Methods and compositions for inducing antigen specific tolerance

Abstract

Because of its myeloid-specific expression, it was hypothesized that CD200R could provide both an inhibitory signal and a target for antigen delivery to antigen presenting cells if antigens are fused recombinantly to a soluble CD200. The examples demonstrate that immunological tolerance can be established using antigen-fused CD200 molecules, including CD200Fc- fused antigen. This tolerance was demonstrated by abrogating responses to immune challenge and induction of production of tolerogenic cytokines, including IL- 10. Accordingly, the polypeptides, compositions, and methods are useful for tolerization of any antigen, such as any antigen related to autoimmune conditions, allergy conditions, anti-drug immunity conditions, among others. Described here is a polypeptide comprising a CD200 polypeptide operatively linked to an antigen. Also provided is a nucleic acid encoding a polypeptide, an expression vector comprising a nucleic acid of the disclosure, host cells comprising a polypeptide of the disclosure. Also described are methods utilizing the polypeptides and compositions.

Description

METHODS AND COMPOSITIONS FOR INDUCING ANTIGEN SPECIFIC TOLERANCECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of U.S. Provisional Application No. 63 / 599,404, filed November 15, 2023, which is hereby incorporated by reference in its entirety.INCORPORATION OF SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 15, 2024, is named ARCDP0825WO.xml and is 68,886 bytes in size.I. Field of the Invention

[0003] The present invention relates generally to medical treatment methods and compositions.IL Background

[0004] Currently, the treatment of allergy, autoimmunity, and immune reactions to the growing class of biologic drugs is primarily based on suppressing the immune system, leaving patients in an immunocompromised state. Especially as antigens seemingly targeted in autoimmune processes have been identified over the past few decades, the interest in developing antigen-specific therapies that can induce tolerance to peptides or proteins has risen. Even since the early 20th century, attempts were made to use grass pollen extracts to treat allergy. Allergen immunotherapy (AIT) is a standard treatment for allergic rhinitis and allergic asthma, and while it can be effective it requires prolonged treatment and is sometimes associated with adverse reactions. Outside of AIT, antigen-specific therapies have showed promising preclinical results but have so far failed to make it into the clinic, particularly in the context of autoimmune diseases like type 1 diabetes and celiac disease. There is a need in the art for more therapies that can treat allergy, autoimmunity, and unwanted immune reactions without immunosuppression.SUMMARY

[0005] Because of its myeloid-specific expression, it was hypothesized that CD200R could provide both an inhibitory signal and a target for antigen delivery to antigen presenting cells if antigens are fused recombinantly to a soluble CD200. The examples demonstrate that immunological tolerance can be established using antigen-fused CD200 molecules, including CD200Fc-fused antigen. This tolerance was demonstrated by abrogating responses to immune challenge and induction of production of tolerogenic cytokines, including IL- 10. Accordingly,the polypeptides, compositions, and methods are useful for tolerization of any antigen, such as any antigen related to autoimmune conditions, allergy conditions, anti-drug immunity conditions, among others. Described here is a polypeptide comprising a CD200 polypeptide operatively linked to an antigen. Also provided is a nucleic acid encoding a polypeptide, an expression vector comprising a nucleic acid of the disclosure, host cells comprising a polypeptide, nucleic acid, and / or expression vector of the disclosure. Compositions include pharmaceutical composition comprising a polypeptide, nucleic acid, expression vector, and / or host cell of the disclosure.

[0006] Methods include a method of making a cell comprising transferring a nucleic acid or expression vector of the disclosure into a cell. Also described is a method for making a polypeptide comprising transferring an expression vector of the disclosure into a cell and incubating the cell under conditions sufficient for expression of the polypeptide encoded on the expression vector. Further methods provide for a method for inducing antigen-specific immune tolerance and / or for inducing tolerogenic cytokines in a subject in need thereof, the method comprising administering a polypeptide or pharmaceutical composition of the disclosure to the subject. Yet further methods describe a method for inducing anergy to an antigen in a subject in need thereof, the method comprising administering a polypeptide or pharmaceutical composition of the disclosure to the subject. Also described is a method for treating an allergy or autoimmune disease, comprising administering a polypeptide or pharmaceutical composition of the disclosure to the subject.

[0007] The CD200 polypeptide may comprise or consist of the extracellular domain of a CD200 protein. The polypeptide may further comprise a Fc region. The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. The Fc region may be from or derived from an IgG, IgA, IgD, IgM, or IgE antibody isotype. A Fc region from or derived from an IgG, IgA, IgD, IgM, or IgE antibody isotype may be excluded. The Fc region may comprise a N-glycosylation site. The CD200 polypeptide is covalently linked to the antigen.

[0008] The CD200 polypeptide may be covalently linked to the antigen through a linker. The CD200 polypeptide may be covalently linked to the Fc region through a linker. The antigen may be covalently linked to the Fc region through a linker. The antigen may be amino-proximal to the CD200 polypeptide and / or Fc region. The antigen may be carboxy -proximal to the CD200 polypeptide and / or Fc region. The Fc region may be amino-proximal to the CD200 polypeptide and / or antigen. The Fc region may be carboxy-proximal to the CD200 polypeptide and / or antigen. The antigen may be amino-proximal to the CD200 polypeptide and / or Fcregion. The antigen may be carboxy-proximal to the CD200 polypeptide and / or Fc region. A first region is 3 ’-proximal to a second region when the first region is attached to the 3’ nucleic acid end of the second region. There may be further intervening amino acid residues between the first and second regions. Thus, the regions need not be immediately adjacent, unless specifically specified as not having intervening amino acid residues. The term “5 ’-proximal” is similarly defined in that a first region is 5 ’-proximal to a second region when the first region is attached to the 5’ nucleic acid end of the second region. Similarly, there may be further intervening amino acid residues between the first and second regions unless stated otherwise.

[0009] The linker may comprise glycine and serine amino acid residues. The linker may comprise or exclude GGS and / or one or more of SEQ ID NOS:2-5 or 54-61 or repeated units of one or more of SEQ ID NOS:2-5 or 54-61, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeats of one or more of SEQ ID NOS:2-5 or 54-61. The polypeptide may comprise or exclude a signal sequence. The signal sequence may comprise or exclude the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that has at least 80% sequence identity to SEQ ID NO:1. The signal sequence may comprise or exclude an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO:1. The signal sequence may be amino-proximal to the CD200 polypeptide, Fc region, and / or antigen. The signal sequence may be carboxy-proximal to the CD200 polypeptide, Fc region, and / or antigen. The signal sequence may be at the amino terminus of the polypeptide.

[0010] The CD200 polypeptide may comprise or exclude the amino acid sequence of one of SEQ ID NOS: 11-14 or an amino acid sequence having at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS: 11-14. The CD200 polypeptide may comprise or exclude an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the amino acid sequence of one of SEQ ID NOS: 11-14.

[0011] The Fc region may comprise or exclude the amino acid sequence of one of SEQ ID NOS:6-9 and 62-67 or an amino acid sequence having at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS: 6-9 and 62-67. The Fc region may comprise or exclude an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, or 100% (or any derivable range therein) sequence identity to the amino acid sequence of one of SEQ ID NOS:6-9 and 62-67.

[0012] The polypeptide may comprise or consist of at least two CD200 polypeptides. The polypeptide may comprise or consist of at least three CD200 polypeptides. The polypeptide may comprise or consist of at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (or any derivable range therein) CD200 polypeptides. The polypeptide may comprise a linker between the CD200 polypeptides. The CD200 polypeptides may be in tandem with a linker that is between the CD200 polypeptides. Each CD200 polypeptide may comprise an amino acid sequence that is independently selected from the amino acid sequence of one of SEQ ID NOS: 11-14, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS: 11-14. Each CD200 polypeptide may comprise an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the amino acid sequence of one of SEQ ID NOS: 11-14. The CD200 polypeptide may comprise or exclude the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 16. The CD200 polypeptide may comprise or exclude an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the amino acid sequence of SEQ ID NO:16.

[0013] The polypeptide may comprise or consist of two Fc regions. The polypeptide may comprise or consist of three Fc regions. The polypeptide may comprise or consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (or any derivable range therein) Fc regions. The polypeptide may comprise a linker between the Fc regions. The Fc regions may be in tandem. The Fc regions may comprise a linker between the Fc regions. Each Fc region may comprise an amino acid sequence that is independently selected from the amino acid sequence of one of SEQ ID NOS:6-9 and 62-67, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS:6-9 and 62-67. Each Fc region may comprise an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the amino acid sequence of one of SEQ ID NOS:6-9 and 62-67.

[0014] The antigen may comprise a disease-associated antigen. The polypeptide may comprise or consist of two antigens. The polypeptide may comprise or consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (or any derivable range therein) antigens. The antigens may comprise different amino acid sequences and / or may be or be derived from different antigens. The antigens may comprise the same amino acid sequence and / or be from or derived from the same antigen. The antigens may be associated with the same disease. The antigens may be associated with different diseases.

[0015] The polypeptide may comprise the amino acid sequence of one of SEQ ID NOS: 16- 20, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS: 16-20. The polypeptide may comprise an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the amino acid sequence of one of SEQ ID NOS: 16-20.

[0016] The antigen may comprise or exclude a therapeutic agent (or antigenic portion thereof), an antigen associated with a food allergy, or an antigen associated with an autoimmune disease. The antigen may comprise or exclude the amino acid sequence of one or more of SEQ ID NOS:31-53, an amino acid sequence comprising at least 80% sequence identity to one or more of SEQ ID NOS:31-53, an antigen comprising an amino acid that is a fragment of one or more of the amino acid sequences of SEQ ID NOS:31-53, or an antigen comprising an amino acid that has at least 80% sequence identity to a fragment of one or more of the amino acid sequences of SEQ ID NOS:31-53. The antigen may comprise or exclude comprise an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the amino acid sequence of one of SEQ ID NOS:31-53. The antigen may comprise or exclude comprise an amino acid sequence that has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to a fragment of one or more of the amino acid sequences of SEQ ID NOS:31-53.

[0017] The subject may include or exclude one that has and / or has been diagnosed with an autoimmune disease or an allergy. The autoimmune disease may include or exclude arthritis, inflammatory bowel disease, scleroderma, inflammatory bowel disease, idiopathic pulmonary fibrosis, multiple sclerosis, type 1 diabetes, Crohn’s disease, psoriasis, rheumatoid arthritis, orceliac disease. The autoimmune disease may include or exclude an autoimmune disease described herein. The administration of the composition may include or exclude systemic administration. The administration of the composition may include or exclude intravenous injection. The administration of the composition may include or exclude local administration. The local administration may be at the site of inflammation. The subject may include or exclude one that has been previously treated with an anti-inflammatory agent, anti-inflammatory therapy, immunosuppressant, and / or autoimmune therapy. The subject may include or exclude one that has been determined to be non-responsive to the previous treatment. The subject may include one that has not been treated previously for the inflammatory or autoimmune disease.

[0018] The method may include or exclude administration of an additional inflammatory or autoimmune therapy. The additional therapy may include or exclude an anti-cytokine agent or a steroid. The additional therapy may include or exclude one or more of steroids, corticosteroids, anti-TNF-alpha therapy, anti-integrin therapy, infliximab, mesalamine, and vedolizumab, fmgolimod, interferon-P, dimethyl fumarate, teriflunomide, integrin a4pi, an anti- aLp2 antibody, an anti-IL-6R agent, an anti-IL-6 agent, and a Janus kinase inhibitor (e.g., tofacitinib, baricitinib, upadacitinib). The steroid may include or exclude dexamethasone, methylprednisolone, and / or prednisolone.

[0019] The term “subject” and “patient” may be used interchangeably and may refer to a human subject. The subject may be defined as a mammalian subject. The subject may also be a mouse, rat, pig, horse, non-human primate, cat, dog, cow, and the like. The subject may be one that does not have cancer. The antigen may exclude a cancer-associated antigen.

[0020] Throughout this application, the term “about” is used according to its plain and ordinary meaning in the area of cell and molecular biology to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0021] The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0022] As used herein, the terms “or” and “and / or” are utilized to describe multiple components in combination or exclusive of one another. For example, “x, y, and / or z” can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.” It is specifically contemplated that x, y, or z may be specifically excluded from an embodiment.

[0023] 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” (andany form of including, such as “includes” and “include”), “characterized by” (and any form of including, such as “characterized as”), 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.

[0024] The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of’ any of the ingredients or steps disclosed throughout the specification. The phrase “consisting of’ excludes any element, step, or ingredient not specified. The phrase “consisting essentially of’ limits the scope of described subject matter to the specified materials or steps and those that do not materially affect its basic and novel characteristics. It is contemplated that embodiments described in the context of the term “comprising” may also be implemented in the context of the term “consisting of’ or “consisting essentially of.”

[0025] Any method in the context of a therapeutic, diagnostic, or physiologic purpose or effect may also be described in “use” claim language such as “Use of’ any compound, composition, or agent discussed herein for achieving or implementing a described therapeutic, diagnostic, or physiologic purpose or effect.

[0026] Use of the one or more sequences or compositions may be employed based on any of the methods described herein. Other embodiments are discussed throughout this application. Any embodiment discussed with respect to one aspect of the disclosure applies to other aspects of the disclosure as well and vice versa.

[0027] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any composition of the invention. Aspects of an embodiment set forth in the Examples are also embodiments that may be implemented in the context of embodiments discussed elsewhere in a different Example or elsewhere in the application, such as in the Summary of Invention, Detailed Description of the Embodiments, Claims, and description of Figure Legends.

