comprising:A (Antigen) - B (CHI) - C (hinge) - D (CH2) - E (Optional Interdomain Linker) - F (CH3) - G (tailpiece)wherein:A an antigen polypeptide sequence comprising a pain mediating polypeptide, or antigenic fragment thereof;B comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

31. A polypeptide chain comprising:A comprises an IL- 10 antigen;B comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 95% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

32. The polypeptide chain of claim 31, wherein:A comprises an IL- 10 antigen;B comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence 100% identical to SEQ ID NO: 27;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

33. A polypeptide chain comprising the below:A (Antigen) - B (CHI) - C (hinge) - D (CH2) - E (Optional Interdomain Linker) - F (CH3) - G (tailpiece)wherein,A comprises an NGF antigen;B comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

34. The polypeptide chain of claim 33, wherein:A comprises an NGF antigen;B comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 95% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

35. The polypeptide chain of claim 33, wherein:A comprises an NGF antigen;B comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence 100% identical to SEQ ID NO: 27;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

36. A polypeptide chain comprising the below:A (Antigen) - B (CHI) - C (hinge) - D (CH2) - E (Optional Interdomain Linker) - F (CH3) - G (tailpiece)wherein,A comprises a substance P, CCL2 / MCP-1, IL-6, IL-17, IL-18, IL-23, IL-33, IL-36, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), HMGB1, ADAMTS-5, MMP-13, Wnt, LRRK2, Glucagon-like peptide receptor, or p75NTR antigen;B comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 90% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

37. The polypeptide chain of claim 36, wherein:A comprises a substance P, CCL2 / MCP-1, IL-6, IL-17, IL-18, IL-23, IL-33, IL-36, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), HMGB1, ADAMTS-5, MMP- 13, Wnt, LRRK2, Glucagon-like peptide receptor, or p75NTR antigen;B comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence at least 95% Identity to SEQ ID NO: 27;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

38. The polypeptide chain of claim 36, wherein:A comprises a substance P, CCL2 / MCP-1, IL-6, IL-17, IL-18, IL-23, IL-33, IL-36, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), HMGB1, ADAMTS-5, MMP-13, Wnt, LRRK2, Glucagon-like peptide receptor, or p75NTR antigen;B comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;C comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;D comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;E is optional and if present comprises an amino acid sequence 100% identical to SEQ ID NO: 27;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

39. A polypeptide chain comprising the below:A (Antigen) - B (Optional Linker) - C (CHI) - D (hinge) - E (CH2) - F (CH3) - G (tailpiece) wherein:A comprises an IL- 13 antigen;B optional, comprises an amino acid sequence with at least 90% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence with at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

40. The polypeptide chain of claim 39, wherein:A comprises an IL- 13 antigen;B optional, comprises an amino acid sequence with at least 95% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

41. The polypeptide chain of claim 39, wherein:A comprises an IL- 13 antigen;B optional, comprises an amino acid sequence 100% identical to SEQ ID NO: 2, if present; C comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

42. A polypeptide chain comprising the below:A (Antigen) - B (optional linker) - C (CHI) - D (hinge) - E (CH2) - F (CH3) - G (tailpiece) wherein,A comprises an IL-4 antigen;B optional, comprises an amino acid sequence with at least 90% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

43. The polypeptide chain of claim 42, wherein:A comprises an IL-4 antigen;B optional, comprises an amino acid sequence with at least 95% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

44. The polypeptide chain of claim 42, wherein:A comprises an IL-4 antigen;B optional, comprises an amino acid sequence 100% identical to SEQ ID NO: 2, if present; C comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

45. A polypeptide chain comprising the below:A (Antigen) - B (optional linker) - C (CHI) - D (hinge) - E (CH2) - F (CH3) - G (tailpiece) wherein,A comprises an IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 antigen;B optional, comprises an amino acid sequence with at least 90% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 90% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 90% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 90% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 90% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 90% identity to SEQ ID NO: 1.

46. The polypeptide chain of claim 45, wherein:A comprises an IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 antigen;B optional, comprises an amino acid sequence with at least 95% identity to SEQ ID NO: 2, if present;C comprises an amino acid sequence at least 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence at least 95% identity to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence at least 95% identity to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence at least 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence at least 95% identity to SEQ ID NO: 1.

