Treatment of b-cell mediated immune disorders by t-cell mediated depletion of b cells, plasmablasts and plasma cells

Abstract

This disclosure provides compositions and methods for T-cell mediated depletion of B cells. The compositions and methods may be used, for example, for the treatment of autoimmune disorders, immune-mediated inflammation disorders and other B-cell mediated immune disorders. In embodiments, the depletion is effected by methods comprising administering to an individual a T cell engaging protein ("TEP"), wherein the TEP comprises: (i) a peptide-major histocompatibility complex ("pMHC") comprising a peptide epitope, a β2-microglobulin ("β2M") polypeptide, and an MHC class I heavy chain polypeptide; (ii) an immunoglobulin ("Ig") Fc polypeptide; (iii) at least one B-cell targeting component; and (iv) optionally one or more activating immunomodulatory polypeptides, wherein each of the at least one B-cell targeting components of the TEP binds to a B cell binding partner on a B cell, a plasmablast, and / or a plasma cell.

Description

TREATMENT OF B-CELL MEDIATED IMMUNE DISORDERS BY T-CELL MEDIATED DEPLETION OF B CELLS, PLASMABLASTS AND PLASMA CELLSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 570,696. filed March 27. 2024 and U.S. Provisional Patent Application No. 63 / 647,472, filed May 14. 2024, which applications are incorporated herein by reference in their entirety.INCORPORATION-BY-REFERENCE OF MATERIAL ELECTRONICALLY SUBMITTED

[0002] A Sequence Listing is provided herewith as a Sequence Listing XML, “CUEB- 161WO SEQLIST” created on March 26, 2025, and having a size of 357,195 bytes. The contents of the Sequence Listing XML are incorporated by reference herein in their entirety.INTRODUCTION

[0003] Depletion of autoreactive B cells by CAR-T therapy has been reported to have a positive therapeutic effect on autoimmune disorders, including systemic lupus erythematosus (SLE), idiopathic inflammatory myositis and systemic sclerosis. There arc well-known drawbacks associated with CAR-T therapy, however. For example, CAR-T therapy is a very expensive, autologous (i.e., patient-specific) therapy that typically requires a complex manufacturing process for making the CAR-T cells and an initial course of lymphodepleting chemotherapy for the patient. CAR-T therapy also has been associated with various risks, including cytokine release syndrome, neurotoxicity, T cell mediated disease flares, and even the risk of cancer. Accordingly, there exists a need for improved methods of depleting B cells for the treatment of autoimmune disorders, immunc-mcdiatcd inflammation disorders and other B-ccll mediated immune disorders.SUMMARY

[0004] This disclosure provides T-cell mediated methods of treating autoimmune disorders, immune-mediated inflammation disorders and other B-cell mediated immune disorders by T-cell mediated depletion of B cells in an individual. Tire method comprises administering to the individual a therapeutic amount of a bispecific T-cell engaging protein (“TEP") that can bind to B cells and mediate a T-cell response that results in a reduction or substantial elimination of the patient's B cells.

[0005] In certain embodiments, the TEP comprises: i) a peptide-major histocompatibility complex C‘pMHC”) comprising a peptide, a (32- microglobulin (“]32M‘’) polypeptide, and an MHC class I heavy chain polypeptide;ii) a scaffold component such as an immunoglobulin (“Ig”) Fc polypeptide; iii) at least one B-cell targeting component (“BCTC”); and iv) optionally one or more activating immunomodulatory polypeptides or “MODs”, wherein each of the at least one B-cell targeting components of the TEP binds to a binding partner on a B celt plasmablast or plasma cell.

[0006] Examples of BCTCs include proteins, including antibodies and fragments of antibodies, that retain specific binding to one or more target antigens on B cells, plasmablasts and / or plasma cells, e.g., CD19, CD20, CD21, CD40, B cell maturation antigen (BCMA), CD38, CD79a, CD79b, CD138 and CD139. Alternatively, BCTCs may comprise autoantigenic proteins, or antigenic portions thereof, which can facilitate selective depletion of pathogenic B cells, plasmablasts and / or plasma cells.

[0007] In a manner similar to an antigen-presenting cell (APC), the pMHC of a TEP that is bound to a B cell can present an epitope that is recognized by a T cell receptor (TCR) of a T cell. Because most humans have been exposed to known viral and bacterial pathogens such as cytomegalovirus (CMV), Epstein-Barr vims (EBV), influenza (flu), tetanus, and SARS-CoV-2 (SCV2), most humans already possess a repertoire of T cells specific for such antigens. Hence, in some embodiments, a TEP that is bound to a B cell and presents an epitope for such a known viral or bacterial antigen will make the B cell appear to the patient’s immune system as a vims- or bacteria-infected cell. The patient’s existing T cells will thus bind to the pMHC of the TEP and release its cytotoxic components, resulting in elimination of the B cell. In this way, the patient’s own immune system accomplishes depletion of tire patient's B cells. As discussed herein, pMHCs that present other epitopes to T cells may be employed in TEPs.

[0008] In some embodiments, the TEP is a dual-targeting TEP that comprises two different BCTCs. e.g., antibodies or antibody fragments that bind to (i) multiple types of B cells, e.g., CD19 or CD20, and (ii) plasmablasts and plasma cells, e.g., BCMA or CD38. In this way, the TEPs likely can eliminate the patient’s B cells, plasmablasts and plasma cells (i.e., antibody secreting B cells). Advantageously, in such embodiments each of the BCTCs will be able to separately bind to its target B cell antigen and the TEP will be able to bind to both target antigens simultaneously.

[0009] In some embodiments, the TEP comprises two different pMHCs, e.g., pMHCs that present epitopes to two different viral antigens. In this way, the TEPs may effect depletion though the action of different anti-viral T cells in a patient’s T cell repertoire. In some embodiments, the patient is first immunized with a vaccine, e.g., an influenza (flu) vaccine, tetanus vaccine, SARS-CoV-2 vaccine, EBV vaccine (in development), a vaccine of peptides, or other vaccine to a pathogen such as a vims or bacteria, or to any other antigen, e.g., a cancer antigen, which causes the production of T cells specific for the pMHC of the TEP, thereby increasing the repertoire of T cells that can bind the TEPs and eliminate the B cells. In certain embodiments, the TEP does not comprise an optional activating MOD.

[0010] This disclosure thus provides methods and off-the-shelf products that can be used for treating autoimmune disorders, immune -mediated inflammation disorders and other B-cell mediated immune disorders by T-cell mediated depletion of B cells. Moreover, T-cell depletion is a highly sensitive process and thus may result in a more-complete depletion of B cells than CAR-T therapy while also only activating a limited population of available T cells with the potential for reduced risk of inflammatory responses such as cytokine release syndrome.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIGS. 1A-1I illustrate configurations for TEPs comprising single-chain pMHCs.

[0012] FIGS. 2A-2D illustrate configurations for TEPs comprising single-chain pMHCs, where the pMHCs comprise intrachain disulfide bonds.

[0013] FIGS. 3A-3B illustrate configurations for dimeric TEPs comprising two identical TEPs, each of which comprises a single-chain pMHC.

[0014] FIGS. 4A-4F illustrate configurations for dimeric TEPs comprising two different TEPs, each of which comprises a single-chain pMHC.

[0015] FIGS. 5A-5G illustrate configurations for TEPs comprising heterodimeric pMHCs.

[0016] FIGS. 6A-6P illustrate configurations for dimeric TEPs comprising two TEPs, each of which comprises a heterodimeric pMHC.

[0017] FIGS. 7A-7E provide amino acid sequences of wild-type HLA-A*0201 (FIG. 7A; SEQ ID NO:4) and variants (FIG. 7B-7E; SEQ ID NOs:5-8, respectively).

[0018] FIGS. 8A-8E provide amino acid sequences of wild-type HLA-A* 1101 (FIG. 8A; SEQ ID NO:9) and variants (FIG. 8B-8E; SEQ ID NOs: 10-13. respectively).

[0019] FIGS. 9A-9E provide amino acid sequences of wild-type HLA-A*2402 (FIG. 9A; SEQ ID NO: 14) and variants (FIG. 9B-9E; SEQ ID NOs: 15-18, respectively).

[0020] FIGS. 10A-10E provide amino acid sequences of wild-type HLA-A* 3303 (FIG. 10A; SEQ ID NO: 19) and variants (FIG. 10B-10E; SEQ ID NOs:20-23, respectively).

[0021] FIGS. 11A-11E provide amino acid sequences of wild-type HLA-A*0301 (FIG. 11A; SEQ ID NO:24) and variants (FIG. 1 IB-1 IE; SEQ ID NOs:25-28, respectively).

[0022] FIGS. 12A-12D provide an alignment of amino acid sequences of wild-type (FIG. 12A and continued in FIG. 12B; SEQ ID NOs:29-37, respectively) and variant (FIG. 12C and continued in FIG.12D; SEQ ID NOs:38-46, respectively) HLA-A polypeptides.

[0023] FIGS. 13A-13D provide an alignment of amino acid sequences of wild-type (FIG. 13A and continued in FIG. 13B; SEQ ID NOs:47-53, respectively) and variant (FIG. 13C and continued in FIG. 13D; SEQ ID NOs:54-60, respectively) HLA-B polypeptides.

[0024] FIGS. 14A-14D provide an alignment of amino acid sequences of wild-type (FIG. 14A and continued in FIG. 14B; SEQ ID NOs:61-69, respectively) and variant (FIG. 14C and continued in FIG. 14D; SEQ ID NOs:70-78, respectively) HLA-C polypeptides.

[0025] FIGS. 15A-15E provide amino acid sequences of wild-type (FIG. 15A; SEQ ID NO: 79) HLA-E heavy chains and variants (FIGS. 15B-15E: SEQ ID NOs:80-83; respectively).

[0026] FIGS. 16A-16E provide amino acid sequences of wild-type (FIG. 16A; SEQ ID NO:84) HLA-E heavy chains and variants (FIGS. 16B-16E; SEQ ID NOs:85-88, respectively).

[0027] FIGS. 17A-17K provide amino acid sequences of (i) the heavy and light chains of the TEPs of Examples 1-4 (FIGS. 17A-17H are SEQ ID NOs:89-96, respectively), (ii) the heavy and light chains of an anti-CD19 antibody (FIGS. 17I-17J are SEQ ID NOs:97-98, respectively), and (iii) an antiCDF scFv (FIG. 17K is SEQ ID NO:99).

[0028] FIGS. 18A-18B illustrate the results of polyacrylamide gel electrophoresis (SDS-PAGE) analysis and analytical size-exclusion chromatography of the TEPs of Example 1.

[0029] FIG. 19 illustrates the results for three dimeric TEPS in assays to determine the binding affinity to, and specificity for, human or mouse target B cell antigen CD 19, using Biolayer Interferometry (BLI).

[0030] FIG. 20 illustrates the results of assays to determine the binding affinity of two dimeric anti-BCMA TEPs to target biotinylated human BCMA, target biotinylated mouse BCMA, and control biotinylated human IL2pR ligands.

[0031] FIG. 21 illustrates the results of an assay to determine the ability of four TEPs to depleteCD19-positive B cells via killing by antigen-specific CD8+ T cells.

[0032] FIG. 22 illustrates the results of an assay to detennine the production of inflammatory cytokines by TEP -mediated killing of B cells.

[0033] FIG. 23 illustrates the results of an assay to determine the dose-dependent killing of B cells observed at three effector-to-target ratios.

[0034] FIG. 24 illustrates the results of an assay to determine whether tire selective binding ofTEPs to B cells occurs via the anti-CD19 BCTC.

[0035] FIGS. 25-26 illustrates the results of assays demonstrating the concentration-dependent killing of B cells by a TEP at 120 hours, and the selectivity of the TEP toward B cells without disturbing other major immune cell subsets.

[0036] FIG. 27 provides tire results of a single-dose PK assessment of a murine surrogate TEP.

[0037] FIG. 28 provides tire results of an assay to detennine the duration of target engagement of a murine surrogate TEP administered at different doses.

[0038] FIG. 29 provides the results of an experiment to determine the ability of a murine surrogate TEP to redirect SARS-CoV2 antigen-specific CD8+ T cells to kill CD 19+ B cells.

[0039] FIG. 30 provides the results of an experiment to determine the ability of a TEP comprising a BCMA-targeting BCTC to provide redirected killing of BCMA+ B cells.

[0040] FIG. 31 illustrates the results of an assay to determine the dose-dependent killing ofBCMA+ B cells at three effector-to-target ratios by a TEP comprising a BCMA-targeting BCTC.

[0041] FIGS. 32A-32C provide the amino acid sequences for constructs 3438 (SEQ ID NO:358), 5026 (SEQ ID NO:359) and 5027 (SEQ ID NO:360).

[0042] FIGS. 33A-33B illustrate the results of polyacrylamide gel electrophoresis (SDS- PAGE) analysis and analytical size-exclusion chromatography of dual -targeting TEP, i.e. a TEP comprising two different BCTCs.

[0043] FIG. 34 provides the results of assays to determine whether a dual -targeting TEP can specifically bind to both of its target B cell antigens.

[0044] FIG. 35 provides the results of assays to detennine whether a dual -targeting TEP can simultaneously bind to both of its target B cell antigens.

[0045] FIG. 36 provides the results of assays to determine whether a dual -targeting anti¬CD 19 / anti-BCMA TEP with a CMV pMHC is capable of redirecting CMV-specific CD8+T cells to kill both CD 19-positive target cells and BCMA -positive target cells.DEFINITIONS

[0046] As used herein, the terms “autoimmune disorders”, “immune-mediated inflammation disorders” and other “B-cell mediated immune disorders” do not include B cell-related cancers such as multiple myeloma, lymphomas, and leukemia. Examples of such cancers include Non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrom macroglobulincmia or WM), cutaneous B-cell lymphoma, and high-grade B-cell lymphoma.

[0047] Tire term “self-antigen” means an individual’s own proteins or molecules that are normally present on the individual’s cells or cell products. A healthy immune system tolerates selfantigens and does not attack them.

[0048] The term “autoantigen” means a self-antigen against w hich the immune system of an individual produces autoantibodies as if the self-antigen w ere a foreign antigen. Tire production of such autoantibodies can lead to chronic inflammation, tissue damage and other symptoms of autoimmune disorders.

[0049] The term “autoantibody” means an antibody against a self-antigen (or a modified selfantigen), which antibody is produced by the immune system of an individual.

[0050] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein, and refer 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. Furthennore, as used herein, a "polypeptide" refers to a protein that includes modifications, such as deletions, additions, and substitutions (generally conservative in nature as would be known to a person in the art) to the native sequence, as long as the protein maintains the desired activity. These modifications can be deliberate, as through site-directed mutagenesis, or can be accidental, such as through mutations of hosts that produce the proteins, or errors due to polymerase chain reaction (PCR) amplification or other recombinant DNA methods. References herein to a specific residue or residue number in a known polypeptide are understood to refer to the amino acid at that position in the wild-type polypeptide. To the extent that the sequence of the wild-type polypeptide is altered, either by addition or deletion of one or more amino acids, one of ordinary skill will understand that a reference to the specific residue or residue number will be correspondingly altered so as to refer to the same specific amino acid in the altered polypeptide, which would be understood to reside at an altered position number. For example, if an MHC class I polypeptide is altered by the addition of one amino acid at the N-terminus. then a reference to position 84 or a specific residue at position 84, will be understood to indicate the amino acids that are at position 85 on the altered polypeptide. Likewise, a reference herein to substitution of a specific amino acid at a specific position, e.g., Y84, is understood to refer to a substitution of an amino acid for the amino acid at position 84 in the wild -type polypeptide. A Y84C substitution is thus understood to be a substitution of a Cys residue for the Tyr residue that is present in the wild-type sequence. If, e.g., the wild-type polypeptide is altered to change the amino acid at position 84 from its wild-type amino acid to an alternate amino acid, then the substitution for the amino acid at position 84 will be understood to refer to the substitution for the alternate amino acid. If in such case the polypeptide is also altered by the addition or deletion of one or more amino acids, then the reference to the substitution will be understood to refer to the substitution for the alternate amino acid at the altered position number. A reference to a “non-naturally occurring Cys residue” in a polypeptide, e.g., an MHC class I polypeptide, means that the polypeptide comprises a Cys residue in a location where there is no Cys in the corresponding wild-type polypeptide. This can be accomplished through routine protein engineering in which a cysteine is substituted for the amino acid that occurs in the wildtype sequence.