[0028] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0030] FIG. 1A-1B. CFSE dilution of OTIs and OTIIs following a three day co-culture with BMDCs that were pre-incubated with OVA or CD200-OVA variants.

[0031] FIG. 2A-2B. OTI and OTII percentages of the blood CD8 and CD4 compartment, respectively, four days after a single injection of OVA alone or CD200-OVA constructs.

[0032] FIG. 3A-3B. OTI and OTII percentage of parent T cell populations in draining lymph nodes following OVA / CFA challenge. Unchallenged mice were not treated during tolerization or challenge.

[0033] FIG. 4A-4B. FIG. 4A: OTII cells previously treated with CD200CD200-OVA are more likely to show an anergic phenotype; FIG. 4B: This effect is not observed across the bulk CD4+ T cell population.

[0034] FIG. 5A-5C. FIG. 5A-5B: Percentage of lymph node CD8 / CD4 T cells that were OTI / OTII one week after challenge; FIG. 5C: IL-10 concentration in the supernatant of the OVA re-stimulation.DETAILED DESCRIPTION OF THE INVENTIONI. Antigens

[0035] Antigens may include or exclude an antigen known in the art for which tolerance is sought. Antigens may include or exclude therapeutic agents that are proteins, peptides, antibodies and antibody-like molecules, including antibody fragments and fusion proteins with antibodies and antibody fragments. These include human, non-human (such as mouse) and non-natural (i.e., engineered) proteins, antibodies, chimeric antibodies, humanized antibodies, and non-antibody binding scaffolds, such as fibronectins, DARPins, knottins, and the like.

[0036] Antigens may include or exclude human allograft transplantation antigens against which transplant recipients develop an unwanted immune response.

[0037] Antigens may include or exclude self-antigens that cause an unwanted, autoimmune response. Those skilled in the art will appreciate that while self-antigens are of an endogenous origin in an autoimmune disease patient, the polypeptides employed in the disclosed compositions are typically synthesized exogenously (as opposed to being purified and concentrated from a source of origin).

[0038] Antigens may include or exclude foreign antigens, such as food, animal, plant and environmental antigens, against which a patient experiences an unwanted immune response. Those skilled in the art will appreciate that while a therapeutic protein can also be considered a foreign antigen due to its exogenous origin, for purposes of clarity in the description of the present disclosure such therapeutics are described as a separate group. Similarly, a plant or an animal antigen can be eaten and considered a food antigen, and an environmental antigen may originate from a plant. They are, however, all foreign antigens. In the interest of simplicity, no attempt will be made to describe distinguish and define all of such potentially overlapping groups, as those skilled in the art can appreciate the antigens that can be employed in the compositions of the disclosure, particularly in light of the detailed description and examples.

[0039] Antigens may include or exclude a complete protein, a portion of a complete protein, a peptide, or the like, and can be derivatized (as discussed above) for attachment to a linker and / or galactosylating moiety, can be a variant and / or can contain conservative substitutions, particularly maintaining sequence identity, and / or can be desialylated.

[0040] The antigen may include or exclude a therapeutic protein, peptide, antibody or antibody-like molecule. The therapeutic protein may include or exclude Abatacept, Abciximab, Adalimumab, Adenosine deaminase, Ado-trastuzumab emtansine, Agalsidase alfa, Agalsidase beta, Aldeslukin, Alglucerase, Al glucosidase alfa, a- 1 -proteinase inhibitor, Anakinra, Anistreplase (anisoylated plasminogen streptokinase activator complex), Antithrombin III, Antithymocyte globulin, Ateplase, Bevacizumab, Bivalirudin, Botulinum toxin type A, Botulinum toxin type B, Cl -esterase inhibitor, Canakinumab, Carboxypeptidase G2 (Glucarpidase and Voraxaze), Certolizumab pegol, Cetuximab, Collagenase, Crotalidae immune Fab, Darbepoetin-a, Denosumab, Digoxin immune Fab, Domase alfa, Eculizumab, Etanercept, Factor Vila, Factor VIII, Factor IX, Factor XI, Factor XIII, Fibrinogen, Filgrastim, Galsulfase, Golimumab, Histrelin acetate, Hyaluronidase, Idursulphase, Imiglucerase, Infliximab, Insulin [including recombinant human insulin (“rHu insulin”) and bovine insulin], Interferon-a2a, Interferon-a2b, Interferon-pia, Interferon-pi b, Interferon-ylb, Ipilimumab, L- arginase, L-asparaginase, L-methionase, Lactase, Laronidase, Lepirudin / hirudin, Mecasermin, Mecasermin rinfabate, Methoxy Natalizumab, Octreotide, Ofatumumab, Oprelvekin, Pancreatic amylase, Pancreatic lipase, Papain, Peg-asparaginase, Peg-doxorubicin HC1, PEG- epoetin-P, Pegfilgrastim, Peg-Interferon-a2a, Peg-Interferon-a2b, Pegloticase, Pegvisomant, Phenylalanine ammonia-lyase (PAL), Protein C, Rasburicase (uricase), Sacrosidase, Salmon calcitonin, Sargramostim, Streptokinase, Tenecteplase, Teriparatide, Tocilizumab (atlizumab), Trastuzumab, Type 1 alpha-interferon, Ustekinumab, vW factor. The therapeutic protein canbe obtained from natural sources (e.g., concentrated and purified) or synthesized, e.g., recombinantly, and includes antibody therapeutics that are typically IgG monoclonal or fragments or fusions.

[0041] Particular therapeutic protein, peptide, antibody or antibody-like molecules may include or exclude Abciximab, Adalimumab, Agalsidase alfa, Agalsidase beta, Aldeslukin, Alglucosidase alfa, Factor VIII, Factor IX, Infliximab, Insulin (including rHu Insulin), L- asparaginase, Laronidase, Natalizumab, Octreotide, Phenylalanine ammonia-lyase (PAL), or Rasburicase (uricase) and generally IgG monoclonal antibodies in their varying formats.

[0042] Antigens may include or exclude hemostatic agents (Factor VIII and IX), Insulin (including rHu Insulin), and the non-human therapeutics uricase, PAL and asparaginase.

[0043] Unwanted immune response in hematology and transplant includes autoimmune aplastic anemia, transplant rejection (generally), and Graft vs. Host Disease (bone marrow transplant rejection). Antigens may include or exclude a human allograft transplantation antigen. Specific sequences can be selected from: subunits of the various MHC class I and MHC class II haplotype proteins (for example, donor / recipient differences identified in tissue cross-matching), and single-amino-acid polymorphisms on minor blood group antigens including RhCE, Kell, Kidd, Duffy and Ss. Such compositions can be prepared individually for a given donor / recipient pair.

[0044] In the embodiments where the antigen is a self-antigen, specific antigens (and the autoimmune disease with which they are associated) can include or exclude a type I diabetes mellitus antigen. The type 1 diabetes mellitus antigen may include or exclude: insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65 or glutamate decarboxylase 2), GAD-67, glucose-6 phosphatase 2 (IGRP or islet-specific glucose 6 phosphatase catalytic subunit related protein), insulinoma-associated protein 2 (IA-2), and insulinoma-associated protein 2p (IA-2P); other antigens include ICA69, ICA12 (SOX-13), carboxypeptidase H, Imogen 38, GLIMA 38, chromogranin-A, HSP-60, caboxypeptidase E, peripherin, glucose transporter 2, hepatocarcinoma-intestine-pancreas / pancreatic associated protein, S100P, glial fibrillary acidic protein, regenerating gene II, pancreatic duodenal homeobox 1, dystrophia myotonica kinase, islet-specific glucose-6-phosphatase catalytic subunit-related protein, and SST G-protein coupled receptors 1-5. It should be noted that insulin is an example of an antigen that can be characterized both as a self-antigen and a therapeutic protein antigen. For example, rHu Insulin and bovine insulin are therapeutic protein antigens (that are the subject of unwanted immune attack), whereas endogenous human insulin is a self-antigen (that is the subject of an unwanted immune attack). Because endogenoushuman insulin is not available to be employed in a pharmaceutical composition a recombinant form is employed in the compositions of the disclosure.

[0045] Human insulin, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence: MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTR REAEDLQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN (SEQ ID NO:31).

[0046] GAD-65, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT Q05329): MASPGSGFWSFGSEDGSGDSENPGTARAWCQVAQKFTGGIGNKLCALLYGDAEKP AESGGSQPPRAAARKAAC ACDQKPC SC SKVDVNYAFLHATDLLPACDGERPTL AFL QDVMNILLQYVVKSFDRSTKVIDFHYPNELLQEYNWELADQPQNLEEILMHCQTTL KYAIKTGHPRYFNQLSTGLDMVGLAADWLTSTANTNMFTYEIAPVFVLLEYVTLKK MREIIGWPGGSGDGIFSPGGAISNMYAMMIARFKMFPEVKEKGMAALPRLIAFTSEH SHFSLKKGAAALGIGTDSVILIKCDERGKMIPSDLERRILEAKQKGFVPFLVSATAGTT VYGAFDPLLAVADICKKYKIWMHVDAAWGGGLLMSRKHKWKLSGVERANSVTW NPHKMMGVPLQCSALLVREEGLMQNCNQMHASYLFQQDKHYDLSYDTGDKALQC GRHVDVFKLWLMWRAKGTTGFEAHVDKCLELAEYLYNIIKNREGYEMVFDGKPQH TNVCFWYIPPSLRTLEDNEERMSRLSKVAPVIKARMMEYGTTMVSYQPLGDKVNFF RMVISNPAATHQDIDFLIEEIERLGQDL (SEQ ID NO:32).

[0047] IGRP, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT QN9QR9): MDFLHRNGVLIIQHLQKDYRAYYTFLNFMSNVGDPRNIFFIYFPLCFQFNQTVGTKMI WVAVIGDWLNLIFKWILFGHRPYWWVQETQIYPNHSSPCLEQFPTTCETGPGSPSGH AMGASCVWYVMVTAALSHTVCGMDKFSITLHRLTWSFLWSVFWLIQISVCISRVFIA THFPHQVILGVIGGMLVAEAFEHTPGIQTASLGTYLKTNLFLFLFAVGFYLLLRVLNI DLLWSVPIAKKWCANPDWIHIDTTPFAGLVRNLGVLFGLGFAINSEMFLLSCRGGNN YTLSFRLLCALTSLTILQLYHFLQIPTHEEHLFYVLSFCKSASIPLTWAFIPYSVHMLM KQSGKKSQ (SEQ ID NO:33).

[0048] In autoimmune diseases of the thyroid, including Hashimoto's thyroiditis and Graves' disease, antigens can include or exclude thyroglobulin (TG), thyroid peroxidase (TPO) and thyrotropin receptor (TSHR); other antigens can include or exclude sodium iodine symporter (NIS) and megalin. In thyroid-associated ophthalmopathy and dermopathy, in addition to thyroid autoantigens including TSHR, an antigen can include or exclude insulin-like growth factor 1 receptor. In hypoparathyroidism, the antigen may include or exclude calcium sensitive receptor.

[0049] In Addison's Disease, antigens may include or exclude 21 -hydroxylase, 17a- hydroxylase, and P450 side chain cleavage enzyme (P450scc); other antigens include ACTH receptor, P450c21 and P450cl7.

[0050] In premature ovarian failure, main antigens can include or exclude FSH receptor and a-enolase.

[0051] In autoimmune hypophysitis, or pituitary autoimmune disease, antigens can include or exclude pituitary gland-specific protein factor (PGSF) la and 2; another antigen can include or exclude type 2 iodothyronine deiodinase.

[0052] In multiple sclerosis, antigens can include or exclude myelin basic protein (“MBP”), myelin oligodendrocyte glycoprotein (“MOG”) and myelin proteolipid protein (“PLP”).

[0053] MBP, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT P02686): MGNHAGKRELNAEKASTNSETNRGESEKKRNLGELSRTTSEDNEVFGEADANQNN GTSSQDTAVTDSKRTADPKNAWQDAHPADPGSRPHLIRLFSRDAPGREDNTFKDRPS ESDELQTIQEDSAATSESLDVMASQKRPSQRHGSKYLATASTMDHARHGFLPRHRDT GILDSIGRFFGGDRGAPKRGSGKDSHHPARTAHYGSLPQKSHGRTQDENPVVHFFKN IVTPRTPPPSQGKGRGLSLSRFSWGAEGQRPGFGYGGRASDYKSAHKGFKGVDAQG TLSKIFKLGGRDSRSGSPMARR (SEQ ID NO:34).

[0054] MOG, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT Q16653): MASLSRPSLPSCLCSFLLLLLLQVSSSYAGQFRVIGPRHPIRALVGDEVELPCRISPGK NATGMEVGWYRPPFSRVVHLYRNGKDQDGDQAPEYRGRTELLKDAIGEGKVTLRI RNVRFSDEGGFTCFFRDHSYQEEAAMELKVEDPFYWVSPGVLVLLAVLPVLLLQITV GLIFLCLQYRLRGKLRAEIENLHRTFDPHFLRVPCWKITLFVIVPVLGPLVALIICYNW LHRRLAGQFLEELRNPF (SEQ ID NO:35).

[0055] PLP, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT P60201): MGLLECCARCLVGAPFASLVATGLCFFGVALFCGCGHEALTGTEKLIETYFSKNYQD YEYLINVIHAFQYVIYGTASFFFLYGALLLAEGFYTTGAVRQIFGDYKTTICGKGLSA TVTGGQKGRGSRGQHQAHSLERVCHCLGKWLGHPDKFVGITYALTVVWLLVFACS AVPVYIYFNTWTTCQSIAFPSKTSASIGSLCADARMYGVLPWNAFPGKVCGSNLLSICKTAEFQMTFHLFIAAFVGAAATLVSLLTFMIAATYNFAVLKLMGRGTKF (SEQ ID NO:36).

