WO2020181062A1 - T-cell modulatory multimeric polypeptides and methods of use thereof - Google Patents

T-cell modulatory multimeric polypeptides and methods of use thereof Download PDF

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Publication number
WO2020181062A1
WO2020181062A1 PCT/US2020/021138 US2020021138W WO2020181062A1 WO 2020181062 A1 WO2020181062 A1 WO 2020181062A1 US 2020021138 W US2020021138 W US 2020021138W WO 2020181062 A1 WO2020181062 A1 WO 2020181062A1
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Prior art keywords
polypeptide
amino acid
acid sequence
mhc class
cases
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English (en)
French (fr)
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Ronald D. Seidel Iii
Rodolfo J. Chaparro
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Cue Biopharma Inc
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Cue Biopharma Inc
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Priority to JP2021543386A priority Critical patent/JP2022522405A/ja
Priority to EP20765925.1A priority patent/EP3935080A4/en
Publication of WO2020181062A1 publication Critical patent/WO2020181062A1/en
Priority to US17/394,972 priority patent/US20220105162A1/en
Anticipated expiration legal-status Critical
Priority to US19/054,201 priority patent/US20250242005A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/385—Haptens or antigens, bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • A61K2039/55533—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/577—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 tolerising response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/605—MHC molecules or ligands thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6056—Antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/73—Fusion polypeptide containing domain for protein-protein interaction containing coiled-coiled motif (leucine zippers)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor

Definitions

  • APCs antigen-presenting cells
  • T cells T cells
  • APCs serve to capture and break the proteins from foreign organisms, or abnormal proteins (e.g., from genetic mutation in cancer cells), into smaller fragments suitable as signals for scrutiny by the larger immune system, including T cells.
  • APCs break down proteins into small peptide fragments, which are then paired with proteins of the major histocompatibility complex (“MHC”) and displayed on the cell surface.
  • MHC major histocompatibility complex
  • Cell surface display of an MHC together with a peptide fragment also known as a T cell epitope, provides the underlying scaffold surveilled by T cells, allowing for specific recognition.
  • the peptide fragments can be pathogen-derived, tumor-derived, or derived from natural host proteins (self proteins).
  • APCs can recognize other foreign components, such as bacterial toxins, viral proteins, viral DNA, viral RNA, etc., whose presence denotes an escalated threat level.
  • the APCs relay this information to T cells through additional costimulatory signals in order to generate a more effective response.
  • T cells recognize peptide-major histocompatibility complex (“pMHC”) complexes through a specialized cell surface receptor, the T cell receptor (“TCR”).
  • TCR T cell receptor
  • the TCR is unique to each T cell; as a consequence, each T cell is highly specific for a particular pMHC target.
  • pMHC peptide-major histocompatibility complex
  • TCR T cell receptor
  • any given T cell, specific for a particular T cell peptide is initially a very small fraction of the total T cell population.
  • Such activated T cell responses are capable of attacking and clearing viral infections, bacterial infections, and other cellular threats including tumors, as illustrated below.
  • the broad, non-specific activation of overly active T cell responses against self or shared antigens can give rise to T cells inappropriately attacking and destroying healthy tissues or cells.
  • HLA class II gene loci include HLA-DM (HLA-DMA and HLA-DMB that encode HLA-DM a chain and HLA- DM b chain, respectively), HLA-DO (HLA-DOA and HLA-DOB that encode HLA-DO a chain and HLA-DO b chain, respectively), HLA-DP (HLA-DPA and HLA-DPB that encode HLA-DP a chain and HLA-DP b chain, respectively), HLA-DQ (HLA-DQA and HLA-DQB that encode HLA-DQ a chain and HLA-DQ b chain, respectively), and HLA-DR (HLA-DRA and HLA-DRB that encode HLA-DR a chain and HLA-DR b chain, respectively).
  • HLA-DM HLA-DMA and HLA-DMB that encode HLA-DM a chain and HLA- DM b chain, respectively
  • HLA-DO HLA-DOA and HLA-DOB that encode HLA-DO
  • the present disclosure provides T-cell modulatory antigen-presenting polypeptides, including single-chain antigen-presenting polypeptides and multimeric antigen-presenting polypeptides.
  • the present disclosure provides nucleic acids comprising nucleotide sequences encoding T-cell modulatory antigen-presenting polypeptides of the present disclosure, as well as cells genetically modified with the nucleic acids.
  • a T-cell modulatory antigen-presenting polypeptide of the present disclosure is useful for modulating activity of a T cell.
  • the present disclosure provides methods of modulating activity of a T cell.
  • FIG. 1A-4C provide schematic depictions of examples of T-cell modulatory antigen-presenting polypeptides of the present disclosure.
  • FIG. 5A-5B provide an amino acid sequences of an immunoglobulin heavy chain CHI domain (FIG. 5 A; SEQ ID NO: 322) and a human kappa light chain constant region (FIG. 5B; SEQ ID NO: 323).
  • FIG. 6 provides an amino acid sequence of an HLA Class II DRA a chain (SEQ ID NO: 324).
  • FIG. 7A-7J provide amino acid sequences of HLA Class II DRB 1 b chains (from top to bottom:
  • FIG. 8A-8C provide amino acid sequences of HLA Class II DRB3 b chains (from top to bottom:
  • FIG. 9 provides an amino acid sequence of an HLA Class II DRB4 b chain (SEQ ID NO: 338).
  • FIG. 10 provides an amino acid sequence of an HLA Class II DRB5 b chain (SEQ ID NO: 339).
  • FIG. 11 provides an amino acid sequence of an HLA Class II DMA a chain (SEQ ID NO: 340).
  • FIG. 12 provides an amino acid sequence of an HLA Class II DMB b chain (SEQ ID NO: 341).
  • FIG. 13 provides an amino acid sequence of an HLA Class II DOA a chain (SEQ ID NO: 342).
  • FIG. 14 provides an amino acid sequence of an HLA Class II DOB b chain (SEQ ID NO: 343).
  • FIG. 15 provides an amino acid sequence of an HLA Class II DPA1 a chain (SEQ ID NO: 344).
  • FIG. 16 provides an amino acid sequence of an HLA Class II DPB1 b chain (SEQ ID NO: 345).
  • FIG. 17 provides an amino acid sequence of an HLA Class II DQA1 a chain (SEQ ID NO: 346).
  • FIG. 18 provides an amino acid sequence of an HLA Class II DQA2 a chain (SEQ ID NO: 347).
  • FIG. 19A-19B provide amino acid sequences of HLA Class II DQB1 b chains (from top to
  • FIG. 20A-20B provide amino acid sequence of HLA Class II DQB2 b chains (from top to
  • FIG. 21A-21G provide amino acid sequences of immunoglobulin Fc polypeptides (from top to bottom: SEQ ID NOs: 352-363).
  • FIG. 22A-22L provide schematic depictions of exemplary multimeric T-cell modulatory
  • FIG. 23A-23I provide schematic depictions of exemplary single-chain T-cell modulatory
  • FIG. 24 depicts production of exemplary antigen-presenting polypeptides of the present
  • FIG. 25A-25B provide the amino acid sequence (FIG. 25A; SEQ ID NO: 364) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 25B; SEQ ID NO 365) encoding same.
  • FIG. 26A-26B provide the amino acid sequence (FIG. 26A; SEQ ID NO: 366) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 26B; SEQ ID NO: 367) encoding same.
  • FIG. 27A-27B provide the amino acid sequence (FIG. 27 A; SEQ ID NO: 368) of an exemplary single-chain T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 27B; SEQ ID NO: 369) encoding same.
  • FIG. 28A-28B provide the amino acid sequence (FIG. 28A; SEQ ID NO: 370) of an exemplary single-chain T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 28B; SEQ ID NO: 371) encoding same.
  • FIG. 29A-29B provide the amino acid sequence (FIG. 29A; SEQ ID NO: 362) of an exemplary single-chain T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 29B; SEQ ID NO: 373) encoding same.
  • FIG. 30A-30B provide the amino acid sequence (FIG. 30A; SEQ ID NO: 374) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 30B; SEQ ID NO: 375) encoding same.
  • FIG. 31A-31B provide the amino acid sequence (FIG. 31 A; SEQ ID NO: 376) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 31B; SEQ ID NO: 377) encoding same.
  • FIG. 32A-32B provide the amino acid sequence (FIG. 32A; SEQ ID NO: 378) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 32B; SEQ ID NO: 379) encoding same.
  • FIG. 33A-33B provide the amino acid sequence (FIG. 33A; SEQ ID NO: 380) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 33B; SEQ ID NO: 381) encoding same.
  • FIG. 34A-34B provide the amino acid sequence (FIG. 34A; SEQ ID NO: 382) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 34B; SEQ ID NO: 383) encoding same.
  • FIG. 35A-35B provide the amino acid sequence (FIG. 35A; SEQ ID NO: 384) of an exemplary polypeptide chain of a multimeric T-cell modulator antigen-presenting polypeptide, and a nucleotide sequence (FIG. 35B; SEQ ID NO: 385) encoding same.
  • FIG. 36 provides a schematic depiction of MHC Class II alpha- and beta-chains with a peptide.
  • FIG. 37A-37C provide schematic depictions of examples of antigen-presenting polypeptides (APPs).
  • APPs antigen-presenting polypeptides
  • FIG. 38A-38B provide schematic depictions of APPs without immunomodulatory (MOD)
  • FIG. 38 A polypeptides
  • FIG. 38B The unmarked rectangle in FIG. 38 represents a dimerization domain (e.g., a bZIP polypeptide).
  • the arrows pointing to the dashed lines indicate possible positions of a MOD polypeptide(s).
  • FIG. 39 provides a table showing associations of HLA class II alleles and haplotypes with risk of autoimmune disease. The table also provides autoantigens associated with the diseases listed.
  • polynucleotide and“nucleic acid,” used interchangeably herein, refer to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides.
  • this term includes, but is not limited to, single-, double-, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases.
  • peptide refers to a polymeric form of amino acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones.
  • a polynucleotide or polypeptide has a certain percent "sequence identity" to another
  • polynucleotide or polypeptide meaning that, when aligned, that percentage of bases or amino acids are the same, and in the same relative position, when comparing the two sequences.
  • Sequence identity can be determined in a number of different ways. To determine sequence identity, sequences can be aligned using various convenient methods and computer programs (e.g., BLAST, T-COFFEE, MUSCLE, MAFFT, etc.), available over the world wide web at sites including ncbi.nlm.nili.gov/BLAST, ebi.ac.uk/Tools/msa/tcoffee/, ebi.ac.uk/Tools/msa/muscle/, mafft.cbrc.jp/alignment/software/. See, e.g., Altschul et al. (1990), J. Mol. Bioi. 215:403-10.
  • a group of amino acids having aliphatic side chains consists of glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic -hydroxyl side chains consists of serine and threonine; a group of amino acids having amide containing side chains consisting of asparagine and glutamine; a group of amino acids having aromatic side chains consists of phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains consists of lysine, arginine, and histidine; a group of amino acids having acidic side chains consists of glutamate and aspartate; and a group of amino acids having sulfur containing side chains consists of cysteine and methionine.
  • Exemplary conservative amino acid substitution groups are: valine-leucine- isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine- valine-glycine, and asparagine- glutamine.
  • binding e.g. with reference to binding of a T-cell modulatory
  • Non-covalent binding refers to a direct association between two molecules, due to, for example, electrostatic, hydrophobic, ionic, and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.
  • Non- covalent binding interactions are generally characterized by a dissociation constant (K D ) of less than 10 6 M, less than 10 7 M, less than 10 8 M, less than 10 9 M, less than 10 10 M, less than 10 11 M, less than 10 12 M, less than 10 13 M, less than 10 14 M, or less than 10 15 M.
  • K D dissociation constant
  • “Affinity” refers to the strength of non-covalent binding, increased binding affinity being correlated with a lower K D -“Specific binding” generally refers to binding with an affinity of at least about 10 7 M or greater, e.g. , 5x 10 7 M, 10 8 M, 5 x 10 8 M, 10 9 M, and greater.“Non-specific binding” generally refers to binding (e.g., the binding of a ligand to a moiety other than its designated binding site or receptor) with an affinity of less than about 10 7 M (e.g., binding with an affinity of 10 6 M, 10 5 M, 10 4 M).
  • “specific binding” can be in the range of from 1 mM to 100 mM, or from 100 mM to 1 mM.
  • “Covalent binding” or“covalent bond,” as used herein, refers to the formation of one or more covalent chemical binds between two different molecules.
  • immunological synapse or“immune synapse” as used herein generally refers to the natural interface between two interacting immune cells of an adaptive immune response including, e.g., the interface between an antigen-presenting cell (APC) or target cell and an effector cell, e.g., a lymphocyte, an effector T cell, a natural killer cell, and the like.
  • An immunological synapse between an APC and a T cell is generally initiated by the interaction of a T cell antigen receptor and major histocompatibility complex molecules, e.g., as described in Bromley et al., Annu Rev Immunol. 2001;19:375-96; the disclosure of which is incorporated herein by reference in its entirety.
  • T cell includes ah types of immune cells expressing CD3, including T-helper cells (CD4 + cells), cytotoxic T-cells (CD8 + cells), T-regulatory cells (Treg), and NK-T cells.
  • the term“immunomodulatory polypeptide” (also referred to as a“co-stimulatory polypeptide”), as used herein, includes a polypeptide on an antigen presenting cell (APC) (e.g., a dendritic cell, a B cell, and the like), or a portion of the polypeptide on an APC, that specifically binds a cognate co-immunomodulatory polypeptide on a T cell, thereby providing a signal which, in addition to the primary signal provided by, for instance, binding of a TCR/CD3 complex with a major histocompatibility complex (MHC) polypeptide loaded with peptide, mediates a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like.
  • APC antigen presenting cell
  • MHC major histocompatibility complex
  • An immunomodulatory polypeptide can include, but is not limited to, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD-L2, 4-1BBL, OX40L, Fas ligand (FasL), inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, lymphotoxin beta receptor, 3/TR6, ILT3, ILT4, HVEM, an agonist or antibody that binds Toll ligand receptor and a ligand that specifically binds with B7-H3.
  • a co-stimulatory polypeptide also encompasses, inter alia, an antibody that specifically binds with a cognate co-stimulatory molecule present on a T cell, such as, but not limited to, IL-2, CD27, CD28, 4-1BB, 0X40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds to CD83.
  • IL-2 IL-2
  • CD27, CD28, 4-1BB 0X40, CD30, CD40, PD-1, ICOS
  • LFA-1 lymphocyte function-associated antigen-1
  • CD2 LIGHT
  • NKG2C NKG2C
  • B7-H3 B7-H3
  • an“immunomodulatory polypeptide” specifically binds a cognate co-immunomodulatory polypeptide on a T cell.
  • An“immunomodulatory domain” (“MOD”) of a TMAPP of the present disclosure binds a cognate co-immunomodulatory polypeptide, which may be present on a target T cell.
  • Heterologous means a nucleotide or polypeptide that is not found in the native nucleic acid or protein, respectively.
  • Recombinant means that a particular nucleic acid (DNA or RNA) is the
  • DNA sequences encoding polypeptides can be assembled from cDNA fragments or from a series of synthetic oligonucleotides, to provide a synthetic nucleic acid which is capable of being expressed from a recombinant transcriptional unit contained in a cell or in a cell-free transcription and translation system.
  • recombinant expression vector or“DNA construct” are used interchangeably herein to refer to a DNA molecule comprising a vector and at least one insert.
  • Recombinant expression vectors are usually generated for the purpose of expressing and/or propagating the insert(s), or for the construction of other recombinant nucleotide sequences.
  • the insert(s) may or may not be operably linked to a promoter sequence and may or may not be operably linked to DNA regulatory sequences.
  • affinity refers to the equilibrium constant for the reversible binding of two agents (e.g., an antibody and an antigen) and is expressed as a dissociation constant (K D ).
  • Affinity can be at least 1-fold greater, at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5-fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, at least 10-fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50-fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90-fold greater, at least 100-fold greater, or at least 1,000-fold greater, or more, than the affinity of an antibody for unrelated amino acid sequences.
  • Affinity of an antibody to a target protein can be, for example, from about 100 nanomolar (nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM to about 1 femtomolar (fM) or more.
  • nM nanomolar
  • pM picomolar
  • fM femtomolar
  • the term“avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution.
  • binding refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.
  • Specific binding refers to binding with an affinity of at least about 10 7 M or greater, e.g., 5x 10 7 M, 10 s M, 5 x 10 s M, and greater.
  • Non- specific binding refers to binding with an affinity of less than about 10 7 M, e.g., binding with an affinity of 10 6 M, 10 5 M, 10 4 M, etc.
  • treatment means obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in ter s of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease or symptom in a mammal, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to acquiring the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease or symptom, i.e., arresting its development; and/or (c) relieving the disease, i.e., causing regression of the disease.
  • the therapeutic agent may be administered before, during or after the onset of disease or injury.
  • the treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment is desirably performed prior to complete loss of function in the affected tissues.
  • the subject therapy will desirably be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.