[0051] A polypeptide has a certain percent "sequence identity" to another polypeptide, meaning that, when aligned, that percentage of amino acids are the same, and in the same relative position, when comparing tire 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 (Basic Local Alignment Search Tool), 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. Biol. 215:403-10. Unless otherwise stated, “sequence identity” as referred to herein is determined by BLAST+2.10.0 using default parameters, which is available over the world wide web at sites including https: / / ncbiinsights.ncbi.nlm.nih.gov / 2019 / 12 / 18 / blast-2-10-0 / .

[0052] “T cell” includes all 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. Unless otherwise indicated, the term “T cell” as used herein refers to a CD8+ T cell.

[0053] The term “activating immunomodulatory polypeptide” (also referred to herein as an“activating MOD”) means a polypeptide that specifically binds a cognate costimulatory polypeptide on a T cell, thereby providing a signal which mediates a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like. As discussed herein, an activating MOD can include, but is not limited to wild-type or variants of wild-type polypeptides such as a cytokine (e.g., IL- 2), CD7, B7-1 (CD80), B7-2 (CD86), and 4-1BBL.

[0054] As used herein the term “zn vz'vo” refers to any process or procedure occurring inside of the body.

[0055] As used herein, "in vitro’’'' refers to any process or procedure occurring outside of the body.

[0056] The terms “antibody” and “antibodies” include antibodies or immunoglobulins of any isotype, fragments of antibodies that retain specific binding to one or more target antigens, including, but not limited to. Fab, Fv, scFv, and Fd fragments, chimeric antibodies, humanized antibodies, single-chain antibodies (scAb), single domain antibodies (dAb), single domain heavy chain antibodies, a single domain light chain antibodies, nanobodies, bi-specific antibodies, multi-specific antibodies, and fusion proteins comprising an antigen-binding (also referred to herein as antigen binding) portion of an antibody and a non-antibody protein. The antibodies can be detectably labeled, e.g., with a radioisotope, an enzyme that generates a detectable product, a fluorescent protein, and the like. The antibodies can be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like. Also encompassed by the term are Fab’, Fv, F(ab’)2. and / or other antibody fragments that retain specific binding to an antigen, and monoclonal antibodies. As used herein, a monoclonal antibody is an antibody produced by a group of identical cells, all of which were produced from a single cell by repetitive cellular replication. That is, the clone of cells only produces a single antibody species. While a monoclonal antibody can be produced using hybridoma production technology, other production methods known to those skilled in the art can also be used (e.g., antibodies derived from antibody phage display libraries). An antibody can be monovalent or bivalent.An antibody can be an Ig monomer, which is a “Y -shaped” molecule that consists of four polypeptide chains: two heavy chains and two light chains connected by disulfide bonds.

[0057] The term “nanobody” (Nb), as used herein, refers to the smallest antigen binding fragment or single variable domain (VHH) derived from a naturally occurring heavy chain antibody and is known to the person skilled in the art. They are derived from heavy chain only antibodies, seen in camelids (Hamers-Casterman et al. (1993) Nature 363:446; Desmyter et al. (1996) Nature Structural Biol. 3:803; and Desmyter et al. (2015) Curr. Opin. Struct. Biol. 32: 1). In the family of "camelids", immunoglobulins devoid of light polypeptide chains are found. "Camelids" comprise old world camelids (Camelus bactrianus and Camelus dromedarius) and new world camelids (for example, Llama paccos. Llama glama. Llama guanicoe and Llama vicugna). A single variable domain heavy chain antibody is referred to herein as a nanobody or a VHH antibody.

[0058] ‘Antibody fragments” comprise a portion of an antibody, for example, the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng. 8(10): 1057-1062 (1995)): domain antibodies (dAb; Holt et al. (2003) Trends Biotechnol. 21:484); single-chain antibody molecules; and multi-specific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigenbinding site, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen binding sites and is still capable of crosslinking antigen.

[0059] ‘Fv” is the minimum antibody fragment that contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0060] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polypeptide linker between the VHand VL domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0061] The tenn ‘diabodies’ refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variabledomain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the co plementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097: WO 93 / 11161; and Hollinger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444- 6448.

[0062] The tenns “treatment’’, “treating” and the like are used herein to generally mean 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 terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein 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 or may not be predisposed to acquiring the disease or symptom but has not yet been diagnosed as having it: (b) inhibiting the disease or one or more symptoms associated with the disease, e.g., arresting its development; and / or (c) relieving the disease, i.e., causing regression of the disease. The therapeutic agent may be administered before, during and / 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. Hie subject therapy will desirably be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.

[0063] The terms “individual,” “subject,” “host,” and “patient,” are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired. 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. Unless otherwise indicated, the terms “individual,” “subject,” “host,” and “patient,” refer to a human.

[0064] Unless indicated otherwise, the term “substantially” is intended to encompass both“wholly ” and “largely but not wholly”. For example, an Ig Fc that “substantially does not induce ADCC” (i.e., antibody-dependent cell cytotoxicity) means an Ig Fc that induces no ADCC at all or that largely does not induce ADCC.

[0065] As used herein, the term “about” used in connection with an amount indicates that the amount can vary by 10% of the stated amount. For example, “about 100” means an amount of from 90- 110. Where about is used in the context of a range, the “about” used in reference to the lower amount of the range means that the lower amount includes an amount that is 10% lower than the lower amount of the range, and “about” used in reference to tire higher amount of the range means that the higher amount includes an amount 10% higher than the higher amount of the range. For example, from about 100 to about 1000 means that the range extends from 90 to 1100.

[0066] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0067] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0068] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, acceptable and / or preferred methods and materials are nowrdescribed. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0069] As used herein and in the appended claims, the singular forms ‘'a,” '‘an,” and “the” include plural referents unless the context clearly dictates otherw ise. Thus, for example, reference to a “T-cell modulatory protein” includes a plurality of such proteins and reference to “the immunomodulatory polypeptide” includes reference to one or more immunomodulatory polypeptides and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection w ith the recitation of claim elements, or use of a “negative” limitation.

[0070] Tire terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (z.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if the range 10- 15 is disclosed, then 11, 12, 13, and 14 are also disclosed. All methods described herein can be perfonned in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the embodiments of the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed.

[0071] The term “and / or” as used herein a phrase such as “A and / or B” is intended to include both A and B: A or B; A (alone); and B (alone). Likewise, the term “and / or” as used herein a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C: A, B. or C; A or C: A or B; B or C; A and C: A and B; B and C; A (alone): B (alone); and C (alone).

[0072] It is understood that aspects and embodiments of the present disclosure described herein include “comprising,” “consisting of,” and “consisting essentially of’ aspects and embodiments.

[0073] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment.Conversely, various features of the disclosure, which are. for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the disclosure are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such subcombination was individually and explicitly disclosed herein.

[0074] The publications discussed herein are provided solely fortheir disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.DETAILED DESCRIPTION

[0075] The present disclosure provides, among other things, methods and compositions of matter for treating an individual who has a B-cell mediated immune disorder such as an autoimmune disorder or an immune -mediated inflammation disorder. The method comprises administering to the individual a therapeutic amount of a bifunctional T-cell engaging protein (“TEP”) that can bind to B cells and mediate a T-cell response that results in a reduction or substantial elimination of the patient’s B cells.

[0076] In certain embodiments, the TEP comprises: i) a peptide-major histocompatibility complex (“pMHC”) comprising a peptide epitope, a (32- microglobulin (“]32M”) polypeptide, and an MHC class I heavy chain polypeptide; ii) a scaffold component such as an immunoglobulin (“Ig”) Fc polypeptide: iii) at least one B-cell targeting component (“BCTC”): and iv) optionally one or more activating immunomodulatory polypeptides,wherein each of the at least one BCTCs of the TEP binds to a binding partner on a B cell, plasmablast or plasma cell. BCTC binding partners can include, e.g., cell surface lineage markers that are common to all B cells or to all plasmablasts and plasma cells, e g., CD 19, CD20, and BCMA, to effect non-specific clonal deletion of B cells, plasmablasts and / or plasma cells. Alternatively, a BCTC can be a protein or a portion of a protein that is a known autoantigen associated with an autoimmune disorder or other disorder involving autoantibodies. In such embodiments, the TEP can effect a targeted clonal deletion of substantially only pathogenic B cells. For example, the proteins desmoglein (DSG) 1 and 3 are known dominant autoantigens associated with various pemphigus disorders, and hence DSG1 and DSG3, or antigenic domains thereof, can serve as BCTCs. As described below, a TEP can be provided in many configurations.T-CELL ENGAGING PROTEINS (TEPS)

[0077] As noted above, TEPs of this disclosure include-: i) a peptide-major histocompatibility complex ("pMHC") comprising a peptide epitope, a p2-microglobulin (' [32M ) polypeptide, and an MHC class I heavy chain polypeptide: ii) an immunoglobulin ("Ig") Fc polypeptide, iii) at least one BCTC, and iv) optionally one or more activating immunomodulatory polypeptides or “MODs”. The TEP presents a peptide-MHC complex (pMHC) that can be specifically bound to a T-cell receptor (TCR) of a T cell. The pMHC is formed by the combination of the peptide epitope, P2M polypeptide and the MHC class I heavy chain polypeptide. An "MHC class I heavy chain polypeptide" is sometimes referred to herein as a human leukocyte antigen (HLA) class 1 heavy chain polypeptide.

[0078] The scaffold component can be, e.g., an immunoglobulin (Ig) Fc polypeptide or a non-IgFc polypeptide, but often will be an Ig Fc polypeptide, which can help provide good manufacturability and prolonged half-life of the TEP. Tire TEP may comprise one or more independently selected peptide linkers between any two of the components of the TEP, e.g., between one or more of: i) the peptide epitope and the (32M polypeptide (in TEPs in which the peptide is part of a fusion protein with the (32M polypeptide); ii) the MHC class I heavy chain polypeptide and the BCTC; iii) the MHC class I heavy chain polypeptide and an Ig Fc polypeptide; iv) an Ig Fc polypeptide and the BCTC; v) an Ig Fc polypeptide and an optional activating MOD; vi) the BCTC and an activating MOD; vii) where the TEP comprises two or more BCTCs in tandem, between the BCTCs, and viii) where the TEP comprises two or more activating MODs in tandem, between the activating MODs.

[0079] Tire re are multiple possible constructs for the pMHC of a TEP (discussed below). Generally speaking, either (i) the peptide epitope of the pMHC will be part of a single-chain or heterodimeric fusion polypeptide, in which case the peptide epitope typically will be joined to the N- terminus of the [32M polypeptide via a peptide linker, or (ii) the peptide epitope of the pMHC will bechemically conjugated to a conjugation site in either the |32M polypeptide or MHC heavy chain polypeptide. These possible constructs are discussed below.

[0080] Where a TEP comprises more than one BCTC, the BCTCs may be the same or different. As noted above, for example, a TEP that comprises more than one BCTC could be a dual -targeting TEP that comprises (i) a first BCTC that is an antibody or fragment that binds to CD 19 or CD20, which are expressed on many types of B cells but not expressed or expressed to a lesser degree on plasmablasts and plasma cells, and (ii) a second BCTC that binds, e.g., to BCMA or CD38, which are expressed on plasma cells and plasmablasts, as well as memory' B cells. In this way, the TEP potentially can eliminate both the patient’s B cells, plasmablasts and plasma cells (i.e., antibody secreting B cells). Similarly, where a TEP comprises more than one activating MOD. the multiple activating MODs can be the same or different.A. TEPs in which the peptide epitope of the pMHC is part of a fusion protein

[0081] As noted above, in some cases, the peptide epitope will be part of a fusion protein. In such cases, the pMHC may comprise either a single polypeptide chain or a heterodimer of two polypeptide chains. Both configurations are discussed below.(i) Single-chain pMHCs

[0082] Schematic examples of TEPs in which the pMHC is a single-chain polypeptide are provided in FIGS. 1A-1I. These figures illustrate some of the many possible combinations of the pMHC. the MHC class 1 heavy chain polypeptide (comprising tire al. a2 and a3 subunits), an 1g Fc polypeptide, the at least one BCTC, one or more optional activating MODs, and linkers (denoted by the lines between the components). The dashed line between the (32M polypeptide and the al subunit of the MHC heavy chain polypeptide represents a peptide linker. Although the Ig Fc polypeptide typically will be connected to the C-tenninus of the MHC heavy chain polypeptide, it is possible that a BCTC and / or MOD could be interposed between the MHC heavy chain polypeptide and Ig Fc polypeptide, as illustrated in FIGS. 1D-1H.

[0083] Examples of single-chain pMHCs are described in WO 2022 / 197970 (‘'WO ‘970”) to Cue Biopharma, Inc., the disclosure of which is expressly incorporated herein by reference. As disclosed in WO ‘970, single-chain pMHCs can comprise one or two disulfide bonds that spontaneously fomr between Cys residues that can be provided in the components of the pMHC. One such disulfide bond can join a Cys residue in the (32M polypeptide to a Cys residue in the MHC heavy chain polypeptide. For example, the pMHC can comprise a disulfide bond between a Cys at amino acid 12 of the (32M polypeptide and a Cys at amino acid 236 of the MHC heavy chain polypeptide. Such disulfide bonds that join a Cys in the 02M polypeptide to a Cys in the MHC heavy chain polypeptide are referred to herein as “body disulfides”. A second disulfide bond can join a Cys that is provided in the linkerbetween the peptide epitope and the (32M polypeptide to a Cys in the MHC heavy chain polypeptide. Such disulfide bonds between (i) a Cys in the linker that joins the peptide epitope and (32M polypeptide and (ii) a Cys in the MHC heavy chain polypeptide, are referred to herein as “linker disulfides”. As disclosed in WO "970, a Cys in the linker may be joined to a Cys at position 84 of the MHC heavy chain polypeptide, which is located in the al subunit of the MHC heavy chain polypeptide. It has also been found that a linker disulfide may be formed between (i) a Cys in the linker between the peptide epitope and the P2M polypeptide and (ii) a Cys at any one of positions 135-143 of the a2 subunit of the MHC heavy chain polypeptide (e.g., a Cys at any one of positions 138-140 of the al subunit, or a Cys at position 139 of the a2 subunit). pMHCs with such linker disulfide bonds have been found to enable proper presentation of the peptide epitope to achieve selective binding to target TCRs.

[0084] Schematic examples of TEPs in which the pMHC is a single-chain polypeptide that comprises one or two of the above -de scribed disulfide bonds are provided in FIGS. 2A-D. Many other configurations are possible. For example, the optional activating MOD and / or BCTC may be interposed between the MHC heavy chain polypeptide and the Ig Fc (not shown).

[0085] In some embodiments, two TEPs comprising single-chain TEPs will form dimers through the spontaneous formation of one or more disulfide bonds between Cys residues in the Ig Fc polypeptides of each TEP. The dimers can comprise two identical TEPs, in which case the dimeric TEP is a homodimer. See, e.g., FIGS 3A and 3B. In such cases, as illustrated in FIGS. 3A and 3B, the two identical single-chain TEPs typically will form dimers through the spontaneous formation of two disulfide bonds between Cys residues in the Ig Fc polypeptides of each TEP.