[0056] Multiple sclerosis associated antigens may include or exclude one or more of MBP13-32: KYLATASTMDHARHGFLPRH (SEQ ID NO:37); MBP83-99:ENPWHFFKNIVTPRTP (SEQ ID NO:38); MBP111-129: LSRFSWGAEGQRPGFGYGG (SEQ ID NO:39); MBP146-170: AQGTLSKIFKLGGRDSRSGSPMARR (SEQ ID NO:40); MOG1-20: GQFRVIGPRHPIRALVGDEV (SEQ ID NO:41); MOG35-55:MEVGWYRPPFSRWHLYRNGK (SEQ ID NO:42); and PLP139-154: HCLGKWLGHPDKFVGI (SEQ ID NO:43).

[0057] Rheumatoid arthritis associated antigens may include or exclude one or more of collagen II, immunoglobulin binding protein, the fragment crystallizable region of immunoglobulin G, double-stranded DNA, and the natural and cirtullinated forms of proteins implicated in rheumatoid arthritis pathology, including fibrin / fibrinogen, vimentin, collagen I and II, and alpha-enolase.

[0058] In autoimmune gastritis, an antigen may include or exclude H+, K+-ATPase.

[0059] In pernicious angemis, an antigen may include or exclude intrinsic factor.

[0060] In celiac disease, antigens may include or exclude are tissue transglutaminase and the natural and deamidated forms of gluten or gluten-like proteins, such as alpha-, gamma-, and omega-gliadin, glutenin, hordein, secalin, and avenin. Those skilled in the art will appreciate, for example, that while the main antigen of celiac disease is alpha gliadin, alpha gliadin turns more immunogenic in the body through deamidation by tissue glutaminase converting alpha gliadin's glutamines to glutamic acid. Thus, while alpha gliadin is originally a foreign food antigen, once it has been modified in the body to become more immunogenic it can be characterized as a self-antigen.

[0061] In vitiligo, an antigen may include or exclude tyrosinase, and tyrosinase related protein 1 and 2.

[0062] MARTI, Melanoma antigen recognized by T cells 1, Melan-A, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT Q16655):MPREDAHFIYGYPKKGHGHSYTTAEEAAGIGILTVILGVLLLIGCWYCRRRNGYRAL MDKSLHVGTQCALTRRCPQEGFDHRDSKVSLQEKNCEPVVPNAPPAYEKLSAEQSP PPYSP (SEQ ID NO:44).

[0063] Tyrosinase, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT P14679):MLLAVLYCLLWSFQTSAGHFPRACVSSKNLMEKECCPPWSGDRSPCGQLSGRGSCQ NILLSNAPLGPQFPFTGVDDRESWPSVFYNRTCQCSGNFMGFNCGNCKFGFWGPNCT ERRLLVRRNIFDLSAPEKDKFFAYLTLAKHTISSDYVIPIGTYGQMKNGSTPMFNDINI YDLFVWMHYYVSMDALLGGSEIWRDIDF AHEAP AFLPWHRLFLLRWEQEIQKLTGD ENFTIPYWDWRDAEKCDICTDEYMGGQHPTNPNLLSP ASFF S S WQI VC SRLEEYNSH QSLCNGTPEGPLRRNPGNHDKSRTPRLPSSADVEFCLSLTQYESGSMDKAANFSFRN TLEGFASPLTGIADASQSSMHNALHIYMNGTMSQVQGSANDPIFLLHHAFVDSIFEQ WLRRHRPLQEVYPEANAPIGHNRESYMVPFIPLYRNGDFFISSKDLGYDYSYLQDSD PDSFQDYIKSYLEQASRIWSWLLGAAMVGAVLTALLAGLVSLLCRHKRKQLPEEKQ PLLMEKEDYHSLYQSHL (SEQ ID NO:45).

[0064] Melanocyte protein PMEL, gplOO, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT P40967): MDLVLKRCLLHLAVIGALLAVGATKVPRNQDWLGVSRQLRTKAWNRQLYPEWTE AQRLDCWRGGQVSLKVSNDGPTLIGANASFSIALNFPGSQKVLPDGQVIWVNNTIIN GSQVWGGQPVYPQETDDACIFPDGGPCPSGSWSQKRSFVYVWKTWGQYWQVLGG P VSGLSIGTGRAMLGTHTMEVTVYHRRGSRS YVPLAHS S SAFTITDQ VPF S VS VSQLR ALDGGNKHFLRNQPLTFALQLHDPSGYLAEADLSYTWDFGDSSGTLISRALWTHTY LEPGPVTAQVVLQAAIPLTSCGSSPVPGTTDGHRPTAEAPNTTAGQVPTTEVVGTTPG QAPTAEPSGTTSVQVPTTEVISTAPVQMPTAESTGMTPEKVPVSEVMGTTLAEMSTP EATGMTPAEVSIVVLSGTTAAQVTTTEWVETTARELPIPEPEGPDASSIMSTESITGSL GPLLDGTATLRLVKRQVPLDCVLYRYGSFSVTLDIVQGIESAEILQAVPSGEGDAFEL TVSCQGGLPKEACMEISSPGCQPPAQRLCQPVLPSPACQLVLHQILKGGSGTYCLNVS LADTNSLAVVSTQLIMPGQEAGLGQVPLIVGILLVLMAVVLASLIYRRRLMKQDFSV PQLPHSSSHWLRLPRIFCSCPIGENSPLLSGQQV (SEQ ID NO:46).

[0065] In myasthenia gravis, an antigen may include or exclude acetylcholine receptor.

[0066] In pemphigus vulgaris and variants, antigens may include or exclude desm oglein 3, 1 and 4; other antigens include pemphaxin, desmocollins, plakoglobin, perplakin, desmoplakins, and acetylcholine receptor.

[0067] In bullous pemphigoid, antigens may include or exclude BP 180 and BP230; other antigens may include or exclude plectin and laminin 5.

[0068] In dermatitis herpetiformis Duhring, antigens may include or exclude endomysium and tissue transglutaminase.

[0069] In epidermolysis bullosa acquisita, an antigen may include or exclude collagen VII.

[0070] In systemic sclerosis, antigens may include or exclude matrix metalloproteinase 1 and 3, the collagen-specific molecular chaperone heat-shock protein 47, fibrillin- 1, and PDGF receptor; other antigens include Scl-70, U1 RNP, Th / To, Ku, Joi, NAG-2, centromere proteins, topoisomerase I, nucleolar proteins, RNA polymerase I, II and III, PM-Slc, fibrillarin, and B23.

[0071] In mixed connective tissue disease, an antigen may include or exclude UlsnRNP.

[0072] In Sjogren's syndrome, antigens may include or exclude nuclear antigens SS-A and SS-B; other antigens include fodrin, poly(ADP-ribose) polymerase and topoisomerase, muscarinic receptors, and the Fc-gamma receptor Illb.

[0073] In systemic lupus erythematosus, antigens may include or exclude nuclear proteins including the “Smith antigen,” SS-A, high mobility group box 1 (HMGB1), nucleosomes, histone proteins and double-stranded DNA (against which auto-antibodies are made in the disease process).

[0074] In Goodpasture's syndrome, antigens may include or exclude glomerular basement membrane proteins including collagen IV.

[0075] In rheumatic heart disease, an antigen may include or exclude cardiac myosin.

[0076] In autoimmune polyendocrine syndrome type 1 antigens may include or exclude aromatic L-amino acid decarboxylase, histidine decarboxylase, cysteine sulfinic acid decarboxylase, tryptophan hydroxylase, tyrosine hydroxylase, phenylalanine hydroxylase, hepatic P450 cytochromes P4501A2 and 2A6, SOX-9, SOX-10, calcium-sensing receptor protein, and the type 1 interferons interferon alpha, beta and omega.

[0077] In neuromyelitis optica, an antigen may include or exclude AQP4.

[0078] Aquaporin-4, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT P55087): MSDRPTARRWGKCGPLCTRENIMVAFKGVWTQAFWKAVTAEFLAMLIFVLLSLGST INWGGTEKPLPVDMVLISLCFGLSIATMVQCFGHISGGHINPAVTVAMVCTRKISIAK SVFYIAAQCLGAIIGAGILYLVTPPSVVGGLGVTMVHGNLTAGHGLLVELIITFQLVFT IFASCDSKRTDVTGSIALAIGFSVAIGHLFAINYTGASMNPARSFGPAVIMGNWENHW IYWVGPIIGAVLAGGLYEYVFCPDVEFKRRFKEAFSKAAQQTKGSYMEVEDNRSQV ETDDLILKPGVVHVIDVDRGEEKKGKDQSGEVLSSV (SEQ ID NO:47).

[0079] In uveitis, antigens may include or exclude Retinal S-antigen or “S-arrestin” and interphotoreceptor retinoid binding protein (IRBP) or retinol-binding protein 3.

[0080] S-arrestin, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT Pl 0523): MAASGKTSKSEPNHVIFKKISRDKSVTIYLGNRDYIDHVSQVQPVDGVVLDLVKGKKVYVTLTCAFRYGQEDIDVIGLTFRRDLYFSRVQVYPPVGAASTPTKLQESLLKKLGS NTYPFLLTFPDYLPCSVMLQPAPQDSGKSCGVDFEVKAFATDSTDAEEDKIPKKSSV RLLIRKVQHAPLEMGPQPRAEAAWQFFMSDKPLHLAVSLNKEIYFHGEPIPVTVTVT NNTEKTVKKIKAFVEQVANVVLYSSDYYVKPVAMEEAQEKVPPNSTLTKTLTLLPL LANNRERRGIALDGKIKHEDTNLASSTIIKEGIDRTVLGILVSYQIKVKLTVSGFLGEL TSSEVATEVPFRLMHPQPEDPAKESYQDANLVFEEFARHNLKDAGEAEEGKRDKND VDE (SEQ ID NO:48).

[0081] IRBP, including an exogenously obtained form useful in the compositions of the disclosure, has the following sequence (UNIPROT Pl 0745): MMREWVLLMSVLLCGLAGPTHLFQPSLVLDMAKVLLDNYCFPENLLGMQEAIQQA IKSHEILSISDPQTLASVLTAGVQSSLNDPRLVISYEPSTPEPPPQVPALTSLSEEELLAW LQRGLRHEVLEGNVGYLRVDSVPGQEVLSMMGEFLVASHVWGNLMGTSALVLDLR HCTGGQVGIPYIISYLHPGNTILHVDTIYNRPSNTTTEIWTLPQVLGERYGADKDVVV LTSSQTRGVAEDIAHILKQMRRAIVVGERTGGGALDLRKLRIGESDFFFTVPVSRSLG PLGGGSQTWEGSGVLPCVGTPAEQALEKALAILTLRSALPGVVHCLQEVLKDYYTL VDRVPTLLQHLASMDFSTWSEEDLVTKLNAGLQAASEDPRLLVRAIGPTETPSWPA PDAAAEDSPGVAPELPEDEAIRQALVDSVFQVSVLPGNVGYLRFDSFADASVLGVLA PYVLRQVWEPLQDTEHLIMDLRHNPGGPSSAVPLLLSYFQGPEAGPVHLFTTYDRRT NITQEHFSHMELPGPRYSTQRGVYLLTSHRTATAAEEFAFLMQSLGWATLVGEITAG NLLHTRTVPLLDTPEGSLALTVPVLTFIDNHGEAWLGGGVVPDAIVLAEEALDKAQE VLEFHQSLGALVEGTGHLLEAHYARPEVVGQTSALLRAKLAQGAYRTAVDLESLAS QLTADLQEVSGDHRLLVFHSPGELVVEEAPPPPPAVPSPEELTYLIEALFKTEVLPGQL GYLRFDAMAELETVKAVGPQLVRLVWQQLVDTAALVIDLRYNPGSYSTAIPLLCSY FFEAEPRQHLYSVFDRATSKVTEVWTLPQVAGQRYGSHKDLYILMSHTSGSAAEAF AHTMQDLQRATVIGEPTAGGALSVGIYQVGSSPLYASMPTQMAMSATTGKAWDLA GVEPDITVPMSEALSIAQDIVALRAKVPTVLQTAGKLVADNYASAELGAKMATKLS GLQSRYSRVTSEVALAEILGADLQMLSGDPHLKAAHIPENAKDRIPGIVPMQIPSPEV FEELIKFSFHTNVLEDNIGYLRFDMFGDGELLTQVSRLLVEHIWKKIMHTDAMIIDMR FNIGGPTS SIPILC S YFFDEGPP VLLDKIYSRPDD S VSELWTHAQVVGERYGSKKSMVI LTSSVTAGTAEEFTYIMKRLGRALVIGEVTSGGCQPPQTYHVDDTNLYLTIPTARSVG ASDGSSWEGVGVTPHVWPAEEALARAKEMLQHNQLRVKRSPGLQDHL (SEQ ID NO:49).