  • mammals include, e.g., humans, non-human primates, rodents (e.g., rats; mice), lagomorphs (e.g., rabbits), ungulates (e.g., cows, sheep, pigs, horses, goats, and the like), etc.
  • rodents e.g., rats; mice
  • lagomorphs e.g., rabbits
  • ungulates e.g., cows, sheep, pigs, horses, goats, and the like
  • the present disclosure provides T-cell modulatory antigen-presenting polypeptides (TMAPPs) that comprise: a) a first polypeptide comprising: i) a peptide epitope; and ii) a first MHC Class II polypeptide; and b) a second polypeptide comprising a second MHC Class II polypeptide, where the first and/or the second polypeptides comprises one or more immunomodulatory polypeptides.
  • TMAPPs T-cell modulatory antigen-presenting polypeptides
  • the present disclosure provides nucleic acids comprising nucleotide sequences encoding TMAPPs of the present disclosure, as well as cells genetically modified with the nucleic acids.
  • a TMAPP of the present disclosure is useful for modulating activity of a T cell.
  • the present disclosure provides methods of modulating activity of a T cell.
  • the present disclosure provides an antigen-presenting polypeptide (APP), where an APP of the present disclosure does not include an immunomodulatory polypeptide.
  • An APP of the present disclosure can be a single chain polypeptide or a multi-chain (multimeric) polypeptide.
  • An APP of the present disclosure is useful for diagnostic applications and therapeutic applications.
  • TMAPPs T-cell modulatory antigen-presenting polypeptides
  • a TMAPP of the present disclosure comprises two polypeptide chains and is sometimes referred to herein as a “multimeric T-cell modulatory antigen-presenting polypeptide.”
  • a TMAPP of the present disclosure comprises a single polypeptide chain.
  • a TMAPP of the present disclosure is also referred to as a“synTac polypeptide.”
  • a TMAPP of the present disclosure comprises one or more immunomodulatory polypeptides. In some cases, a TMAPP of the present disclosure comprises a single immunomodulatory polypeptide. In some cases, a TMAPP of the present disclosure comprises two or more immunomodulatory polypeptides (e.g., 2, 3, 4, or 5 immunomodulatory polypeptides).
  • a TMAPP of the present disclosure comprises two or more immunomodulatory polypeptides. In some cases, where a TMAPP of the present disclosure comprises a first polypeptide and a second polypeptide, the two or more immunomodulatory polypeptides are present in the first polypeptide chain only. In some cases, where a TMAPP of the present disclosure comprises a first polypeptide and a second polypeptide, the two or more
  • immunomodulatory polypeptides are present in the second polypeptide chain only.
  • a TMAPP of the present disclosure comprises a first polypeptide and a second polypeptide
  • at least one of the two or more immunomodulatory polypeptides are present in the first polypeptide chain; and at least one of the two or more immunomodulatory polypeptides are present in the second polypeptide chain.
  • a TMAPP of the present disclosure comprises two immunomodulatory polypeptides
  • the two immunomodulatory polypeptides have the same amino acid sequence, i.e., the TMAPP comprises two copies of an immunomodulatory polypeptide.
  • the two immunomodulatory polypeptides do not have the same amino acid sequence; e.g., one of the two immunomodulatory polypeptides comprises a first amino acid sequence and the second of the two immunomodulatory polypeptides comprises a second amino acid sequence, where the first and the second amino acid sequences are not identical.
  • the first and the second amino acid sequences differ from one another in amino acid sequence by from 1 amino acid to 10 amino acids, from 10 amino acids to 25 amino acids, or more than 25 amino acids. In some cases, the first and the second amino acid sequences share less than 98%, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, or less than 70%, amino acid sequence identity with one another.
  • a TMAPP of the present disclosure modulates activity of a T cell.
  • a TMAPP of the present disclosure reduces activity of an autoreactive T cell and/or an autoreactive B cell.
  • a TMAPP of the present disclosure increases the number and/or activity of a regulator T cell (Treg), resulting in reduced activity of an autoreactive T cell and/or an autoreactive B cell.
  • Treg regulator T cell
  • Immunomodulatory polypeptides that are suitable for inclusion in a TMAPP of the present disclosure include, but are not limited to, IL-2, transforming growth factor-beta (TOHb), JAG1, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD-L2, 4-1BBL, OX40L, Fas ligand (FasL), inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, and ILT4.
  • IL-2 transforming growth factor-beta
  • TOHb transforming growth factor-beta
  • an immunomodulatory polypeptide suitable for inclusion in a TMAPP of the present disclosure is a variant that comprises from 1 to 10 amino acid substitutions relative to a wild-type or naturally-occurring immunomodulatory polypeptide, and that exhibits reduced affinity to its cognate co-immunomodulatory polypeptide (e.g., a co-immunomodulatory polypeptide present on the surface of a T cell), compared to the affinity of the wild- type or naturally-occurring immunomodulatory polypeptide for the cognate co-immunomodulatory polypeptide.
  • co-immunomodulatory polypeptide e.g., a co-immunomodulatory polypeptide present on the surface of a T cell
  • a TMAPP of the present disclosure comprises: i) a peptide epitope (a peptide recognized and bound by a TCR); ii) an MHC Class II a chain polypeptide; iii) an MHC Class II b chain polypeptide; and iv) an immunomodulatory polypeptide (also referred to herein as a“MOD polypeptide” or a“MOD domain”).
  • the TMAPP comprises two polypeptide chains; such a TMAPP is referred to herein as a multimeric TMAPP.
  • a TMAPP of the present disclosure can further include one or both of: a dimerizer polypeptide; and an immunoglobulin scaffold (e.g., an Ig Fc polypeptide) or a non-immunoglobulin scaffold.
  • a dimerizer polypeptide e.g., an Ig Fc polypeptide
  • an immunoglobulin scaffold e.g., an Ig Fc polypeptide
  • a non-immunoglobulin scaffold e.g., an Ig Fc polypeptide
  • a TMAPP of the present disclosure comprises a single immunomodulatory
  • a TMAPP of the present disclosure comprises 2 copies of an immunomodulatory polypeptide. In some cases, a TMAPP of the present disclosure comprises 3 copies of an immunomodulatory polypeptide. Where a TMAPP of the present disclosure comprises 2 or 3 copies of an immunomodulatory polypeptide, in some cases, the 2 or 3 copies are in tandem. Where a TMAPP of the present disclosure comprises 2 or 3 copies of an immunomodulatory polypeptide, in some cases, the 2 or 3 copies are separated from one another by a linker.
  • a TMAPP of the present disclosure can include one or more linkers, where the one or more linkers are between one or more of: i) an MHC Class II polypeptide and an Ig Fc polypeptide, where such a linker is referred to herein as“LI”; ii) an immunomodulatory polypeptide and an MHC Class II polypeptide, where such a linker is referred to herein as“L2”; iii) a first immunomodulatory polypeptide and a second immunomodulatory polypeptide, where such a linker is referred to herein as“L3”; iv) a peptide antigen (“epitope”) and an MHC Class II polypeptide; v) an MHC Class II polypeptide and a dimerization polypeptide (e.g., a first or a second member of a dimerizing pair); and vi) a dimerization polypeptide (e.g., a first or a second member of a dimerizing pair) and
  • an LI linker comprises (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • an L2 linker comprises (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • an L3 linker comprises (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • a linker comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; and iii) an MHC Class II a2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii)
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II a 1 polypeptide; iii) an MHC Class II a2 polypeptide; and iv) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an
  • immunomodulatory polypeptide ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) an Ig Fc polypeptide. This arrangement is depicted schematically in FIG. 1A.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) an Ig Fc polypeptide; and iv) an immunomodulatory polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) an immunomodulatory polypeptide; and iv) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by
  • the immunomodulatory polypeptide(s) can be on the same polypeptide chain as the MHC Class II al and a2 polypeptides, as illustrated schematically in FIG. 1A-1C.
  • the peptide antigen (“epitope”) can be on the same polypeptide chain as the MHC Class II b ⁇ and b2 polypeptides, as illustrated schematically in FIG. ID and FIG. IE.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; iii) an MHC Class II b ⁇ polypeptide; and iv) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; and iii) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) a peptide antigen (an “epitope”) that is recognized (e.g
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C- terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an immunomodulatory polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; and iii) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C- terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by
  • the TMAPP can include a single immunomodulatory polypeptide.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker.
  • the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • a TMAPP of the present disclosure comprises two immunomodulatory polypeptides
  • the first immunomodulatory polypeptide is linked to the second immunomodulatory polypeptide by a linker (an“L3” linker); e.g., a linker of from about 2 amino acids to 50 amino acids in length.
  • Suitable L3 linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide. In any of the above embodiments, in some cases, the Ig Fc is an IgG4 Fc polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a PD-L1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasL polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen).
  • the two polypeptide chains of a TMAPP of the present disclosure can be covalently linked, e.g., via a disulfide bond.
  • the two polypeptide chains of a TMAPP of the present disclosure can also associate with one another non-covalently.
  • the two polypeptide chains of a TMAPP of the present disclosure can be linked via interaction between a first dimerization domain present in the first polypeptide, and a second dimerization domain present in the second polypeptide.
  • the first polypeptide chain of a TMAPP of the present disclosure can include an Ig CHI polypeptide as a first dimerization domain; and the second polypeptide chain of a TMAPP of the present disclosure can include the constant region of an immunoglobulin k chain, as the second dimerization domain.
  • a suitable Ig CHI polypeptide has a length of from about 90 amino acids to about 120 amino acids (e.g., from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, from about 100 amino acids to about 105 amino acids, from about 105 amino acids to about 110 amino acids, from about 110 amino acids to about 115 amino acids, or from about 110 amino acids to about 120 amino acids); and can comprise an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following CHI amino acid sequence:
  • a suitable Ig k chain constant region polypeptide has a length of from about 90 amino acids to about 120 amino acids (e.g., from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, from about 100 amino acids to about 105 amino acids, from about 105 amino acids to about 110 amino acids, from about 110 amino acids to about 115 amino acids, or from about 110 amino acids to about 120 amino acids); and can comprise an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following k chain constant region amino acid sequence:
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) a CHI polypeptide.
  • a peptide antigen an“epitope”
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; iv) a CHI polypeptide; and v) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; iv) a CHI polypeptide; and v) an Ig Fc polypeptide.
  • a TMAPP An example of such a TMAPP is depicted
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) an immunomodulatory polypeptide; iv) a CHI polypeptide; and v) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an Ig k constant region polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C- terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) a CHI polypeptide; iv) an immunomodulatory polypeptide; and v) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) a CHI polypeptide; iv an Ig Fc polypeptide; and v) an immunomodulatory polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (
  • the TMAPP can include a single immunomodulatory polypeptide.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker.
  • the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • immunomodulatory polypeptide is linked to the second immunomodulatory polypeptide by a linker (an“L3” linker); e.g., a linker of from about 2 amino acids to 50 amino acids in length.
  • Suitable L3 linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • immunomodulatory polypeptides are separated by a linker (an“L3); where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • linker between any two components of the TMAPP comprises the amino acid sequence
  • the Ig Fc is an IgGl Fc polypeptide. In any of the above embodiments, in some cases, the Ig Fc is an IgG4 Fc polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a PD-L1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasL polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen).
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an immunomodulatory polypeptide; and v) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; and iii) a CHI polypeptide.
  • a peptide antigen an“epitope”
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an immunomodulatory polypeptide; and v) an Ig K chain constant region polypeptide; and b) a second polypeptide comprising: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) a CHI polypeptide; and v) an Ig Fc polypeptide.
  • a first polypeptide comprising: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II
  • a TMAPP of the present disclosure comprises, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; iii) an MHC Class II b ⁇ polypeptide; iv) an MHC Class II b2 polypeptide; and v) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) a CHI polypeptide; and v) an Ig Fc polypeptide.
  • a TMAPP of the present disclosure comprises, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an immunomodulatory polypeptide; and v) an Ig k chain constant region polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) a CHI polypeptide; and v) an Ig Fc polypeptide.
  • an“epitope” an“epitope”
  • a TMAPP of the present disclosure comprises, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an Ig k chain constant region polypeptide; and v) an immunomodulatory polypeptide; and b) a second polypeptide comprising, in order from N- terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; iii) a CHI polypeptide; and v) an Ig Fc polypeptide.
  • a TMAPP is depicted schematically in FIG. 3C.
  • a TMAPP is depicted schematically in FIG. 3C.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker. In any one of the above embodiments, the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • a TMAPP of the present disclosure comprises two immunomodulatory polypeptides, in some cases, the first immunomodulatory polypeptide is linked to the second immunomodulatory polypeptide by a linker (an“L3” linker); e.g., a linker of from about 2 amino acids to 50 amino acids in length.
  • Suitable L3 linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises two immunomodulatory polypeptides
  • the two immunomodulatory polypeptides are separated by a linker (an“L3); where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide.
  • the Ig Fc is an IgG4 Fc polypeptide.
  • the immunomodulatory polypeptide is a PD-F1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasF polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen).
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; and iv) an MHC Class II a2 polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; and ii) an MHC Class II b2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an M
  • the second polypeptide comprises, in order from N-terminus to C- terminus: i) an immunomodulatory polypeptide; and ii) an MHC Class II b2 polypeptide.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; and v) an immunoglobulin or non-immunoglobulin scaffold polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; and ii) an MHC Class II b2 polypeptide.
  • the second polypeptide comprises
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; and v) an Ig Fc polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; and ii) an MHC Class II b2 polypeptide.
  • the second polypeptide comprises, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; and ii) an MHC Class II b2 polypeptide.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; and v) a first member of a dimerizer pair; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; iii) a second member of the dimerizer pair.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; and v) a first leucine zipper polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; and iii) a second leucine zipper polypeptide.
  • the second polypeptide comprises, in order from N- terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; and iii) a second leucine zipper polypeptide.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C- terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; v) a first leucine zipper polypeptide; and vi) an Ig Fc polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; and iii) a second leucine zipper polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C- terminus: i) a peptide antigen (an“epitope”) that is recognized (e
  • the second polypeptide comprises, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; and iii) a second leucine zipper polypeptide.
  • the TMAPP can include a single immunomodulatory polypeptide.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker.
  • the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; v) a first leucine zipper polypeptide; and vi) an Ig Fc polypeptide; and b) a second polypeptide comprising: i) a first immunomodulatory polypeptide; ii) a second
  • the immunomodulatory polypeptide comprises, in order from N-terminus to C-terminus: i) a first immunomodulatory polypeptide; ii) a second immunomodulatory polypeptide; iii) an MHC Class II b2 polypeptide; and iv) a second leucine zipper polypeptide.
  • the first and the second immunomodulatory polypeptides comprise the same amino acid sequences.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; and v) an Ig Fc polypeptide; and b) a second polypeptide comprising: i) a first immunomodulatory polypeptide; ii) a second immunomodulatory polypeptide; and iii) an MHC Class II b2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound)
  • the second polypeptide comprises, in order from N-terminus to C-terminus: i) a first immunomodulatory polypeptide; ii) a second immunomodulatory polypeptide; and iii) an MHC Class II b2 polypeptide.
  • the first and the second immunomodulatory polypeptides comprise the same amino acid sequences.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; and iv) an MHC Class II a2 polypeptide; and b) a second polypeptide comprising: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; and iii) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II
  • the second polypeptide comprises, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; and iii) an Ig Fc polypeptide.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; and iv) an MHC Class II a2 polypeptide; and b) a second polypeptide comprising: i) a first immunomodulatory polypeptide; ii) a second immunomodulatory polypeptide; iii) an MHC Class II b2 polypeptide; iv) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound)
  • the second polypeptide comprises, in order from N-terminus to C-terminus: i) a first immunomodulatory polypeptide; ii) a second immunomodulatory polypeptide; iii) an MHC Class II b2 polypeptide; iv) an Ig Fc polypeptide.
  • the first and the second immunomodulatory polypeptides comprise the same amino acid sequence.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) an
  • immunomodulatory polypeptide ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; and iv) an MHC Class II a2 polypeptide; and b) a second polypeptide comprising: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b2 polypeptide; and iii) an Ig Fc polypeptide.
  • the second polypeptide comprises, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b2 polypeptide; and iii) an Ig Fc polypeptide.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a first immunomodulatory polypeptide; ii) a second
  • immunomodulatory polypeptide iii) an MHC Class II b ⁇ polypeptide; iv) an MHC Class II al polypeptide; and v) an MHC Class II a2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b2 polypeptide; and iii) an Ig Fc polypeptide.
  • a peptide antigen an“epitope”
  • the second polypeptide comprises, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b2 polypeptide; and iii) an Ig Fc polypeptide.
  • the first and the second immunomodulatory polypeptides comprise the same amino acid sequence.
  • a TMAPP of the present disclosure comprises two immunomodulatory polypeptides
  • the first immunomodulatory polypeptide is linked to the second immunomodulatory polypeptide by a linker (an“L3” linker); e.g., a linker of from about 2 amino acids to 50 amino acids in length.
  • Suitable L3 linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO:
  • the TMAPP comprises two immunomodulatory polypeptides
  • the two immunomodulatory polypeptides are separated by a linker (an“L3); where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide.
  • the Ig Fc is an IgG4 Fc polypeptide.