[0086] In some embodiments, the dimeric TEP comprises non-identical TEPs, in which case the dimeric TEP is a heterodimer. In such cases, the two TEPs of the dimeric TEP typically will have interspecific dimerization sequences, e.g.. Knob-in-Hole dimerization sequences, that facilitate the selective dimerization of the two different single-chain TEPs. See, e.g., FIGS. 4A-4F, which illustrate a few of the many possible combinations of two different TEPs. In FIG. 4A, the dimeric TEP comprises two single-chain TEPs that have different B-cell targeting components, e.g., anti-CD19 and anti-BCMA scFvs. In FIG. 4B, the dimeric TEP comprises two single-chain TEPs that have different B-cell targeting components, e.g., anti-CD19 and anti-BCMA scFvs, and one of the single-chain TEPs further comprises an activating MOD. In FIG. 4C, the dimeric TEP comprises two single-chain TEPs that have the same B-cell targeting components, but different peptide epitopes. For example, combinations of different viral peptide epitopes from common viruses such as CMV, EBV and SARS-CoV-2 can be employed to increase tire potential response by an individual’s existing T cell repertoire. In FIG. 4D, the dimeric TEP comprises two single-chain TEPs that have different B-cell targeting components and different peptide epitopes, and one of the single-chain TEPs further comprises an activating MOD. In FIG. 4E, the dimeric TEP comprises two single-chain TEPs that have different B-cell targeting components e.g.. anti-CD19 and anti-BCMA scFvs, and different peptide epitopes, e.g., an EBV peptide epitope and a SARS- CoV-2 peptide epitope. In FIG. 4F, the dimeric TEP comprises two single-chain TEPs that have the same B-cell targeting components and the same activating MODs, but different peptide epitopes, e.g., a CMV peptide epitope and an EBV peptide epitope. Hie dimeric TEPs in FIGS. 4A-4F are illustrated with Knob-in-Hole interspecific binding sequences, but other interspecific binding sequences are well known and could be used instead. Such interspecific dimerization sequences are disclosed in WO 2022 / 197970 to Cue Biopharma, Inc., the disclosure of which as it pertains to interspecific dimerization sequences is expressly incorporated herein by reference. See, e.g., paragraph

[0210] , As illustrated in FIGS. 1D-1H, it also is possible to position the BCTC and / or optional activating MOD N-terminal to the Ig Fc polypeptide in any of the homodimeric or heterodimeric configurations of single-chain TEPs.(ii) Heterodimeric pMHCs

[0087] In some cases, the pMHC of the TEP is a heterodimer formed by first and second polypeptides, where the first polypeptide comprises the peptide epitope, |32M polypeptide and connecting linker, and the second polypeptide comprises the MHC heavy chain polypeptide. The Ig Fc and BCTC are also positioned on the second polypeptide. The optional activating MODs, if present, typically will be a component of the second polypeptide chain, but also may be linked to the C-terminus of the [32M polypeptide on the first polypeptide. The pMHC may further comprise a body disulfide bond and also a linker disulfide bond as discussed above. Heterodimeric pMHCs comprising body disulfide bonds and linker disulfide bonds are described in WO 2020 / 132138 (to Cue Biopharma, Inc.), the disclosure of which as it pertains to such heterodimeric pMHCs is expressly incorporated by reference.

[0088] Examples of TEPs in which the pMHC is heterodimeric are provided in FIGS. 5A-5G, which illustrate a few of the many possible combinations of BCTC(s) and optional activating MOD(s) on the second polypeptide chain, as well as some of the possible body disulfide bond and linker disulfide bond combinations that may be employed. The BCTCs may be positioned C-terminal to the MHC heavy chain polypeptide, as shown in FIGS. 5A, B and E, in which the BCTC is positioned C-terminal to the Ig Fc. Alternatively, the BCTC may be positioned N-terminal to the MHC heavy chain polypeptide, as shown in FIGS. 5C and D. Alternatively, BCTCs may be positioned both N-terminal to the MHC heavy chain polypeptide and C-tenninal to heavy chain as shown in FIGS. 5F and G. In FIG. 5F, the BCTCs are the same, and in FIG. 5G they are different. The BCTCs also may be interposed between the MHC heavy chain polypeptide and the Ig Fc, or between the optional activating MOD(s) and another component of the second polypeptide (not shown). The optional activating MOD(s) likewise may be located at any position along the second polypeptide that is N-terminal or C-terminal to the MHC heavy chain polypeptide. For example, tire optional activating MOD may be interposed between the MHC heavy chain polypeptide and the Ig Fc, between the MHC heavy chain polypeptide and a BCTC, or between the Ig Fc and BCTC (all not shown).

[0089] TEPs comprising a heterodimeric pMHC also may form dimeric TEPs through the spontaneous formation of one or more disulfide bonds between Cys residues in the Ig Fc polypeptides of each TEP. FIGS. 6A-L illustrate some of tire many possible configurations for such dimeric TEPs comprising the TEPs having heterodimeric pMHCs described above.

[0090] In embodiments where the two TEPs are identical in structure, the two identical singlechain TEPs typically will form dimers through the spontaneous formation of disulfide bonds (typically two disulfide bonds) between Cys residues in the Ig Fc polypeptides of each TEP. FIGS. 6A-6F illustrate some of the many possible configurations of dimeric TEPs that are homodimers of two identical TEPs. FIGS. 6A and B illustrate dimeric TEPs comprising C-terminal BCTCs. FIG. 6A illustrates a dimeric TEP with a body disulfide, and FIG. 6B illustrates a dimeric TEP w ith both a body disulfide and a linker disulfide.

[0091] FIGS. 6C, D and E illustrate dimeric TEPs comprising N-terminal BCTCs. FIG. 6C illustrates a dimeric TEP with both a body disulfide and a linker disulfide. FIG. 6D illustrates a dimeric TEP w ith both a body disulfide and a linker disulfide, as well as optional activating MODs positioned at the C-terminus of the Ig Fc. FIG. 6E illustrates a dimeric TEP having BCTCs that are N-terminal to the MHC heavy chain polypeptide and optional activating MODs that are N-tenninal to the BCTCs. Hie dimeric TEP of FIG. 6E comprises a body disulfide but not a linker disulfide.

[0092] FIG. 6F illustrates a dimeric TEP comprising TEPs that have a BCTC that is C-terminal to the Ig Fc and a different BCTG that is N-terminal to the MHC heavy chain polypeptide. Alternatively, all four BCTCs could be the same. The dimeric TEP of FIG. 6F comprises both a body disulfide and a linker disulfide.

[0093] In some embodiments, the dimeric TEP comprises non-identical TEPs. In such cases, the two TEPs of the dimeric TEP typically will have interspecific dimerization sequences, e.g., Knob-in- Hole dimerization sequences, that facilitate the selective dimerization of the two different TEPs. FIGS. 6G-6O illustrate a few of the many possible configurations in which the dimeric TEP comprises two different TEPs. In FIGS. 6G and 6H, the dimeric TEP comprises two TEPs that have different B-cell targeting components (e.g., anti-CD19 and anti-BCMA scFvs) that are positioned C-terminal to the Ig Fc polypeptides of the two TEPs. The dimeric TEP illustrated in FIG. 6G comprises a body disulfide (FIG. 6G), whereas the dimeric TEP illustrated in FIG. 6H comprises both a body disulfide and a linker disulfide. In FIG. 61, the dimeric TEP comprises two N-terminal TEPs that are positioned N-terminal to the MHC heavy chain polypeptide and comprise different B-cell targeting components (e.g., anti-CD19 and anti-BCMA scFvs). In FIG. 6 J, the dimeric TEP comprises two TEPs that comprise the same B-cell targeting components (e.g., anti-CD19 and anti-BCMA scFvs) positioned N-terminal to the MHC heavy chain polypeptide, but one of the TEPs additionally comprises an activating MOD positioned C-terminal to the Ig Fc polypeptide. The dimeric TEP in FIGS. 61 and 6J comprise both a body disulfide and alinker disulfide. In FIG. 6K, the dimeric TEP comprises two TEPs that comprise different B-cell targeting components (e.g., anti-CD19 and anti-BCMA scFvs) positioned C-terminal to the Ig Fc polypeptide. In the dimeric TEP of FIG. 6K, each TEP comprises a body disulfide. Tire dimeric TEP in FIG. 6K also comprises an activating MOD N-tenninal to the MHC heavy chain polypeptide on one of the TEPs. In FIG. 6L, the dimeric TEP comprises two TEPs that have the same B-cell targeting components C-terminal to the MHC heavy chain and comprises both a body disulfide and a linker disulfide. The dimeric TEP in FIG. 6K also comprises an activating MOD C-terminal to the MHC heavy chain polypeptide on one of the TEPs. FIGS. 6M-6O illustrate the same dimers as illustrated in FIGS. 6I-6L, except that tire two TEPs that comprise the dimers of 6M-6O each have different peptide epitopes. As noted above, combinations of different viral peptide epitopes from common viruses such as CMV, EBV and SARS-CoV-2 can be employed to increase the potential response by an individual’s existing T cell repertoire. Many other configurations for such dimeric TEPs are possible. Moreover, although the dimeric TEPs in FIGS. 6G to 6L are illustrated with Knob-in-Hole interspecific binding sequences, other interspecific binding sequences are well known to persons of skill in the art and could be used instead.

[0094] Further, although the dimeric TEPs comprising two different TEPs discussed above(FIGS. 4A-F and 6A-P) have been illustrated as having the same body disulfides and linker disulfides in each TEP, the two different TEPs could have different body disulfides and / or linker disulfides. For example, a dimeric TEP could comprise a first TEP that has a body disulfide and a second TEP that has both a body disulfide and a linker disulfide. As another example, a dimeric TEP could comprise two TEPs that have both a body disulfide and a linker disulfide, where the linker disulfide of one TEP comprises a disulfide bond linking a Cys in the |32m-peptide epitope linker to a Cys at position 84 in its MHC heavy chain and the other TEP comprises a disulfide bond linking a Cys in the (32m-peptide epitope linker to a Cys at position 139 in its MHC heavy chain.(iii) pMHCs presented by multimeric antigen-presenting polypeptides (MAPPs)

[0095] In some cases, where the pMHC of a TEP is a single-chain polypeptide or a heterodimeric complex as described above, the pMHC may be provided as a component, i.e., as a presenting sequence or presenting complex, of a multimeric antigen-presenting polypeptide (MAPP) as described in WO 2021 / 242935 (Cue Biopharma, Inc.) or WO 2022 / 099157 (Cue Biophanna, Inc.), the disclosures of which are expressly incorporated by reference. Such MAPPs thus would comprise the pMHC, an Ig Fc and a BCTC. The MAPPs optionally may also comprise one or more activating MODs, and as noted above, combinations of different BCTCs can be employed to provide enhanced depletion, and / or different viral peptide epitopes from common viruses such as CMV, EBV and SARS-CoV-2 can be employed to increase the potential response by an individual’s existing T cell repertoire.B. TEPs in which the peptide epitope is chemically conjugated to the pMHC

[0096] Unlike the above TEPs in which the peptide epitope of the pMHC is part of a fusion protein with (i) the |32M polypeptide in the case of heterodimeric TEPs, or (ii) both the 02M polypeptide and the MHC class I polypeptide in the case of single-chain TEPs, in some cases the TEP may comprise a peptide epitope that is chemically conjugated to either the 02M polypeptide or the MHC class I polypeptide.

[0097] In some cases, TEPs comprising chemically conjugated peptide epitopes comprise a heterodimer of MHC polypeptides, i.e., the 02M polypeptide and MHC heavy chain polypeptide are not on the same polypeptide chain. In such cases, the peptide epitope is chemically conjugated to either the 02M polypeptide or MHC heavy chain polypeptide. See, e.g., WO 2019 / 051127. WO 2020 / 132365, WO 2020 / 132366. and WO 2020 / 132368 (Cue Biopharma, Inc.), the disclosures of which as they pertain to pMHCs comprising a chemically conjugated peptide epitope are expressly incorporated by reference.

[0098] In some cases, TEPs comprising chemically conjugated peptide epitopes comprise single-chain MHC polypeptides, i.e., the |32M polypeptide and MHC heavy chain polypeptide are in the same polypeptide chain. In such cases, the peptide epitope is chemically conjugated to either the 02M polypeptide orthe MHC heavy chain polypeptide. See. e g., WO 2022 / 015880, WO 2022 / 099156 and WO 2022 / 137158 (Cue Biopharma. Inc.), the disclosures of which as they pertain to single-chain pMHCs comprising a chemically conjugated peptide epitope are expressly incorporated by reference.

[0099] Dimeric TEPs comprising two TEPs comprising chemically conjugated peptide epitopes as described above (either two identical TEPs or two different TEPs) also may be formed. As described above, Ig Fc polypeptides comprising interspecific binding sequences typically will be used in embodiments where a dimeric TEP comprises two different TEPs, and Ig Fc polypeptides comprising non-interspecific binding sequences typically will be used in embodiments where a dimeric TEP comprises two identical TEPs. And as noted above, combinations of different viral peptide epitopes from common viruses such as CMV, EBV and SARS-CoV-2 can be employed to increase the potential response by an individual’s existing T cell repertoire.MHC POLYPEPTIDESA. p2M polypeptides

[0100] Hie 02M polypeptide present in tire TEP can comprise an amino acid sequence having at least 90%, at least 95%. at least 98%, at least 99%, or 100%, amino acid sequence identity to the following 02M ammo acid sequence: IQRTPK1QVY SRHPAENGKS NFLNCYVSGF HPSDIEVDLLKNGERIEKVE HSDLSFSKDW SFYLLYYTEF TPTEKDEYAC RVNHVTLSQP KIVKWDRDM (SEQ ID NO: 1) In some cases, a 02M polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity tothe following 02M amino acid sequence: IQRTPKIQVY SCHPAENGKS NFLNCYVSGF HPSDIEVDLLKNGERIEKVE HSDLSFSKDW SFYLLYYTEF TPTEKDEYAC RVNHVTLSQP KIVKWDRDM (SEQ ID NO:2), where amino acid 12 is a Cys. In some cases, a 02M polypeptide comprises the amino acid sequence IQRTPKIQVY SCHPAENGKS NFLNCYVSGF HPSDIEVDLLKNGERIEKVE HSDLSFSKDW SFYLLYYTEF TPTEKDEYAC RVNHVTLSQP KIVKWDRDM (SEQ ID NO:3).B. MHC class I heavy chain polypeptides

[0101] As noted above, the pMHC of a TEP comprises an MHC class I heavy chain polypeptide. Suitable MHC class I heavy chain polypeptides include a human MHC class I heavy chain polypeptide, where human MHC polypeptides are also referred to as “human leukocyte antigen” (“HLA”) polypeptides. Class I HLA heavy chain polypeptides include HLA-A heavy chain polypeptides, HLA-B heavy chain polypeptides, HLA-C heavy chain polypeptides, HLA-E heavy chain polypeptides, HLA-F heavy chain polypeptides, and HLA-G heavy chain polypeptides.

[0102] Unless otherwise specified below, the amino acid numbering of an MHC class I heavy chain polypeptide present in a pMHC polypeptide is based on the amino acid numbering of the MHC class I heavy' chain polypeptide depicted in FIG. 7A. It should be noted that the amino acid numbering of the MHC class I heavy chain polypeptide depicted in FIG. 7A applies equally to tire amino acid numbering of the MHC class I heavy chain polypeptides depicted in FIGS. 12A-12B (alignment of amino acid sequences of wild-type HLA-A heavy chain polypeptides), FIGS. 13A-13B (alignment of amino acid sequences of wild-type HLA-B heavy chain polypeptides), FIGS. 14A-14B (alignment of amino acid sequences of wild-type HLA-C heavy chain polypeptides), and FIGS. 15A and FIG. 16A (amino acid sequences of wild-type HLA-E heavy chain polypeptides).