[0082] In the embodiments where the antigen is a foreign antigen against which an unwanted immune response can be developed, such as food antigens, specific antigens caninclude or exclude: from peanut: conarachin (Ara h l), allergen II (Ara h 2), arachis agglutinin, conglutin (Ara h 6); conarachin, for example has the sequence identified as UNIPROT Q6PSU6; from apple: 31 kda major allergen / disease resistance protein homolog (Mai d 2), lipid transfer protein precursor (Mai d 3), major allergen Mai d 1.03D (Mai d 1); from milk: a- lactalbumin (ALA), lactotransferrin; from kiwi: actinidin (Act c 1, Act d 1), phytocy statin, thaumatin-like protein (Act d 2), kiwellin (Act d 5); from egg whites: ovomucoid, ovalbumin, ovotransferrin, and lysozyme; from egg yolks: livetin, apovitillin, and vosvetin; from mustard: 2S albumin (Sin a l), 1 IS globulin (Sin a 2), lipid transfer protein (Sin a 3), profilin (Sin a 4); from celery: profilin (Api g 4), high molecular weight glycoprotein (Api g 5); from shrimp: Pen a 1 allergen (Pen a 1), allergen Pen m 2 (Pen m 2), tropomyosin fast isoform; from wheat and / or other cerials: high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin and / or avenin.

[0083] Antigens associated with Celiac Disease may include or DQ-2 relevant, Alphagliadin “33-mer” native: LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF (SEQ ID NO:50), DQ-2 relevant, Alpha-gliadin “33-mer” deamidated: LQLQPFPQPELPYPQPELPYPQPELPYPQPQPF (SEQ ID NO:51); DQ-8 relevant, Alphagliadin: QQYPSGQGSFQPSQQNPQ (SEQ ID NO:52); DQ-8 relevant, Omega-gliadin (wheat, U5UA46): QPFPQPEQPFPW (SEQ ID NO:53); from strawberry: major strawberry allergy Fra a 1-E (Fra a 1); and from banana: profilin (Mus xp 1).

[0084] In the embodiments where the antigen is a foreign antigen against which an unwanted immune response is developed, such as to animal, plant and environmental antigens, specific antigens can include or exclude antigens from: cat, mouse, dog, horse, bee, dust, tree and goldenrod, including the following proteins or peptides derived from: weeds, (including ragweed allergens amb a 1, 2, 3, 5, and 6, and Amb 15; pigweed Che a 2 and 5; and other weed allergens Par j 1, 2, and 3, and Par o 1); grass (including major allergens Cyn d 1, 7, and 12; Dac g 1, 2, and 5; Hol I 1.01203; Lol p 1, 2, 3, 5, and 11; Mer a 1; Pha a 1; Poa p 1 and 5); pollen from ragweed and other weeds (including curly dock, lambs quarters, pigweed, plantain, sheep sorrel, and sagebrush), grass (including Bermuda, Johnson, Kentucky, Orchard, Sweet vernal, and Timothy grass), and trees (including catalpa, elm, hickory, olive, pecan, sycamore, and walnut); dust (including major allergens from species Dermatophagoides pteronyssinus, such as Der p 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 18, 20, 21, and 23; from species Dermatophagoides farina, such as Der f 1, 2, 3, 6, 7, 10, 11, 13, 14, 15, 16, 18, 22, and 24; from species Blomia tropicalis such as Bio 1 1, 2, 3, 4, 5, 6, 10, 11, 12, 13, 19, and 21; also allergens Eur m 2 from Euroglyphus maynei, Tyr p 13 from Tyrophagus putrescentiae, and allergens Biag 1, 2, and 4; Per a 1, 3, and 7 from cockroach); pets (including cats, dogs, rodents, and farm animals; major cat allergens include Fel d 1 through 8, cat IgA, BLa g 2, and cat albumin; major dog allergens include Can f 1 through 6, and dog albumin); bee stings, including major allergens Api m 1 through 12; and fungus, including allergens derived from, species of Aspergillus and Penicillium, as well as the species Altemaria altemata, Davidiella tassiana, and Trichophyton rubrum.

[0085] As will be appreciated by those skilled in the art, a patient can be tested to identify an antigen against which an unwanted immune response has developed, and a protein, peptide or the like can be developed based on that antigen and incorporated as X in a composition of the present disclosure.

[0086] Sialated antigens, antibodies, and antibody fragments can include or exclude antigens, antibodies, and / or antibody fragments having sialylation that can be removed to leave glycosylation: follicle stimulating hormone (FSH), human chorionic gonadotropin (HCG), luteinizing hormone (LH), osteopontin, thyroid stimulating hormone (TSH), agalsidase alfa, agalsidase beta (FABRAZYME®; Genzyme), epoetin alfa and epoetin beta, follitropin alfa (GONAL-F®; Merck / Serono) and follitropin beta (FOLLISTIM®; Schering-Plough), insulin growth factor binding protein 6 (IGFBP-6), lutropin alfa (LUVERIS®; Merck / Serono), transforming growth factor pi, antithrombin (ATryn® / TROMBATE-III®; Genzyme / Talecris Biotherapeutics), thyrotropin alfa (THYROGEN®; Genzyme), lenograstim, sargramostim (LEUKINE®; Genzyme), interleukin-3, prourokinase, lymphotoxin, Cl -esterase inhibitor (Berinert®; CSL), IgG-like antibodies, interferon beta, coagulation factor Vila (NOVOSEVEN®; Novo Nordisk), coagulation factor VIII (moroctocog alfa), coagulation factor IX (nonacog alfa) (BENEFIX®; Wyeth), and the p55 tumor necrosis receptor fusion protein. (See: Byrne et al., Drug Discovery Today, Vol 12, No. 7 / 8, pages 319-326, April 2007 and Sola et al., BioDrugs. 2010; 24(1): 9-21). Pharmaceutically relevant proteins that have previously been hyperglycosylated and can be desialylated for hepatocyte-ASGPR taregeting include: interferon alfa and gamma, luteinizing hormone, Fv antibody fragments, asparaginase, cholinesterase, darbepoetin alfa (AraNESP®; Amgen), trombopoietin, leptin, FSH, IFN-a2, serum albumin, and corifollitropin alfa.

[0087] Proteins with glycans that do not normally terminate in sialic acids, including proteins produced in bacteria or yeast (such as arginase, some insulins, and uricase) would not be amenable to desialylation.Further antigens may include or exclude: Abciximab, Adalimumab, Agalsidase alfa, Agalsidase beta, Aldeslukin, Alglucosidase alfa, Factor VIII, Factor IX, L-asparaginase,Laronidase, Octreotide, Phenylalanine ammonia-lyase, Rasburicase, Insulin: (SEQ ID N0:31), GAD-65 (SEQ ID NO:32), IGRP (SEQ ID NO:33), MBP (SEQ ID NO:34), MOG (SEQ ID NO:35), PLP (SEQ ID NO:36), MBP13-32 (SEQ ID NO:37), MBP83-99 (SEQ ID NO:38), MBP1 11-129 (SEQ ID NO:39), MBP146-170 (SEQ ID NO:40), MOG1-20 (SEQ ID NO:41), MOG35-55 (SEQ ID NO:42), PLP139-154 (SEQ ID NO:43), MARTI (SEQ ID NO:44), Tyrosinase (SEQ ID NO:45), PMEL (SEQ ID NO:46), Aquaporin-4 (SEQ ID NO:47), S- arrestin (SEQ ID NO:48), IRBP (SEQ ID NO:49), Conarachin (UNIPROT Q6PSU6), Alphagliadin “33-mer” native (SEQ ID NO:50),Alpha-gliadin “33-mer” deamidated (SEQ ID NO:51), Alpha-gliadin (SEQ ID NO:52), Omega-gliadin (SEQ ID NO:53), Fel d 1A (UNIPROT P30438), Cat albumin (UNIPROT P49064), Can f 1 (UNIPROT 018873), Dog albumin (UNIPROT P49822), and RhCE example (UNIPROT Pl 8577).II. Linkers

[0088] The polypeptides of the disclosure can include peptide linkers (sometimes referred to as a linker). A peptide linker may be used to separate any of the peptide domain / regions described herein. As an example, a linker may be between the CD200 polypeptide and the Fc region, between the CD200 polypeptide an the antigen, between tandem CD200 polypeptides, between tandem antigens, between tandem Fc regions, and / or between the Fc region and the antigen. The peptide linker may have any of a variety of amino acid sequences. Domains and regions can be joined by a peptide linker that is generally of a flexible nature, although other chemical linkages are not excluded. A linker can be a peptide of between about 6 and about 40 amino acids in length, or between about 6 and about 25 amino acids in length. These linkers can be produced by using synthetic, linker- encoding oligonucleotides to couple the proteins.

[0089] Peptide linkers with a degree of flexibility can be used. The peptide linkers may have virtually any amino acid sequence, bearing in mind that suitable peptide linkers will have a sequence that results in a generally flexible peptide. The use of small amino acids, such as glycine and alanine, are of use in creating a flexible peptide. The creation of such sequences is routine to those of skill in the art.

[0090] Suitable linkers can be readily selected and can be of any suitable length, such as from 1 amino acid (e.g., Gly) to 20 amino acids, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6, or 7 amino acids.

[0091] Suitable linkers can be readily selected and can be of any of a suitable of different lengths, such as from 1 amino acid (e.g., Gly) to 20 amino acids, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6, or 7 amino acids.

[0092] Example flexible linkers include glycine polymers (G)n, glycine- serine polymers. Glycine-alanine polymers, alanine- serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers can be used; both Gly and Ser are relatively unstructured, and therefore can serve as a neutral tether between components. Glycine polymers can be used; glycine accesses significantly more phi-psi space than even alanine, and is much less restricted than residues with longer side chains. Exemplary linkers can include or exclude amino acid sequences such as GS, GSGGS, (SEQ ID NO: 54), GGGGS (SEQ ID NO: 5) GGGS (SEQ ID NO:55), GGSG (SEQ ID NO:56), GGSGG (SEQ ID NO:57), GSGSG (SEQ ID NO:58), GSGGG (SEQ ID NO:59), GGGSG (SEQ ID NO:60), GSSSG (SEQ ID NO:61), and the like. The linker may comprise a repeat, such as a contiguous repeat of one or more of SEQ ID NOS:2-5 or 54-61, such as a linker comprising an amino acid sequence that corresponds to one of SEQ ID NOS:61-66, repeated at least, at most, or exactly 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, or any range derivable therein.III. Proteinaceous Compositions

[0093] The polypeptides or polynucleotides of the disclosure may include, may include at least, or may include at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more variant amino acids or nucleic acid substitutions or be at least 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% similar, identical, or homologous with at least, or at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118,119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156,157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175,176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194,195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213,214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232,233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 300,400, 500, 550, 1000 or more contiguous amino acids or nucleic acids, or any range derivable therein, of SEQ ID NOs:l-67.

[0094] The polypeptides or polynucleotides of the disclosure may include, may include at least, or may include at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116,117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154,155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173,174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192,193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230,231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249,250, 300, 400, 500, 550, 1000 or more contiguous amino acids, or any range derivable therein, of SEQ ID NO: 1-67.

[0095] A polypeptide of the disclosure may comprise amino acids 1 to 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126,127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164,165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183,184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240,241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259,260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278,279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316,317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335,336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354,355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373,374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392,393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411,412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430,431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449,450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468,469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487,488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506,507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525,526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544,545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563,564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582,583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601,602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, or 615 (or any derivable range therein) of SEQ ID NOs:l-67.

[0096] A polypeptide of the disclosure may comprise, comprise at least, or comprise at most 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122,123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141,142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160,161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179,180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198,199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217,218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236,237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255,256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274,275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293,294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312,313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331,332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350,351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369,370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388,389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407,408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426,427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445,446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464,465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483,484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502,503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521,522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559,560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578,579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597,598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, or 615 (or any derivable range therein) contiguous amino acids of SEQ ID NOs:l-67.

[0097] The polypeptides of the disclosure may comprise, may comprise at least, or may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136,137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155,156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174,175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193,194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212,213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231,232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250,251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269,270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288,289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307,308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326,327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345,346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364,365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383,384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402,403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440,441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459,460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478,479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497,498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516,517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535,536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554,555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573,574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592,593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611,612, 613, 614, or 615 (or any derivable range therein) contiguous amino acids of SEQ ID NOs:l-67 that are at least, at most, or exactly 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% similar, identical, or homologous with any one of SEQ ID NOS: 1-67.

[0098] A polypeptide of the disclosure may have, have at least, or have at most 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any range derivable therein) sequence identity or homology with one of SEQ ID NOS: 1-67.

[0099] The disclosure includes a nucleic acid molecule or polypeptide starting at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102,103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140,1, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159,0, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178,9, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197,8, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216,7, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235,6, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254,5, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273,4, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292,3, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311,2, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330,1, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349,0, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368,9, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387,8, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406,7, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425,6, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444,5, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463,4, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482,3, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501,2, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520,1, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539,0, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558,9, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577,8, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596,7, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, or5 of any of SEQ ID NOS: 1-67 and comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,3, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131,2, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,1, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169,0, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207,208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226,227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245,246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264,265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283,284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302,303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340,341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359,360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378,379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397,398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416,417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435,436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454,455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473,474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492,493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511,512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530,531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549,550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568,569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587,588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606,607, 608, 609, 610, 611, 612, 613, 614, or 615 contiguous nucleotides or amino acids of any of SEQ ID NOS: 1-67.

[0100] The polypeptides and nucleic acids of the disclosure may include, may include at least, or may include at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134,135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153,154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172,173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191,192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248,249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286,287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305,306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324,325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343,344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362,363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381,382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400,401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438,439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457,458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476,477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495,496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514,515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533,534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552,553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571,572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590,591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609,610, 611, 612, 613, 614, or 615 substitutions (or any range derivable therein).