  • the immunomodulatory polypeptide is a PD-L1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasL polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen).
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C- terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; and iii) an MHC Class II a2 polypeptide; and iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide;
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II al polypeptide; and iii) an MHC Class II a2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C- terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide.
  • a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; and iii) an MHC Class II a2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; and
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide; and v) a first member of a dimerizer pair (e.g., a first leucine zipper polypeptide); and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) a second member of a dimerizer pair (
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C- terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide; and v) and v) a first member of a dimerizer pair (e.g., a first leucine zipper polypeptide); and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) a second member of a dimerizer pair
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) a first member of a dimerizer pair (e.g., a first leucine zipper polypeptide); and b) a second polypeptide comprising, in order from N-terminus to C- terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide; and v) a second member of a dimerizer pair (
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) a first member of a dimerizer pair (e.g., a first leucine zipper polypeptide); and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an immunoglobulin or non
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker. In any one of the above embodiments, the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker. In some cases, the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO:
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the two immunomodulatory polypeptides are separated by a linker (an“L3); where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide.
  • the Ig Fc is an IgG4 Fc polypeptide.
  • the immunomodulatory polypeptide is a PD-F1 polypeptide.
  • the immunomodulatory polypeptide is a TGF-b polypeptide.
  • the immunomodulatory polypeptide is a FasF polypeptide.
  • the epitope is an auto-epitope (an epitope of a self antigen).
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an immunomodulatory polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; and ii) an MHC Class II a2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an immunomodulatory polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; and iii) an immunoglobulin or non-immunoglobulin scaffold polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) an immunomodulatory polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; and iii) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an immunomodulatory polypeptide; and v) a first member of a dimerizer pair; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; and iii) a second member of the dimerizer pair.
  • a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an immunomodulatory polypeptide; and v) a first leucine zipper polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an MHC Class II al polypeptide; ii) an MHC Class II a2 polypeptide; and iii) a second leucine zipper polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized
  • the TMAPP can include a single immunomodulatory polypeptide.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker.
  • the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide. In any of the above embodiments, in some cases, the Ig Fc is an IgG4 Fc polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a PD-L1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasL polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen).
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; and iii) an MHC Class II a2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) an immunoglobulin or non-immunoglobulin scaffold polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; and iii) an MHC Class II b2 polypeptide; and b) a second polypeptide comprising, in order from N- terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) an Ig Fc polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) a first member of a dimerizer pair; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; and iv) a second member of the dimerizer pair.
  • a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; and iv) a first leucine zipper polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II a 1 polypeptide; iii) an MHC Class II a2 polypeptide; and iv) a second leucine zipper polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”)
  • the TMAPP can include a single immunomodulatory polypeptide.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker.
  • the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide. In any of the above embodiments, in some cases, the Ig Fc is an IgG4 Fc polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a PD-L1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasL polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen).
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MF1C Class II b ⁇ polypeptide; iii) an MF1C Class II al polypeptide; and iv) an MF1C Class II a2 polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; and ii) an MF1C Class II b2 polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; i
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MF1C Class II b ⁇ polypeptide; iii) an MF1C Class II al polypeptide; iv) an MF1C Class II a2 polypeptide; and v) an immunoglobulin or non-immunoglobulin scaffold polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; and ii) an MF1C Class II b2 polypeptide.
  • a peptide antigen an“epitope”
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MF1C Class II b ⁇ polypeptide; iii) an MF1C Class II al polypeptide; iv) an MF1C Class II a2 polypeptide; and v) an Ig Fc polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MF1C Class II b ⁇ polypeptide; iii) an MF1C Class II al polypeptide; iv) an MF1C Class
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MF1C Class II b ⁇ polypeptide; iii) an MF1C Class II al polypeptide; iv) an MF1C Class II a2 polypeptide; and v) a first member of a dimerizer pair; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MF1C Class II b2 polypeptide; and iii) a second member of the dimerizer pair.
  • a TMAPP of the present disclosure comprises: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MF1C Class II b ⁇ polypeptide; iii) an MF1C Class II al polypeptide; iv) an MF1C Class II a2 polypeptide; and v) a first leucine zipper polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) an immunomodulatory polypeptide; ii) an MHC Class II b2 polypeptide; and iii) a second leucine zipper polypeptide.
  • a first polypeptide comprising, in order from N-terminus to C-terminus: i) a peptide antigen (an “epit
  • the TMAPP can include a single immunomodulatory polypeptide.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker.
  • the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises a linker (an“L2”) between the immunomodulatory polypeptide and the MHC polypeptide, where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide. In any of the above embodiments, in some cases, the Ig Fc is an IgG4 Fc polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a PD-L1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasL polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen).
  • a TMAPP of the present disclosure is a single-chain (a single polypeptide chain) TMAPP.
  • a single-chain TMAPP of the present disclosure comprises: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an MHC Class II al polypeptide; v) an MHC Class II a2 polypeptide; and vi) at least one
  • a single-chain TMAPP of the present disclosure can also include an Ig Fc polypeptide.
  • a single-chain TMAPP of the present disclosure can comprise two or more immunomodulatory polypeptides, where the two or more immunomodulatory polypeptides can have the same amino acid sequence or different amino acid sequences.
  • the arrangement of the components, including the placement of the immunomodulatory polypeptide, of a single-chain TMAPP of the present disclosure can vary. Non-limiting examples are depicted in FIG. 4A-4C.
  • a single-chain TMAPP of the present disclosure can comprise, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II al polypeptide; iii) an MHC Class II a2 polypeptide; iv) an MHC Class II b ⁇ polypeptide; v) an MHC Class II b2 polypeptide; and vi) an Ig Fc polypeptide, where the immunomodulatory polypeptide of the single-chain TMAPP is located at one or more of: i) at the N-terminus (N- terminal to the peptide antigen); ii) between the peptide antigen (“epitope”) and the MHC Class II al polypeptide; iii) between the MHC Class II a2 polypeptide and the MHC Class II b ⁇ polypeptide; i
  • a single-chain TMAPP of the present disclosure can comprise, in order from N-terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II b2 polypeptide; iv) an MHC Class II al polypeptide; v) an MHC Class II a2 polypeptide; and vi) an Ig Fc polypeptide, where the immunomodulatory polypeptide of the single-chain TMAPP is located at one or more of: i) at the N-terminus (N-terminal to the peptide antigen); ii) between the peptide antigen (“epitope”) and the MHC Class II b ⁇ polypeptide; iii) between the MHC Class II b2
  • a single-chain TMAPP of the present disclosure can comprise, in order from N- terminus to C-terminus: i) a peptide antigen (an“epitope”) that is recognized (e.g., is capable of being recognized and bound) by a TCR; ii) an MHC Class II b ⁇ polypeptide; iii) an MHC Class II al polypeptide; iv) an MHC Class II a2 polypeptide; v) an MHC Class II b2 polypeptide; and vi) an Ig Fc polypeptide, where the immunomodulatory polypeptide of the single -chain TMAPP is located at one or more of: i) at the N-terminus (N-terminal to the peptide antigen); ii) between the peptide antigen (“epitope”) and the MHC Class II b ⁇ polypeptide; iii) between the MHC Class II al poly
  • the TMAPP can include a single immunomodulatory polypeptide.
  • the TMAPP can include 2 copies of the immunomodulatory polypeptide; the 2 copies can be in tandem, or can be separated by a linker.
  • the TMAPP can include 3 copies of the immunomodulatory polypeptide; the 3 copies can be in tandem, or can be separated by a linker.
  • the TMAPP comprises a linker (an“LI”) between the MHC polypeptide and the Ig Fc polypeptide; where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the TMAPP comprises two immunomodulatory polypeptides
  • the two immunomodulatory polypeptides are separated by a linker (an“L3); where exemplary suitable linkers include (GGGGS)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, or 8.
  • the linker between any two components of the TMAPP comprises the amino acid sequence GGSAAAGG (SEQ ID NO: 2).
  • the Ig Fc is an IgGl Fc polypeptide.
  • the Ig Fc is an IgG4 Fc polypeptide.
  • the immunomodulatory polypeptide is a PD-L1 polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a TGF-b polypeptide. In any of the above embodiments, in some cases, the immunomodulatory polypeptide is a FasL polypeptide. In some cases, the epitope is an auto-epitope (an epitope of a self antigen
  • a TMAPP of the present disclosure comprises Class II MHC polypeptides.
  • Naturally occurring Class II MHC polypeptides comprise an a chain and a b chain.“Class II MHC polypeptides” include human leukocyte antigen (HLA) a- and b-chains. MHC Class II polypeptides include MCH Class II DP a and b polypeptides, DM a and b polypeptides, DOA a and b polypeptides, DOB a and b polypeptides, DQ a and b polypeptides, and DR a and b polypeptides.
  • HLA human leukocyte antigen
  • a“Class II MHC polypeptide” can comprise a class II MHC a chain polypeptide, a class II MHC b chain polypeptide, or only a portion of a class II MHC a or b chain polypeptide.
  • a“Class II MHC polypeptide” can be a polypeptide that includes: i) only the al domain of a class II MHC a chain polypeptide; ii) only the a2 domain of a class II MHC a chain; iii) only the al domain and an a2 domain of a class II MHC a chain; iv) only the b ⁇ domain of a class II MHC b chain; v) only the b2 domain of a class II MHC b chain; vi) only the b ⁇ domain and the b2 domain of a class II MHC b chain; vii) the al domain of a class II MHC a chain, the b ⁇ domain of a class II MHC b chain, and the b2 domain of a class II MHC; and the like.
  • Class II MHC polypeptides include allelic forms.
  • the HLA locus is highly polymorphic in
  • the HLA System (www.anthonynolan.com/HIG/) showed there are 3 DRA alleles, 494 DRB 1 alleles, 1 DRB2 alleles, 44 DRB 3 alleles, 13 DRB4 alleles, 18 DRB 5 alleles, 3 DRB 6 alleles, 2 DRB 7 alleles, 10 DRB 8 alleles, 1 DRB9 alleles, 34 DQA1 alleles, 83 DQB1 alleles, 23 DPA1, 126 DPB1 alleles, 4 DMA alleles, 7 DMB alleles, 12 DOA alleles and 9 DOB alleles.
  • the term“Class II MHC polypeptide” includes allelic forms of any known Class II MHC polypeptide.
  • a TMAPP of the present disclosure comprises a Class II MHC a chain, without the leader, transmembrane, and intracellular portions (e.g., cytoplasmic tails) that may be present in a naturally-occurring Class II MHC a chain.
  • a TMAPP of the present disclosure comprises only the al and a2 portions of a Class II MHC a chain; and does not include the leader, transmembrane, and intracellular portions (e.g., cytoplasmic tails) that may be present in a naturally-occurring Class II MHC a chain.
  • a TMAPP of the present disclosure comprises a Class II MHC b chain, without the leader, transmembrane, and intracellular portions (e.g., cytoplasmic tails) that may be present in a naturally-occurring Class II MHC b chain.
  • a TMAPP of the present disclosure comprises only the b ⁇ and b2 portions of a Class II MHC b chain; and does not include the leader, transmembrane, and intracellular portions (e.g., cytoplasmic tails) that may be present in a naturally-occurring Class II MHC b chain.
  • MHC Class II alpha chains comprise an al domain and an a2 domain.
  • the al domain and the a2 domain present in an antigen-presenting cell are from the same MHC Class II a chain polypeptide.
  • the al domain and the a2 domain present in an antigen- presenting cell are from two different MHC Class II a chain polypeptides.
  • MHC Class II alpha chains suitable for inclusion in a TMAPP e.g., a multimeric TMAPP; a single-chain TMAPP
  • An MHC Class II alpha chain suitable for inclusion in a multimeric polypeptide of the present disclosure can have a length of from about 60 amino acids to about 190 amino acids; for example, an MHC Class II alpha chain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 60 amino acids to about 80 amino acids, from about 80 amino acids to about 100 amino acids, from about 100 amino acids to about 120 amino acids, from about 120 amino acids to about 140 amino acids, from about 140 amino acids to about 160 amino acids, from about 160 amino acids to about 180 amino acids, or from about 180 amino acids to about 200 amino acids.
  • An MHC Class II al domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 95 amino acids; for example, an MHC Class II al domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, or from about 90 amino acids to about 95 amino acids.
  • An MHC Class II a2 domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 95 amino acids; for example, an MHC Class II a2 domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, or from about 90 amino acids to about 95 amino acids.
  • a suitable MHC Class II a chain polypeptide is a DRA polypeptide.
  • a DRA DRA
  • polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 26-203 of the DRA amino acid sequence depicted in FIG. 6.
  • the DRA polypeptide has a length of about 178 amino acids (e.g., 175, 176, 177, 178, 179, or 180 amino acids).
  • A“DRA polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DRA polypeptide comprises the following amino acid sequence: IKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQG ALANIA V DKANLEIMTK RSNYTPITNV PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO: 5, amino acids 26-203 of DRA*01:02:01, see FIG.
  • allelic variant is the DRA*01:01:01:01 allelic variant that differs from DRA*01:02:01 by having a valine in place of the leucine at position 242 of the sequence in FIG. 6.
  • a suitable DRA al domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIAV DKANLEIMTK RSNYTPITN (SEQ ID NO: 6); and can have a length of about 84 amino acids (e.g., 80, 81, 82, 83, 84, 85, or 86 amino acids).
  • a suitable DRA al domain can comprise the following amino acid sequence: VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGAEANIAV DKANEEIMTK RSNYTPITN (SEQ ID NO: 6), or a naturally- occurring allelic variant.
  • a suitable DRA a2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: V PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF
  • RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO: 7); and can have a length of about 94 amino acids (e.g., 90, 91, 92, 93, 94, 95, 96, 97, or 98 amino acids).
  • a suitable MHC Class II a chain polypeptide is a DMA polypeptide.
  • a DMA polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 27-217 of the DMA amino acid sequence depicted in FIG. 11.
  • the DMA polypeptide has a length of about 191 amino acids (e.g., 188, 189, 190, 191, 192, or 193 amino acids).
  • A“DMAA polypeptide” includes allelic variants, e.g., naturally occurring allelic
  • a suitable DMAA polypeptide comprises the following amino acid sequence: VPEA PTPMWPDDLQ NHTFLHTVYC QDGSPSVGLS EAYDEDQLFF
  • a suitable DMA al domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: VPEA PTPMWPDDLQ
  • a suitable DMA al domain can comprise the following amino acid sequence: VPEA PTPMWPDDLQ
  • a suitable DMA a2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: GFPIAE VFTLKPLEFG KPNTLVCFVS NLFPPMLTVN WQHHSVPVEG FGPTFVSAVD GLSFQAFSYL
  • NFTPEPSDIF SCIVTHEIDR YTAIAYW (SEQ ID NO: 10); and can have a length of about 93 amino acids (e.g., 90, 91, 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DMA a2 domain can comprise the following amino acid sequence: GFPIAE VFTLKPLEFG KPNTLVCFVS
  • DOA NLFPPMLTVN WQHHSVPVEG FGPTFVSAVD GLSFQAFSYL NFTPEPSDIF SCIVTHEIDR YTAIAYW
  • a suitable MHC Class II a chain polypeptide is a DOA polypeptide.
  • DOA polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 26-204 of the DOA amino acid sequence depicted in FIG. 13.
  • the DOA polypeptide has a length of about 179 amino acids (e.g., 175, 176, 177, 178, 179, 180, 181, or 182 amino acids).
  • A“DOA polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DOA polypeptide comprises the following amino acid sequence: TKADH MGSYGPAFYQ SYGASGQFTH EFDEEQLFSV DLKKSEAVWR LPEFGDFARF DPQGGLAGIA AIKAHLDILV ERSNRSRAIN VPPRVTVLPK SRVELGQPNI LICIVDNIFP PVINITWLRN GQTVTEGVAQ TSFYSQPDHL FRKFHYLPFV PSAEDVYDCQ VEHWGLDAPL LRHW (SEQ ID NO: 11; amino acids 26-204 of DOA*01:01:01:01, see FIG. 13), or an allelic variant thereof.
  • allelic variant may be the DOA*01:02 by having an arginine in place of the cysteine (R80C) at position 80 or the DOA*01:03 variant having a valine in place of the leucine at position 74 (L74V) relative to DOA*01:01:01:01.
  • a suitable DOA al domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: TKADH MGSYGPAFYQ
  • SYGASGQFTH EFDEEQLFSV DLKKSEAVWR LPEFGDFARF DPQGGLAGIA AIKAHLDILV ERSNRSRAIN (SEQ ID NO: 12); and can have a length of about 85 amino acids (e.g., 83, 84, 85, 86, 87, or 88 amino acids).
  • Suitable al domain sequence may incorporate the L74V and/or R80C substitutions found in DOA*01:02 and DOA*01:03 (the amino acids corresponding to L74 and R 80 are shown italicized and bolded).
  • a suitable DOA al domain can comprise the following amino acid sequence: TKADH MGSYGPAFYQ SYGASGQFTH EFDEEQLFSV DLKKSEAVWR LPEFGDFARF DPQGGLAGIA AIKAHLDILV ERSNRSRAIN (SEQ ID NO: 12), or a naturally-occurring allelic variant.