[0103] In some cases, the MHC class I heavy chain is a heavy chain from an HLA-A, -B, -C, - E. -F, or -G allele. In some cases, the MHC class I heavy chain is a heavy chain from HLA-A*0101, A*0201, A*030L A* HOL A*2301, A*2402. A*2407. A*3303, and / or A*3401. In some cases, the MHC class I heavy chain is a heavy7chain from HLA-B* 0702, B*0801 , B* 1502, B*3802, B*4001, B*4601, and / or B*5301. In some cases, the MHC class I heavy7chain is a heavy chain from HLA- C*0102, C*0303, C*0304, C*0401, C*0602, C*0701, C*702, C*0801, and / or C* 1502. In some cases, the MHC class I heavy chain is a heavy chain from HLA-E*0101 (HLA-E*01:01:01:01), HLA- E*01:03(HLA-E*0I:03:01:01), HLA-E*01:04, HLA-E*01:05, HLA-E*01:06, HLA-E*01:07, HLA- E* 01:09, and HLA-E*01: 10. Two HLA-E alleles that have a significant prevalence in humans are HLA- E* 0101 (HLA-E* 01 : 01 : 01 : 01 ) and HLA-E* 01:03 (HLA-E* 01 : 03 : 01 : 01 ), and both have identical peptide-binding grooves.

[0104] Unless expressly stated otherwise, a pMHC polypeptide does not include membrane anchoring domains (transmembrane regions) of an MHC class I heavy chain, or a part of MHC class I heavy chain sufficient to anchor the resulting pMHC to a cell (e.g., eukaryotic cell such as a mammalian cell) in which it is expressed. In some cases, the MHC class I heavy chain present in a pMHC does not include a signal peptide, a transmembrane domain, or an intracellular domain (cytoplasmic tail) associated with a native MHC class I heavy chain. Thus, e.g., in some cases, the MHC class I heavy chain present in a pMHC polypeptide includes only the al, a2, and a3 domains of an MHC class I heavy chain. In some cases, the MHC class I heavy chain present in a pMHC has a length of from about 270 amino acids (aa) to about 290 aa. In some cases, the MHC class I heavy chain present in a pMHC has a length of 270 aa, 271 aa, 272 aa, 273 aa, 274 aa, 275 aa, 276 aa, 277 aa. 278 aa. 279 aa, 280 aa, 281 aa, 282 aa, 283 aa, 284 aa, 285 aa, 286 aa, 287 aa, 288 aa, 289 aa, or 290 aa.

[0105] In some cases, an MHC class I heavy chain polypeptide present in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to all or part (e.g., 50, 75, 100, 150, 200, or 250 contiguous amino acids) of the amino acid sequence of any of the human HLA heavy chain polypeptides depicted in FIGS. 7-16, where the MHC class I heavy chain polypeptide comprises a Cys at amino acid 84 or at any one of amino acids 135-143 (e.g.. at amino acid 139). Wire re the MHC class I heavy chain polypeptide comprises a Cys at any one of amino acids 135-143 (e.g, a Cys at amino acid 139), an amino acid other than Cys is at position 84. Conversely, where the MHC class I heavy chain polypeptide comprises a Cys at position 84, amino acids 135-143 are other than Cys. In some cases, the MHC class I heavy chain has a length of 270 aa, 271 aa, 272 aa, 273 aa, 274 aa, 275 aa. 276 aa, 277 aa, 278 aa, 279 aa, 280 aa, 281 aa, 282 aa, 283 aa, 284 aa, 285 aa, 286 aa, 287 aa, 288 aa. 289 aa. or 290 aa.

[0106] In some cases, a pMHC polypeptide comprises an HLA-A heavy chain polypeptide with the above-noted amino acid substitution(s). The HLA-A heavy chain polypeptides, or portions thereof, that may be that may be incorporated into a pMHC polypeptide include, but are not limited to, the alleles: A*0101, A*0201, A*0301, A* 1101, A*2301, A*2402, A*2407, A*3303, and A*3401. In some cases, a pMHC polypeptide comprises an HLA-B heavy chain polypeptide with the above-noted amino acid substitution(s). In some cases, a pMHC polypeptide comprises an HLA-C heavy chain polypeptide with the above-noted amino acid substitution(s). In some cases, a pMHC polypeptide comprises an HLA- E heavy chain polypeptide with the above-noted amino acid substitution(s).C. Intrachain disulfide bonds

[0107] As discussed above, a pMHC of this disclosure may be a single-chain or heterodimeric polypeptide (or dimer thereof) that may comprise one or more disulfide bonds. As also discussed above, a pMHC may comprises a linker disulfide bond formed between: i) a Cys at amino acid 84 in the alsubunit of the MHC heavy chain polypeptide or any one of amino acids 135-143 (e.g., amino acid 139) in the a2 subunit of the MHC heavy chain polypeptide, based on the numbering of the MHC class I heavy chain polypeptide depicted in FIG. 7A; and a Cys present in the first peptide linker, where the first peptide linker is interposed between the peptide epitope and the (32M polypeptide. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 84. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 135. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 136. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 137. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 138. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 139. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 140. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 141. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 142. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises a Cys at position 143.

[0108] Tirus, for example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence CADMAAQTT (SEQ ID NO: 100). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence ACDMAAQTT (SEQ ID NO: 101). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AACMAAQTT (SEQ ID NO: 102). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADCAAQTT (SEQ ID NO: 103). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMCAQTT (SEQ ID NO: 104). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMACQTT (SEQ ID NO: 105). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMAACTT (SEQ ID NO: 106). As another example, in some cases, amino acids 135-143 of the MHC class 1 heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMAAQCT (SEQ ID NO: 107). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMAAQTC (SEQ ID NO: 108).

[0109] As another example, in some cases, amino acids 135-143 of tire MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence CADMAAQIT (SEQ ID NO: 109). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHCpolypeptide comprises the amino acid sequence ACDMAAQIT (SEQ ID NO: 110). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AACMAAQIT (SEQ ID NO: 111). As another example, in some cases, amino acids 135-143 of tire MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADCAAQIT (SEQ ID NO: 112). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMCAQIT (SEQ ID NO: 113). As another example, in some cases, amino acids 135-143 ofthe MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMACQIT (SEQ ID NO: 114). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMAACIT (SEQ ID NO: 115). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMAAQCT (SEQ ID NO: 116). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADMAAQIC (SEQ ID NO: 117).

[0110] As another example, in some cases, amino acids 135-143 ofthe MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence CADTAAQIT (SEQ ID NO: 118). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence ACDTAAQIT (SEQ ID NO: 119). As another example, in some cases, amino acids 135-143 ofthe MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AACTAAQIT (SEQ ID NO: 120). As another example, in some cases, amino acids 135-143 of tire MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADCAAQIT (SEQ ID NO: 121). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADTCAQ1T (SEQ ID NO: 122). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADTACQIT (SEQ ID NO: 123). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADTAACIT (SEQ ID NO: 124). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADTAAQCT (SEQ ID NO: 125). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AADTAAQIC (SEQ ID NO: 126).

[0111] As another example, in some cases, amino acids 135-143 ofthe MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence CVDTAAQIS (SEQ ID NO: 127). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence ACDTAAQIS (SEQ ID NO: 128). As another example.in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AVCTAAQIS (SEQ ID NO: 129). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AVDCAAQIS (SEQ ID NO: 130). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AVDTCAQIS (SEQ ID NO: 131). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AVDTACQIS (SEQ ID NO: 132). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AVDTAACIS (SEQ ID NO: 133). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AVDTAAQCS (SEQ ID NO: 134). As another example, in some cases, amino acids 135-143 of the MHC class I heavy chain of a pMHC polypeptide comprises the amino acid sequence AVDTAAQIC (SEQ ID NO: 135).

[0112] In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-A amino acid sequences depicted in FIGS. 8C-8D. where either (i) amino acid 84 is Cys, and where amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys, and amino acid 84 is other than a Cys (e.g., where amino acid 84 is Ala, Gly, or Vai). In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-A amino acid sequences depicted in FIG. 8C-8D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is other than a Cys (e.g.. where amino acid 84 is Tyr) such that amino acid 84 is unable to form a disulfide bond with the Cys in the linker that is interposed between the peptide epitope and the P2M polypeptide. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-A amino acid sequences depicted in FIG. 8C-8D. where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of tire HLA-A amino acid sequences depicted in FIG. 8C-8D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Cys. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%.at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-A amino acid sequences depicted in FIG. 8C-8D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys, where amino acid 84 is Ala, and where amino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%. at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-A amino acid sequences depicted in FIG. 8C-8D, where amino acid 139 is Cys, where amino acid 84 is Ala, and where amino acid 236 is Cys. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to any one of the HLA-A amino acid sequence depicted in FIG. 7B-7E. FIG. 8B-8E, FIG. 9B-9E, FIG. 10B-10E. and FIG. 11B-11E.

[0113] In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-B amino acid sequences depicted in FIGS. 13C-13D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is other than a Cys (e.g.. where amino acid 84 is Ala. Gly, or Vai). In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-B amino acid sequences depicted in FIGS. 13C-13D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is other than a Cys (e.g.. where amino acid 84 is Tyr. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%. at least 90%, at least 95%, at least 97%, at least 98%. or at least 99%, amino acid sequence identity to any one of the HLA-B amino acid sequences depicted in FIGS. 13C-13D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%. at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-B amino acid sequences depicted in FIGS. 13C-13D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Cys. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%. amino acid sequence identity to any one of the HLA-B amino acid sequences depicted in FIGS. 13C-13D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys. or (ii) amino acid 139 is Cys and amino acid 84 is Ala, and whereamino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-B amino acid sequences depicted in FIGS. 13C-13D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and where amino acid 84 is Ala, and where amino acid 236 is Cys.

[0114] In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-C amino acid sequences depicted in FIGS. 14C-14D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is other than a Cys (e.g.. where amino acid 84 is Ala. Gly, or Vai). In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-C amino acid sequences depicted in FIGS. 14C-14D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is other than a Cys (e.g.. where amino acid 84 is Tyr. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%. at least 90%, at least 95%, at least 97%, at least 98%. or at least 99%, amino acid sequence identity to any one of the HLA-C amino acid sequences depicted in FIGS. 14C-14D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%. at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-C amino acid sequences depicted in FIGS. 14C-14D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Cys. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%. amino acid sequence identity to any one of the HLA-C amino acid sequences depicted in FIGS. 14C-14D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Ala, and where amino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, amino acid sequence identity to any one of the HLA-C amino acid sequences depicted in FIGS. 14C-14D, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Ala, and where amino acid 236 is Cys.

[0115] In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to any one of the HLA-E amino acid sequences depicted in FIGS. 15B-15E and 16B-16E, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is other than a Cys (e.g.. where amino acid 84 is Ala, Gly, or Vai). In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to any one of the HLA-E amino acid sequences depicted in FIGS. 15B-15E and 16B-16E, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and where amino acid 84 is other than a Cys (e.g., where amino acid 84 is Tyr. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to any one of the HLA-E amino acid sequences depicted in FIGS. 15B-15E and 16B-16E, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%. at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to any one of the HLA-E amino acid sequences depicted in FIGS. 15B-15E and 16B-16E, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Tyr, and where amino acid 236 is Cys. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to any one of the HLA-E amino acid sequences depicted in FIGS. 15B-15E and 16B-16E, where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Ala, and where amino acid 236 is Ala. In some cases, the MHC class I heavy chain polypeptide in a pMHC polypeptide comprises an amino acid having at least 85%, at least 90%, at least 95%, at least 97%, at least 98%. at least 99%, or 100%, amino acid sequence identity to any one of the HLA-E amino acid sequences depicted in FIGS. 15B-15E and 16B-16E. where either (i) amino acid 84 is Cys and amino acid 139 is other than a Cys, or (ii) amino acid 139 is Cys and amino acid 84 is Ala, and where amino acid 236 is Cys.

[0116] In some cases, the TEP comprises an MHC class I HLA-A allele heavy chain. In some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%. at least 98%, at least 99%, or 100%, amino acid sequence identity to the following HLA-A heavy chain amino acid sequence:

[0117] GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQ EGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQ YAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENG KETLQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGD GTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE (SEQ ID NO: 136).

[0118] In some cases, the MHC class I heavy chain polypeptide comprises an Ala at position 84 and a Cys at position 236. Thus, e.g., in some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following HLA-A heavy chain amino acid sequence:

[0119] GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQ EGPEYWDGETRKVKAHSQTHRVDLGTLRGAYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQ YAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENG KETLQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPCGD GTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE (SEQ ID NO: 137), where ammo acid 84 is an Ala and amino acid 236 is a Cys.

[0120] In some cases, the MHC class I heavy chain polypeptide comprises a Cys at position 84 and a Cys at position 236. Thus, e.g., in some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following HLA-A heavy chain amino acid sequence:

[0121] GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQ EGPEYWDGETRKVKAHSQTHRVDLGTLRGCYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQ YAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENG KETLQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPCGD GTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE (SEQ ID NO: 138), where amino acid 84 is a Cys and amino acid 236 is a Cys.

[0122] In some cases, the MHC class I heavy chain polypeptide comprises an Ala at position 84, a Cys at any one of positions 135-143 (e.g., at position 139), and a Cys at position 236. Thus, e.g., in some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following HLA-A heavy chain amino acid sequence:

[0123] GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQ EGPEYWDGETRKVKAHSQTHRVDLGTLRGAYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQ YAYDGKDYIALKEDLRSWTAADMCAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETLQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPCGD GTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE (SEQ ID NO: 139), where amino acid 84 is an Ala, amino acid 139 is a Cys, and amino acid 236 is a Cys.PEPTIDE EPITOPES

[0124] As discussed above, the pMHC of a TEP comprises a peptide epitope. As used herein, the term ‘"peptide epitope" means a peptide that can be presented by the MHC polypeptides (in one of the manners described above), such that the pMHC presents an epitope that can be specifically recognized and bound by a TCR of a target T cell.

[0125] A peptide epitope present in a pMHC polypeptide can have a length of at least 4 amino acids, e.g., from 4-25 aa (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), including a range of from 6-15 aa, 8-12 aa, 8-16 aa, 8- 10 aa. 9-11 aa, 5-10 aa, 10-15 aa, 15-20 and 20-25 aa in length. In some cases, the peptide epitope is 8. 9. 10. 11 or 12 amino acids in length.

[0126] Suitable epitopes presented by a pMHC include, but are not limited to, epitopes present in an infectious disease agent, e.g., a viral infectious disease agent or other infectious agent such as a bacteria or other pathogen. Alternatively, a pMHC may present an epitope to any other antigen that are found in a human, e.g.. a cancer antigen (e g., a melanoma-associated or MAGE antigen), or may be induced in a human through vaccination. In some embodiments, the epitope will be one for which a patient has or is likely to have a preexisting T cell repertoire due to a prior infection and / or vaccination.