47. The polypeptide chain of claim 45, wherein:A comprises an IL-lra, IL-lRacP, IL-17, IL-17C, IL-18, IL-22, IL-23pl9, IL-25, IL-33, IL-36, OSMR, IL31RA, 0X40, GLP-1, TSLP, Periostin, or Desmoglein-1 antigen;B optional, comprises an amino acid sequence 100% identical to SEQ ID NO: 2, if present; C comprises an amino acid sequence 100% identical to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5;D comprises an amino acid sequence 100% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11;E comprises an amino acid sequence 100% identical to SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17;F comprises an amino acid sequence 100% identical to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, or SEQ ID NO: 23; andG comprises an amino acid sequence 100% identical to SEQ ID NO: 1.

48. A fusion protein comprising a polypeptide chain of any one of claims 30 - 47.

49. The fusion protein of claim 48, wherein the polypeptide chains form an oligomer, and wherein the fusion protein increases an immune response in an animal relative to antigen alone.

50. The fusion protein of any one of claims 48 or 49, wherein the fusion protein is in the form of a cyclic hexamer.

51. A nucleic acid encoding a fusion protein of any one of claims 1 to 29 or 48 - 50 or a polypeptide according to any one of claims 30-47.

52. A cell comprising the nucleic acid of claim 51.

53. A method of producing a fusion protein of any one of claims 1 - 29 or 48 - 50 by expressing the fusion protein in the cell of claim 50, and purifying the fusion protein.

54. A composition of comprising a fusion protein of any one of claims 1 - 29 or 48 - 50 or a polypeptide according to any of claims 30-47.

55. The composition of claim 54 wherein the composition further comprises an adjuvant.

56. The composition of claim 55, wherein the adjuvant is selected from the group consisting of one or more of Quil A, CARBOPOL, CARBOPOL® 934, and CARBOPOL® 941 NF, aluminumhydroxide, aluminum phosphate, and aluminum potassium sulfate, and water and oil-based emulsions.

57. The composition of claim 56 wherein the adjuvant comprises Quil A.

58. The composition of any one of claims 54 - 57, wherein the adjuvants is present in the composition in an amount of from about 50 pg to 1000 pg / dose, 50 pg to 150 pg / dose from about 100 pg to 500 pg / dose, from about 100 pg to 300 pg / dose, about 100 pg / dose, about 200 pg / dose, about 300 pg / dose, about 500 pg / dose, or more than 600 pg / dose.

59. The composition of any one of claims 54 - 57, wherein the fusion protein is present in the composition in an amount of from about 5 pg per kg per dose to about 10 pg per kg per dose, from about 9 pg per kg per dose to 50 pg per kg per dose, from about 9 pg per kg per dose to 30 pg per kg per dose, about 9 pg per kg per dose, about 18 pg per kg per dose, about 25 pg per kg per dose, about 45 pg per kg per dose, or more than about 55 pg per kg per dose.

60. The composition of any one of claims 54 - 57, wherein the composition comprises an adjuvant in an amount of from about 50 pg to 1000 pg / dose, 50 pg to 150 pg / dose from about 100 pg to 500 pg / dose, from about 100 pg to 300 pg / dose, about 100 pg / dose, about 200 pg / dose, about 300 pg / dose, about 500 pg / dose, or more than 600 pg / dose and a fusion protein in an amount of from about 50 pg to 1000 pg / dose, from about 100 pg to 500 pg / dose, from about 100 pg to 300 pg / dose, from about 100 pg to 400 pg / dose, about 100 pg / dose, about 200 pg / dose, about 300 pg / dose, about 500 pg / dose, or more than 600 pg / dose.

61. The fusion protein of any one of claims 1 - 29 or 48 - 50, wherein the fusion protein increases a B cell response in an animal relative to an antigen alone by about 10 fold to about 50 fold, about 10 fold to about 100 fold, about 10 fold to about 500 fold, about 10 fold to about 1,000 fold, about 50 fold to about 100 fold, about 50 fold to about 500 fold, about 50 fold to about 1,000 fold, about 100 fold to about 500 fold, about 100 fold to about 1,000 fold, or about 500 fold to about 1,000 fold.

62. A method of inducing an immune response in an animal by administering the fusion protein of any one of claims 1 - 29 or 48 - 50 or the composition of any one of claims 54 - 60 into the animal.

63. The method of claim 62, wherein the immune response is induced by administering the fusion protein to an animal by subcutaneous, intradermal, intratumoral, intranodal, intramedullary, intramuscular, intravenous, or intraperitoneal administration.

64. The method of claim 62 or 63 wherein the method comprises administering the composition once, twice, or three times to an animal.

65. The method of any one of claims 62 - 64, wherein the fusion protein is administered by dosing in an amount of from about 5 pg per kg per dose to about 10 pg per kg per dose, from about 9 pg per kg per dose to 50 pg per kg per dose, from about 9 pg per kg per dose to 30 pg per kg per dose, about 9 pg per kg per dose, about 18 pg per kg per dose, about 25 pg per kg per dose, about 45 pg per kg per dose, or more than 55 pg per kg per dose.