  • a suitable DOA a2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: VPPRVTVLPK SRVELGQPNI LICIVDNIFP PVINITWLRN GQTVTEGVAQ TSFYSQPDHL FRKFHYLPFV PSAEDVYDCQ VEHWGLDAPL LRHW (SEQ ID NO: 13); and can have a length of about 94 amino acids (e.g., 91, 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DOA a2 domain can comprise the following amino acid sequence: VPPRVTVLPK SRVELGQPNI LICIVDNIFP PVINITWLRN GQTVTEGVAQ TSFYSQPDHL FRKFHYLPFV PSAEDVYDCQ VEHWGLDAPL LRHW (SEQ ID NO: 13), or a naturally-occurring allelic variant thereof.
  • DPA1 VPPRVTVLPK SRVELGQPNI LICIVDNIFP PVINITWLRN GQTVTEGVAQ TSFYSQPDHL FRKFHYLPFV PSAEDVYDCQ VEHWGLDAPL LRHW
  • a suitable MHC Class II a chain polypeptide is a DPA1 polypeptide.
  • DPA1 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 29-209 of the DPA1 amino acid sequence depicted in FIG. 15.
  • the DPA1 polypeptide has a length of about 181 amino acids (e.g., 178, 179, 180, 181, 182, 183, or 184 amino acids).
  • A“DPA1 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DPA1 polypeptide comprises the following amino acid sequence: AG AIKADHVSTY AAFVQTHRPT GEFMFEFDED EMFYVDLDKK ETVWHLEEFG QAFSFEAQGG LANIAILNNN LNTLIQRSNH TQATNDPPEV TVFPKEPVEL GQPNTLICHI DKFFPPVLNV TWLCNGELVT EGVAESLFLP RTDYSFHKFH YLTFVPSAED FYDCRVEHWG LDQPLLKHW (SEQ ID NO: 14, amino acids 29-209 of DPA1*01:03:01:01, see FIG. 15), or an allelic variant thereof.
  • a suitable DPA1 al domain may comprise an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: AIKADHVSTY AAFVQTHRPT GEFMFEFDED EMFYVDLDKK ETVWHLEEFG QAFSFEAQGG LANIAILNNN LNTLIQRSNH TQATN (SEQ ID NO: 15); and can have a length of about 87 amino acids (e.g., 84, 85, 86, 87, 88, or 89 amino acids).
  • a suitable DPA1 al domain can comprise the following amino acid sequence: AIKADHVSTY AAFVQTHRPT GEFMFEFDED EMFYVDLDKK ETVWHLEEFG QAFSFEAQGG LANIAILNNN LNTLIQRSNH TQATN (SEQ ID NO: 15), or a naturally-occurring allelic variant.
  • a suitable DPA1 a2 domain may comprise an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: DPPEV TVFPKEPVEL
  • GQPNTLICHI DKFFPPVLNV TWLCNGELVT EGVAESLFLP RTDYSFHKFH YLTFVPSAED FYDCRVEHWG LDQPLLKHW (SEQ ID NO: 16); and can have a length of about 97 amino acids (e.g., 91, 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DPA1 a2 domain can comprise the following amino acid sequence: DPPEV TVFPKEPVEL GQPNTLICHI DKFFPPVLNV TWLCNGELVT EGVAESLFLP RTDYSFHKFH YLTFVPSAED FYDCRVEHWG LDQPLLKHW (SEQ ID NO: 16), or a naturally-occurring allelic variant thereof.
  • DPA1 polypeptides comprise the sequence:
  • a suitable DPA1 al domain may comprise an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the amino acids 29-115 of DPA1*02:01:01:01, SEQ ID NO: 17; and can have a length of about 87 amino acids (e.g., 84, 85, 86, 87, 88, or 89 amino acids.
  • a suitable DPA1 a2 domain may comprise an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 116 to 209 of DPA1*02:01:01:01, SEQ ID NO: 17; and can have a length of about 97 amino acids (e.g., 91, 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable MHC Class II a chain polypeptide is a DQA1 polypeptide.
  • DQA1 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 24-204 of any of the DQA1 amino acid sequences depicted in FIG. 17.
  • the DQA1 polypeptide has a length of about 181 amino acids (e.g., 177, 178, 179, 180, 181, 182, or 183 amino acids).
  • a DQA1 a chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DQA1 *01:01 a chain amino acid in FIG. 17, ImMunoGeneTics (“IMGT”)/HLA Acc No:HLA00601.
  • IMGT ImMunoGeneTics
  • a DQA1 a chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DQA1 *01:02 a chain amino acid in FIG.
  • a DQA1 a chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DQA1 *02:01 a chain amino acid in FIG. 17, IMGT/HLA Acc No:HLA00607.
  • a DQA1 a chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DQA1 *03:01: a chain amino acid in FIG. 17, IMGT/HLA Acc No:HLA00609.
  • a DQA1 a chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DQA1*04:01 a chain amino acid in FIG. 17, IMGT/HLA Acc No:HLA00612.
  • a DQA1 a chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DQA1*05:01 a chain amino acid in FIG. 17, IMGT/HLA Acc No:HLA00613.
  • a DQA1 a chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DQA1 *06:01 a chain amino acid in FIG. 17, IMGT/HLA Acc No:HLA00620.
  • A“DQA1 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DQA1 polypeptide comprises the following amino acid sequence: EDIVADH VASCGVNLYQ FYGPSGQYTH EFDGDEQFYV DLERKET AWR WPEFSKFGGF DPQGALRNMA VAKHNLNIMI KRYNSTAATN EVPEVTVFSK SPVTLGQPNT LICLVDNIFP PVVNITWLSN GQSVTEGVSE TSFLSKSDHS FFKISYLTFL PSADEIYDCK VEHWGLDQPL LKHW (SEQ ID NO: 18), or an allelic variant thereof.
  • a suitable DQA1 al domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: EDIVADH VASCGVNLYQ FYGPSGQYTH EFDGDEQFYV DLERKET AWR WPEFSKFGGF DPQGALRNMA VAKHNLNIMI KRYNSTAATN (SEQ ID NO: 19); and can have a length of about 87 amino acids (e.g., 84, 85, 86, 87, 88, or 89 amino acids).
  • a suitable DQA1 al domain can comprise the following amino acid sequence: EDIVADH VASCGVNLYQ FYGPSGQYTH EFDGDEQFYV DLERKET AWR WPEFSKFGGF DPQGALRNMA VAKHNLNIMI KRYNSTAATN (SEQ ID NO: 19), or a naturally-occurring allelic variant.
  • a suitable DQA1 a2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: EVPEVTVFSK SPVTLGQPNT LICLVDNIFP PVVNITWLSN GQSVTEGVSE TSFLSKSDHS FFKISYLTFL PSADEIYDCK VEHWGLDQPL LKHW (SEQ ID NO: 20); and can have a length of about 94 amino acids (e.g., 91, 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DQA1 a2 domain can comprise the following amino acid sequence: EVPEVTVFSK SPVTLGQPNT LICLVDNIFP PVVNITWLSN GQSVTEGVSE TSFLSKSDHS FFKISYLTFL PSADEIYDCK VEHWGLDQPL LKHW (SEQ ID NO: 20), or a naturally-occurring allelic variant thereof.
  • a suitable MHC Class II a chain polypeptide is a DQA2 polypeptide.
  • DQA2 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 24-204 of the DQA2 amino acid sequence depicted in FIG. 18.
  • the DQA2 polypeptide has a length of about 181 amino acids (e.g., 177, 178, 179, 180, 181, 182, or 183 amino acids).
  • A“DQA2 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DQA2 polypeptide comprises the following amino acid sequence: EDIVADH VASYGVNFYQ SHGPSGQYTH EFDGDEEFYV DLETKETVWQ LPMFSKFISF DPQSALRNMA V GKHTLEFMM RQSNSTAATN EVPEVTVFSK FPVTLGQPNT LICLVDNIFP PVVNITWLSN GHSVTEGVSE TSFLSKSDHS FFKISYLTFL PSADEIYDCK VEHW GLDEPL LKHW (SEQ ID NO: 21), or an allelic variant thereof.
  • a suitable DQA2 al domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: EDIVADH VASYGVNFYQ SHGPSGQYTH EFDGDEEFYV DLETKETVWQ LPMFSKFISF DPQSALRNMA V GKHTLEFMM RQSNSTAATN (SEQ ID NO: 22); and can have a length of about 87 amino acids (e.g., 84, 85, 86, 87, 88, or 89 amino acids).
  • a suitable DQA2 al domain can comprise the following amino acid sequence: EDIVADH VASYGVNFYQ SHGPSGQYTH EFDGDEEFYV DLETKETVWQ LPMFSKFISF DPQSALRNMA V GKHTLEFMM RQSNSTAATN (SEQ ID NO: 22), or a naturally-occurring allelic variant.
  • a suitable DQA2 a2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: EVPEVTVFSK FPVTLGQPNT LICLVDNIFP PVVNITWLSN GHSVTEGVSE TSFLSKSDHS FFKISYLTFL PSADEIYDCK VEHWGLDEPL LKHW (SEQ ID NO: 23); and can have a length of about 94 amino acids (e.g., 91, 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DQA2 a2 domain can comprise the following amino acid sequence: EVPEVTVFSK FPVTLGQPNT LICLVDNIFP PVVNITWLSN GHSVTEGVSE TSFLSKSDHS FFKISYLTFL PSADEIYDCK VEHWGLDEPL LKHW (SEQ ID NO: 23), or a naturally-occurring allelic variant thereof.
  • MHC Class II beta chains
  • MHC Class II beta chains comprise a b ⁇ domain and a b2 domain.
  • the b ⁇ domain and the b2 domain present in an antigen-presenting cell are from the same MHC Class II b chain polypeptide.
  • the b ⁇ domain and the b2 domain present in an antigen- presenting cell are from two different MHC Class II b chain polypeptides.
  • MHC Class II beta chains suitable for inclusion in a TMAPP e.g., a multimeric
  • TMAPP a single-chain TMAPP of the present disclosure lack a signal peptide.
  • An MHC Class II beta chain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 60 amino acids to about 210 amino acids; for example, an MHC Class II beta chain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 60 amino acids to about 80 amino acids, from about 80 amino acids to about 100 amino acids, from about 100 amino acids to about 120 amino acids, from about 120 amino acids to about 140 amino acids, from about 140 amino acids to about 160 amino acids, from about 160 amino acids to about 180 amino acids, from about 180 amino acids to about 200 amino acids, or from about 200 amino acids to about 210 amino acids.
  • An MHC Class II b ⁇ domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 105 amino acids; for example, an MHC Class II b ⁇ domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, or from about 100 amino acids to about 105 amino acids.
  • An MHC Class II b2 domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 105 amino acids; for example, an MHC Class II b2 domain suitable for inclusion in a TMAPP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, or from about 100 amino acids to about 105 amino acids.
  • a suitable MHC Class II b chain polypeptide is a DRB1 polypeptide.
  • a DRB1 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of any DRB1 amino acid sequence depicted in FIG. 7, which displays the DRB1 precursor proteins in which amino acids 1-29 are the signal sequence (underlined), 30-124 form the b ⁇ region (bolded), 125-227 for the b2 region (bolded and underlined), and 228-250 the transmembrane region.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRBl-1 (DRB1*01:01) beta chain amino acid sequence Swiss-Prot/ UniProt reference (“sp”) P04229.2 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-3 (DRB1*03:01) beta chain amino acid sequence sp P01912.2 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-4 (DRB1*04:01) beta chain amino acid sequence sp P13760.1 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-7 (DRB1*07:01) beta chain amino acid sequence sp P13761.1 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-8 (DRB1*08:01) beta chain amino acid sequence sp Q30134.2 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-9 (DRB1*09:01) beta chain amino acid sequence sp Q9TQE0.1 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRBl-10 (DRB 1*10:01) beta chain amino acid sequence sp Q30167.2 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRBl-11 (DRB1*11:01) beta chain amino acid sequence sp P20039.1 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-12 (DRB1*12:01) beta chain amino acid sequence sp Q95IE3.1 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB 1-13 (DRB1*13:01) beta chain amino acid sequence sp Q5Y7A7.1 in FIG. 7.
  • a DRB 1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-14 (DRB 1*14:01) beta chain amino acid sequence sp Q9GIY3.1 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB 1-15 (DRB 1*15:01) beta chain amino acid sequence sp P01911 in FIG. 7.
  • a DRB1 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB 1-16 (DRB 1*16:01) beta chain amino acid sequence sp Q29974.1 in FIG. 7.
  • the DRB 1 b chain polypeptide has a length of about 198 amino acids (e.g., 195, 196, 197, 198, 199, 200, 201, or 202 amino acids).
  • A“DRB 1 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DRB 1 polypeptide comprises the following amino acid sequence: DTRPRFLEQVKHECHFFNGTERVRFLDRYFYHQEEYVRFDSDVGEYRAVTELGRPDAE YWNSQKDLLEQKRA A VDT Y CRHN Y GV GESFT V QRR V YPE VT V YPAKT QPLQHHNLLV CSVNGFYPGSIEVRWFRNGQEEKTGVVSTGLIQNGDWTFQTLVMLETVPRSGEVYTCQ VEHPSLTSPLTVEWRARSESAQSK (SEQ ID NO: 24) (amino acids 31-227 of DRB 1-4, see FIG. 7 A), or an allelic variant thereof.
  • a suitable DRB 1 b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence:
  • DTRPRFLEQVKHECHFFNGTERVRFLDRYFYHQEEYVRFDSDVGEYRAVTELGRPDAE YWNSQKDLLEQKRA A VDT Y CRHN Y GV GESFT V QRR V (SEQ ID NO: 25); and can have a length of about 95 amino acids (e.g., 92, 93, 94, 95, 96, 97, or 98 amino acids).
  • a suitable DRB 1 b ⁇ domain can comprise the following amino acid sequence:
  • DTRPRFLEQVKHECHFFNGTERVRFLDRYFYHQEEYVRFDSDVGEYRAVTELGRPDAE YWNSQKDLLEQKRA A VDT Y CRHN Y GV GESFT V QRR V (SEQ ID NO: 25), or a naturally- occurring allelic variant.
  • a suitable DRB 1 b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence:
  • a suitable DRB1 b2 domain can comprise the following amino acid sequence:
  • a suitable MHC Class II b chain polypeptide is a DRB3 polypeptide.
  • a DRB3 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of any DRB3 amino acid sequence depicted in FIG. 8, which displays the DRB3 precursor proteins in which amino acids 1-29 are the signal sequence (underlined), 30-124 form the b ⁇ region (shown bolded), 125-227 for the b2 region, and 228-250 the transmembrane region.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-3 (DRB3*01:01) beta chain amino acid sequence GenBank NP_072049.1 in FIG. 8.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-3 beta chain amino acid sequence in GenBank accession EAX03632.1 in FIG. 8.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-3 (DRB3*02:01) beta chain amino acid sequence GenBank CAA23781.1 in FIG. 8.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB1-3 (DRB3*03:01) beta chain amino acid sequence GenBank AAN 15205.1 in FIG. 8.
  • A“DRB3 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DRB3 polypeptide comprises the following amino acid sequence: DTRPRFFEFR KSECHFFNGT ERVRYFDRYF HNQEEFFRFD SDVGEYRAVT EFGRP V AES W NSQKDFFEQK RGRVDNYCRH NYGVGESFTV QRRVHPQVTV YPAKTQPFQH HNFFVCSVSG FYPGSIEVRW FRNGQEEKAG VVSTGFIQNG DWTFQTFVMF ETVPRSGEVY TCQVEHPSVT SAFTVEWRAR SESAQSK (SEQ ID NO: 27), or an allelic variant thereof.
  • a suitable DRB3 b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: DTRPRFLELR KSECHFFNGT ERVRYLDRYF HNQEEFLRFD SDVGEYRAVT ELGRP V AES W NSQKDLLEQK RGRVDNYCRH NYGVGESFTV QRRV (SEQ ID NO: 28); and can have a length of about 95 amino acids (e.g., 93, 94, 95, 96, 97, or 98 amino acids).
  • a suitable DRB3 b ⁇ domain can comprise the following amino acid sequence: DTRPRFLELR KSECF1FFNGT ERVRYLDRYF HNQEEFLRFD SDVGEYRAVT ELGRPV AES W NSQKDLLEQK RGRVDNYCRH NYGVGESFTV QRRV (SEQ ID NO: 28), or a naturally-occurring allelic variant.
  • a suitable DRB3 b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: HPQVTV YPAKTQPLQH HNLLVCSVSG FYPGSIEVRW FRNGQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSVT SALTVEWRAR SESAQSK (SEQ ID NO: 29); and can have a length of about 103 amino acids (e.g., 100, 101, 102, 103, 104, or 105 amino acids).
  • a suitable DRB3 b2 domain can comprise the following amino acid sequence: HPQVTV YPAKTQPLQH HNLLVCSVSG FYPGSIEVRW FRNGQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSVT SALTVEWRAR SESAQSK (SEQ ID NO: 29), or a naturally- occurring allelic variant thereof.