[0127] Examples of viral infectious disease agents include, e.g., Adenoviruses, Adeno-associated virus, Alphaviruses (Togaviruses), Eastern equine encephalitis vims, Eastern equine encephalomyelitis vims, Venezuelan equine encephalomyelitis vaccine strain TC-83, Western equine encephalomyelitis vims, Arenaviruses, Lymphocytic choriomeningitis vims (non-neurotropic strains), Tacaribe vims complex, Bunyaviruses, Bunyamwera vims, Rift Valley fever vims vaccine strain MP-12, Chikungunya vims, Calcivimses, Coronaviruses, Cowpox vims, Flavivimses (Togaviruses), Group B Arbovimses, Dengue vims serotypes 1, 2, 3, and 4, Yellow fever vims vaccine strain 17D, Hepatitis A, B, C, D, and E viruses, the Cytomegalovirus, Epstein Barr vims (EBV), Eastern Equine encephalitis vims, Herpes simplex types 1 and 2, Herpes zoster, Human herpesvirus types 6 and 7, hepatitis C vims (HVC), hepatitis B vims (HBV), Influenza viruses types A, B, and C, Papovavimses, Newcastle disease vims, Measles vims, Mumps vims. Parainfluenza vimses types 1, 2, 3, and 4, polyomaviruses (JC vims, BK vims), Respiratory syncytial vims. Human parvovirus (B 19), Coxsackie vimses types A and B, Echovimses, Polioviruses, Rhinoviruses, Alastrim (Variola minor vims), Smallpox (Variola major vims). Whitepox Reovimses, Coltivims, human Rotavirus, and Orbivims (Colorado tick fever vims), Rabies vims, Vesicular stomatitis vims, measles, vims, Rubivims (rubella), Semliki Forest vims, St. Louisencephalitis virus, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Arenaviruses (a.k.a. South American Hemorrhagic Fever virus), Flexal, Lymphocytic choriomeningitis virus (LCM) (neurotropic strains), Hantaviruses including Hantaan virus, Rift Valley fever virus, Japanese encephalitis virus, Yellow fever virus. Monkeypox virus, Human immunodeficiency virus (HIV) types 1 and 2, Human T cell lymphotropic virus (HTLV) types 1 and 2, Simian immunodeficiency virus (SIV), Vesicular stomatitis virus, Guanarito virus, Lassa fever virus, Junin virus, Machupo virus, Sabia, Crimean-Congo hemorrhagic fever virus, Ebola viruses, Marburg virus, Tick-borne encephalitis virus complex (flavi) including Central European tick-borne encephalitis, Far Eastern tick-borne encephalitis, Hanzalova, Hypr, Kumlinge, Kyasanur Forest disease, Omsk hemorrhagic fever, and Russian Spring Summer encephalitis viruses, Herpesvirus simiae (Herpes B or Monkey B virus), Cercopithecine herpesvirus 1 (Herpes B virus), Equine morbillivirus (Hendra and Hendra-like viruses). Nipah virus. Variola major virus (Smallpox virus). Variola minor virus (Alastrim), African swine fever virus, African horse sickness virus, Akabane virus, Avian influenza virus (highly pathogenic). Blue tongue vims, Camel pox vims, Classical swine fever vims, Cowdria ruminantium (heartwater), Foot and mouth disease vims, Goat pox vims, Japanese encephalitis vims, Lumpy skin disease vims. Malignant catarrhal fever vims, Menangle vims, Newcastle disease vims (VVND), Vesicular stomatitis vims (exotic), and Zika vims. Antigens encoded by such vimses are known in the art; a peptide epitope suitable for use in a TEP of the present disclosure can include a peptide from any known viral antigen.

[0128] Examples of bacterial infectious disease agents include, e.g., Clostridium tetani (responsible for tetanus), corynebacterium diphtheriae (responsible for diphtheria), bordetella pertussis (responsible for whooping cough), streptococcus pneumoniae (responsible for pneumonia, meningitis, and other serious illnesses), mycobacterium tuberculosis (responsible for TB), pneumococcal bacteria, Neisseria meningitidis (responsible for meningococcal infections), Haemophilus influenzae type b (Hib) (responsible for meningitis and pneumonia). Vibrio cholerae (responsible for cholera), and anthrax. Notably, vaccines are commonly available for many of these agents, and thus patients already may have received such vaccines and thus have a pre-existing repertoire of T cells that will recognize a pMHC that presents an epitope of the vims. Alternatively, as discussed below, patients can be given such vaccines prior to treatment with a TEP.

[0129] In some cases, an epitope presented by a pMHC is an epitope present in an antigen encoded by a vims or bacteria that infects a majority of the human population and / or for which a majority of the humans have been vaccinated or can be vaccinated. Exemplary vimses include, e.g., flu, measles, cytomegalovirus (CMV), Epstein-Barr vims (EBV), HPV, tetanus, bordetella pertussis, adenovirus, coronavimses such as the SARS-CoV-2, smallpox, yellow fever, and the like. Exemplary bacterial agents for which vaccines are widely administered include, e.g., Clostridium tetani (responsible for tetanus), corynebacterium diphtheriae (responsible for diphtheria), bordetella pertussis (responsible forwhooping cough), and Haemophilus influenzae type b (Hib) (responsible for meningitis and pneumonia). Vaccines are commonly available for many of these viral and bacterial agents and are known to elicit a strong immunodominant response, and thus patients already may have received such vaccines and have a pre-existing repertoire of T cells that will recognize a pMHC that presents an epitope of the virus or bacteria. Alternatively, as discussed below, patients can be given such vaccines prior to treatment with a TEP.

[0130] In some cases, the epitope presented by a pMHC of a TEP is an epitope specific to an EILA-A, - B, -C, -E, -F, or -G allele. In an embodiment, the epitope peptide present in a TEP presents an epitope restricted to HLA-A* 0101, A* 0201, A* 0301, A* 1101, A*2301, A* 2402, A* 2407, A* 3303, and / or A* 3401. In an embodiment, the epitope peptide present in a TEP presents an epitope restricted to HLA- B*0702, B*0801. B* 1502, B*3802, B*4001, B*4601, and / or B*5301. In an embodiment, the epitope peptide present in a TEP presents an epitope restricted to HLA-C*0102, C*0303, C*0304, C*0401, C*0602, C*0701, C*702, C*0801, and / or C* 1502. In an embodiment, the epitope peptide present in a TEP presents an epitope restricted to HLA-E, e.g., highly prevalent HLA-E alleles such as HLA-E*0101 and HLA-E* 01.03. A few exemplary peptide epitopes are discussed below.A. CMV Peptide Epitopes

[0131] In some cases, a TEP of the present disclosure comprises a CMV peptide epitope, i.e., a peptide that when in an MHC / peptide complex (e.g., an HLA / peptide complex), presents a CMV epitope (i.e., an epitope present in a CMV antigen) to a T cell. As with other peptide epitopes of this disclosure, a CMV peptide epitope has a length of at least 4 amino acids, e.g., from 4 amino acids to about 25 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, 20 aa, 21 aa, 22 aa, 23 aa, 24 aa, or 25 aa, including within a range of from 4 to 20 aa., from 6 to 18 aa., from 8 to 15 aa. from 8 to 12 aa., from 5 to 10 aa., from 10 to 15 aa., from 15 to 20 aa., from 10 to 20 aa., or from 15 to 25 aa. in length).

[0132] A given CMV epitope -specific T cell binds an epitope having a reference amino acid sequence of a given CMV epitope but does not substantially bind an epitope that differs from the reference amino acid sequence. For example, a given CMV epitope -specific T cell binds a CMV epitope 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 10bM, less than 10’5M, or less than 10’4M. A given CMV epitope -specific T cell can bind an epitope for which it is specific with an affinity of at least 10‘7M, at least 10'8M, at least 10‘9M, or at least 1010M.

[0133] In some cases, a CMV peptide epitope present in a TEP of the present disclosure is a peptide from CMV pp65. In some cases, a CMV peptide epitope present in a TEP of the present disclosure is a peptide from CMV gB (glycoprotein B).

[0134] For example, in some cases, a CMV peptide epitope present in a TEP of the present disclosure is a peptide of a CMV polypeptide having a length of at least 4 amino acids, e.g., from 4 amino acids to about 25 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. 20 aa, 21 aa, 22 aa, 23 aa, 24 aa, or 25 aa, including within a range of from 4 to 20 aa., from 6 to 18 aa., from 8 to 15 aa. from 8 to 12 aa., from 5 to 10 aa.. from 10 to 15 aa., from 15 to 20 aa., from 10 to 20 aa., or from 15 to 25 aa. in length), and comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following CMV pp65 amino acid sequence:

[0135] MESRGRRCPE MISVLGPISG HVLKAVFSRG DTPVLPHETR LLQTGIHVRV SQPSLILVSQ YTPDSTPCHR GDNQLQVQHT YFTGSEVENV SVNVHNPTGR SICPSQEPMS IYVYALPLKM LNIPSINVHH YPSAAERKHR HLPVADAVIH ASGKQMWQAR LTVSGLAWTR QQNQWKEPDV YYTSAFVFPT KDVALRHVVC AHELVCSMEN TRATKMQVIG DQYVKVYLES FCEDVPSGKL FMHVTLGSDV EEDLTMTRNP QPFMRPHERN GFTVLCPKNM IIKPGKISHI MLDVAFTSHE HFGLLCPKSI PGLSISGNLL MNGQQIFLEV QAIRETVELR QYDPVAALFF FDIDLLLQRG PQYSEHPTFT SQYRIQGKLE YRHTWDRHDE GAAQGDDDVW TSGSDSDEEL VTTERKTPRV TGGGAMAGAS TSAGRKRKSA SSATACTSGV MTRGRLKAES TVAPEEDTDE DSDNEIHNPA VFTWPPWQAG ILARNLVPMV ATVQGONLKY QEFFWDANDI YRIFAELEGV WQPAAQPKRR RHRQDALPGP CIASTPKKHR G (SEQ ID NO: 140).

[0136] As one non-limiting example, a CMV peptide epitope present in a TEP of the present disclosure has the amino acid sequence NLVPMVATV (SEQ ID NO: 141) and has a length of 9 amino acids.

[0137] In some cases, a CMV peptide epitope present in a TEP of the present disclosure is a peptide having a length of at least 4 amino acids, e.g.. from 4 amino acids to about 25 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. 20 aa, 21 aa, 22 aa, 23 aa, 24 aa, or 25 aa, including within a range of from 4 to 20 aa., from 6 to 18 aa., from 8 to 15 aa. from 8 to 12 aa., from 5 to 10 aa., from 10 to 15 aa., from 15 to 20 aa., from 10 to 20 aa., or from 15 to 25 aa. in length) of a CMV polypeptide comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following CMV gB amino acid sequence:

[0138] MESR1WCLVVCVNLC1VCLGAAVSSSSTSHATSSTHNGSHTSRTTSAQTRSVYSQHVTSS EAVSHRANETIYNTTLKYGDVVGVNTTKYPYRVCSMAQGTDLIRFERNIICTSMKPINEDLDEGI MVVYKRNIVAHTFKVRVYQKVLTFRRSYAYIYTTYLLGSNTEYVAPPMWEIHHINKFAQCYSS YSRVIGGTVFVAYHRDSYENKTMQLIPDDYSNTHSTRYVTVKDQWHSRGSTWLYRETCNLNC MLTITTARSKYPYHFFATSTGDVVYISPFYNGTNRNASYFGENADKFFIFPNYTIVSDFGRPNAAP ETHRLVAFLERADSVISWDIQDEKNVTCQLTFWEASERTIRSEAEDSYHFSSAKMTATFLSKKQE VNMSDSALDCVRDEAINKLQQIFNTSYNQTYEKYGNVSVFETSGGLVVFWQGIKQKSLVELERLANRSSLNITHRTRRSTSDNNTTHLSSMESVHNLVYAQLQFTYDTLRGYINRALAQIAEAWCVD QRRTLEVFKELSKINPSAILSAIYNKPIAARFMGDVLGLASCVTINQTSVKVLRDMNVKESPGRC YSRPVVIFNFANSSYVQYGQLGEDNEILLGNHRTEECQLPSLKIFIAGNSAYEYVDYLFKRMIDL SSISTVDSMIALDIDPLENTDFRVLELYSQKELRSSNVFDLEEIMREFNSYKQRVKYVEDKVVDP LPPYLKGLDDLMSGLGAAGKAVGVAIGAVGGAVASVVEGVATFLKNPFGAFTIILVAIAVVIIT YLIYTRQRRLCTQPLQNLFPYLVSADGTTVTSGSTKDTSLQAPPSYEESVYNSGRKGPGPPSSDA STAAPPYTNEQAYQMLLALARLDAEQRAQQNGTDSLDGQTGTQDKGQKPNLLDRLRHRKNGY RHLKDSDEEENV (SEQ ID NO: 142).

[0139] In some cases, the CMV epitope present in a TEP of the present disclosure presents an epitope specific to an HLA-A, -B, -C. -E, -F, or -G allele. In some cases, the epitope peptide present in a TEP presents an epitope restricted to HLA-A*0101, A*0201, A*0301. A* 1101, A*2301, A*2402. A*2407, A*3303, and / or A*3401. In some cases, the CMV epitope present in a TEP of the present disclosure presents an epitope restricted to HLA- B*0702, B*0801, B* 1502, B*3802, B*4001, B*4601, and / or B*5301. In some cases, tire CMV epitope present in a TEP of tire present disclosure presents an epitope restricted to C*0102, C*0303, C*0304, C*040I, C*0602, C*070I, C*702, C*080I, and / or C* 1502. As one example, in some cases, a TEP of the present disclosure comprises: a) a CMV peptide epitope having amino acid sequence NLVPMVATV (SEQ ID NO: 141) and having a length of 9 amino acids; b) an HLA-A*0201 class I heavy chain polypeptide; and c) a 2M polypeptide.

[0140] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a CD 19 polypeptide present on the surface of a B cell; and comprises, as the epitope a CMV peptide epitope. In some cases, the CMV peptide epitope is a peptide of a CMV pp65 polypeptide. In some cases, the CMV peptide epitope is a peptide of a CMV gB polypeptide. In some cases, the CMV peptide epitope has the amino acid sequence NLVPMVATV (SEQ ID NO: 141) and has a length of 9 amino acids.

[0141] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a BCMA polypeptide present on the surface of a B cell; and comprises, as the epitope a CMV peptide epitope. In some cases, the CMV peptide epitope is a peptide of a CMV pp65 polypeptide. In some cases, the CMV peptide epitope is a peptide of a CMV gB polypeptide. In some cases, the CMV peptide epitope has the amino acid sequence NLVPMVATV (SEQ ID NO: 141) and has a length of 9 amino acids.

[0142] In some cases, a TEP of the present disclosure is a dual-targeting TEP that comprises two different BCTCs, e.g., a scFv or ananobody specific for CD19 and a scFv or a nanobody specific for BCMA, or a scFv or a nanobody specific for CD20 and a scFv or a nanobody specific for CD38; and comprises, as the epitope a CMV peptide epitope. In some cases, the CMV peptide epitope is a peptide of a CMV pp65 polypeptide. In some cases, the CMV peptide epitope is a peptide of a CMV gBpolypeptide. In some cases, the CMV peptide epitope has the amino acid sequence NLVPMVATV (SEQ ID NO: 141) and has a length of 9 amino acids.

[0143] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for one or more of the following proteins found on B cells, plasmablasts and / or plasma cells: CD20, CD21. CD40, CD38, CD79a, CD79b, CD138. and CD139, and comprises, as the epitope a CMV peptide epitope. In some cases, the CMV peptide epitope is a peptide of a CMV pp65 polypeptide. In some cases, the CMV peptide epitope is a peptide of a CMV gB polypeptide. In some cases, the CMV peptide epitope has the amino acid sequence NLVPMVATV (SEQ ID NO: 141) and has a length of 9 amino acids.B. SARS-CoV-2 Peptide Epitopes

[0144] In some cases, a TEP can comprise a peptide epitope of a Betacoronavirus (e.g., SARS-CoV-2). Such peptide epitopes are typically at least about 4 amino acids in length and present a SARS-CoV-2 epitope to a T cell when in an MHC / peptide complex (e.g., an HLA / peptide complex).