[0101] The substitution may be at amino acid position or nucleic acid position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123,124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142,143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161,162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180,181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199,200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218,219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237,238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256,257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275,276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294,295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313,314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332,333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351,352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370,371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389,390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408,409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446,447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465,466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484,485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503,504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522,523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541,542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560,561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579,580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598,599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, or 615 of one of SEQ ID NO: 1-67. One or more of these substitutions may be specifically excluded from an aspect.

[0102] The amino acid at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151,152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170,171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189,190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208,209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227,228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246,247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265,266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303,304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322,323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341,342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360,361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379,380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398,399, or 400 of the peptide or polypeptide of one of SEQ ID NOS: 1-67 may be substituted with an alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0103] Peptides, polypeptides, and proteins of the disclosure may have, may have at least, or may have at most 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% identity to any one of SEQ ID NOS: 1-67 and may includes a fragment or segment starting at amino acid 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128,129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147,148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166,167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, or 200 (or any range derivable therein) and ending at amino acid 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116,117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154,155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173,174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, or 205 (or any range derivable therein).

[0104] Substitutional variants typically contain the exchange of one amino acid for another at one or more sites within the protein, and may be designed to modulate one or more properties of the polypeptide, with or without the loss of other functions or properties. Substitutions may be conservative, that is, one amino acid is replaced with one of similar shape and charge. Conservative substitutions are well known in the art and include, for example, the changes of: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine. Alternatively, substitutions may be non-conservative such that a function or activity of the polypeptide is affected. Nonconservative changes typically involve substituting a residue with one that is chemically dissimilar, such as a polar or charged amino acid for a nonpolar or uncharged amino acid, and vice versa. One or more of these substitutions may be specifically excluded from an aspect.

[0105] Proteins may be recombinant, or synthesized in vitro. Alternatively, a nonrecombinant or recombinant protein may be isolated from bacteria. It is also contemplated that bacteria containing such a variant may be implemented in compositions and methods. Consequently, a protein need not be isolated.

[0106] The term “functionally equivalent codon” is used herein to refer to codons that encode the same amino acid, such as the six codons for arginine or serine, and also refers to codons that encode biologically equivalent amino acids.

[0107] It also will be understood that amino acid and nucleic acid sequences may include additional residues, such as additional N- or C-terminal amino acids, or 5' or 3' sequences, respectively, and yet still be essentially as set forth in one of the sequences disclosed herein, so long as the sequence meets the criteria set forth above, including the maintenance of biological protein activity where protein expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences that may, for example, include various noncoding sequences flanking either of the 5' or 3' portions of the coding region.

[0108] The following is a discussion based upon changing of the amino acids of a protein to create an equivalent, or even an improved, second-generation molecule. For example,certain amino acids may be substituted for other amino acids in a protein structure without appreciable loss of interactive binding capacity. Structures such as, for example, an enzymatic catalytic domain or interaction components may have amino acid substituted to maintain such function. Since it is the interactive capacity and nature of a protein that defines that protein’ s biological functional activity, certain amino acid substitutions can be made in a protein sequence, and in its underlying DNA coding sequence, and nevertheless produce a protein with like properties. It is thus contemplated by the inventors that various changes may be made in the DNA sequences of genes without appreciable loss of their biological utility or activity.

[0109] In other aspects, alteration of the function of a polypeptide is intended by introducing one or more substitutions. For example, certain amino acids may be substituted for other amino acids in a protein structure with the intent to modify the interactive binding capacity of interaction components. Structures such as, for example, protein interaction domains, nucleic acid interaction domains, and catalytic sites may have amino acids substituted to alter such function. Since it is the interactive capacity and nature of a protein that defines that protein’ s biological functional activity, certain amino acid substitutions can be made in a protein sequence, and in its underlying DNA coding sequence, and nevertheless produce a protein with different properties. It is thus contemplated by the inventors that various changes may be made in the DNA sequences of genes with appreciable alteration of their biological utility or activity.

[0110] In making such changes, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, 1982). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like.[oni] It also is understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Patent 4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein. It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still produce a biologically equivalent and immunologically equivalent protein.

[0112] As outlined above, amino acid substitutions generally are based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take into consideration the various foregoing characteristics are well known and include: arginine and lysine;glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

[0113] In specific aspects, all or part of proteins described herein can also be synthesized in solution or on a solid support in accordance with conventional techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols. See, for example, Stewart and Young, (1984); Tam et al., (1983); Merrifield, (1986); and Barany and Merrifield (1979), each incorporated herein by reference. Alternatively, recombinant DNA technology may be employed wherein a nucleotide sequence that encodes a peptide or polypeptide is inserted into an expression vector, transformed or transfected into an appropriate host cell and cultivated under conditions suitable for expression.

[0114] One aspect includes the use of gene transfer to cells, including microorganisms, for the production and / or presentation of proteins. The gene for the protein of interest may be transferred into appropriate host cells followed by culture of cells under the appropriate conditions. A nucleic acid encoding virtually any polypeptide may be employed. The generation of recombinant expression vectors, and the elements included therein, are discussed herein. Alternatively, the protein to be produced may be an endogenous protein normally synthesized by the cell used for protein production.IV. Nucleic Acids

[0115] In certain aspects, the current disclosure concerns recombinant polynucleotides encoding the polypeptides of the disclosure. Therefore, certain aspects relate to nucleotides encoding for polypeptides, chimeric polypeptides, or multimeric polypeptides of the disclosure.

[0116] As used in this application, the term “polynucleotide” refers to a nucleic acid molecule that either is recombinant or has been isolated free of total genomic nucleic acid. Included within the term “polynucleotide” are oligonucleotides (nucleic acids of 100 residues or less in length), recombinant vectors, including, for example, plasmids, cosmids, phage, viruses, and the like. Polynucleotides include, in certain aspects, regulatory sequences, isolated substantially away from their naturally occurring genes or protein encoding sequences. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be RNA, DNA (genomic, cDNA or synthetic), analogs thereof, or a combination thereof. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide.

[0117] In this respect, the term “gene,” “polynucleotide,” or “nucleic acid” is used to refer to a nucleic acid that encodes a protein, polypeptide, or peptide (including any sequencesrequired for proper transcription, post-translational modification, or localization). As will be understood by those in the art, this term encompasses genomic sequences, expression cassettes, cDNA sequences, and smaller engineered nucleic acid segments that express, or may be adapted to express, proteins, polypeptides, domains, peptides, fusion proteins, and mutants. A nucleic acid encoding all or part of a polypeptide may contain a contiguous nucleic acid sequence of: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370,380, 390, 400, 410, 420, 430, 440, 441, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550,560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740,750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930,940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1095, 1100, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 9000, 10000, or more nucleotides, nucleosides, or base pairs (or any range derivable therein), including all values and ranges there between, of a polynucleotide encoding one or more amino acid sequence described or referenced herein. It also is contemplated that a particular polypeptide may be encoded by nucleic acids containing variations having slightly different nucleic acid sequences but, nonetheless, encode the same or substantially similar protein.

[0118] In particular aspects, the invention concerns isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide or peptide of the disclosure. The term “recombinant” may be used in conjunction with a polynucleotide or polypeptide and generally refers to a polypeptide or polynucleotide produced and / or manipulated in vitro or that is a replication product of such a molecule.

[0119] In other aspects, the invention concerns isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide or peptide of the disclosure.

[0120] The nucleic acid segments used in the current disclosure can be combined with other nucleic acid sequences, such as promoters, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length may vary considerably. It is therefore contemplated that a nucleic acid fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant nucleic acid protocol. In some cases, a nucleic acid sequence may encode a polypeptide sequence with additional heterologous coding sequences, for example to allow for purification of the polypeptide, transport, secretion, post-translational modification, or for therapeutic benefits such as targeting or efficacy. As discussed above, a tag or other heterologous polypeptide may be added to the modified polypeptide-encoding sequence, wherein “heterologous” refers to a polypeptide that is not the same as the modified polypeptide.

[0121] In certain aspects, the current disclosure provides polynucleotide variants having substantial identity to the sequences disclosed herein; those comprising at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% or higher sequence identity, including all values and ranges there between, compared to a polynucleotide sequence of this disclosure using the methods described herein (e.g., BLAST analysis using standard parameters).

[0122] The disclosure also contemplates the use of polynucleotides which are complementary to all the above described polynucleotides.A. Vectors

[0123] Polypeptides of the disclosure may be encoded by a nucleic acid molecule comprised in a vector. The term “vector” is used to refer to a carrier nucleic acid molecule into which a heterologous nucleic acid sequence can be inserted for introduction into a cell where it can be replicated and expressed. A nucleic acid sequence can be “heterologous,” which means that it is in a context foreign to the cell in which the vector is being introduced or to the nucleic acid in which is incorporated, which includes a sequence homologous to a sequence in the cell or nucleic acid but in a position within the host cell or nucleic acid where it is ordinarily not found. Vectors include DNAs, RNAs, plasmids, cosmids, viruses (bacteriophage, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs). One of skill in the art would be well equipped to construct a vector through standard recombinant techniques (for example Sambrook et al., 2001; Ausubel et al., 1996, both incorporated herein by reference). In addition to encoding a polypeptide of the disclosure, the vector can encode other polypeptide sequences such as a one or more other bacterial peptide, a tag, or an immunogenicity enhancing peptide. Useful vectors encoding such fusion proteins include pIN vectors (Inouye et al., 1985), vectors encoding a stretch of histidines, and pGEX vectors, for use in generating glutathione S- transferase (GST) soluble fusion proteins for later purification and separation or cleavage.

[0124] The term “expression vector” refers to a vector containing a nucleic acid sequence coding for at least part of a gene product capable of being transcribed. In some cases, RNA molecules are then translated into a protein, polypeptide, or peptide. Expression vectors can contain a variety of “control sequences,” which refer to nucleic acid sequences necessary for the transcription and possibly translation of an operably linked coding sequence in a particular host organism. In addition to control sequences that govern transcription and translation,vectors and expression vectors may contain nucleic acid sequences that serve other functions as well and are described herein.B. Promoters and Enhancers

[0125] A “promoter” is a control sequence. The promoter is typically a region of a nucleic acid sequence at which initiation and rate of transcription are controlled. It may contain genetic elements at which regulatory proteins and molecules may bind such as RNA polymerase and other transcription factors. The phrases “operatively positioned,” “operatively linked,” “under control,” and “under transcriptional control” mean that a promoter is in a correct functional location and / or orientation in relation to a nucleic acid sequence to control transcriptional initiation and expression of that sequence. A promoter may or may not be used in conjunction with an “enhancer,” which refers to a cis-acting regulatory sequence involved in the transcriptional activation of a nucleic acid sequence.

[0126] Naturally, it may be important to employ a promoter and / or enhancer that effectively directs the expression of the DNA segment in the cell type or organism chosen for expression. Those of skill in the art of molecular biology generally know the use of promoters, enhancers, and cell type combinations for protein expression (see Sambrook et al., 2001, incorporated herein by reference). The promoters employed may be constitutive, tissue-specific, or inducible and in certain aspects may direct high level expression of the introduced DNA segment under specified conditions, such as large-scale production of recombinant proteins or peptides.

[0127] The particular promoter that is employed to control the expression of peptide or protein encoding polynucleotide of the invention is not believed to be critical, so long as it is capable of expressing the polynucleotide in a targeted cell, preferably a bacterial cell. Where a human cell is targeted, it is preferable to position the polynucleotide coding region adjacent to and under the control of a promoter that is capable of being expressed in a human cell. Generally speaking, such a promoter might include either a bacterial, human or viral promoter.C. Initiation Signals and Internal Ribosome Binding Sites (IRES)

[0128] A specific initiation signal also may be required for efficient translation of coding sequences. These signals include the ATG initiation codon or adjacent sequences. Exogenous translational control signals, including the ATG initiation codon, may need to be provided. One of ordinary skill in the art would readily be capable of determining this and providing the necessary signals.

[0129] In certain aspects of the invention, the use of internal ribosome entry sites (IRES) elements are used to create multigene, or polycistronic, messages. IRES elements are able tobypass the ribosome scanning model of 5’ methylated Cap dependent translation and begin translation at internal sites (Pelletier and Sonenberg, 1988; Macejak and Sarnow, 1991). IRES elements can be linked to heterologous open reading frames. Multiple open reading frames can be transcribed together, each separated by an IRES, creating polycistronic messages. Multiple genes can be efficiently expressed using a single promoter / enhancer to transcribe a single message (see U.S. Patents 5,925,565 and 5,935,819, herein incorporated by reference).D. Selectable and Screenable Markers

[0130] In certain aspects of the invention, cells containing a nucleic acid construct of the current disclosure may be identified in vitro or in vivo by encoding a screenable or selectable marker in the expression vector. When transcribed and translated, a marker confers an identifiable change to the cell permitting easy identification of cells containing the expression vector. Generally, a selectable marker is one that confers a property that allows for selection. A positive selectable marker is one in which the presence of the marker allows for its selection, while a negative selectable marker is one in which its presence prevents its selection. An example of a positive selectable marker is a drug resistance marker.V. Host Cells

[0131] As used herein, the terms “cell,” “cell line,” and “cell culture” may be used interchangeably. All of these terms also include their progeny, which is any and all subsequent generations. It is understood that all progeny may not be identical due to deliberate or inadvertent mutations. In the context of expressing a heterologous nucleic acid sequence, “host cell” refers to a prokaryotic or eukaryotic cell, and it includes any transformable organism that is capable of replicating a vector or expressing a heterologous gene encoded by a vector. A host cell can, and has been, used as a recipient for vectors or viruses. A host cell may be “transfected” or “transformed,” which refers to a process by which exogenous nucleic acid, such as a recombinant protein-encoding sequence, is transferred or introduced into the host cell. A transformed cell includes the primary subject cell and its progeny.