  • a suitable MHC Class II b chain polypeptide is a DRB4 polypeptide.
  • DRB4 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB4 amino acid sequence depicted in FIG. 9.
  • the DRB4 polypeptide has a length of about 198 amino acids (e.g., 195, 196, 197, 198, 199, 200, 201, or 202 amino acids).
  • A“DRB4 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DRB4 polypeptide comprises the following amino acid sequence: T VLSSPLALAG DTQPRFLEQA KCECHFLNGT ERVWNLIRYI YNQEEYARYN SDLGEYQAVT ELGRPDAEYW NSQKDLLERR RAEVDTYCRY NYGVVESFTV QRRVQPKVTV YPSKTQPLQH HNLLVCSVNG FYPGSIEVRW FRNGQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSMM SPLTVQWSAR SESAQSK (SEQ ID NO: 30), or an allelic variant thereof.
  • a suitable DRB4 b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: T VLSSPLALAG DTQPRFLEQA KCECHFLNGT ERVWNLIRYI YNQEEYARYN SDLGEYQAVT ELGRPDAEYW NSQKDLLERR RAEVDTYCRY NYGVVESFTV QRRV (SEQ ID NO: 31); and can have a length of about 95 amino acids (e.g., 93, 94, 95, 96, 97, or 98 amino acids).
  • a suitable DRB4 b ⁇ domain can comprise the following amino acid sequence: T VLSSPLALAG DTQPRFLEQA KCECHFLNGT ERVWNLIRYI YNQEEYARYN SDLGEYQAVT ELGRPDAEYW NSQKDLLERR RAEVDTYCRY NYGVVESFTV QRRV (SEQ ID NO: 31), or a naturally- occurring allelic variant.
  • a suitable DRB4 b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: QPKVTV YPSKTQPLQH
  • HNLLVCSVNG FYPGSIEVRW FRNGQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSMM SPLTVQWSAR SESAQSK (SEQ ID NO: 32); and can have a length of about 103 amino acids (e.g., 100, 101, 102, 103, 104, or 105 amino acids).
  • a suitable DRB4 b2 domain can comprise the following amino acid sequence: QPKVTV YPSKTQPLQH HNLLVCSVNG FYPGSIEVRW FRNGQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSMM SPLTVQWSAR SESAQSK (SEQ ID NO: 32), or a naturally- occurring allelic variant thereof.
  • a suitable MHC Class II b chain polypeptide is a DRB5 polypeptide.
  • DRB5 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DRB5 amino acid sequence depicted in FIG. 10.
  • the DRB5 polypeptide has a length of about 198 amino acids (e.g., 195, 196, 197, 198, 199, 200, 201, or 202 amino acids).
  • A“DRB5 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DRB5 polypeptide comprises the following amino acid sequence: M VLSSPLALAG DTRPRFLQQD KYECHFFNGT ERVRFLHRDI YNQEEDLRFD SDVGEYRAVT ELGRPDAEYW NSQKDFLEDR RAAVDTYCRH NYGVGESFTV QRRVEPKVTV YPARTQTLQH HNLLVCSVNG FYPGSIEVRW FRNSQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSVT SPLTVEWRAQ SESAQS
  • a suitable DRB5 b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: M VLSSPLALAG
  • DTRPRFLQQD KYECHFFNGT ERVRFLHRDI YNQEEDLRFD SDVGEYRAVT ELGRPDAEYW NSQKDFLEDR RAAVDTYCRH NYGVGESFTV QRRV (SEQ ID NO: 34); and can have a length of about 95 amino acids (e.g., 93, 94, 95, 96, 97, or 98 amino acids).
  • a suitable DRB5 b ⁇ domain can comprise the following amino acid sequence: M VLSSPLALAG DTRPRFLQQD KYECHFFNGT ERVRFLHRDI YNQEEDLRFD SDVGEYRAVT
  • a suitable DRB5 b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: EPKVTV YPARTQTLQH HNLLVCSVNG FYPGSIEVRW FRNSQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSVT SPLTVEWRAQ SESAQS (SEQ ID NO: 35); and can have a length of about 103 amino acids (e.g., 100, 101, 102, 103, 104, or 105 amino acids).
  • a suitable DRB5 b2 domain can comprise the following amino acid sequence: EPKVTV YPARTQTLQH HNLLVCSVNG FYPGSIEVRW FRNSQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY TCQVEHPSVT SPLTVEWRAQ SESAQS (SEQ ID NO: 35), or a naturally- occurring allelic variant thereof.
  • a suitable MHC Class II b chain polypeptide is a DMB polypeptide.
  • DMB polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 19-207 of the DMB amino acid sequence depicted in FIG. 12. In some cases, the DMB polypeptide has a length of about 189 amino acids (e.g., 187, 188, 189, 190, or 191 amino acids).
  • A“DMB polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DMB polypeptide comprises the following amino acid sequence: GG FVAHVESTCL LDDAGTPKDF TYCISFNKDL LTCWDPEENK MAPCEFGVLN SLANVLSQHL NQKDTLMQRL RNGLQNCATH TQPFWGSLTN RTRPPSVQVA KTTPFNTREP VMLACYVWGF YPAEVTITWR KNGKLVMPHS SAHKTAQPNG DWTYQTLSHL ALTPSYGDTY TCVVEHTGAP EPILRDW (SEQ ID NO: 36), or an allelic variant thereof.
  • a suitable DMB b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: GG FVAHVESTCL
  • LDDAGTPKDF TYCISFNKDL LTCWDPEENK MAPCEFGVLN SLANVLSQHL NQKDTLMQRL RNGLQNCATH TQPFWGSLTN RT (SEQ ID NO: 37); and can have a length of about 94 amino acids (e.g., 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DMB b ⁇ domain can comprise the following amino acid sequence: GG FVAHVESTCL LDDAGTPKDF TYCISFNKDL LTCWDPEENK MAPCEFGVLN SLANVLSQHL NQKDTLMQRL RNGLQNCATH TQPFWGSLTN RT (SEQ ID NO: 37), or a naturally-occurring allelic variant.
  • a suitable DMB b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: RPPSVQVA KTTPFNTREP VMLACYVWGF YPAEVTITWR KNGKLVMPHS SAHKTAQPNG DWTYQTLSHL ALTPSYGDTY TCVVEHTGAP EPILRDW (SEQ ID NO: 38); and can have a length of about 95 amino acids (e.g., 93, 94, 95, 96, 97, or 98 amino acids).
  • a suitable DMB b2 domain can comprise the following amino acid sequence: RPPSVQVA KTTPFNTREP VMLACYVWGF YPAEVTITWR KNGKLVMPHS SAHKTAQPNG DWTYQTLSHL ALTPSYGDTY TCVVEHTGAP EPILRDW (SEQ ID NO: 38), or a naturally-occurring allelic variant thereof.
  • DOB RPPSVQVA KTTPFNTREP VMLACYVWGF YPAEVTITWR KNGKLVMPHS SAHKTAQPNG DWTYQTLSHL ALTPSYGDTY TCVVEHTGAP EPILRDW
  • a suitable MHC Class II b chain polypeptide is a DOB polypeptide.
  • DOB polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 27-214 of the DOB amino acid sequence depicted in FIG. 14. In some cases, the DOB polypeptide has a length of about 188 amino acids (e.g., 186, 187, 188, 189, or 190 amino acids).
  • A“DOB polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DOB polypeptide comprises the following amino acid sequence: TDSP EDFVIQAKAD CYFTNGTEKV QFVVRFIFNL EEYVRFDSDV GMFV ALTKLG QPDAEQWNSR LDLLERSRQA VDGVCRHNYR LGAPFT V GRK VQPEVTVYPE RTPLLHQHNL LHCSVTGFYP GDIKIKWFLN GQEERAGVMS TGPIRNGDWT FQTVVMLEMT PELGHVYTCL VDHSSLLSPV SVEW (SEQ ID NO: 39), or an allelic variant thereof.
  • a suitable DOB b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: TDSP EDFVIQAKAD
  • CYFTNGTEKV QFVVRFIFNL EEYVRFDSDV GMFV ALTKLG QPDAEQWNSR LDLLERSRQA VDGVCRHNYR LGAPFT V GRK (SEQ ID NO: 40); and can have a length of about 94 amino acids (e.g., 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DOB b ⁇ domain can comprise the following amino acid sequence: TDSP EDFVIQAKAD CYFTNGTEKV QFVVRFIFNL EEYVRFDSDV GMFV ALTKLG QPDAEQWNSR LDLLERSRQA VDGVCRHNYR LGAPFTVGRK (SEQ ID NO: 40), or a naturally-occurring allelic variant.
  • a suitable DOB b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: VQPEVTVYPE RTPLLHQHNL LHCSVTGFYP GDIKIKWFLN GQEERAGVMS TGPIRNGDWT FQTVVMLEMT
  • PELGHVYTCL VDHSSLLSPV SVEW (SEQ ID NO: 41); and can have a length of about 94 amino acids (e.g., 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DOB b2 domain can comprise the following amino acid sequence: VQPEVTVYPE RTPLLHQHNL LHCSVTGFYP GDIKIKWFLN GQEERAGVMS TGPIRNGDWT FQTVVMLEMT PELGHVYTCL VDHSSLLSPV SVEW (SEQ ID NO: 41), or a naturally-occurring allelic variant thereof.
  • a suitable MHC Class II b chain polypeptide is a DPB1 polypeptide.
  • DPB1 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-215 of any of the DPB1 amino acid sequences depicted in FIG. 16. In some cases, the DPB1 polypeptide has a length of about 186 amino acids (e.g., 184, 185, 186, 187, or 188 amino acids).
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB1*01:01 beta chain amino acid sequence in FIG. 16 IMGT/HLA Acc No: HLA00514.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB 1*01:01 beta chain amino acid sequence in FIG. 16, IMGT/HLA Acc No: HLA00517.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB1*03:01 beta chain amino acid sequence in FIG. 16, IMGT/HLA Acc No: HLA00520.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB 1*04:01 beta chain amino acid sequence in FIG.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB106:01 beta chain amino acid sequence in FIG. 16, IMGT/HLA Acc No: HLA00524.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB1*11:01 beta chain amino acid sequence in FIG. 16, IMGT/HLA Acc No: HLA00528.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB 1*71:01 beta chain amino acid sequence in FIG. 16, IMGT/HLA Acc No:HLA00590.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB1*104:01 beta chain amino acid sequence in FIG. 16, IMGT/HLA Acc No: HLA02046.
  • a DRB3 b chain polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 30-227 of the DPB1*141:01 beta chain amino acid sequence in FIG. 16, IMGT/HLA Acc No: HLA10364.
  • A“DPB1 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DPB1 polypeptide comprises the following amino acid sequence: R ATPENYLFQG RQECYAFNGT QRFLERYIYN REEFARFDSD VGEFRAVTEL GRPAAEYWNS QKDILEEKRA VPDRMCRHNY ELGGPMTLQR RVQPRVNVSP SKKGPLQHHN LLVCHVTDFY PGSIQVRWFL NGQEETAGVV STNLIRNGDW TFQILVMLEM TPQQGDVYTC QVEHTSLDSP VTVEW (SEQ ID NO: 42), or an allelic variant thereof.
  • a suitable DPB1 b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: R ATPENYLFQG
  • RQECYAFNGT QRFLERYIYN REEFARFDSD VGEFRAVTEL GRPAAEYWNS QKDILEEKRA VPDRMCRHNY ELGGPMTLQR R (SEQ ID NO: 43); and can have a length of about 92 amino acids (e.g., 90, 91, 92, 93, or 94 amino acids).
  • a suitable DPB1 b ⁇ domain can comprise the following amino acid sequence: R ATPENYLFQG RQECYAFNGT
  • a suitable DPB1 b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: VQPRVNVSP SKKGPLQHHN LLVCHVTDFY PGSIQVRWFL NGQEETAGVV STNLIRNGDW TFQILVMLEM TPQQGDVYTC QVEHTSLDSP VTVEW (SEQ ID NO: 44); and can have a length of about 94 amino acids (e.g., 92, 93, 94, 95, 96, or 97 amino acids).
  • a suitable DPB1 b2 domain can comprise the following amino acid sequence: VQPRVNVSP SKKGPLQHHN LLVCHVTDFY PGSIQVRWFL NGQEETAGVV STNLIRNGDW TFQILVMLEM TPQQGDVYTC QVEHTSLDSP VTVEW (SEQ ID NO: 44), or a naturally-occurring allelic variant thereof.
  • DQB1 VQPRVNVSP SKKGPLQHHN LLVCHVTDFY PGSIQVRWFL NGQEETAGVV STNLIRNGDW TFQILVMLEM TPQQGDVYTC QVEHTSLDSP VTVEW (SEQ ID NO: 44), or a naturally-occurring allelic variant thereof.
  • a suitable MHC Class II b chain polypeptide is a DQB1 polypeptide.
  • DQB1 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 33-220 of the DQB1 amino acid sequence depicted in FIG. 19A or FIG. 19B or FIG. 19C.
  • the DQB1 polypeptide has a length of about 188 amino acids (e.g., 186, 187, 188, 190, 191, or 192 amino acids).
  • A“DQB1 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DQB1 polypeptide comprises the following amino acid sequence: RDSPEDFV FQFKGMCYFT NGTERVRLVT RYIYNREEYA RFDSDVGVYR AVTPQGRPDA EYWNSQKEVL EGTRAELDTV CRHNYEVAFR GILQRRVEPT VTISPSRTEA LNHHNLLVCS VTDFYPGQIK VRWFRNDQEE TAGVVSTPLI RNGDWTFQIL VMLEMTPQRG DVYTCHVEHP SLQSPITVEW (SEQ ID NO: 45), or an allelic variant thereof.
  • a suitable DQB1 b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: RDSPEDFV FQFKGMCYFT NGTERVRLVT RYIYNREEYA RFDSDVGVYR AVTPQGRPDA EYWNSQKEVL EGTRAELDTV CRHNYEVAFR GILQRR (SEQ ID NO: 46); and can have a length of about 94 amino acids (e.g., 92, 93, 94, 95, or 96 amino acids).
  • a suitable DQB1 b ⁇ domain can comprise the following amino acid sequence: RDSPEDFV FQFKGMCYFT NGTERVRLVT
  • a suitable DQB1 b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: VEPT VTISPSRTEA
  • LNHHNLLVCS VTDFYPGQIK VRWFRNDQEE TAGVVSTPLI RNGDWTFQIL VMLEMTPQRG DVYTCHVEHP SLQSPITVEW (SEQ ID NO: 47); and can have a length of about 94 amino acids (e.g., 92, 93, 94, 95, or 96 amino acids).
  • a suitable DQB1 b2 domain can comprise the following amino acid sequence: VEPT VTISPSRTEA LNHHNLLVCS
  • a suitable MHC Class II b chain polypeptide is a DQB2 polypeptide.
  • DQB2 polypeptide can have at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity with amino acids 33-215 of the DQB2 amino acid sequence depicted in FIG. 20A or FIG. 20.
  • the DQB2 polypeptide has a length of about 182 amino acids (e.g., 175, 176, 177, 178, 179, 180, 181, or 182 amino acids).
  • A“DQB2 polypeptide” includes allelic variants, e.g., naturally occurring allelic variants.
  • a suitable DQB2 polypeptide comprises the following amino acid sequence: DFLVQFK GMCYFTNGTE RVRGVARYIY NREEYGRFDS DVGEFQAVTE LGRSIEDWNN YKDFLEQERA AVDKV CRHNY EAELRTTLQR QVEPTVTISP SRTEALNHHN LLVCSVTDFY PAQIKVRWFR NDQEETAGVV STSLIRNGDW TFQILVMLEI TPQRGDIYTC QVEHPSLQSP ITVEW (SEQ ID NO: 48), or an allelic variant thereof.
  • a suitable DQB2 b ⁇ domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: DFLVQFK GMCYFTNGTE RVRGVARYIY NREEYGRFDS DVGEFQAVTE LGRSIEDWNN YKDFLEQERA AVDKVCRHNY EAELRTTLQR QVEPTV (SEQ ID NO: 49); and can have a length of about 94 amino acids (e.g., 92 93, 94, 95, 96, or 97 amino acids).
  • a suitable DQB2 b ⁇ domain can comprise the following amino acid sequence: DFLVQFK GMCYFTNGTE RVRGVARYIY NREEYGRFDS DVGEFQAVTE LGRSIEDWNN YKDFLEQERA AVDKVCRHNY EAELRTTLQR QVEPTV (SEQ ID NO: 49), or a naturally-occurring allelic variant.
  • a suitable DQB2 b2 domain comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: TISP SRTEALNHHN
  • LLVCSVTDFY PAQIKVRWFR NDQEETAGVV STSLIRNGDW TFQILVMLEI TPQRGDIYTC QVEHPSLQSP ITVEW (SEQ ID NO: 50); and can have a length of about 94 amino acids (e.g., 92 93, 94, 95, 96, or 97 amino acids).