[0145] A SARS-CoV-2 peptide epitope present in a TEP can have a length of at least 4 amino acids, e.g., from 4 amino acids to about 25 amino acids in length (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, 20 aa, 21 aa, 22 aa, 23 aa, 24 aa, or 25 aa, including within a range of from 4 to 20 amino acids, from 6 to 18 amino acids, from 8 to 15 amino acids, from 8 to 12 amino acids, from 9-11 amino acids, from 9-10 amino acids, from 5 to 10 amino acids, from 10-15 amino acids, from 10 to 20 amino acids, and from 15 to 25 amino acids in length), for example, lengths of 9, 10, 1 1, 12, 13 or 14 amino acids.

[0146] A SARS-CoV-2 peptide epitope present in a TEP is a peptide specifically bound by a T-cell, i.e., the epitope is specifically bound by an epitope -specific T cell. An epitope-specific T cell binds an epitope having a reference amino acid sequence but does not substantially bind an epitope that differs from the reference amino acid sequence. For example, an epitope -specific T cell binds an epitope 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‘bM, less than 10-5M, or less than 10-4M. An epitope -specific T cell can bind an epitope for which it is specific with an affinity of at least 10'7M, at least 10'8M, at least 10'9M, or at least IO10M.

[0147] In certain embodiments, the peptide epitope present in a TEP is a peptide of a Betacoronavinis- encoded polypeptide. In some cases, the peptide epitope is a SARS-CoV-2 peptide (i.e., a peptide of a SARS-CoV-2 -encoded polypeptide). In some cases, the peptide epitope is a SARS-CoV-2 peptide from a SARS-CoV-2-encoded surface glycoprotein. In some cases, the peptide epitope is a SARS-CoV-2 peptide from a SARS-CoV-2 -encoded membrane glycoprotein. In some cases, the peptide epitope is a SARS-CoV-2 peptide from a SARS-CoV-2 -encoded nucleocapsid phosphoprotein.

[0148] In some cases, a peptide present in a TEP is a SARS-CoV-2 peptide from a SARS-CoV-2 - encoded surface glycoprotein. Examples of such peptide epitopes are: NLTTRTQL (SEQ ID NO: 143), LPPAYTNSF (SEQ ID NO: 144), KVFRSSVLH (SEQ ID NO: 145), LPFFSNVTW (SEQ ID NO: 146), PFFSNVTWF (SEQ ID NO: 147), RFDNPVLPF (SEQ ID NO: 148), LPFNDGVYF (SEQ ID NO: 149), GVYFASTEK (SEQ ID NO: 150), TEKSNIIRGW (SEQ ID NO: 151), TLDSKTQSL (SEQ ID NO: 152), GVYYHKNNK (SEQ ID NO: 153), YYHKNNKSW (SEQ ID NO: 154), VYSSANNCTF (SEQ ID NO: 155), FEYVSQPFL (SEQ ID NO: 156), EYVSQPFLM (SEQ ID NO: 157), FVFKNIDGY (SEQ ID NO: 158), TPINLVRDL (SEQ ID NO: 159), LPQGFSAL (SEQ ID NO: 160), LPIGINITRF (SEQ ID NO: 161), INITRFQTL (SEQ ID NO: 162), LLALHRSYL (SEQ ID NO: 163), WTAGAAAYY (SEQ ID NO: 164), YYVGYLQPRTF (SEQ ID NO: 165), YLQPRTFLL (SEQ ID NO: 166), YLQPRTFL (SEQ ID NO: 167), SETKCTLKSF (SEQ ID NO: 168), TLKSFTVEK (SEQ ID NO: 169), QPTESIVRF (SEQ ID NO: 170), RFPNITNLCPF (SEQ ID NO: 171), GEVFNATRF (SEQ ID NO: 172), NATRFASVY (SEQ ID NO: 173), LYNSASFSTF (SEQ ID NO: 174), NSASFSTFK (SEQ ID NO: 175), RQIAPGQTGK (SEQ ID NO: 176), KIADYNYKL (SEQ ID NO: 177), NYNYLYRLF (SEQ ID NO: 178), RLFRKSNLK (SEQ ID NO: 179), KPFERDISTEI (SEQ ID NO: 180), YFPLQSYGF (SEQ ID NO: 181), QPYRVVVL (SEQ ID NO: 182), PYRVVVLSF (SEQ ID NO: 183). GPKKSTNLV (SEQ ID NO: 184), TSNQVAVLY (SEQ ID NO: 185), VYSTGSNVF (SEQ ID NO: 186). AEHVNNSY (SEQ ID NO: 187), IPIGAGICASY (SEQ ID NO: 188), SPRRARSVA (SEQ ID NO: 189), VASQSIIAY (SEQ ID NO: 190), SIIAYTMSL (SEQ ID NO: 191), LGAENSVAY (SEQ ID NO: 192), AYSNNSIAIPTNF (SEQ ID NO: 193), IPTNFTISV (SEQ ID NO: 194), TEILPVSMTK (SEQ ID NO: 195), QEVFAQVKQIY (SEQ ID NO: 196), KQIYKTPPIK (SEQ ID NO: 197), IYKTPPIKDF (SEQ ID NO: 198), LLFNKVTLA (SEQ ID NO: 199), TLADAGFIK (SEQ ID NO:200), LADAGFIKQY (SEQ ID NO:201), ADAGFIKQY (SEQ ID NO:202), VLPPLLTDEMIAQY (SEQ ID NO:203). IPFAMQMAY (SEQ ID NO:204).SSTASALGK (SEQ ID NO:205), VLNDILSRL (SEQ ID NO:206), RLDKVEAEV (SEQ ID NO:207), VEAEVQIDRL (SEQ ID NO:208), AEVQIDRLI (SEQ ID NO:209), LITGRLQSL (SEQ ID NO:210), RLQSLQTYV (SEQ ID NO:211), AEIRASANL (SEQ ID NO:212), ASANLAATK (SEQ ID NO:213), HLMSFPQSA (SEQ ID NO:214), FPQSAPHGVVF (SEQ ID NO:215), APHGVVFL (SEQ ID NO:216), VTYVPAQEK (SEQ ID NO:217), TYVPAQEKNF (SEQ ID NO:218), REGVFVSNGTHW (SEQ ID NO:219), GTHWFVTQR (SEQ ID NO:220), TVYDPLQPELDSFK (SEQ ID NO:221). KEIDRLNEV (SEQ ID NO:222), QELGKYEQYIKW (SEQ ID NO:223), YEQYIKWPW (SEQ ID NO:224), QYIKWPWYI (SEQ ID NO:225), FIAGLIAIV (SEQ ID NO:226), and SEPVLKGVKL (SEQ ID NO: 227).

[0149] In some cases, a peptide present in a TEP is a SARS-CoV-2 peptide from a SARS-CoV-2 - encoded membrane glycoprotein. Examples of such peptide epitopes are:: GTITVEELK (SEQ ID NO:228). EELKKLLEQW (SEQ ID NO:229), KLLEQWNLV (SEQ ID NO:230), FAYANRNRF (SEQID NO:231), YANRNRFLY (SEQ ID NO:232), SYFIASFRLF (SEQ ID NO:233), RLFARTRSM (SEQ ID NO:234), VPLHGTIL (SEQ ID NO:235), SELVIGAVIL (SEQ ID NO:236), HLRIAGHHL (SEQ ID NO:237), RIAGHHLGR (SEQ ID NO:238), KEITVATSRTL (SEQ ID NO:239), ATSRTLSYYK (SEQ ID NO:240), ASQRVAGDSGFAAY (SEQ ID NO:241), and VAGDSGFAAY (SEQ ID NO:242).

[0150] In some cases, the peptide epitope is a SARS-CoV-2 peptide from a SARS-CoV-2 -encoded nucleocapsid phosphoprotein. Examples of such peptide epitopes are: LPNNTASWF (SEQ ID NO:243), KFPRGQGVPI (SEQ ID NO:244), NTNSSPDDQIGYY (SEQ ID NO:245), SPRWYFYYL (SEQ ID NO:246), LLLDRLNQL (SEQ ID NO:247), KAYNVTQAF (SEQ ID NO:248), QELIRQGTDYKHW (SEQ ID NO:249), ASAFFGMSR (SEQ ID NO:250), SRIGMEVTPSGTW (SEQ ID NO:251), GMEVTPSGTWL (SEQ ID NO:252), TPSGTWLTY (SEQ ID NO:253). AYKTFPPTEPK (SEQ ID NO:254), and LPAADLDDF (SEQ ID NO:255).

[0151] In some cases, the peptide epitope is RLQSLQTYV (SEQ ID NO:256). In some cases, the peptide epitope is YLQPRTFLL (SEQ ID NO:257). In some cases, a TEP comprises an HLA-A*02:01 heavy chain polypeptide and comprises the peptide epitope YLQPRTFLL (SEQ ID NO:257).

[0152] In some cases, the peptide epitope is one that can be presented in a complex with a |32M polypeptide and an HLA-E polypeptide. As one non-limiting example, in some cases, the peptide epitope is a peptide of a SARS-CoV-2 Nspl3 polypeptide. In some cases, the peptide epitope is VMPLSAPTL (SEQ ID NO:258). In some cases, a TEP comprises an HLA-E heavy chain polypeptide and comprises the peptide epitope VMPLSAPTL (SEQ ID NO: 258).

[0153] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a CD 19 polypeptide present on the surface of a B cell; and comprises, as the epitope a SARS-CoV-2 peptide epitope.

[0154] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a BCMA polypeptide present on the surface of a B cell; and comprises, as the epitope a SARS-CoV-2 peptide epitope.

[0155] In some cases, a TEP of the present disclosure is a dual-targeting TEP that comprises two different BCTCs, e.g., a scFv or ananobody specific for CD19 and a scFv or a nanobody specific for BCMA. or a scFv or a nanobody specific for CD20 and a scFv or a nanobody specific for CD38; and comprises, as the epitope a SARS-CoV-2 peptide epitope.

[0156] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for one or more of the following proteins found on B cells, plasmablasts and / or plasma cells: CD20, CD21, CD40, CD38, CD79a, CD79b, CD138, and CD139, and comprises, as the epitope a SARS-CoV-2 peptide epitope.

[0157] Numerous additional SARS-CoV-2 peptide epitopes are disclosed in WO 2023 / 137156 to CueBiopharma, the disclosure of which as it relates to SARS-CoV-2 peptide epitopes is expressly incorporated herein by reference.C. HPV Peptide Epitopes

[0158] As noted above, a TEP can comprise an HPV peptide epitope. As used herein, the term “peptide epitope" means a peptide that can be bound to MHC polypeptides (e.g.. MHC class I polypeptides) and form a pMHC complex, such that the pMHC presents an epitope that can be specifically bound to a T- cell receptor (TCR) of a T cell.

[0159] In some cases, an HPV peptide suitable for inclusion in a pMHC polypeptide can be a peptide of an HPV E6 polypeptide or an HPV E7 polypeptide. The HPV epitope can be an epitope of HPV of any of a variety of genotypes, including, e.g., HPV16, HPV18, HPV31, HPV33, HPV35, HPV39. HPV45, HPV51. HPV52, HPV56, HPV58, HPV59, HPV68. HPV73, or HPV82. In some cases, the peptide is an HPV E6 peptide. In some cases, the peptide is an HPV E7 peptide. An amino acid sequence of an HPV16 E6 polypeptide is SEQ ID NO:259. An amino acid sequence of an HPV16 E7 polypeptide is SEQ ID NO:260. In some cases, an HPV peptide is a peptide of from 4-20 aa, e.g., 6-15 aa, 8-12 aa, 8-10 aa, 9-11 aa, 5-10 aa, 10-15 aa, or 15-20 aa in length of an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the HPV E6 amino acid sequence set forth in SEQ ID NO:259 or the HPV E7 amino acid sequence set forth in SEQ 1D NO:260.

[0160] Examples of HPV E6 peptides suitable for inclusion in a TEP include, but are not limited to, E6 18-26 (KLPQLCTEL; SEQ ID NO:261); E6 26-34 (LQTTIHDII; SEQ ID NO:262); E6 49-57 (VYDFAFRDL; SEQ ID NO:263); E6 52-60 (FAFRDLCIV; SEQ ID NO:264); E6 75-83 (KFYSKISEY; SEQ ID NO:265); and E6 80-88 (ISEYRHYCY; SEQ ID NO:266).

[0161] Examples of HPV E7 peptides suitable for inclusion in a TEP include, but are not limited to, E7 7-15 (TLHEYMLDL; SEQ ID NO:267); E7 11-19 (YMLDLQPET; SEQ ID NO:268); E7 11-20 (YMLDLQPETT; SEQ ID NO:269); E7 44-52 (QAEPDRAHY; SEQ ID NO:270); E7 49-57 (RAHYNIVTF (SEQ ID NO:271); E7 61-69 (CDSTLRLCV; SEQ ID NO:272); and E7 67-76 (LCVQSTHVDI; SEQ ID NO:273); E7 82-90 (LLMGTLGIV; SEQ ID NO:274); E7 86-93 (TLGIVCPI; SEQ ID NO:275); and E7 92-93 (LLMGTLGIVCPI; SEQ ID NO:276).

[0162] In some cases, a suitable HPV peptide for inclusion in a TEP is an HPV E6 peptide that binds HLA-A24 (e.g., is an HLA-A2401 -restricted epitope). Non-limiting examples include: VYDFAFRDL (SEQ ID NO:277) CYSLYGTTL (SEQ ID NO:278); EYRHYCYSL (SEQ ID NO:279); KLPQLCTEL (SEQ ID NO:280); DPQERPRKL (SEQ ID NO:281); HYCYSLYGT (SEQ ID NO:282); DFAFRDLCI (SEQ ID NO:283); LYGTTLEQQY (SEQ ID NO:284); HYCYSLYGTT (SEQ ID NO:285);EVYDFAFRDL (SEQ ID NO:286); EYRHYCYSLY SEQ ID NO:287); VYDFAFRDLC (SEQ ID NO:288); YCYSIYGTTL (SEQ ID NO:289); VYCKTVLEL (SEQ ID NO:290); VYGDTLEKL (SEQ ID NO:291); and LTNTGLYNLL (SEQ ID NO:292).

[0163] In some cases, a suitable HPV peptide for inclusion in a TEP is selected from the group consisting of: DLQPETTDL (SEQ ID NO:293); TLHEYMLDL (SEQ ID NO:294); TPTLHEYML (SEQ ID NO:295); RAHYNIVTF (SEQ ID NO:296); GTLGIVCPI (SEQ ID NO:297); EPDRAHYNI (SEQ ID NO:298); QLFLNTLSF (SEQ ID NO:299); FQQLFLNTL (SEQ ID N0:300); and AFQQLFLNTL (SEQ ID NO:301).

[0164] In some cases, a suitable HPV peptide presents an HLA-A*2401 -restricted epitope. Non-limiting examples of HPV peptides presenting an HLA-A*2401-restricted epitope include: VYDFAFRDL (SEQ ID NO:302); RAHYNIVTF (SEQ ID NO:303); CDSTLRLCV (SEQ ID NO:304); and LCVQSTHVDI (SEQ ID NO:305).

[0165] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a CD 19 polypeptide present on the surface of a B cell; and comprises, as the epitope an HPV peptide epitope.

[0166] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a BCMA polypeptide present on the surface of a B cell; and comprises, as the epitope an HPV peptide epitope.

[0167] In some cases, a TEP of the present disclosure is a dual -targeting TEP that comprises two different BCTCs, e.g., a scFv or ananobody specific for CD19 and a scFv or a nanobody specific for BCMA, or a scFv or a nanobody specific for CD20 and a scFv or a nanobody specific for CD38; and comprises, as the epitope an HPV peptide epitope.