[0132] Host cells may be derived from prokaryotes or eukaryotes, including bacteria, yeast cells, insect cells, and mammalian cells for replication of the vector or expression of part or all of the nucleic acid sequence(s). Numerous cell lines and cultures are available for use as a host cell, and they can be obtained through the American Type Culture Collection (ATCC), which is an organization that serves as an archive for living cultures and genetic materials (available on the world wide web at atcc.org).

[0133] Numerous expression systems exist that comprise at least a part or all of the compositions discussed above. Prokaryote- and / or eukaryote-based systems can be employedfor use with the present invention to produce nucleic acid sequences, or their cognate polypeptides, proteins and peptides. Many such systems are commercially and widely available.

[0134] The insect cell / baculovirus system can produce a high level of protein expression of a heterologous nucleic acid segment, such as described in U.S. Patents 5,871,986, 4,879,236, both herein incorporated by reference, and which can be bought, for example, under the name MAXBAC® 2.0 from INVITROGEN® and BACPACK™ BACULO VIRUS EXPRESSION SYSTEM FROM CLONTECH®.

[0135] In addition to the disclosed expression systems of the invention, other examples of expression systems include STRATAGENE®’ s COMPLETE CONTROL > Inducible Mammalian Expression System, which involves a synthetic ecdysone-inducible receptor, or its pET Expression System, an E. coli expression system. Another example of an inducible expression system is available from INVITROGEN®, which carries the T-REX™ (tetracycline-regulated expression) System, an inducible mammalian expression system that uses the full-length CMV promoter. INVITROGEN® also provides a yeast expression system called the Pichia methanolica Expression System, which is designed for high-level production of recombinant proteins in the methylotrophic yeast Pichia methanolica. One of skill in the art would know how to express a vector, such as an expression construct, to produce a nucleic acid sequence or its cognate polypeptide, protein, or peptide.VI. Combination Therapy

[0136] The compositions and related methods of the present disclosure, particularly administration of the polypeptides of the disclosure may also be used in combination with the administration of additional therapies such as the additional therapeutics described herein or in combination with other traditional therapeutics known in the art for the treatment of autoimmune or inflammatory conditions.

[0137] The therapeutic compositions and treatments disclosed herein may precede, be cocurrent with and / or follow another treatment or agent by intervals ranging from minutes to weeks. In aspects where agents are applied separately to a cell, tissue or organism, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapeutic agents would still be able to exert an advantageously combined effect on the cell, tissue or organism. For example, in such instances, it is contemplated that one may contact the cell, tissue or organism with two, three, four or more agents or treatments substantially simultaneously (i.e., within less than about a minute). In other aspects, one or more therapeutic agents or treatments may be administered or providedwithin 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 hours, 1 day,2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 1 week, 2 weeks,3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more, and any range derivable therein, prior to and / or after administering another therapeutic agent or treatment.

[0138] In some aspects, more than one course of therapy may be employed. It is contemplated that multiple courses may be implemented.VII. Treatment of disease

[0139] The polypeptides and compositions of the disclosure find use in a variety of applications including, as will be appreciated by those in the art, treatment of transplant rejection, immune response against a therapeutic agent, autoimmune disease, and food allergy. The compositions of the disclosure may be used to modulate, particularly down-regulate, antigen-specific undesirable immune response.

[0140] The present disclosure provides compositions and methods to treat unwanted immune response to self-antigens and foreign antigens, which can include or exclude: a foreign transplant antigen against which transplant recipients develop an unwanted immune response (e.g., transplant rejection), a foreign antigen to which patients develop an unwanted immune (e.g., allergic or hypersensitivity) response, a therapeutic agent to which patients develop an unwanted immune response (e.g., hypersensitivity and / or reduced therapeutic activity), a self antigen to which patients develop an unwanted immune response (e.g., autoimmune disease).

[0141] Autoimmune disease states can be treated using the methods and compositions provided herein. Autoimmune diseases can include or exclude: Acute Disseminated Encephalomyelitis (ADEM); Acute interstital allergic nephritis (drug allergies); Acute necrotizing hemorrhagic leukoencephalitis; Addison's Disease; Alopecia areata; Alopecia universalis; Ankylosing Spondylitis; Arthritis, juvenile; Arthritis, psoriatic; Arthritis, rheumatoid; Atopic Dermatitis; Autoimmune aplastic anemia; Autoimmune gastritis; Autoimmune hepatitis; Autoimmune hypophysitis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune poly endocrine syndrome type 1; Autoimmune poly endocrine syndrome type 2; Autoimmune thyroiditis; Behcet's disease; Bronchiolitis obliterans; Bullouspemphigoid; Celiac disease; Churg-Strauss syndrome; Chronic inflammatory demyelinating polyneuropathy; Cicatricial pemphigoid; Crohn's disease; Coxsackie myocarditis; Dermatitis herpetiformis Duhring; Diabetes mellitus (Type 1); Erythema nodosum; Epidermolysis bullosa acquisita, Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Goodpasture's syndrome; Graves' disease; Guillain-Barre syndrome; Hashimoto's encephalitis; Hashimoto's thyroiditis; IgG4-related sclerosing disease; Lambert-Eaton syndrome; Mixed connective tissue disease; Mucha-Habermann disease; Multiple sclerosis; Myasthenia gravis; Optic neuritis; Neuromyelitis optica; Pemphigus vulgaris and variants; Pernicious angemis; Pituitary autoimmune disease; Polymyositis; Postpericardiotomy syndrome; Premature ovarian failure; Primary Biliary Cirrhosis; Primary sclerosing cholangitis; Psoriasis; Rheumatic heart disease; Sjogren's syndrome; Systemic lupus erythematosus; Systemic sclerosis; Ulcerative colitis; Undifferentiated connective tissue disease (UCTD); Uveitis; Vitiligo; and Wegener's granulomatosis.

[0142] Autoimmune diseases can include or exclude: Acute necrotizing hemorrhagic leukoencephalitis; Addison's Disease; Arthritis, psoriatic; Arthritis, rheumatoid; Autoimmune aplastic anemia; Autoimmune hypophysitis; Autoimmune gastritis; Autoimmune polyendocrine syndrome type 1; Bullous pemphigoid; Celiac disease; Coxsackie myocarditis; Dermatitis herpetiformis Duhring; Diabetes mellitus (Type 1); Epidermolysis bullosa acquisita; Giant cell myocarditis; Goodpasture's syndrome; Graves' disease; Hashimoto's thyroiditis; Mixed connective tissue disease; Multiple sclerosis; Myasthenia gravis; Neuromyelitis optica; Pernicious angemis; Pemphigus vulgaris and variants; Pituitary autoimmune disease; Premature ovarian failure; Rheumatic heart disease; Systemic sclerosis; Sjogren's syndrome; Systemic lupus erythematosus; and Vitiligo.

[0143] In the embodiments employing an antigen against which an unwanted immune response is developed, such as food antigens, treatment can include or exclude treatments for reactions against: peanut, apple, milk, egg whites, egg yolks, mustard, celery, shrimp, wheat (and other cereals), strawberry and banana.

[0144] The method may treat a disease and / or the antigen may be a disease-associated antigen. The disease may include or exclude one or more of diabetes, graft rejection, GVHC, arthritis (rheumatoid arthritis such as acute arthritis, chronic rheumatoid arthritis, gout or gouty arthritis, acute gouty arthritis, acute immunological arthritis, chronic inflammatory arthritis, degenerative arthritis, type II collagen-induced arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, Still’s disease, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans,polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, atopy including atopic diseases such as hay fever and Job’s syndrome, dermatitis including contact dermatitis, chronic contact dermatitis, exfoliative dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, nummular dermatitis, seborrheic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, and atopic dermatitis, x-linked hyper IgM syndrome, allergic intraocular inflammatory diseases, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, myositis, polymyositis / dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as systemic sclerosis, multiple sclerosis (MS) such as spino-optical MS, primary progressive MS (PPMS), and relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, ataxic sclerosis, neuromyelitis optica (NMO), inflammatory bowel disease (IBD) (for example, Crohn’s disease, autoimmune- mediated gastrointestinal diseases, colitis such as ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, and transmural colitis, and autoimmune inflammatory bowel disease), bowel inflammation, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, respiratory distress syndrome, including adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, rheumatoid synovitis, hereditary angioedema, cranial nerve damage as in meningitis, herpes gestationis, pemphigoid gestationis, pruritis scroti, autoimmune premature ovarian failure, sudden hearing loss due to an autoimmune condition, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen’s encephalitis and limbic and / or brainstem encephalitis, uveitis, such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome such as chronic or acute glomerulonephritis such as primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), including Type I and Type II, and rapidly progressive GN, proliferative nephritis, autoimmune polyglandular endocrine failure, balanitis including balanitis circumscripta plasmacellularis, balanoposthitis, erythema annulare centrifugum, erythema dyschromicum perstans, eythema multiform, granuloma annulare, lichen nitidus,lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, lichen planus, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant keratosis, pyoderma gangrenosum, allergic conditions and responses, allergic reaction, eczema including allergic or atopic eczema, asteatotic eczema, dyshidrotic eczema, and vesicular palmoplantar eczema, asthma such as asthma bronchiale, bronchial asthma, and auto-immune asthma, conditions involving infiltration of T cells and chronic inflammatory responses, immune reactions against foreign antigens such as fetal A-B-0 blood groups during pregnancy, chronic pulmonary inflammatory disease, autoimmune myocarditis, leukocyte adhesion deficiency, lupus, including lupus nephritis, lupus cerebritis, pediatric lupus, non-renal lupus, extra-renal lupus, discoid lupus and discoid lupus erythematosus, alopecia lupus, systemic lupus erythematosus (SLE) such as cutaneous SLE or subacute cutaneous SLE, neonatal lupus syndrome (NLE), and lupus erythematosus disseminatus, juvenile onset (Type I) diabetes mellitus, including pediatric insulin-dependent diabetes mellitus (IDDM), and adult onset diabetes mellitus (Type II diabetes) and autoimmune diabetes. Also contemplated are immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, sarcoidosis, granulomatosis including lymphomatoid granulomatosis, Wegener’s granulomatosis, agranulocytosis, vasculitides, including vasculitis, large-vessel vasculitis (including polymyalgia rheumatica and gianT cell (Takayasu’s) arteritis), medium -vessel vasculitis (including Kawasaki’s disease and polyarteritis nodosa / periarteritis nodosa), microscopic polyarteritis, immunovasculitis, CNS vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, necrotizing vasculitis such as systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS) and ANCA- associated small-vessel vasculitis, temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), Addison’s disease, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, Alzheimer’s disease, Parkinson’s disease, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex-mediated diseases, anti -glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Behcet’s disease / syndrome, Castleman’s syndrome, Goodpasture’s syndrome, Reynaud’s syndrome, Sjogren’s syndrome, Stevens- Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus (including pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membrane pemphigoid, and pemphigus erythematosus), autoimmune polyendocrinopathies, Reiter’sdisease or syndrome, thermal injury, preeclampsia, an immune complex disorder such as immune complex nephritis, antibody-mediated nephritis, polyneuropathies, chronic neuropathy such as IgM polyneuropathies or IgM-mediated neuropathy, autoimmune or immune-mediated thrombocytopenia such as idiopathic thrombocytopenic purpura (ITP) including chronic or acute ITP, scleritis such as idiopathic cerato-scleritis, episcleritis, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune endocrine diseases including thyroiditis such as autoimmune thyroiditis, Hashimoto’s disease, chronic thyroiditis (Hashimoto’s thyroiditis), or subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave’ s disease, polyglandular syndromes such as autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis such as allergic encephalomyelitis or encephalomyelitis allergica and experimental allergic encephalomyelitis (EAE), experimental autoimmune encephalomyelitis, myasthenia gravis such as thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan’s syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, gianT cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphoid interstitial pneumonitis (LIP), bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger’s disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular dermatosis, transient acantholytic dermatosis, cirrhosis such as primary biliary cirrhosis and pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac or Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis such as refractory or relapsed or relapsing polychondritis, pulmonary alveolar proteinosis, Cogan’s syndrome / nonsyphilitic interstitial keratitis, Bell’s palsy, Sweet’s disease / syndrome, rosacea autoimmune, zoster-associated pain, amyloidosis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndrome, channelopathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS,autism, inflammatory myopathy, focal or segmental or focal segmental glomerulosclerosis (FSGS), endocrine opthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt’s syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases and chronic inflammatory demyelinating polyneuropathy, Dressier’s syndrome, alopecia greata, alopecia totalis, CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyl), and telangiectasia), male and female autoimmune infertility, e.g., due to anti-spermatozoan antibodies, mixed connective tissue disease, Chagas’ disease, rheumatic fever, recurrent abortion, farmer’s lung, erythema multiforme, postcard! otomy syndrome, Cushing’s syndrome, bird-fancier’s lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport’s syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, parasitic diseases such as leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampler’s syndrome, Caplan’s syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman’s syndrome, Felty’s syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis (acute or chronic), or Fuch’ s cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, SCID, acquired immune deficiency syndrome (AIDS), echovirus infection, sepsis, endotoxemia, pancreatitis, thyroxicosis, parvovirus infection, rubella virus infection, postvaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan’s syndrome, autoimmune gonadal failure, Sydenham’s chorea, post-streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, gianT cell polymyalgia, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, transplant organ reperfusion, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway / pulmonary disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders, asperniogenese, autoimmune hemolysis, Boeck’s disease, cryoglobulinemia, Dupuytren’s contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman-Rich’s disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis,ophthalmia symphatica, orchitis granulomatosa, pancreatitis, polyradiculitis acuta, pyoderma gangrenosum, Quervain’s thyreoiditis, acquired spenic atrophy, non-malignant thymoma, vitiligo, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, autoimmune polyglandular syndrome type I, adultonset idiopathic hypoparathyroidism (A0H4), cardiomyopathy such as dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, an eosinophil -related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Loffler’s syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton’s syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia syndrome, angiectasis, autoimmune disorders associated with collagen disease, rheumatism, neurological disease, lymphadenitis, reduction in blood pressure response, vascular dysfunction, tissue injury, cardiovascular ischemia, hyperalgesia, renal ischemia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, ischemic re-perfusion disorder, reperfusion injury of myocardial or other tissues, lymphomatous tracheobronchitis, inflammatory dermatoses, dermatoses with acute inflammatory components, multiple organ failure, bullous diseases, renal cortical necrosis, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, narcolepsy, acute serious inflammation, chronic intractable inflammation, pyelitis, endarterial hyperplasia, peptic ulcer, valvulitis, graft versus host disease, contact hypersensitivity, asthmatic airway hyperreaction, and endometriosis.VIII. Sequences