  • a suitable DQB2 b2 domain can comprise the following amino acid sequence: TISP SRTEALNHHN LLVCSVTDFY
  • HLA-autoimmune disease associations and autoantigens can be found at, e.g., the following: 1) Fernando, et al., PFoS Genetics, Volume 4 (4) el000024 (2008); 2) Jones, et al., Nature Reviews Immunology, 6: 271-282 (2006); 3) Gough, et al., Current Genomics, 2007, 8, 453-465 (2007); 4) Autoimmunity from Bench to Bedside, Anaya et al. Eds. Center for Autoimmune Diseases Research, CREA Texts Collection, School of Medicine and Health Sciences, El Rosario University (2013); see e.g., Cruz-Tapias et al.,
  • HLA haplotypes and alleles associated with increased risk that an individual expressing such HLA haplotypes and/or alleles will develop a given autoimmune disease are provided in the table provided in FIG. 39.
  • a TMAPP of the present disclosure can include any of the HLA haplotypes and/or alleles set out in the table provided in FIG. 39.
  • the table provided in FIG. 39 also provides examples of autoantigens associated with particular autoimmune diseases.
  • a TMAPP of the present disclosure can include a peptide epitope (e.g., a peptide epitope of from 4 amino acids to about 25 amino acids in length) of any of the autoantigens set out in the table.
  • DQ2 haplotype 1) DQ3 alleles include DQB1*03 alleles such as DQB1*03:01 to DQB1*03:05 proteins; 3) DQ5 alleles include DQB1*05 alleles such as DQB1*05:01 to DQB1*05:04 and may be associated with DQA1*01:01; 4) DR2 alleles include DRBI*15:01-15:04 and
  • DRB1* 16:01-16:06; 5) DR3 haplotypes include: DRB1*03:01, DRB1*03:02, DRB1*03:03, and DRB1*03:04; 6) DR4 haplotypes include: DRB1*04:01 through DRB1*04:13; 7) AH ancestral haplotype; 7) Simmonds et al., Am. J. Hum. Genet.
  • HLAs with odds ratios greater than 1.5 include the following DRB1, DAB1 and DQAlalleles: DRB1*-03:01 to 05, -10:01, -08:01 to 11, -16:01 to 6, -11:01 to 21, -01:01 to 04, -04:01 to 22, and -15:01 to 05; DQB1* -02, -04, -03:01, 03:04, -05, -06:01 to 09, and -03:02; and HLA- DQA1* -05:01 to 02, -06:01, -04:01, -01:01, -01:04, -01:02, -01:03, -03:11, and -03:12; 8) Li et al., Mol Med Rep.; 17(5): 6533-6541 (2016) noting epitopes from auto antigens including:
  • SMD1 NCBI Accession: CAE11897.1
  • SMD2 NCBI Accession: AAC13776.1
  • SMD3 NCBI Accession: AAA57034.1
  • PCNA Proliferating cell nuclear antigen
  • PI Acidic ribosomal phosphoprotein
  • P2 Acidic ribosomal phosphoprotein
  • NCBI Accession: AAA36472.1 snRNP-B/B'
  • NP_003277.1 Ul-SnRNP 68/70 KDa (NCBI Accession: P08621.2).
  • HLA-DR3 serotype is associated with early-age onset myasthenia gravis, Hashimoto’s thyroiditis, autoimmune hepatitis, primary Sjogren’s syndrome, and SLE. Certain DRB1 alleles are associated with increased risk that an individual expressing such alleles will develop a particular autoimmune disease or diseases.
  • a TMAPP of the present disclosure comprises a DRB 1*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*01:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*01 :02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*01 :02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*01:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*01 :03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*01 :03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*01 :03 amino acid sequence provided below.
  • DRB 1*0301 (“DRB1*03:01” in FIG. 7) is associated with increased risk of developing early onset Grave’s disease and/or type 1 autoimmune hepatitis.
  • a TMAPP of the present disclosure comprises a DRB 1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*03:01 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRB 1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*03:01 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRB 1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*03:01 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRB 1*03:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*03:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*03:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*03:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*03:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*03:02 amino acid sequence provided below.
  • DRB 1*0304 is associated with Grave’s disease.
  • a TMAPP of the present disclosure comprises a DRB 1*03:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*03:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*03:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB1*03:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*03:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*03:04 amino acid sequence provided below.
  • DRB 1*04:01 is associated with increased risk of developing multiple sclerosis and/or rheumatoid arthritis.
  • a TMAPP of the present disclosure comprises a DRB1*04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*04:01 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRB 1*04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*04:01 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRB 1*04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*04:01 amino acid sequence depicted in FIG. 7.
  • DRB 1 *04:02 is associated with increased risk of developing idiopathic pemphigus vulgaris, and/or SLE (e.g., SLE-associated anti-cardiolipin; SLE-associated ah0-b2 glycoprotein I).
  • SLE e.g., SLE-associated anti-cardiolipin; SLE-associated ah0-b2 glycoprotein I.
  • a TMAPP of the present disclosure comprises a DRB 1*04:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*04:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*04:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*04:02 amino acid sequence provided below.
  • DRB 1*0403 is associated with increased risk of developing SLE (e.g., increased risk of developing SLE-associated anti-cardiolipin antibodies and/or SLE-associated ah0-b2 glycoprotein I antibodies).
  • a TMAPP of the present disclosure comprises a DRB 1*04:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30 to 227 of the DRB 1*04:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*04:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*04:03 amino acid sequence provided below.
  • DRB 1 *04:04 is associated with increased risk of developing rheumatoid arthritis (e.g., increased risk of developing high titers of circulating anti-cyclic citrullinated peptide antibodies) and/or autoimmune hepatitis.
  • a TMAPP of the present disclosure comprises a DRB 1*04:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*04:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB1*04:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*04:04 amino acid sequence provided below.
  • DRB 1*04:05 is associated with increased risk of developing rheumatoid arthritis and/or autoimmune hepatitis.
  • a TMAPP of the present disclosure comprises a DRB1*04:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*04:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB1*04:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*04:05 amino acid sequence provided below.
  • DRB 1 *04:06 is associated with increased risk of developing anti-caspase-8
  • a TMAPP of the present disclosure comprises a DRB 1*04:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*04:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*04:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*04:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*04:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:08 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*04:08 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:08 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*04:08 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*04:08 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*04:08 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*08:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*08:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*08:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*08:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*08:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*08:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*08:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*08:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*08:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*08:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*08:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*08:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*08:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*08:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*08:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*08:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*08:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*08:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*09:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*09:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*09:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*09:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*09:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*09:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*10:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*10:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*10:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*10:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*10:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*10:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*11:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*11:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*11:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*11:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*11:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*11:01 amino acid sequence provided below.
  • TERVRFLDRYF YN QEE Y VRFDS D V GEFR A VTELGRPDEE YWN S QKDFLEDRRA A VDT YCRHN Y G V GES FT V QRR VHPKVT V YPS KTQPLQHHNLL VCS V S GF YPGS I E VRWFRN GQEEKTG V V S TGLIHN GD WTF QTLVMLET VPRS GE V YTC Q VEHPS V TS PLT VE WRARS ES AQS KMLS G V GGFVLGLLFLG AGLFIYFRNQKGHS GLQPRG FLS (SEQ ID NO: 78).
  • a TMAPP of the present disclosure comprises a DRB1*11:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*11:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*11:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*11:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*11:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*11:03 amino acid sequence provided below.
  • TERVRFLDRYF YN QEE Y VRFDS D V GEFR A VTELGRPDEE YWN S QKDFLEDER A A VDT YCRHN Y G V VES FT V QRR VHPKVT V YPS KTQPLQHHNLL VCS V S GF YPGS I E VRWFRN GQEEKTG V V S TGLIHN GD WTF QTLVMLET VPRS GE V YTC Q VEHPS V TS PLT VE WRARS ES AQS KMLS G V GGFVLGLLFLG AGLFIYFRNQKGHS GLQPRG FLS (SEQ ID NO: 79).
  • a TMAPP of the present disclosure comprises a DRB 1 * 11 :04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*11:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*11:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*11:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*11:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*11:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*13:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*13:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*13:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB1*13:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*13:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*13:01 amino acid sequence provided below. [00224] DRB1*13:01:
  • a TMAPP of the present disclosure comprises a DRB 1*13:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*13:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*13:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*13:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*13:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*13:031 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*14:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*14:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*14:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*14:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*14:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*14:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*14:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*14:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*14:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*14:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*14:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*14:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*14:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*14:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*14:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*14:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB 1*14:06 amino acid sequence provided below.
  • DR2 serotypes are associated with increased risk of SLE and/or MS.
  • HLA alleles are associated with increased risk of SLE and/or MS.
  • a TMAPP of the present disclosure comprises a DRB1*1501 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*1501 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRB 1*1501 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30- 124 of the DRB 1*1501 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRBl*1501polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*1501 amino acid sequence depicted in FIG. 7.
  • a TMAPP of the present disclosure comprises a DRB 1*1502 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*1502 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1502 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*1502 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1502 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*1502 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1503 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*1503 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1503 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*1503 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1503 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*1503 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1504 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*1504 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1504 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*1504 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*1504 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*1504 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*15:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*15:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*15:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB 1*15:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*15:05 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*15:05 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*15:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*15:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*15:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*15:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*15:06 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*15:06 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*15:07 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB1*15:07 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB1*15:07 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB 1*15:07 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB 1*15:07 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB1*15:07 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises an MHC Class II b chain polypeptide of a DRB 3 allele.
  • a TMAPP of the present disclosure comprises a DRB3*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB3*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB3*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB3*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB3*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB3*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB3*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB3*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB3*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB3*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB3*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB3*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises an MHC Class II b chain polypeptide of a DRB4 allele.
  • a TMAPP of the present disclosure comprises a
  • a TMAPP of the present disclosure comprises a DRB4*01 :01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB4*01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB4*01 :01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB4*01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB3*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB4*01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises an MHC Class II b chain polypeptide of a DRB5 allele.
  • a TMAPP of the present disclosure comprises a DRB5*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-227 of the DRB5*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB5*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-124 of the DRB5*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRB5*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 125-227 of the DRB5*01:01 amino acid sequence provided below.
  • DQB1 alleles are associated with increased risk that an individual expressing such an allele will develop an autoimmune disease such as multiple sclerosis. For example,
  • DQB 1*0301, and DQB 1*0602 are associated with an increased risk of developing MS and/or a more severe MS phenotype (e.g., more severe inflammatory and neurodegenerative damage).
  • a TMAPP of the present disclosure comprises a DQB 1*02:01
  • a TMAPP of the present disclosure comprises a DQB 1*02:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-220 of the DQB1*02:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*02:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*02:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*02:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*02:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*02:02
  • a TMAPP of the present disclosure comprises a DQB 1*02:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*02:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*02:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*02:02 amino acid sequence provided below.
  • FTN GTERVRLV S RS IYNREEI VRFDS D V GEFR A VTLLGLP A AE YWN S QKDILERK R AA VDR V CRHN Y QLELRTTLQRR VEPT VTIS PS RTE ALNHHNLL VCS VTDF YP A QIKVRWFRN GQEET AG V V S TPLIRN GD WTF QIL VMLEMTPQRGD V YTCH VEHP S LQS PIT VEWR AQS ES AQS KMLS GIGGFVLGLIFLGLGLIIHHRS QKGLLH (SEQ ID NO: 97).
  • a TMAPP of the present disclosure comprises a DQB 1*0301 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-220 of the DQB1*0301 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB1*0301 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB 1*0301 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*0301 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*0301 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*0302 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-220 of the DQB1*0302 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB1*0302 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB 1*0302 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1 *0302 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*0302 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*03:03
  • a TMAPP of the present disclosure comprises a DQB 1*03:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-220 of the DQB1*03:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*03:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*03:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*03:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB1*03:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*03:04
  • a TMAPP of the present disclosure comprises a DQB 1*03:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*03:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*03:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB1*03:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*04:01
  • a TMAPP of the present disclosure comprises a DQB 1*04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*04:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*04:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*04:02
  • a TMAPP of the present disclosure comprises a DQB 1*04:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*04:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*04:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*04:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*04:01
  • a TMAPP of the present disclosure comprises a DQB 1*05:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*05:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*05:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB1*05:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*05:03
  • a TMAPP of the present disclosure comprises a DQB 1*05:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*05:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*05:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB1*05:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*06:01
  • a TMAPP of the present disclosure comprises a DQB 1*06:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB1*06:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*06:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*06:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQB 1*0602 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-220 of the DQB1*0602 amino acid sequence depicted in FIG. 19A.
  • a TMAPP of the present disclosure comprises a DQB1*0602 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 33-126 of the DQB 1*0602 amino acid sequence depicted in FIG. 19A.
  • a TMAPP of the present disclosure comprises a DQB 1 *0602 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 127-220 of the DQB 1*0602 amino acid sequence depicted in FIG. 19 A.
  • a TMAPP of the present disclosure can include an MHC Class II b chain of a DPB1 allele.
  • a TMAPP of the present disclosure comprises a
  • a TMAPP of the present disclosure comprises a DPB1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-215 of the DPB1*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-121 of the DPB1*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB 1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 122-215 of the DPB 1*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • a TMAPP of the present disclosure comprises a DPB 1*09:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-215 of the DPB 1*09:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB 1*09:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-121 of the DPB1*09:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB 1*09:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 122-215 of the DPB 1*09:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • a TMAPP of the present disclosure comprises a DPB 1*13:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-215 of the DPB1*13:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB 1*13:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-121 of the DPB1*13:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB 1*13:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 122-215 of the DPB 1*13:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • DPB1*35:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-215 of the DPB1*35:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB 1*35:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 30-121 of the DPB1*35:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DPB 1*35:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 122-215 of the DPB 1*35:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises an MHC Class II a chain polypeptide of a DQA1 allele.
  • a TMAPP of the present disclosure comprises a
  • DQA1*01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA1 *01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *01:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-110 of the DQA1*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *01 :01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA1*01:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *01:02
  • a TMAPP of the present disclosure comprises a DQA*01:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA*01:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA*01:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24- 110 of the DQA*01:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA*01:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA*01:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *01:03
  • a TMAPP of the present disclosure comprises a DQA*01:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA*01:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA*01:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24- 110 of the DQA*01:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA*01:03 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA*01:03 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • a TMAPP of the present disclosure comprises a DQA*01:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA*01:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA*01:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-110 of the DQA*01:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA*01:04 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA*01:04 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • a TMAPP of the present disclosure comprises a DQA1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA1*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1*03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-110 of the DQA1*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *03:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA1*03:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • DQA1*03:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA1*03:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1*03:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-110 of the DQA1*03:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *03:02 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA 1*03:02 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • a TMAPP of the present disclosure comprises a DQA1 *04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA1 *04:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-110 of the DQA1*04:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *04:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA1*04:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • DQA1*05:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA1*05:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1*05:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-110 of the DQA1*05:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *05:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA1*05:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a
  • DQA1*06:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-204 of the DQA1 *06:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1 *06:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 24-110 of the DQA1*06:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DQA1*06:01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 111-204 of the DQA1*06:01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises an MHC Class II a chain polypeptide of a DRA1 allele.
  • a TMAPP of the present disclosure comprises a
  • DRA1*01 :01 (also referred to as“DRA*01 :01”; referred to in FIG. 39 as“DRA1*01 :01) polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 26-203 of the DRA1*01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRA 1*01 :01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 26-109 of the DRA1*01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure comprises a DRA1 *01 :01 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 110-203 of the DRA1 *01 :01 amino acid sequence provided below.
  • a TMAPP of the present disclosure can comprise any combination of MF1C a chains and MF1C b chains, e.g., where the a chain is a DRA a chain and the b chain is a DRB b chain; where the a chain is a DQA a chain and the b chain is a DQB b chain, etc.
  • the following are examples of possible combinations (haplotypes).
  • a TMAPP of the present disclosure comprises: i) an MF1C a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DQA1 *01:01 a chain polypeptide; and ii) an MF1C b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DRA1 *01:01 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DRA1 *01:01 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DRA1 *01:01 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DQA1 *01:02 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DQA1 *03:01 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DQA1 *01:04 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DRA1 *01:01 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DQA1 *04:01 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DQA1 *03:02 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises: i) an MHC a chain
  • polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 aa) of a DQA1 *01:03 a chain polypeptide; and ii) an MHC b chain polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 70 amino acids to about 200 amino acids (e.g., from about 70 aa to about 100 aa, or from about 100 aa to about 150 aa, or from about 150 aa to about 200 a
  • a TMAPP of the present disclosure comprises an MHC Class II a- and/or b- chain allele that is associated with increased risk of developing a disease, e.g., where the individual to be treated with the TMAPP expresses the MHC Class II a- and/or b- chain allele.
  • a TMAPP of the present disclosure can comprise an immunoglobulin or non-immunoglobulin scaffold.
  • a TMAPP polypeptide of the present disclosure can comprise an Fc polypeptide, or can comprise another suitable scaffold polypeptide.
  • Suitable scaffold polypeptides include antibody-based scaffold polypeptides and non- antibody-based scaffolds.
  • Non-antibody-based scaffolds include, e.g., albumin, an XTEN (extended recombinant) polypeptide, transferrin, an Fc receptor polypeptide, an elastin-like polypeptide (see, e.g., Flassouneh et al. (2012) Methods Enzymol.