[0168] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for one or more of the following proteins found on B cells, plasmablasts and / or plasma cells: CD20, CD21, CD40, CD38, CD79a, CD79b, CD138, and CD139, and compnses, as the epitope an HPV peptide epitope.D. Influenza Peptide Epitopes

[0169] Numerous publications have reported HLA-rcstrictcd peptides associated with influenza virus. See. e.g., Nicholas, et al., Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands, PLOS Pathogens. 2022; Jan, 18(1).Pederson, et al.. Immunogenicity of HLA Class I and II Double Restricted Influenza A-Derived Peptides, PLOS ONE 2016; (11)1, Habel, et al., and HLA-A* 1 l:01-restricted CD8+ T cell immunity against influenza A and influenza B viruses in Indigenous and non-Indigenous people, PLOS Pathogens, 2022 Mar.; 18(3), and Hogan, et al., Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cellresponse, Nature Immunology, 12 October 2023, published online at https: / / doi.org / 10.1038 / s41590-023- 01644-5, which describes the HLA-E restricted peptide SLQGRTLIL (SEQ ID NO: / / ) and mRNA vaccine capable of eliciting T cells that recognize that peptide presented by nonclassical MHC-Ib, in particular MHC-E (HLA-E in humans).

[0170] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a CD 19 polypeptide present on the surface of a B cell: and comprises, as the epitope an influenza peptide epitope.

[0171] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a BCMA poly peptide present on the surface of a B cell; and comprises, as the epitope an influenza peptide epitope.

[0172] In some cases, a TEP of the present disclosure is a dual-targeting TEP that comprises two different BCTCs, e.g., a scFv or a nanobody specific for CD 19 and a scFv or a nanobody specific for BCMA, or a scFv or a nanobody specific for CD20 and a scFv or a nanobody specific for CD38; and comprises, as the epitope an influenza peptide epitope.

[0173] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for one or more of the following proteins found on B cells, plasmablasts and / or plasma cells: CD20, CD21. CD40, CD38, CD79a, CD79b, CD138. and CD139, and comprises, as the epitope an influenza peptide epitope.E. Epstein-Barr Virus Peptide Epitopes

[0174] Numerous publications have reported HLA -restricted peptides associated with Epstein-Barr Virus (EBV). See, e.g., Vietzen, et al., HLA-E-restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD, Blood, March 30, 2023, 141(13): 1560-1573, reporting that EBV strains encoding for the specific LMP-1 peptide variants GGDPHLPTL or GGDPPLPTL, presented by HLA-E, elicit strong inhibitory NKG2A+ NK and CD8+T-cell responses. See also: Huisman, et al., Identification of Functional HLA-A*01 :01-Restricted Epstein-Barr Latent Membrane Protein 2- Specific T-Cell Receptors, . / . Infect Dis, 2022 Sep 1 : 226(5):833-842, reporting HLA-A*01 :01 restricted peptide for EBV; Jilek, et al., HLA-B7-Restricted EBV-Specific CD8+ T Cells Are Dysregulated in Multiple Sclerosis, J. Immunol (2012) 188 (9):4671-4680; and Zheng, et al., Human Leukocyte Antigen (HLA) A* 1101-Restricted Epstein-Barr Virus-Specific T-cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma, Cancer Immunology Research (2015) 3 (10): 1138-1147. One example of an HLA-A* 1101 restricted EBV epitope is IVTDFSVIK (SEQ ID NO:306). Examples of an HLA-A*02 restricted EBV epitopes are FLDKGTYTL(SEQ ID NO:307) and YLLEMLWRL(SEQ ID NO:308).

[0175] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a CD 19 polypeptide present on the surface of a B cell; and comprises, as the epitope an EBV peptide epitope.

[0176] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a BCMA polypeptide present on the surface of a B cell; and comprises, as the epitope an EBV peptide epitope.

[0177] In some cases, a TEP of the present disclosure is a dual -targeting TEP that comprises two different BCTCs, e.g., a scFv or ananobody specific for CD19 and a scFv or a nanobody specific for BCMA, or a scFv or a nanobody specific for CD20 and a scFv or a nanobody specific for CD38; and comprises, as the epitope an EBV peptide epitope.

[0178] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for one or more of the following proteins found on B cells, plasmablasts and / or plasma cells: CD20, CD21, CD40, CD38, CD79a, CD79b, CD138, and CD139, and comprises, as the epitope an EBV peptide epitope.F. Cancer Peptide Epitopes

[0179] As noted above, a pMHC can present an epitope of a cancer antigen such as a melanoma- associated antigen such as any one of the MAGE antigens, e.g., MAGE-A1, MAGE-A2, MAGE-A3 and MAGE-A4.

[0180] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a CD 19 polypeptide present on the surface of a B cell; and comprises, as the epitope a cancer-associated peptide epitope.

[0181] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for a BCMA polypeptide present on the surface of a B cell; and comprises, as the epitope a cancer-associated peptide epitope.

[0182] In some cases, a TEP of the present disclosure is a dual -targeting TEP that comprises two different BCTCs, e.g., a scFv or ananobody specific for CD 19 and a scFv or a nanobody specific for BCMA, or a scFv or a nanobody specific for CD20 and a scFv or a nanobody specific for CD38; and comprises, as the epitope a cancer-associated peptide epitope.

[0183] In some cases, a TEP of the present disclosure comprises, as the BCTC, a scFv or a nanobody specific for one or more of the following proteins found on B cells, plasmablasts and / or plasma cells: CD20, CD21, CD40, CD38, CD79a, CD79b, CD138, and CD139, and comprises, as the epitope a cancer-associated peptide epitope.G. Other Peptide Epitopes

[0184] As also noted above, a pMHC can present an epitope of any other target antigen, including antigens that can be provided via vaccination, e g., in a vaccine that provides antigenic peptides.SCAFFOLD POLYPEPTIDES

[0185] As noted above, a TEP typically comprises a scaffold polypeptide such as an Ig Fc polypeptide or a non-Ig Fc polypeptide.

[0186] An Ig Fc polypeptide of a TEP can be a human IgGl Fc, a human IgG2 Fc. a human IgG3 Fc, a human IgG4 Fc, etc., or a variant of a wild-type Ig Fc polypeptide. Variants include naturally occurring variants, non-naturally occurring variants, and combinations thereof. In some cases, for example, the Ig Fc can be a variant of a Fc polypeptide such as a human IgGl Fc, which variant has a reduced or substantially eliminated Fc-mediated effector function such as complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and / or antibody-dependent cellular phagocytosis (ADCP).

[0187] In some cases, e.g., where TEP comprises a heterodimer of first and second polypeptides, the Ig Fc may be at the C-terminus of the second polypeptide. In such cases, the Ig Fc polypeptide optionally does not comprise a C-terminal Lys.

[0188] In some cases, the Fc polypeptide present in a TEP is an IgGl Fc polypeptide, or a variant of an IgGl Fc polypeptide. For example, in some cases, the IgGl Fc polypeptide present in a TEP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%. at least 95%. at least 98%, at least 99%, or 100%, amino acid sequence identity to the following human IgGl Fc polypeptide amino acid sequence: DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RWSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTKNQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG (SEQ ID NO:309). Such IgGl Fc polypeptides may or may not comprise a C-terminal lysine.

[0189] In some cases, the Fc polypeptide present in a TEP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following human IgGl Fc polypeptide amino acid sequence: DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RWSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQWT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK (SEQ ID NO:310).

[0190] In some cases, the Ig Fc polypeptide present in a TEP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acidsequence identity to the Ig Fc polypeptide amino acid sequence set forth in SEQ ID NO: / / or SEQ ID NO: / / , where amino acid 14 is an Ala and amino acid 15 is an Ala. (As discussed below, substitutions of Ala for Leu at amino acids 14 and 15 are known as the "LA LA" mutations.) Tirus, in some cases, the Ig Fc polypeptide present in a TEP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%. at least 98%, at least 99%, or 100%, amino acid sequence identity to the following Ig Fc amino acid sequence:DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:311), where amino acid 14 is an Ala and amino acid 15 is an Ala. and where the Ig Fc omits a C-terminal Lys.

[0191] In some cases, the Ig Fc polypeptide present in a TEP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following Ig Fc amino acid sequence:DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:312), where amino acid 14 is an Ala and amino acid 15 is an Ala, and where the Ig Fc comprises a C-terminal Lys.B-CELL TARGETING COMPONENTS

[0192] In some embodiments, the BCTC is a polypeptide that binds to one or more target antigens on B cells, plasmablasts, and / or plasma cells. In some embodiments, the BCTC is a protein, typically an antibody or binding fragment thereof, that causes the TEP to non-specifically bind to binding partners found on both pathogenic and non-pathogenic B cells, plasmablasts, and / or plasma cells. For example, the BCTC can be an antibody or binding fragment thereof that binds to CD 19, CD20. CD21, CD40, BCMA, CD38, CD79a, CD79b, CD138 or CD139.

[0193] As noted above, in other embodiments, the BCTC is a protein that causes the TEP to specifically bind to a binding partner found substantially only on pathogenic B cells. TEPs comprising such BCTCs may be useful for treating autoimmune disorders for which there is a known, dominant autoantigen or for which there are only a few known, dominant autoantigens. In such embodiments, the TEP can effect a targeted, clonal deletion of substantially only pathogenic B cells. For example, as noted above the desmoglein proteins DSG1 and DGS3 are known, dominant autoantigens associated with various pemphigus disorders. For example, autoantibodies to DSG3 (and sometimes also DSG1) are known to be the cause of pemphigus disorders such as pemphigus vulgaris and pemphigus vegetans, andautoantibodies to DSG1 are known to be the associated with pemphigus disorders such as pemphigus erythematosus and pemphigus follaceus. Accordingly, DSG3 and DSG1, or antigenic portions thereof, can be BCTCs for TEPs useful for treating such pemphigus disorders. As discussed above, a TEP can have more than one BCTC and thus, for example, a TEP comprising both DSG3 and DSG1, or antigenic portions thereof, may be useful for treating pemphigus disorders such as pemphigus vulgaris, which can be associated with autoantibodies to both proteins. Similarly, autoantibodies against BP180 and BP230 are associated with bullous pemphigoid, and thus BP180 and BP230, or antigenic portions thereof, can be BCTCs. Other examples of autoantigens and their associated disorders are discussed below.

[0194] Where a TEP comprises more than one BCTC, the BCTCs may be the same or different. As noted above, for example, a TEP that comprises more than one BCTC can comprise (i) a first BCTC that is an antibody or fragment that binds to antigens expressed on many types of B cells, e.g.. CD 19 or CD20, and (ii) a second BCTC that binds to antigens expressed on plasmablasts and plasma cells, e.g., BCMA or CD38, which are expressed on plasma cells and plasmablasts, as well as memory B cells. In this way, the TEP potentially can substantially eliminate the patient’s B cells, plasmablasts and plasma cells. Alternatively, as mentioned above, a TEP can comprise more than one BCTC where the BCTCs are proteins, or antigenic portions of a protein, that are known, dominant autoantigens associated with an immune disorder. For example, a TEP comprising both DSG3 and DSG1, or antigenic portions thereof, may be useful for certain pemphigus disorders, or a TEP comprising both BP180 and BP230, or antigenic portions thereof, may be useful for bullous pemphigoid. Provided below are examples of some possible BCTCs.A. Anti-CDl 9 Antibodies

[0195] Anti-CD 19 antibodies are known in the art; and tire VH and VL, or the VH and VL CDRs, of any anti-CD19 antibody can be used in a TEP. See e.g., WO 2005 / 012493.

[0196] In some cases, an anti-CD19 antibody includes a VL CDR1 comprising the amino acid sequence KASQSVDYDGDSYLN (SEQ ID NO:313); a VL CDR2 comprising the amino acid sequence DASNLVS (SEQ ID NO:314); and a VL CDR3 comprising the amino acid sequence QQSTEDPWT (SEQ ID NO:315). In some cases, an anti-CD19 antibody includes a VH CDR1 comprising the amino acid sequence SYWMN (SEQ ID NO: 316); a VH CDR2 comprising the amino acid sequence QIWPGDGDTNYNGKFKG (SEQ ID NO:317); and a VH CDR3 comprising the amino acid sequence RETTTVGRYYYAMDY (SEQ ID NO:318). In some cases, an anti-CD19 antibody includes a VL CDR1 comprising the ammo acid sequence KASQSVDYDGDSYLN (SEQ ID NO:313); a VL CDR2 comprising the amino acid sequence DASNLVS (SEQ ID NO:314); a VL CDR3 comprising the amino acid sequence QQSTEDPWT (SEQ ID NO:315); a VH CDR1 comprising the amino acid sequence SYWMN (SEQ ID NO:316); a VH CDR2 comprising the amino acid sequenceQIWPGDGDTNYNGKFKG (SEQ ID N0:317); and a VH CDR3 comprising the amino acid sequence RETTTVGRYYYAMDY (SEQ ID NO:318).

[0197] In some cases, an anti-CD19 antibody is a scFv. For example, in some cases, an anti-CD19 scFv comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence:DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRF SGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIKGGGGSGGGGSGGGGSQVQ LQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFK GKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVS (SEQ ID NO:319).

[0198] In some cases, an anti-CD19 antibody is a scFv. For example, in some cases, an anti-CD19 scFv comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to either or both the Vn and VL amino acid sequences set forth in FIGS. 171 and 17J. In embodiments, these sequences may be joined by a peptide linker, e.g., a (GGGGS)n linker, where n=l-10, e g., n=2, n=3 or n=4, optionally where n=3.

[0199] In some cases, an anti-CD19 antibody is a scFv 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 the amino acid sequence set forth in FIG. 17K.B. Anti-BCMA Antibodies

[0200] Anti-BCMA (B-cell maturation antigen) antibodies are known in the art; and the VH and VL, or the VH and VL CDRs, of any anti-BCMA antibody can be used in a TEP. See, e.g., WO 2014 / 089335; US 2019 / 0153061; and WO 2017 / 093942.

[0201] In some cases, an anti-BCMA antibody comprises a) a light chain 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 the following amino acid sequence:

[0202] QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIFNYHQRPSGVP DRFSGSKSGSSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVLGQPKAAPSVTLFPP SSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPDSKQSNNKYAASSYLSLTPE QWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 320); and

[0203] b) a heavy chain 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 the following amino acid sequence: EVQLVESGGGLVKPGGSLRLSCAASGFTFGDYALSWFRQAPGKGLEWVGVSRSKAYGGTTDY AASVKGRFTISRDDSKSTAYLQMNSLKTEDTAVYYCASSGYSSGWTPFDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK (SEQ ID NO:321).

[0204] In some cases, an anti-BCMA antibody comprises a VL present in the light chain amino acid sequence provided above; and a VH present in the heavy chain amino acid sequence provided above. For example, an anti-BCMA antibody can comprise a) a VL 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 the amino acid sequence:

[0205] QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIFNYHQRPSGVP DRFSGSKSGSSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVLG (SEQ ID NO:322); and b) a VH 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 the amino acid sequence:

[0206] EVQLVESGGGLVKPGGSLRLSCAASGFTFGDYALSWFRQAPGKGLEWVGVSRSKAYG GTTDYAASVKGRFTISRDDSKSTAYLQMNSLKTEDTAVYYCASSGYSSGWTPFDYWGQGTLVT VSSASTKGPSV (SEQ ID NO:323).

[0207] In some cases, an anti-BCMA antibody comprises VL CDR1, VL CDR2, and VL CDR3 present in the light chain amino acid sequence provided above; and VH CDR1, CDR2, and CDR3 present in the heavy chain amino acid sequence provided above.