[0145] DNA sequences

[0146] Amino Acid SequencesIX. Examples

[0147] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.Example 1: Myeloid targeting via CD200-antigen fusion for the induction of antigenspecific toleranceA. Background

[0148] Currently, the treatment of allergy, autoimmunity, and immune reactions to the growing class of biologic drugs is primarily based on suppressing the immune system, leaving patients in an immunocompromised state. Especially as antigens seemingly targeted in autoimmune processes have been identified over the past few decades, the interest in developing antigen-specific therapies that can induce tolerance to peptides or proteins has risen. Even since the early 20th century, attempts were made to use grass pollen extracts to treat allergy (1,2). Allergen immunotherapy (AIT) is a standard treatment for allergic rhinitis and allergic asthma, and while it can be effective it requires prolonged treatment and is sometimes associated with adverse reactions (3-5). Outside of AIT, antigen-specific therapies haveshowed promising preclinical results but have so far failed to make it into the clinic, particularly in the context of autoimmune diseases like type 1 diabetes and celiac disease (6-8).

[0149] CD200R is an immune checkpoint receptor primarily restricted to the myeloid compartment: it’s expressed on macrophages and monocytes, neutrophils and other granulocytes, dendritic cells, mast cells, and microglia (18,19). It signals through a cytoplasmic noncanonical tyrosine-based (NPxY) inhibitory motif that ultimately results in the suppression of inflammatory innate immune cell activation and significant alteration of the immune environment (19-22). It binds to CD200, a primarily surface-bound receptor expressed on lymphocytes, endothelia, neurons, and other cells (23). It has a very small intracellular domain that lacks known immunoreceptor inhibitory receptor motifs and is not believed to signal in the context of CD200R binding (24,25).

[0150] Clinically, CD200 has only been targeted as a checkpoint interaction in cancer. Samalizumab (Alexion), an antibody that targets CD200 to block its binding to CD200R, was used in relapsing / refractory B-cell chronic lymphocytic leukemia (B-CLL) or multiple myeloma (NCT00648739) (35-37). Treatment was associated with reduced tumor burden in the majority of the 23 B-CLL patients. In these patients, a maximum tolerated dose was not reached, with the treatment being generally well -tolerated. The trial was terminated for administrative reasons. In an ongoing Phase I trial by 0X2 Therapeutics (NCT04642937), a peptide inhibitor of the CD200R, CD200AR-L, is used with an allogeneic vaccine in recurrent glioblastoma patients and has been both well-tolerated and showed initial signs of immune activation in the four patients examined (38-40).

[0151] Because of its myeloid-specific expression, the inventors hypothesized that CD200R could provide both an inhibitory signal and a target for antigen delivery to antigen presenting cells if antigens are fused recombinantly to a soluble CD200. By influencing the antigen presenting cell phenotype and the environment of T cell priming through CD200R signaling, it was hypothesized that antigen-specific tolerance induction can be improved over peptide or protein antigen immunotherapy alone. Here, the inventors demonstrate that CD200 can be associated, for example by recombinant fusion, to antigens to serve multiple purposes, namely targeting the antigen through CD200R binding intended for tolerization to myeloid cells for antigen presentation and myeloid cell modulation through CD200R signaling.B. Methods and Results1. Protein expression and purification; Mice

[0152] Proteins were expressed using the Freestyle™ 293 -F Expression System (Thermo). Purification for all variants was performed first using the HisTrap™ HP (Cytiva) and then sizeexclusion chromatography. CD200 protein variants for the following experiments include 1-2 copies of CD200 (as indicated) or CD200 followed by an IgG Fc region (CD200Fc). All antigens were fused to the C-terminal end of all proteins. Protein labels below are written N to C to indicate the protein structure. C57B / 6 mice between 8-10 weeks at the beginning of each study were purchased from Jackson Laboratory.2. In vitro antigen uptake assessment by BMDC / OT co-culture

[0153] Bone marrow-derived dendritic cells (DCs) were prepared as previously described and harvested at day 9. Cells were plated at 10,000 cells / well in a 96 well plate and incubated with OVA or CD200-OVA variants at 500 pM OVA for 6 hours with 5 ng / mL lipopolysaccharide (LPS). At this time, the media was aspirated off the adherent DCs, they were washed once with fresh media, and then plated with 100,000 cells / well OTI or OTII OVA- specific carboxyfluorescein succinimidyl ester

[0154] (CFSE)-labeled T cells. These cells were allowed to incubate at 37 °C for 3 days, after which time they were collected and analyzed by flow cytometry for cell proliferation.

[0155] The fusion of OVA to CD200, whether a single copy or as CD200Fc, drastically increased the T cell proliferation. This is taken to be the result of improved antigen uptake by the dendritic cells during the initial incubation with OVA through the fusion constructs over the free protein alone.3. In vivo proliferation of OVA-specific T cells after CD200-OVA variant treatments

[0156] An adoptive transfer of 500,000 OTI and 500,000 OTII cells (with CFSE labeling) was performed into 8-week-old C57BL / 6 mice. After 24 hours, these mice received a single 20 pg (OVA equivalent) dose of OVA, or one of several CD200-OVA variants. Four days later, blood was analyzed by flow cytometry for the presence of proliferating, antigen-experienced OT cells.

[0157] None of the variants showed a significant difference in OTI expansion relative to OVA at 4 days, but CD200Fc-OVA trended towards this increase. Both constructs containing two copies of CD200, which bind with approximately equal affinity, result in a significant increase in OTII cell proliferation at the 4 day timepoint. This corroborates the in vitro data suggesting an enhancement in antigen presentation to antigen-specific T cells.4. Complete Freund’s adjuvant challenge after tolerization with two doses of CD200-antigen

[0158] An adoptive transfer of 500,000 OTI and 500,000 OTII cells (with CFSE labeling) was performed into 8-week-old C57BL / 6 mice. Two 1 mg (OVA equivalent) doses of OVA orCD200-OVA were administered subcutaneously equally distributed across the four limbs one week apart, and one week after the final dose the mice were challenged with a 20 mg dose of OVA in Complete Freund’s Adjuvant (25 pL per limb). Four days after the challenge, the draining (inguinal, popliteal, axillary, and brachial) lymph nodes were collected and pooled for analysis.

[0159] The CD200CD200-OVA fusion was able to better suppress the expansion of the antigen-specific CD8 (OTI) and CD4 OTII) cells in response to the CFA challenge than OVA alone (FIG. 3). Additionally, the OTII cells that were present were more anergic (CD73+FR4+) in the CD200CD200-OVA treated groups.

[0160] With a slightly adjusted timeline, two doses of the OVA / CD200-OVA variants were administered one week before, as previously. One week after the last dose, 250,000 naive OTI and OTII cells were adoptively transferred. One day later, 20 pg OVA in CFA was administered as above. Lymph nodes (popliteal, inguinal, brachial, axillary) were collected one week post-challenge for flow cytometry. The cells were also plated (500,000 unsorted cells) and incubated with OVA at 50 pg / mL for 3 days, after which time the supernatant was collected for analysis by Biolegend Legendplex™.

[0161] In this experiment, CD200Fc-OVA was able to suppress the naive OT proliferation in both the CD4 and CD8 compartments, demonstrating the effects of the endogenous tolerized compartment. While OVA alone was also able to do this successfully, we see trending (though not significant) improvement over antigen alone in the suppression of OT proliferation, particularly OTII. There is also a trending increase in the production of IL- 10, an immunosuppressive cytokine, in the supernatant of the CD200Fc-OVA-treated cells that were incubated for 3 days with OVA ex vivo.

[0162] These results thus show that immunological tolerance can be established using antigen-fused CD200 molecules, including CD200Fc-fused antigen. This tolerance was demonstrated by abrogating responses to immune challenge and induction of production of tolerogenic cytokines, including IL- 10. In principle, any antigen intended for tolerization can be incorporated, related to autoimmune conditions, allergy conditions, anti-drug immunity conditions, among others.* * *

[0163] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in thesequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.REFERENCES

[0164] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.1. Ring, J. & Gutermuth, J. 100 years of hyposensitization: history of allergen-specific immunotherapy (ASIT). Allergy 66, 713-724 (2011).2. Noon, L. Prophylactic Inoculation against Hay Fever. Lancet 177, 1572-1573 (1911).3. Pavon-Romero, G. F. et al. Allergen Immunotherapy: Current and Future Trends. Cells 11, 212 (2022).4. Durham, S. R. & Shamji, M. H. Allergen immunotherapy: past, present and future. Nat. Rev. Immunol. 23, 317-328 (2023).5. Penagos, M. & Durham, S. R. Allergen immunotherapy for long-term tolerance and prevention. J. Allergy Clin. Immunol. 149, 802-811 (2022).6. Zhang, X. et al. Antigen-specific immunotherapies in type 1 diabetes. J. Trace Elem. Med. Biol. 73, 127040 (2022).7. Sharkey, P. & Thomas, R. Immune tolerance therapies for autoimmune diseases: Shifting the goalpost to cure. Curr. Opin. Pharmacol. 65, 102242 (2022).8. Moorman, C. D., Sohn, S. J. & Phee, H. Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy. Front. Immunol. 12, 657768 (2021).9. Kontos, S., Kourtis, I. C., Dane, K. Y. & Hubbell, J. A. Engineering antigens for in situ erythrocyte binding induces T-cell deletion. Proc. Natl. Acad. Sci. 110, E60-E68 (2013).10. Lorentz, K. M., Kontos, S., Diaceri, G., Henry, H. & Hubbell, J. A. Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase. Sci. Adv. 1, el500112 (2015).11. Grimm, A. J., Kontos, S., Diaceri, G., Quaglia-Thermes, X. & Hubbell, J. A. Memory of tolerance and induction of regulatory T cells by erythrocyte-targeted antigens. Sci. Rep. 5, 15907 (2015).12. Watkins, E. A. et al. Persistent antigen exposure via the eryptotic pathway drives terminal T cell dysfunction. Sci. Immunol. (2021) doi:10.1126 / sciimmunol.abel801.13. Wilson, D. S. et al. Synthetically glycosylated antigens induce antigen-specific tolerance and prevent the onset of diabetes. Nat. Biomed. Eng. 3, 817-829 (2019).14. Tremain, A. C. et al. Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses. Nat. Biomed. Eng. 7, 1142-1155 (2023).15. Kanyos Bio, Inc., a wholly-owned subsidiary of Anokion SA. A Phase 1 Study of the Safety and Tolerability of Single and Multiple Doses of KAN-101 in Patients With Celiac Disease (ACeD). https: / / clinicaltrials.gov / study / NCT04248855 (2021).16. Kanyos Bio, Inc., a wholly-owned subsidiary of Anokion SA. A Phase IB Open- label / Phase 2 Double-blind Placebo- Controlled Study for Pharmacodynamic (PD) Activity, Pharmacokinetics (PK), Safety, and Tolerability of KAN-101 In Patients With Celiac Disease (CeD). https: / / clinicaltrials.gov / study / NCT05574010 (2023).17. Murray, J. A. et al. Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trial. Lancet Gastroenterol. Hepatol. 8, 735-747 (2023).18. Wright, G. J. et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J. Immunol. Baltim. Md 1950 171, 3034-3046 (2003).19. Hoek, R. M. et al. Down-Regulation of the Macrophage Lineage Through Interaction with OX2 (CD200). Science 290, 1768-1771 (2000).20. Zhang, S., Cherwinski, H., Sedgwick, J. D. & Phillips, J. H. Molecular Mechanisms of CD200 Inhibition of Mast Cell Activation. J. Immunol. 173, 6786-6793 (2004).21. Fallarino, F. et al. Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement. J. Immunol. Baltim. Md 1950 173, 3748-3754 (2004).22. Jenmalm, M. C., Cherwinski, H., Bowman, E. P., Phillips, J. H. & Sedgwick, J. D. Regulation of Myeloid Cell Function through the CD200 Receptorl. J. Immunol. 176, 191— 199 (2006).23. Wright, G. J., Jones, M., Puklavec, M. J., Brown, M. H. & Barclay, A. N. The unusual distribution of the neuronal / lymphoid cell surface CD200 (OX2) glycoprotein is conserved in humans. Immunology 102, 173-179 (2001).24. Gorczynski, R. M., Yu, K. & Clark, D. Receptor Engagement on Cells Expressing a Ligand for the Tolerance-Inducing Molecule OX2 Induces an Immunoregulatory Population That Inhibits Alloreactivity In Vitro and In Vivol. J. Immunol. 165, 4854-4860 (2000).25. Chen, Z. et al. Cell membrane-bound CD200 signals both via an extracellular domain and following nuclear translocation of a cytoplasmic fragment. Leuk. Res. 69, 72-80 (2018).26. Gorczynski, R. M. et al. An Immunoadhesin Incorporating the Molecule OX-2 Is a Potent Immunosuppressant That Prolongs Allo- and Xenograft Survivall . J. Immunol. 163, 1654-1660 (1999).27. Gorczynski, R. M., Chen, Z., Yu, K. & Hu, J. CD200 immunoadhesin suppresses collagen-induced arthritis in mice. Clin. Immunol. Orlando Fla 101, 328-334 (2001).28. Liu, Y. et al. CD200R1 Agonist Attenuates Mechanisms of Chronic Disease in a Murine Model of Multiple Sclerosis. J. Neurosci. 30, 2025-2038 (2010).29. Yin, Y., Zhao, L., Zhang, F. & Zhang, X. Impact of CD200-Fc on dendritic cells in lupus-prone NZB / WF 1 mice. Sci. Rep. 6, 31874 (2016).30. Patoine, D. et al. CD200Fc limits dendritic cell and B-cell activation during chronic allergen exposures. J. Leukoc. Biol. 114, 84-91 (2023).31. Gorczynski, R. M. et al. Potent Immunosuppression by a Bivalent Molecule Binding to CD200R and TGF-PR. Transplantation 90, 150 (2010).32. Kretz-Rommel, A. et al. Blockade of CD200 in the Presence or Absence of Antibody Effector Function: Implications for Anti-CD200 Therapy. J. Immunol. 180, 699-705 (2008).33. Erin, N. et al. CD200fc enhances anti-tumoral immune response and inhibits visceral metastasis of breast carcinoma. Oncotarget 9, 19147-19158 (2018).34. Rastogi, N. et al. Use of an anti-CD200-blocking antibody improves immune responses to AML in vitro and in vivo. Br. J. Haematol. 193, 155-159 (2021).35. Al exion. A Phase I / II Open Label Study To Evaluate The Safety, Pharmacokinetics And Pharmacodynamics Of ALXN6000 In Patients With Relapsing Or Refractory B-Cell Chronic Lymphocytic Leukemia Or Multiple Myeloma. https: / / clinicaltrials.gov / study / NCT00648739 (2019).36. Mahadevan, D. et al. First-In-Human Phase I Dose Escalation Study of a Humanized Anti-CD200 Antibody (Samalizumab) In Patients with Advanced Stage B Cell Chronic Lymphocytic Leukemia (B-CLL) or Multiple Myeloma (MM). Blood 116, 2465 (2010).37. Mahadevan, D. et al. Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200. J. Immunother. Cancer 7, 227 (2019).38. Xiong, Z. et al. Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy. Immunotherapy 8, 1059-1071 (2016).39. 0X2 Therapeutics. Study of CD200 Activation Receptor Ligand (CD200AR-L) and Allogeneic Tumor Lysate Vaccine Immunotherapy for Recurrent Glioblastoma. https: / / clinicaltrials.gov / study / NCT04642937 (2023).40. Olin, M. R., Neil, E. C., Eaton, A., Lunn, S. & Moertel, C. L. Abstract CT245: First in human CD200 activation receptor ligand and tumor lysate vaccine immunotherapy for recurrent glioblastoma in adults. Cancer Res. 82, CT245 (2022).