  • Suitable XTEN polypeptides include, e.g., those disclosed in WO 2009/023270, WO
  • Suitable albumin polypeptides include, e.g., human serum albumin.
  • Suitable scaffold polypeptides will in some cases be a half-life extending polypeptides.
  • a suitable scaffold polypeptide increases the in vivo half-life (e.g., the serum half-life) of the multimeric polypeptide, compared to a control multimeric polypeptide lacking the scaffold polypeptide.
  • a scaffold polypeptide increases the in vivo half-life (e.g., the serum half-life) of the multimeric polypeptide, compared to a control multimeric polypeptide lacking the scaffold polypeptide, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 50%, at least about 2-fold, at least about 2.5-fold, at least about 5-fold, at least about 10-fold, at least about 25-fold, at least about 50-fold, at least about 100-fold, or more than 100-fold.
  • an Fc polypeptide increases the in vivo half-life (e.g., the serum half-life) of the multimeric polypeptide, compared to a control multimeric polypeptide lacking the Fc polypeptide, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 50%, at least about 2-fold, at least about 2.5-fold, at least about 5-fold, at least about 10-fold, at least about 25-fold, at least about 50-fold, at least about 100-fold, or more than 100-fold.
  • the in vivo half-life e.g., the serum half-life
  • the first and/or the second polypeptide chain of a TMMP of the present disclosure comprises an Fc polypeptide.
  • the Fc polypeptide of a TMMP of the present disclosure can be a human IgGl Fc, a human IgG2 Fc, a human IgG3 Fc, a human IgG4 Fc, etc.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to an amino acid sequence of an Fc region depicted in FIG. 21A-21G.
  • the Fc region comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgGl Fc polypeptide depicted in FIG. 21A. In some cases, the Fc region comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgGl Fc polypeptide depicted in FIG.
  • the Fc polypeptide comprises an N77A substitution.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG2 Fc polypeptide depicted in FIG.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 99- 325 of the human IgG2 Fc polypeptide depicted in FIG. 21A.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG3 Fc polypeptide depicted in FIG.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 19-246 of the human IgG3 Fc polypeptide depicted in FIG. 21A.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgM Fc polypeptide depicted in FIG.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 1-276 to the human IgM Fc polypeptide depicted in FIG. 21B.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgA Fc polypeptide depicted in FIG.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 1-234 to the human IgA Fc polypeptide depicted in FIG. 21C.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG4 Fc polypeptide depicted in FIG. 21C.
  • the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 100 to 327 of the human IgG4 Fc polypeptide depicted in FIG. 21C.
  • the IgG4 Fc polypeptide comprises the following amino acid sequence:
  • the Fc polypeptide present in a TMMP comprises the amino acid
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21A (human IgGl Fc), except for a substitution of N297 (N77 of the amino acid sequence depicted in FIG. 21 A) with an amino acid other than asparagine.
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21C (human IgGl Fc comprising an N297A substitution, which is N77 of the amino acid sequence depicted in FIG. 21A).
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG.
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21A (human IgGl Fc), except for a substitution of L235 (L15 of the amino acid sequence depicted in FIG. 21 A) with an amino acid other than leucine.
  • the Fc polypeptide present in a TMMP comprises the amino acid
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21E.
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21F.
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21G (human IgGl Fc comprising an L234A substitution and an L235A substitution, corresponding to positions 14 and 15 of the amino acid sequence depicted in FIG. 21G).
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21A (human IgGl Fc), except for a substitution of P331 (PI 11 of the amino acid sequence depicted in FIG.
  • the substitution is a P331S substitution.
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21 A (human IgGl Fc), except for substitutions at L234 and L235 (L14 and L15 of the amino acid sequence depicted in FIG. 21A) with amino acids other than leucine.
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21 A (human IgGl Fc), except for substitutions at L234 and L235 (L14 and L15 of the amino acid sequence depicted in FIG.
  • the Fc polypeptide present in a TMMP comprises the amino acid sequence depicted in FIG. 21E (human IgGl Fc comprising L234F, L235E, and P331S substitutions (corresponding to amino acid positions 14, 15, and 111 of the amino acid sequence depicted in FIG. 21E).
  • the Fc polypeptide present in a TMMP is an IgGl Fc polypeptide that comprises L234A and L235A substitutions (substitutions of L14 and L15 of the amino acid sequence depicted in FIG. 21 A with Ala), as depicted in FIG. 21G.
  • a TMAPP of the present disclosure can include a linker peptide
  • an epitope and an MHC polypeptide interposed between, e.g., an epitope and an MHC polypeptide; between an MHC polypeptide and an Ig Fc polypeptide; between a first MHC polypeptide and a second MHC polypeptide; etc.
  • Suitable linkers can be readily selected and can be of any of a number of suitable lengths, such as from 1 amino acid to 25 amino acids, from 3 amino acids 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.
  • a suitable linker can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids in length.
  • a suitable linker can be from 25 to 35 amino acids in length.
  • a suitable linker can be 25, 26, 27,
  • a suitable linker can be from 35 to 45 amino acids in length.
  • a suitable linker can be 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 amino acids in length.
  • a suitable linker can be from 45 to 50 amino acids in length.
  • a suitable linker can be 45, 46, 47, 48, 49, or 50 amino acids in length.
  • Exemplary linkers include glycine polymers (G) n , glycine-serine polymers (including, for example, (GS) adjective, (GSGGS) n (SEQ ID NO: 61) and (GGGS) n (SEQ ID NO: 62), where n is an integer of at least one), 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 (see Scheraga, Rev. Computational Chem. 11173-142 (1992)).
  • Exemplary linkers can comprise amino acid sequences including, but not limited to, GGSG (SEQ ID NO: 63), GGSGG (SEQ ID NO: 64), GSGSG (SEQ ID NO: 65), GSGGG (SEQ ID NO: 66), GGGSG (SEQ ID NO: 67), GSSSG (SEQ ID NO: 68), and the like.
  • linkers can include, e.g., Gly(Ser4)n, (SEQ ID NO: 69) where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • a linker comprises the amino acid sequence (GSSSS)n (SEQ ID NO:
  • a linker comprises the amino acid sequence (GSSSS)n (SEQ ID NO: 69), where n is 4.
  • a linker comprises the amino acid sequence (GSSSS)n (SEQ ID NO: 69), where n is 5.
  • Exemplary linkers can include, e.g., (GlyGlyGlyGlySer)n (SEQ ID NO: 1), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 1.
  • a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 2.
  • a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 3.
  • a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 4. In some cases, a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 5. In some cases, a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 6. In some cases, a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 7. In some cases, a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 8. In some cases, a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 9. In some cases, a linker comprises the amino acid sequence (GGGGS)n (SEQ ID NO: 1), where n is 10. In some cases, a linker comprises the amino acid sequence AAAGG (SEQ ID NO: 70).
  • a linker polypeptide present in a TMAPP of the present disclosure is a linker polypeptide present in a TMAPP of the present disclosure
  • a suitable linker comprises the amino acid sequence GCGASGGGGSGGGGS (SEQ ID NO: 71).
  • a peptide epitope (also referred to herein as a“peptide antigen” or“epitope-presenting peptide” or“epitope”) present in a TMAPP of the present disclosure presents an epitope to a TCR on the surface of a T cell.
  • An epitope -presenting peptide can have a length of from about 4 amino acids to about 25 amino acids, e.g., the epitope can have a length of from 4 amino acids (aa) to 10 aa, from 10 aa to 15 aa, from 15 aa to 20 aa, or from 20 aa to 25 aa.
  • an epitope present in a TMAPP of the present disclosure can have a length of 4 amino acids (aa), 5 aa, 6 aa, 7, aa, 8 aa, 9 aa, 10 aa, 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, 20 aa, 21 aa, 22 aa, 23 aa, 24 aa, or 25 aa.
  • an epitope-presenting peptide present in a TMAPP of the present disclosure has a length of from 5 amino acids to 10 amino acids, e.g., 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa.
  • an epitope-specific T cell binds an epitope-presenting peptide having a reference amino acid sequence, but does not substantially bind an epitope that differs from the reference amino acid sequence.
  • an epitope-specific T cell binds an epitope -presenting peptide having a reference amino acid sequence, and binds an epitope that differs from the reference amino acid sequence, if at all, with an affinity that is less than 10 6 M, less than 10 5 M, or less than 10 4 M.
  • An epitope-specific T cell can bind an epitope-presenting peptide for which it is specific with an affinity of at least 10 7 M, at least 10 s M, at least 10 9 M, or at least 10 10 M. Cancer epitopes
  • Suitable epitope -presenting peptides include, but are not limited to, epitope-presenting peptides present in a cancer-associated antigen.
  • Cancer-associated antigens include, but are not limited to, a-folate receptor; carbonic anhydrase IX (CAIX); CD19; CD20; CD22; CD30; CD33; CD44v7/8; carcinoembryonic antigen (CEA); epithelial glycoprotein-2 (EGP-2); epithelial glycoprotein-40 (EGP-40); folate binding protein (FBP); fetal acetylcholine receptor;
  • ganglioside antigen GD2 Her2/neu; IL-13R-a2; kappa light chain; LeY; LI cell adhesion molecule; melanoma-associated antigen (MAGE); MAGE-A1; mesothelin; MUC1; NKG2D ligands; oncofetal antigen (h5T4); prostate stem cell antigen (PSCA); prostate-specific membrane antigen (PSMA); tumor-associate glycoprotein-72 (TAG-72); and vascular endothelial growth factor receptor-2 (VEGF-R2).
  • the epitope is a human papilloma virus E7 antigen epitope; see, e.g., Ramos et al. (2013) J.
  • a suitable peptide epitope is a peptide fragment of from about 4 amino acids to about 20 amino acids (e.g., 4 amino acids (aa), 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, 10 aa, 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, or 20 aa) in length of a MUC1 polypeptide, a human papillomavirus (HPV) E6 polypeptide, an LMP2 polypeptide, an HPV E7 polypeptide, an epidermal growth factor receptor (EGFR) vIII polypeptide, a HER-2/neu polypeptide, a melanoma antigen family A, 3 (MAGE A3) polypeptide, a p53 polypeptide, a mutant p53 polypeptide, an NY-ESO-1
  • MUC1 (GenBank CAA56734); LMP2 (GenBank CAA47024); HPV E6 (GenBank AAD33252); HPV E7 (GenBank AHG99480); EGFRvIII (GenBank NP_001333870); HER-2/neu (GenBank AAI67147); MAGE-A3 (GenBank AAH11744); p53 (GenBank BAC16799); NY-ESO-1 (GenBank CAA05908); PSMA (GenBank AAH25672); CEA (GenBank AAA51967);
  • NP_001888 AKAP-4 (GenBank NP_003877); SSX2 (GenBank CAA60111); XAGE1 (GenBank NP_001091073; XP_001125834; XP_001125856; and XP_001125872); B7H3 (GenBank NP_001019907; XP_947368; XP_950958; XP_950960; XP_950962; XP_950963; XP_950965; and XP_950967); LGMN1 (GenBank NP_001008530); TIE-2 (GenBank
  • NP_000450 PAGE4 (GenBank NP_001305806); VEGFR2 (GenBank NP_002244); MAD-CT- 1 (GenBank NP_005893 NP_056215); FAP (GenBank NP_004451); PDGF ' P (GenBank NP_002600); MAD-CT-2 (GenBank NP_001138574); FOSL (GenBank NP_005429); and WT-1 (GenBank NP_000369).
  • PAGE4 GeneBank NP_001305806
  • VEGFR2 GeneBank NP_002244
  • MAD-CT- 1 GeneBank NP_005893 NP_056215
  • FAP GeneBank NP_004451
  • PDGF ' P GeneBank NP_002600
  • MAD-CT-2 GeneBank NP_001138574
  • FOSL GenBank NP_005429
  • WT-1 GeneBank NP_000369
  • the epitope is HPV16E7/82-90 (LLMGTLGIV; SEQ ID NO: 404). In some cases, the epitope is HPV16E7/86-93 (TLGIVCPI; SEQ ID NO: 405). In some cases, the epitope is HPV16E7/11-20 (YMLDLQPETT; SEQ ID NO: 406). In some cases, the epitope is HPV16E7/11-19 (YMLDLQPET; SEQ ID NO: 407). See, e.g., Ressing et al. ((1995) J.
  • the peptide epitope is an epitope associated with or present in a“self’ antigen (an autoantigen).
  • Antigens associated with autoimmune disease can be autoantigens associated with autoimmune diseases such as Addison disease (autoimmune adrenalitis, Morbus Addison), alopecia areata, Addison's anemia (Morbus Biermer), autoimmune hemolytic anemia (AIHA), autoimmune hemolytic anemia (AIHA) of the cold type (cold hemagglutinin disease, cold autoimmune hemolytic anemia (AIHA) (cold agglutinin disease), (CHAD)), autoimmune hemolytic anemia (AIHA) of the warm type (warm AIHA, warm autoimmune hemolytic anemia (AIHA)), autoimmune hemolytic Donath-Landsteiner anemia (paroxysmal cold
  • Addison disease autoimmune adrenalitis, Morbus Addison
  • Addison's anemia Morbus Biermer
  • AIHA autoimmune hemolytic anemia
  • autoimmune arthritis arteriitis temporalis, Takayasu arteriitis (Takayasu's disease, aortic arch disease), temporal arteriitis/giant cell arteriitis, autoimmune chronic gastritis, autoimmune infertility, autoimmune inner ear disease (AIED), Basedow's disease (Morbus Basedow), Bechterew's disease (Morbus Bechterew, ankylosing spondylitis, spondylitis ankylosans), Behcet's syndrome (Morbus Behcet), bowel disease including autoimmune inflammatory bowel disease (including colitis ulcerosa (Morbus Crohn, Crohn's disease), autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (DCM), chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIDP), chronic polyarthritis, Churg-Strauss syndrome,
  • Calcinosis cutis Raynaud phenomenon, motility disorders of the esophagus, sklerodaktylia and teleangiectasia), Crohn's disease (Morbus Crohn, colitis ulcerosa), dermatitis herpetiformis during, dermatologic autoimmune diseases, dermatomyositis, essential mixed cryoglobulinemia, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Goodpasture syndrome (anti- GBM mediated glomerulonephritis), graft versus host disease, Guillain-Barre syndrome (GBM, Polyradikuloneuritis), hematologic autoimmune diseases, Hashimoto thyroiditis, hemophilia, acquired hemophilia, autoimmune hepatitis, idiopathic pulmonary fibrosis (IPF), idiopathic thrombocytopenic purpura, Immuno-thrombocytopenic purpura (Morbus Werlhof, I
  • autoimmune syndrome syndrome
  • PSS progressive systemic sclerosis
  • RA rheumatoid arthritis
  • RA chronic polyarthritis
  • rheumatic disease of the joints rheumatic fever
  • sarcoidosis Morbus Boeck, Besnier-Boeck-Schaumann disease
  • stiff-man syndrome Sclerodermia, Scleroderma, Sjogren's syndrome, autoimmune uveiitis, and Wegner's disease (Morbus Wegner, Wegner's granulomatosis).
  • a peptide epitope present in a TMMP of the present disclosure is a
  • Autoantigens include, e.g., aggrecan, alanyl-tRNA syntetase (PL-12), alpha beta
  • alpha fodrin Sptan 1
  • alpha-actinin al antichymotrypsin
  • al antitripsin al microglobulin
  • aldolase aminoacyl-tRNA synthetase, an amyloid
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • BPI bactericidal/permeability-increasing protein
  • phospholipids phosphatidyl inositol, platelet derived growth factors, polymerase beta (POLB), potassium channel KIR4.1, proliferating cell nuclear antigen (PCNA), proteinase-3, proteolipid protein, proteoglycan, prothrombin, recoverin, rhodopsin, ribonuclease, a ribonucleoprotein, ribosomes, a ribosomal phosphoprotein, RNA, an Sm protein, SplOO nuclear protein, SRP54 (signal recognition particle 54 kDa), a selectin, smooth muscle proteins, sphingomyelin, streptococcal antigens, superoxide dismutase, synovial joint proteins, T1F1 gamma collagen, threonyl-tRNA synthetase (PL-7), tissue transglutaminase, thyroid peroxidase, thyroglobulin, thyroid stimulating hormone receptor, transferrin, trios
  • the antigens/epitopes included in a TMAPP of the present disclosure are those that are useful for treating an autoimmune disease other than (or in addition to) T1D and celiac disease. Accordingly, the present disclosure encompasses only protein constructs (e.g., TMAPPs) and methods of preparing protein constructs (e.g., TMAPPs) (as well as compositions comprising such protein constructs) comprising antigens/epitopes useful for treating an autoimmune disease other than (or in addition to) celiac disease or T1D. Likewise, the present disclosure
  • an TMAPP comprising an antigen/epitope that is useful for treating an autoimmune disease other than T1D and/or celiac disease is not excluded from the scope of this disclosure if it also may provide some therapeutic benefit for the treatment of T1D and/or celiac disease.
  • a method of treating, or treatment of, an autoimmune disease other than T1D and/or celiac disease is not excluded from the scope of this disclosure if it also may have a use as a method of treating or treatment of T1D or celiac disease.