66. The fusion protein of any one of claims 1 - 4, 9 - 28, wherein said fusion protein is used for reducing pain sensation or pain perception in an animal.

67. The fusion protein of any one of claims 1 - 29, wherein said fusion protein is used for vaccination or immunization.

68. The composition of any one of claims 33 - 39 or 50, wherein said composition is used for reducing pain sensation or pain perception in an animal.

69. The composition of any one of claims 33 - 39 or 50, wherein said composition is used for vaccination or immunization.

70. A method of treating, alleviating, mediating, or preventing pain in an a mammal or animal comprising administering a fusion protein of any of claims 1 -4, 9 -28 or a polypeptide of any of claims 30 - 35.

71. The method of claim 70, wherein the pain comprises arthritic conditions and pain associated with arthritic conditions.

72. The method of any one of claims 70-71, wherein said mammal is a canine or feline.

73. Use of a fusion protein of any of claims 1 - 4, 9 - 28 or a polypeptide of any of claims 30 - 35 for treating, alleviating, mediating, or preventing pain in an a mammal.

74. The use of claim 73, wherein the pain comprises arthritic conditions and pain associated with arthritic conditions.

75. The use of any one of claims 70 - 71, wherein said mammal is a canine or feline.

76. A method of treating a dermatological condition in an a mammal or animal comprising administering a fusion protein of any of claims 5 -27 and 29 a polypeptide of any of claims 36 -47.

77. The method of claim 76, wherein the dermatological condition comprises atopic dermatitis or pruritus.

78. The method of any one of claims 76 - 77, wherein said mammal is a canine or feline.

79. Use of a fusion protein of any of claims 5 -27 and 29 or a polypeptide of any of claims 36 - 47 for treating a dermatological condition in an a mammal or animal.

80. The use of claim 79, wherein the dermatological condition comprises atopic dermatitis or pruritus.

81. The use of any one of claims 79 - 80, wherein said mammal is a canine or feline.

82. A fusion polypeptide comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region;wherein the polypeptide chains form an oligomer, andwherein the fusion polypeptide increases a B cell response in an animal relative to antigen alone.

83. A fusion polypeptide comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence;(b) a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence;wherein the polypeptide chains form an oligomer, andwherein the fusion polypeptide increases a B cell response in an animal relative to antigen alone.

84. A fusion protein comprising(a) an infectious disease antigen;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region; andoptionally wherein the fusion protein increases an immune response in a canine or feline relative to the antigen alone and / or wherein the fusion protein increases a canine or feline immune response in the canine or feline relative to the antigen alone.

85. The fusion protein of claim 84, wherein the infectious disease antigen comprises a polypeptide from a pathogenic virus, fungus, bacterium, or protist.

86. The fusion protein of claims 84 or 85, wherein the immune response inhibits one or more infections from Lyssavirus rabies, canine parvovirus, canine distemper virus, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper virus, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocy tophilum, or other canine or feline pathogen.

87. A fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) An infectious disease antigen;(b) optionally a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

88. A fusion protein comprising polypeptide chains, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising one of a Lyssavirus rabies, canine parvovirus, canine distemper virus, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper virus, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocy tophilum, or other canine or feline pathogen polypeptides;(b) an Fc receptor binding polypeptide sequence comprising an immunoglobulin heavy chain constant region connected to the antigen sequence; and(c) a tailpiece polypeptide sequence connected to the C-terminal to the immunoglobulin heavy chain constant region.

89. The fusion protein of claim 88, wherein each polypeptide chain comprises:(a) an antigen polypeptide sequence comprising one of a Lyssavirus rabies, canine parvovirus, canine distemper virus, pseudorabies, canine herpesvirus, canine coronavirus, canine influenza, anaplasma, leptospirosis, Bordatella bronchiseptica, Borrelia burgdorferi, Giardia lamblia, Isospora species, feline distemper virus, feline panleukopenia, feline immunodeficiency virus, feline coronavirus, feline leukemia virus, Bartonella henselae, Rickettsia felis, Anaplasma phagocy tophilum, or other canine or feline pathogen polypeptides;(b) optionally, a linker connected to the antigen polypeptide sequence;(c) a CHI polypeptide sequence connected to the linker;(d) a hinge polypeptide sequence;(e) a CH2 polypeptide sequence;(f) a CH3 polypeptide sequence; and(g) a tailpiece polypeptide sequence.

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