Claims

WHAT IS CLAIMED:

1. A fusion protein comprising a CD200 polypeptide having the amino acid sequence of SEQ ID NO: 13 fused to an IgG fragment crystallizable (Fc) region.

2. A method for inducing antigen-specific immune tolerance in a subject in need thereof, the method comprising administering a CD200-Fc fusion protein, wherein the CD200 comprises SEQ ID NO: 13 and the fragment crystallizable (Fc) region comprises a IgG Fc region.

3. A polypeptide comprising a CD200 polypeptide operatively linked to an antigen.

4. The polypeptide of claim 3, wherein the CD200 polypeptide comprises the extracellular domain of a CD200 protein.

5. The polypeptide of claim 3 or 4, wherein the polypeptide further comprises a Fc region.

6. The polypeptide of any one of claims 3-5, wherein the CD200 polypeptide is covalently linked to the antigen.

7. The polypeptide of claim 6, wherein the CD200 polypeptide is covalently linked to the antigen through a linker.

8. The polypeptide of claim 6 or 7, wherein the CD200 polypeptide is covalently linked to the Fc region through a linker.

9. The polypeptide of any one of claims 7-8, wherein the antigen is covalently linked to the Fc region through a linker.

10. The polypeptide of any one of claims 3-9, wherein the antigen is amino-proximal to the CD200 polypeptide and / or Fc region.

11. The polypeptide of any one of claims 3-9, wherein the antigen is carboxy -proximal to the CD200 polypeptide and / or Fc region.

12. The polypeptide of any one of claims 5-11, wherein the Fc region is amino-proximal to the CD200 polypeptide and / or antigen.

13. The polypeptide of any one of claims 5-11, wherein the Fc region is carboxy-proximal to the CD200 polypeptide and / or antigen.

14. The polypeptide of any one of claims 3-12, wherein the antigen is amino-proximal to the CD200 polypeptide and / or Fc region.

15. The polypeptide of any one of claims 3-12, wherein the antigen is carboxy-proximal to the CD200 polypeptide and / or Fc region.

16. The polypeptide of any one of claims 7-16, wherein the linker comprises glycine and serine amino acid residues.

17. The polypeptide of claim 16, wherein the linker comprise GGS and / or one or more of SEQ ID NOS:2-5.

18. The polypeptide of any one of claims 3-17, wherein the polypeptide comprises a signal sequence.

19. The polypeptide of claim 18, wherein the signal sequence comprises SEQ ID NO:1.

20. The polypeptide of claim 18 or 19, wherein the signal sequence is amino-proximal to the CD200 polypeptide, Fc region, and / or antigen.

21. The polypeptide of claim 18 or 19, wherein the signal sequence is carboxy -proximal to the CD200 polypeptide, Fc region, and / or antigen.

22. The polypeptide of any one of claims 18-20, wherein the signal sequence is at the amino terminus of the polypeptide.

23. The polypeptide of any one of claims 3-22, wherein the CD200 polypeptide comprises the amino acid sequence of one of SEQ ID NOS: 11-14 or an amino acid sequence having at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS: 11-14.

24. The polypeptide of any one of claims 3-23, wherein the Fc region comprises the amino acid sequence of at least one of SEQ ID NOS: 6-9 and 62-67 or an amino acid sequence having at least 80% sequence identity to the amino acid sequence of at least one of SEQ ID NOS:6-9 and 62-67.

25. The polypeptide of any one of claims 3-24, wherein the polypeptide comprises at least two CD200 polypeptides.

26. The polypeptide of any one of claims 3-25, wherein the polypeptide comprises at least three CD200 polypeptides.

27. The polypeptide of claim 25 or 26, wherein the polypeptide comprises a linker between the CD200 polypeptides.

28. The polypeptide of any one of claims 25-27, wherein the CD200 polypeptides are in tandem with a linker that is between the CD200 polypeptides.

29. The polypeptide of any one of claims 25-28, wherein each CD200 polypeptide comprises an amino acid sequence that is independently selected from the amino acid sequence of one of SEQ ID NOS: 11-14, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS:11-14.

30. The polypeptide of any one of claims 25-29, wherein the CD200 polypeptide comprises the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 16.

31. The polypeptide of any one of claims 3-30, wherein the polypeptide comprises at least two Fc regions.

32. The polypeptide of any one of claims 3-31, wherein the polypeptide comprises at least three Fc regions.

33. The polypeptide of claim 31 or 32, wherein the polypeptide comprises a linker between the Fc regions.

34. The polypeptide of any one of claims 31-33, wherein the Fc regions are in tandem.

35. The polypeptide of claim 34, wherein the polypeptide comprises a linker between the Fc regions.

36. The polypeptide of any one of claims 31-35, wherein each Fc region comprises an amino acid sequence that is independently selected from the amino acid sequence of one of SEQ IDNOS:6-9 and 62-67, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS: 6-9 and 62-67.

37. The polypeptide of any one of claims 3-36, wherein the antigen comprises a disease- associated antigen.

38. The polypeptide of any one of claims 3-37, wherein the polypeptide comprises at least two antigens.

39. The polypeptide of claim 38, wherein the two antigens comprise a different amino acid sequence and / or are different antigens.

40. The polypeptide of claim 38, wherein the two antigens comprise the same amino acid sequence and / or are from the same antigen.

41. The polypeptide of any one of claims 37-40, wherein the two antigens are associated with the same disease.

42. The polypeptide of any one of claims 3-41, wherein the polypeptide comprises the amino acid sequence of one of SEQ ID NOS: 16-20, or an amino acid sequence that has at least 80% sequence identity to the amino acid sequence of one of SEQ ID NOS:16-20.

43. The polypeptide of any one of claims 3-42, wherein the antigen is a therapeutic agent, an antigen associated with a food allergy, or an antigen associated with an autoimmune disease.

44. The polypeptide of any one of claims 3-43, wherein the antigen comprises the amino acid sequence of one or more of SEQ ID NOS:31-53, an amino acid sequence comprising at least 80% sequence identity to one or more of SEQ ID NOS:31-53, an antigen comprising an amino acid that is a fragment of one or more of the amino acid sequences of SEQ ID NOS:31- 53, or an antigen comprising an amino acid that has at least 80% sequence identity to a fragment of one or more of the amino acid sequences of SEQ ID NOS:31-53.

45. A nucleic acid encoding the polypeptide of any one of claims 3-44.

46. An expression vector comprising the nucleic acid of claim 45.

47. A host cell comprising the polypeptide of any one of claims 3-44, the nucleic acid of claim 45, or the expression vector of claim 46.

48. A pharmaceutical composition comprising the polypeptide of any one of claims 3-44, the nucleic acid of claim 45, the expression vector of claim 46, or the host cell of claim 47.

49. A method of making a cell comprising transferring the nucleic acid of claim 45 or the expression vector of claim 46 into a cell.

50. A method for making a polypeptide comprising transferring the expression vector of claim 46 into a cell and incubating the cell under conditions sufficient for expression of the polypeptide encoded on the expression vector.

51. A method for inducing antigen-specific immune tolerance and / or for inducing tolerogenic cytokines in a subject in need thereof, the method comprising administering the polypeptide of any one of claims 3-44 or the pharmaceutical composition of claim 48 to the subject.

52. A method for inducing anergy to an antigen in a subject in need thereof, the method comprising administering the polypeptide of any one of claims 3-44 or the pharmaceutical composition of claim 48 to the subject.

53. A method for treating an allergy or autoimmune disease, comprising administering the polypeptide of any one of claims 3-44 or the pharmaceutical composition of claim 48 to the subject.

54. The method of anyone of claims 51-53, wherein the subject has and / or has been diagnosed with an autoimmune disease or an allergy.

55. The method of claim 53 or 54, wherein the autoimmune disease comprises arthritis, inflammatory bowel disease, scleroderma, inflammatory bowel disease, idiopathic pulmonary fibrosis, multiple sclerosis, type 1 diabetes, Crohn’s disease, psoriasis, rheumatoid arthritis, or celiac disease.

56. The method of any one of claims 51-55, wherein the composition is administered systemically.

57. The method of claim 56, wherein the composition is administered by intravenous injection.

58. The method of any one of claims 51-57, wherein the composition is administered locally.

59. The method of any one of claims 51-58, wherein the subject has been previously treated with an anti-inflammatory agent, anti-inflammatory therapy, immunosuppressant, and / or autoimmune therapy.

60. The method of claim 59, wherein the subject has been determined to be non-responsive to the previous treatment.

61. The method of any one of claims 51-58, wherein the subject has not been treated previously for the inflammatory or autoimmune disease.

62. The method of any one of claims 51-61, wherein the method further comprises administration of an additional inflammatory or autoimmune therapy.

63. The method of claim 62, wherein the additional therapy comprises an anti-cytokine agent or a steroid.

64. The method of claim 62 or 63, wherein the additional inflammatory or autoimmune therapy comprises one or more of steroids, corticosteroids, anti-TNF-alpha therapy, anti- integrin therapy, infliximab, mesalamine, and vedolizumab, fmgolimod, interferon-P, dimethyl fumarate, teriflunomide, integrin a4pi, an anti- aLp2 antibody, an anti-IL-6R agent, an anti- IL-6 agent, and a Janus kinase inhibitor (e.g., tofacitinib, baricitinib, upadacitinib).

65. The method of any one of claims 62-64, wherein the additional inflammatory or autoimmune therapy comprises tofacitinib, baricitinib, and / or Upadacitinib.

66. The method of claim 64, wherein the steroid comprises dexamethasone, methylprednisolone, and / or prednisolone67. The method of any one of claims 51-66, wherein the subject is a human subject.

68. The method of any one of claims 51-67, wherein the subject does not have cancer.

69. The method of any one of claims 62-68, wherein the antigen is not a cancer-associated antigen.

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