  • Autoantigens associated with alopecia areata include, e.g., hair follicle keratinocyte polypeptides, melanogenesis-associated autoantigens, and melanocyte polypeptides.
  • An example of a melanocyte autoantigen is tyrosinase.
  • Autoantigens associated with autoimmune alopecia also include trichohyalin (Leung et al. (2010) J. Proteome Res.
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of a hair follicle keratinocyte polypeptide, a melanocyte polypeptide, a melanogenesis-associated polypeptide, tyrosinase, trichohyalin, or keratin 16.
  • Autoantigens associated with Addison’s disease include, e.g., 21 -hydroxylase.
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope- presenting peptide of from 4 amino acids to about 25 amino acids in length of 21 -hydroxylase.
  • Autoantigens associated with autoimmune thyroiditis include, e.g., thyroglobulin, thyroid peroxidase, thyroid Stimulating Hormone Receptor (TSH-Receptor), thyroidal iodide transporters Na + /I- symporter (NIS), pendrin, and the like.
  • TSH-Receptor thyroid Stimulating Hormone Receptor
  • NIS thyroidal iodide transporters Na + /I- symporter
  • pendrin pendrin
  • a suitable epitope- presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope- presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned Hashimoto’s thyroiditis-associated polypeptides.
  • Autoantigens associated with Crohn’s disease include, e.g., pancreatic secretory granule membrane glycoprotein-2 (GP2).
  • GP2 pancreatic secretory granule membrane glycoprotein-2
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of GP2.
  • Autoantigens associated with Goodpasture’s disease include, e.g., the a3 chain of type
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope- presenting peptide of from 4 amino acids to about 25 amino acids in length of the a3 chain of type IV collagen.
  • Autoantigens associated with Grave’s disease include, for example, thyroglobulin, thyroid peroxidase, and thyrotropin receptor (TSH-R).
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned Grave’s disease- associated antigens.
  • Autoantigens associated with mixed connective tissue disease include, e.g., U1
  • ribonucleoprotein (Ul-RNP) polypeptide also known as snRNP70. Sato et al. (2010) Mol. Cell. Biochem. 106:55.
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope -presenting peptide of from 4 amino acids to about 25 amino acids in length of Ul-RNP polypeptide.
  • Autoantigens associated with multiple sclerosis include, e.g., myelin basic protein, myelin oligodendrocyte glycoprotein, and myelin proteolipid protein.
  • a suitable epitope- presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope- presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned multiple sclerosis-associated antigens.
  • the peptide epitope can comprise the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO: 408).
  • a TMAPP of the present disclosure comprises a DRB1*15:01 MHC class II b chain; and a peptide epitope of the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO: 408).
  • Autoantigens associated with myasthenia gravis include, e.g., acetylcholine receptor
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned myasthenia gravis-associated antigens.
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure is an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of an AchR.
  • Autoantigens associated with Parkinson’s disease include, e.g., a-synuclein.
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope- presenting peptide of from 4 amino acids to about 25 amino acids in length of a-synuclein.
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure includes a peptide of from 5 amino acids to the entire length of any one of the following: GKTKEGVLYVGSKTK (SEQ ID NO: 409); KTKEGVLYVGSKTKE (SEQ ID NO: 410); MPVDPDNEAYEMPSE (SEQ ID NO: 411); DNEAYEMPSEEGY QD (SEQ ID NO:
  • EMPSEEGY QD YEPE SEQ ID NO: 413
  • SEEGY QD YEPEA SEQ ID NO: 4144, where“S” denotes phosphoserine.
  • foliaceus, bullous pemphigoid include pemphigus vulgaris immunogens such as desmosomal cadherin desmoglein 3 (Dsg3); pemphigus foliaceus immunogens such as Dsgl; bullous pemphigoid immunogens such as hemidesmosome peptides including BP230 antigen, GPAGla, and BPAGlb. See, e.g., Cirillo et al. (2007) Immunology 121:377.
  • Dsg3 desmosomal cadherin desmoglein 3
  • pemphigus foliaceus immunogens such as Dsgl
  • bullous pemphigoid immunogens such as hemidesmosome peptides including BP230 antigen, GPAGla, and BPAGlb. See, e.g., Cirillo et al. (2007) Immunology 121:377.
  • Autoantigens associated with bullous pemphigoid include bullous pemphigoid antigen 1 (BPAG1; also known as BP230 or dystonin), bullous pemphigoid antigen 2 (BPAG2; also known as BP180 or type XVII collagen), and subunits of human integrins a-5 and b-4.
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope -presenting peptide of from 4 amino acids to about 25 amino acids in length of any of the aforementioned pemphigus-associated antigens.
  • Autoantigens associated with myositis include, e.g., histidyl tRNA synthetase.
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope -presenting peptide of from 4 amino acids to about 25 amino acids in length of histidyl tRNA synthetase.
  • Autoantigens associated with rheumatoid arthritis include, e.g., collagen, vimentin, aggregan, fibrinogen, cyclic citrullinated peptides, a-enolase, histone polypeptides, lactoferrin, catalase, actinin, and actins (cytoplasmic 1 and 2(b/g).
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned rheumatoid arthritis-associated antigens.
  • Autoantigens associated with scleroderma include nuclear antigens.
  • a suitable epitope- presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope- presenting peptide of from 4 amino acids to about 25 amino acids in length of a nuclear antigen associated with scleroderma.
  • Autoantigens associated with Sjogren’s syndrome include, e.g., Ro/La ribonucleoprotein
  • RNP alpha-fodrin
  • beta-fodrin islet cell autoantigen
  • PARP poly(ADP)ribose polymerase
  • NuMA nuclear mitotic apparatus
  • NOR-90 nuclear mitotic apparatus
  • Ro60 kD autoantigen Ro52 antigen
  • La antigen see, e.g., GenBank Accession No. NP_001281074.1
  • p27 antigen e.g., GenBank Accession No. NP_001281074.1
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope- presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned Sjogren’s syndrome-associated antigens.
  • Autoantigens associated with systemic lupus erythematosus include, e.g., Ro60 autoantigen, low-density lipoproteins, Sm antigens of the U-l small nuclear ribonucleoprotein complex (B/B', Dl, D2, D3, E, F, G), a-actin 1, a-actin 4, annexin AI, Clq/tumor necrosis factor-related protein, catalase, defensins, chromatin, histone proteins, transketolase, hCAP18/LL37, and ribonucleoproteins (RNPs).
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned SLE-associated antigens.
  • Autoantigens associated with thrombocytopenia purpura include ADAMTS13 (a
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of an ADAMTS13 polypeptide or a VWFCP polypeptide.
  • Autoantigens associated with vasculitis include proteinase-3, lysozyme C, lactoferrin, leukocyte elastase, cathepsin G, and azurocidin.
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any of the aforementioned vasculitis-associated antigens.
  • Autoantigens associated with vitiligo include SOX9, SOX10, PMEL (Premelanosomal protein), tyrosinase, TYRP1 (Tyrosine related protein 1), DDT (D-Dopachrome tautomerase), Rab38, and MCHR1 (Melanin-concentrating receptor.
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned vitiligo- associated polypeptides.
  • Autoantigens associated with autoimmune uveitis include, for example, interphotoreceptor retinoid-binding protein (IRBP).
  • IRBP interphotoreceptor retinoid-binding protein
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length IRBP.
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned antigens.
  • Autoantigens associated with autoimmune polyendocrine syndrome include, e.g., 17- alpha hydroxylase, histidine decarboxylase, tryptophan hydroxylase, and tyrosine hydroxylase.
  • a suitable epitope -presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope -presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned autoimmune polyendocrine syndrome-associated antigens.
  • Autoantigens associated with psoriasis include ADAMTS15. See, e.g., Prinz (2017)
  • a suitable epitope-presenting peptide for inclusion in a TMAPP of the present disclosure can be an epitope -presenting peptide of from 4 amino acids to about 25 amino acids in length of an ADAMTS15 polypeptide.
  • MODs Immunomodulatory polypeptides
  • Immunomodulatory polypeptides that are suitable for inclusion in a TMAPP of the present disclosure include, but are not limited to, IL-2, CD7, B7-1 (CD80), B7-2 (CD86), PD- Ll, PD-L2, 4-1BBL, OX40L, Fas ligand (FasL), inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, and ILT4.
  • IL-2 intercellular adhesion molecule
  • TMAPP of the present disclosure and their cognate costimulatory receptors (also referred to herein as“co-immunomodulatory polypeptides” or“coMODs”) include the following:
  • CD80 MOD
  • CD28 Co-MOD
  • CD86 MOD
  • CD28 Co-MOD
  • FasL Fas ligand
  • Fas Fas (Co-MOD)
  • CD83 MOD
  • CD83L Co-MOD
  • CD70 MOD
  • CD27 Co-MOD
  • CD80 MOD
  • CTLA4 Co-MOD
  • TGF-bI TGF-bI
  • TOH-b2 TGF ⁇ 3
  • TGF-b Receptor e.g., TGFBR1 and/or TGFBR2
  • Co-MOD TGF-b Receptor
  • the immunomodulatory polypeptide is selected from a 4-1BBF
  • the immunomodulatory polypeptide can comprise only the extracellular portion of a full-length immunomodulatory polypeptide.
  • the immunomodulatory polypeptide can in some cases exclude one or more of a signal peptide, a transmembrane domain, and an intracellular domain normally found in a naturally-occurring immunomodulatory polypeptide.
  • an immunomodulatory polypeptide suitable for inclusion in a TMAPP of the present disclosure comprises all or a portion of (e.g., an extracellular portion of) the amino acid sequence of a naturally-occurring immunomodulatory polypeptide.
  • an immunomodulatory polypeptide suitable for inclusion in a TMAPP of the present disclosure is a variant immunomodulatory polypeptide that comprises at least one amino acid substitution compared to the amino acid sequence of a naturally-occurring immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide exhibits a binding affinity for a co immunomodulatory polypeptide that is lower than the affinity of a corresponding naturally- occurring immunomodulatory polypeptide (e.g., an immunomodulatory polypeptide not comprising the amino acid substitution(s) present in the variant) for the co-immunomodulatory polypeptide.
  • immunomodulatory domain can have from 1 amino acid (aa) to 20 aa differences from a wild- type immunomodulatory domain.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure differs in amino acid sequence by 1 aa, 2 aa, 3 aa, 4 aa, 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa, from a corresponding wild-type immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure differs in amino acid sequence by 1 aa, 2 aa, 3 aa, 4 aa, 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa, from a corresponding wild-type immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure differs in amino acid sequence by 1 aa
  • immunomodulatory polypeptide present in a TMAPP of the present disclosure differs in amino acid sequence by 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, or 20 aa, from a corresponding wild-type immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes l, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes a single amino acid substitution compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 2 amino acid substitutions (e.g., no more than 2 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 3 amino acid substitutions (e.g., no more than 3 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 4 amino acid substitutions (e.g., no more than 4 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 5 amino acid substitutions (e.g., no more than 5 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 6 amino acid substitutions (e.g., no more than 6 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 7 amino acid substitutions (e.g., no more than 7 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 8 amino acid substitutions (e.g., no more than 8 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 9 amino acid substitutions (e.g., no more than 9 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 10 amino acid substitutions (e.g., no more than 10 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 11 amino acid substitutions (e.g., no more than 11 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 12 amino acid substitutions (e.g., no more than 12 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 13 amino acid substitutions (e.g., no more than 13 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 14 amino acid substitutions (e.g., no more than 14 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 15 amino acid substitutions (e.g., no more than 15 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 16 amino acid substitutions (e.g., no more than 16 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 17 amino acid substitutions (e.g., no more than 17 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 18 amino acid substitutions (e.g., no more than 18 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 19 amino acid substitutions (e.g., no more than 19 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. In some cases, a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure includes 20 amino acid substitutions (e.g., no more than 20 amino acid substitutions) compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide. [00437] As discussed above, a variant immunomodulatory polypeptide suitable for inclusion in a
  • TMAPP of the present disclosure exhibits reduced affinity for a cognate co-immunomodulatory polypeptide, compared to the affinity of a corresponding wild- type immunomodulatory polypeptide for the cognate co-immunomodulatory polypeptide.
  • Exemplary pairs of immunomodulatory polypeptide and cognate co-immunomodulatory polypeptide include, but are not limited to:
  • PD-L1 immunomodulatory polypeptide
  • PD1 cognate co-immunomodulatory polypeptide
  • IL-2 immunomodulatory polypeptide
  • IL-2 receptor cognate
  • CD80 immunomodulatory polypeptide
  • CD28 cognate co-immunomodulatory polypeptide
  • CD86 immunomodulatory polypeptide
  • CD28 cognate co-immunomodulatory polypeptide
  • Fas ligand immunomodulatory polypeptide
  • Fas cognate co-immunomodulatory polypeptide
  • ICOS-F immunomodulatory polypeptide
  • ICOS cognate co-immunomodulatory polypeptide
  • ICAM immunomodulatory polypeptide
  • FFA-1 cognate co-immunomodulatory polypeptide
  • CD30F immunomodulatory polypeptide
  • CD30 cognate co-immunomodulatory polypeptide
  • CD40 immunomodulatory polypeptide
  • CD40F cognate co-immunomodulatory polypeptide
  • CD83 immunomodulatory polypeptide
  • CD83F cognate co-immunomodulatory polypeptide
  • HVEM immunomodulatory polypeptide
  • CD 160 cognate co
  • immunomodulatory polypeptide [00453] o) JAG1 (immunomodulatory polypeptide) and CD46 (cognate co-immunomodulatory polypeptide);
  • CD80 immunomodulatory polypeptide
  • CTLA4 cognate co-immunomodulatory polypeptide
  • CD86 immunomodulatory polypeptide
  • CTLA4 cognate co-immunomodulatory polypeptide
  • CD70 immunomodulatory polypeptide
  • CD27 cognate co-immunomodulatory polypeptide
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure has a binding affinity for a cognate co-immunomodulatory polypeptide that is from 100 nM to 100 mM.
  • a variant immunomodulatory polypeptide present in a TMAPP of the present disclosure has a binding affinity for a cognate co immunomodulatory polypeptide that is from about 100 nM to 150 nM, from about 150 nM to about 200 nM, from about 200 nM to about 250 nM, from about 250 nM to about 300 nM, from about 300 nM to about 350 nM, from about 350 nM to about 400 nM, from about 400 nM to about 500 nM, from about 500 nM to about 600 nM, from about 600 nM to about 700 nM, from about 700 nM to about 800 nM, from about 800 nM to about 900 nM, from about
  • immunomodulatory polypeptide can be determined by bio-layer interferometry (BLI) using purified immunomodulatory polypeptide and purified cognate co-immunomodulatory polypeptide. Binding affinity between a TMAPP and its cognate co-immunomodulatory polypeptide can also be determined by BLI using purified TMAPP and the cognate co immunomodulatory polypeptide. BLI methods are well known to those skilled in the art. See, e.g., Lad et al. (2015) J. Biomol. Screen. 20(4):498-507; and Shah and Duncan (2014) J. Vis.
  • a BLI assay can be carried out using an Octet RED 96 (Pal ForteBio) instrument, or a similar instrument, as follows.
  • a TMAPP (e.g., a TMAPP of the present disclosure; a control TMAPP (where a control TMAPP comprises a wild-type immunomodulatory polypeptide)) is immobilized onto an insoluble support (a“biosensor”).
  • the immobilized TMAPP is the“target.”
  • Immobilization can be effected by immobilizing a capture antibody onto the insoluble support, where the capture antibody immobilizes the TMAPP.
  • immobilization can be effected by immobilizing anti-Fc (e.g., anti-human IgG Fc) antibodies onto the insoluble support, where the immobilized anti-Fc antibodies bind to and immobilize the TMAPP (where the TMAPP comprises an IgFc polypeptide).
  • anti-Fc e.g., anti-human IgG Fc

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WO2022240916A1 (en) * 2021-05-10 2022-11-17 The Regents Of The University Of Colorado, A Body Corporate Engineered hla alleles for treating autoimmunity
WO2023010047A1 (en) * 2021-07-29 2023-02-02 Nantcell, Inc. Modified t cell receptors for the prevention and treatment of viral infections and cancer
US11932867B2 (en) 2017-04-28 2024-03-19 National Jewish Health Methods of treating rheumatoid arthritis using RNA-guided genome editing of HLA gene
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EP4326754A4 (en) * 2021-04-21 2025-02-19 Cue Biopharma, Inc. Mhc class ii t-cell modulatory polypeptides for treating type 1 diabetes mellitus (t1d) and methods of use thereof
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US11932867B2 (en) 2017-04-28 2024-03-19 National Jewish Health Methods of treating rheumatoid arthritis using RNA-guided genome editing of HLA gene
US12006348B2 (en) 2017-09-07 2024-06-11 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptide with conjugation sites and methods of use thereof
US12485183B2 (en) 2020-05-12 2025-12-02 Cue Biopharma, Inc. Multimeric T-cell modulatory polypeptides and methods of use thereof
US12485184B2 (en) 2020-05-12 2025-12-02 Cue Biopharma, Inc. Multimeric T-cell modulatory polypeptides and methods of use thereof
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