[0208] For example, an anti-BCMA antibody can comprise a VL CDR1 having the amino acid sequence SSNIGSNT (SEQ ID NO:324), a VL CDR2 having the amino acid sequence NYH. a VL CDR3 having the amino acid sequence AAWDDSLNGWV (SEQ ID NO:325), a VH CDR1 having the amino acid sequence GFTFGDYA (SEQ ID NO:326), a VH CDR2 having the amino acid sequence SRSKAYGGTT (SEQ ID NO:327), and a VH CDR3 having the amino acid sequence ASSGYSSGWTPFDY (SEQ ID NO:328).

[0209] An anti-BCMA antibody can be a scFv. As one non-limiting example, an anti-BCMA scFv can comprise the following amino acid sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYY NQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYNGYDVLDNWGQGTLVTVSSGG GGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKL LIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR (SEQ ID NO:329).

[0210] As another example, an anti-BCMA scFv can comprise the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRGGGGSGGGGSGGGGSGGGGSQ VQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYN QKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYNGYDVLDNWGQGTLVTVSS (SEQ ID NO:330).

[0211] In some cases, an anti-BCMA antibody can comprise a VL CDR1 having the amino acid sequence SASQDISNYLN (SEQ ID NO:331); a VL CDR2 having the amino acid sequence YTSNLHS (SEQ ID NO:332); a VL CDR3 having the amino acid sequence QQYRKLPWT (SEQ ID NO:333); a VH CDR1 having the amino acid sequence NYWMH (SEQ ID NO:334); a VH CDR2 having the amino acid sequence ATYRGHSDTYYNQKFKG (SEQ ID NO:335); and a VH CDR3 having the amino acid sequence GAIYNGYDVLDN (SEQ ID NO:336).

[0212] In some cases, an anti-BCMA antibody comprises a) a light chain 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 the following amino acid sequence:DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR (SEQ ID NO:337).

[0213] In some cases, an anti-BCMA antibody comprises a) a heavy chain 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 the following amino acid sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYY NQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS (SEQ ID NO:338).

[0214] In some cases, an anti-BCMA antibody (e.g., an antibody referred to in the literature as belantamab) comprises a light chain comprising the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR (SEQ ID NO:339); and a heavy chain comprising the amino acid sequence:QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYY NQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS (SEQ ID NO:340).C. Anti-CD20 Antibodies

[0215] Anti-CD20 antibodies are known in the art (e.g., rituximab, veltuzumab, obinutuzumab, 90Y- ibritumomab tiuxetan, and tositumomab), and the VH and VL, or the VH and VL CDRs, of any such anti-CD20 antibody can be used in a TEP.D. Anti-CD38 Antibodies

[0216] Anti-CD38 antibodies are known in the art (e.g., daratumumab and isatuximab), and the VH and VL, or the VH and VL CDRs, of any such anti-CD38 antibody can be used in a TEP.E. Autoantigens

[0217] As discussed above, BCTCs may comprise autoantigenic proteins, or antigenic portions thereof. Examples of autoantigens and their associated immune disorders include:• DSG1 and DSG3 (discussed above), which are associated with pemphigus disorders such as pemphigus vulgaris:• BP 180 and BP230, which are associated with bullous pemphigoid;• Insulin and Glutamic Acid Decarboxylase (GAD65), which are associated with type 1 diabetes;• Myeloperoxidase (MPO), which is associated with anti -neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly in a subtype called microscopic polyangiitis (MPA) ANCA-vasculitis, and also associated with multiple sclerosis and rheumatoid arthritis;• PR3 (Proteinase-3), which is associated with anti-neutrophil cytoplasmic antibody (ANCAs), specifically the c-ANCA subtype, which are often found in patients with granulomatosis with polyangiitis (GPA), an autoimmune vasculitis;• Aquaporin-4, which is associated with Neuromyelitis Optica (NMO) or Devic’s Disease;• Nicotinic acetylcholine receptor- 1 (nAChR-1), which is associated with Myasthenia Gravis;• Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), which are associated with multiple sclerosis (MS);• Myelin-Associated Glycoprotein (MAG) and Proteolipid Protein (PLP) are also autoantigens associated with MS;• Thyroglobulin, which is associated with Hashimoto’s thyroiditis:• Rheumatoid factor (RF), which is found in rheumatoid arthritis:• Ro / SSA and La / SSB, w'hich are associated with Sjogren's Syndrome and Systemic Lupus Erythematosus; as well as• Centromere Protein B (CENP-B), which are linked to Systemic Sclerosis.

[0218] Additional autoantigens are known. See, e.g., AAgAtlas, which catalogues human autoantigens and their associated diseases (extracted from biomedical literature), available at: https: / / pubmed.ncbi.nlm.nih.gov / 32162267 / IMMUNOMODULATORY POLYPEPTIDES

[0219] As noted above, a TEP optionally comprises one or more activating immunomodulatory polypeptides (“MODs”). In some cases, a MOD present in the TEP is a wild-type (“wt”) MOD. In other cases, a MOD present in a TEP is a variant of a wt MOD that has reduced affinity for a binding partner on a T cell (a “co-MOD”), including e.g.. reduced binding to one or more chains or domains of the co- MOD compared to the affinity of a corresponding wild-type MOD for the co-MOD. Suitable MODs that exhibit reduced affinity for a co-MOD can have from 1 amino acid (aa) to 20 aa differences from a wildtype MOD. For example, in some cases, a variant MOD present in a TEP 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 MOD. As another example, in some cases, a variant MOD present in a TEP 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 MOD. For example, a variant MOD present in a TEP may bind its co-MOD with an affinity that it at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, at least 75% less, at least 80% less, at least 85% less, at least 90% less, at least 95% less, or more than 95% less, than the affinity of a corresponding wild-type MOD for the co-MOD.

[0220] Exemplary pairs of activating MODs and their co-MODs include, but are not limited to those set out in Table 1, below:Table 1

[0221] Wild-type activating immunomodulatory polypeptides and variants, including reduced affinity variants, such as CD80, CD86, 4-1BBL and IL-2 are described in the published literature, e.g., published PCT application WO2020132138A1 and W02019 / 051091 (Cue Biopharma, Inc.), the disclosures of which as they pertain to MODs and specific variant MODs of CD80, CD86, 4-1BBL, IL-2 are expressly incorporated herein by reference, including specifically paragraphs

[0260] -

[0455] of WO2020132138A1 and paragraphs

[0157] -

[0352] of WO2019 / 051091.

[0222] Of interest are MODs that are variants of the cytokine IL-2. Wild-type IL-2 binds to IL-2 receptor (IL-2R) on the surface of a T cell. Wild-type IL-2 has a strong affinity for IL-2R and will bind to activate most or substantially all CD8+ T cells. For this reason, synthetic forms of wild type IL-2 such as the drag Aldesleukin (trade name Proleukin®) are known to have severe side-effects when administered to humans for the treatment of cancer because the IL-2 indiscriminately activates both target and non-target T cells.

[0223] An IL-2 receptor is in some cases a heterotrimeric polypeptide comprising an alpha chain (IL- 2Ra; also referred to as CD25), a beta chain (IL-2RP; also referred to as CD122: and a gamma chain (IL- 2Ry; also referred to as CD 132). Amino acid sequences of human IL-2, human IL-2Ra, IL2R0, and IL- 2Ry are known. See, e.g., published PCT applications WO2020132138A1 and W02019 / 051091, discussed above.

[0224] In some cases, an IL-2 variant MOD of this disclosure exhibits decreased binding to IL-2Ra. thereby minimizing or substantially reducing the activation of Tregs by the IL-2 variant. Alternatively, or additionally, in some cases, an IL-2 variant MOD of this disclosure exhibits decreased binding to IL- 2R and / or IL-2Ry such that the IL-2 variant MOD exhibits an overall reduced affinity for IL-2R. Insome cases, an IL-2 variant MOD of this disclosure exhibits both properties, i.e., it exhibits decreased or substantially no binding to IL-2Ra, and also exhibits decreased binding to I L-2 R[3 and / or IL-2Ry such that the IL-2 variant polypeptide exhibits an overall reduced affinity for IL-2R. For example, IL-2 variants having substitutions at H16 and F42 have shown decreased binding to IL-2Ra and IL-2R(3. See, Quayle et al., Clin Cancer Res; 26(8) April 15, 2020, which discloses that the binding affinity of an IL-2 polypeptide with H16A and F42A substitutions for human IL-2Ra and IL-2RP was decreased 110- and 3-fold, respectively, compared with wild-type IL2 binding, predominantly due to a faster off-rate for each of these interactions. TEPs comprising such variants, including variants that exhibit decreased binding to IL-2Ra and IL-2RB, can thus preferentially bind to and activate IL-2 receptors on T cells that contain the target TCR that is specific for the epitope presented by the pMHC of the TEP, and are thus less likely to deliver IL-2 to non-target T cells, i.e., T cells that do not contain a TCR that specifically binds the epitope presented by the pMHC of the TEP. That is, the binding of the IL-2 variant MOD to its costiniulatory polypeptide on the T cell achieves greater selectivity because the binding of the TEP is substantially driven by the binding of the MHC -epitope moiety rather than by the binding of the variant IL-2 polypeptide to IL-2R receptors on the T cell.

[0225] Suitable IL-2 variant MODs thus include a polypeptide that comprises an amino acid sequence having at least 90%, at least 95%. at least 97%, at least 98%, or at least 99% amino acid sequence identity to the wild-type IL-2 amino acid sequence:APTSSSTKKT QLQLEHLLLD LQM1LNG1NN YKNPKLTRML TFKFYMPKKA TELKHLQCLEEELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT (SEQ ID NO:341) and that have one or more amino acid differences from the above wild-type IL-2 amino acid sequence. In some cases, such a variant IL-2 polypeptide of this disclosure exhibits reduced binding affinity to IL- 2R, compared to the binding affinity of an IL-2 polypeptide comprising the wild-type IL-2 amino acid sequence when assayed under the same conditions. For example, in some cases, a variant IL-2 polypeptide binds IL-2R with a binding affinity that Is at least 10% less, at least 15% less, at least 20% less, at least 25%, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, at least 75% less, at least 80% less, at least 85% less, at least 90% less, at least 95% less, or more than 95% less, than the binding affinity of an IL-2 polypeptide comprising the wild-type IL-2 amino acid sequence:

[0226] Some exemplary combinations of mutations that reduce binding of an IL-2 variant polypeptide to IL-2Ra and IL-2R0 include the following from Table 2:Table 2

[0227] In some cases, a suitable variant IL-2 polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identityto the amino acid sequence: APTSSSTKKT QLQLEXiLLLD LQMILNGINN YKNPKLTRML TX2KFYMPKKA TELKHLQCLEEELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT (SEQ ID NO: 342), where Xi is an amino acid other than His, and where X2is an amino acid other than Phe. In some cases, a suitable variant IL-2 polypeptide comprises an amino acid sequence having at least 90%, at least 95%. at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence: APTSSSTKKT QLQLEXiLLLD LQMILNGINN YKNPKLTRML TX2I<FYMPI<I<A TELKHLQCLEEELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT (SEQ ID NO:343), where: i) Xi is Ala, Arg, Asn, Asp, Cys, Gin, Glu. Gly, He, Leu, Lys, Met, Phe, Pro, Ser. Thr, Trp, Tyr, or Vai; and ii) X2is Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, He, Leu, Lys, Met. Pro. Ser, Thr, Trp, Tyr, or Vai. In some cases. Xi is Ala and X2is Ala. In some cases. Xi is Thr and X2is Ala. In some cases, Xi is Asp and X2is Ala. In some cases, Xi is Glu and X2is Ala.

[0228] In some cases, a suitable variant IL-2 polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence: APTSSSTKKT QLQLEALLLD LQMILNGINN YKNPKLTRML TAKFYMPKKA TELKHLQCLEEELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT (SEQ ID NO:344). i.e., the variant IL-2 polypeptide has the amino acid sequence of wild-type IL-2 but with H16A and F42A substitutions (shown in bold). Alternatively, the foregoing sequence, but with substitutions other than Ala at H16 and / or F42 may be employed, e.g., H16T may be employed instead of H16A. In some cases, a variant IL-2 polypeptide present in a TEP comprises the amino acid sequence: APTSSSTKKT QLQLEALLLD LQMILNGINN YKNPKLTRML TAKFYMPKKA TELKHLQCLEEELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT (SEQ ID NO:345). In some cases, a variant IL-2 polypeptide present in a TEP comprises the amino acid sequence: APTSSSTKKT QLQLETLLLD LQMILNGINN YKNPKLTRML TAKFYMPKKA TELKHLQCLEEELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT (SEQ ID NO:346). In some cases, a TEP comprises two copies of such a variant IL-2 polypeptide. Where a TEP comprises two copies of a variant IL-2 polypeptide, in some cases, the two copies are in tandem. Where a TEP comprises two copies of a variant IL-2 polypeptide, and where the two copies are in tandem, in some cases, the TEP comprises a peptide linker between the two copies.LINKERS

[0229] A TEP of the present disclosure can include one or more peptide linkers interposed between any two components of the TEP. For example, one or more linkers may be interposed between one or more of: i) a peptide epitope and a 02M polypeptide; ii) an MHC class I heavy chain polypeptide and an Ig Fcpolypeptide; iii) an MHC class I heavy chain polypeptide and a BCTC; iv) an MHC class I heavy chain polypeptide and a MOD; v) an Ig Fc polypeptide and a MOD; vi) an Ig Fc polypeptide and a BCTC; vii) a BCTC and a MOD; and vii) where a TEP comprises two or more BCTCs and / or MODs in tandem, between the BCTCs and / or MODs. As used herein, the phrase an optional peptide linker between any two of the components of a TEP” refers to a peptide linker between any two adjacent polypeptides in a polypeptide chain of the TEP.

[0230] Linkers may be a flexible peptide linker, including a short flexible peptide linker, or a rigid peptide linker. Rigid linkers and short flexible peptide linkers may be used in TEPs when it is desired to minimize the interaction of different polypeptides of the TEP. Tire use of rigid linkers and / or short flexible peptide linkers can help maintain spatial separation between the polypeptides and thereby possibly impart improved stability and / or manufacturability to the TEP. Such linkers are disclosed in WO 2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to such linkers is expressly incorporated herein by reference, including specifically, but not limited to, paragraphs

[0188] -

[0196] .

[0231] As noted above, the linker between a peptide epitope and a 02M polypeptide may comprise a single Cys residue that can form a linker disulfide bond with a Cys in the MHC class I heavy chain polypeptide. Such Cys -containing linkers are disclosed in WO 2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to such peptide linkers is expressly incorporated herein by reference, including specifically, but not limited to, paragraphs

[0202] -

[0207] ,

[0232] In some cases, the Cys-containing peptide linker between the peptide and the 02M polypeptide comprises the amino acid sequence GCGGS (SEQ ID NO:347). hi some cases, the Cys-containing peptide linker between the peptide and the 02M polypeptide comprises the amino acid sequence GCGGS(GGGGS)n (SEQ ID NO:348). where n is 1, 2. 3, 4, 5, 6. 7, 8, 9, or 10; e.g., 1, 2. or 3. In some cases, the Cys-containing peptide linker between the peptide and the 02M polypeptide comprises the amino acid sequence GCGGS(GGGGS)n (SEQ ID NO:349), where n is 2.

[0233] In some cases, the Cys-containing peptide linker between the peptide and the 02M polypeptide comprises the amino acid sequence CGGGS (SEQ ID NO:350). In some cases, the Cys-containing peptide linker comprises the amino acid sequence CGGGS(GGGGS)n (SEQ ID NO:3 1), where n is 1. 2. 3, 4, 5, 6. 7, 8, 9. or 10; e.g., 1, 2. or 3.

[0234] In some cases, the Cys-containing peptide linker between the peptide and the 02M polypeptide comprises the amino acid sequence GGCGS (SEQ ID NO:352). In some cases, the Cys-containing peptide linker comprises the amino acid sequence GGCGS(GGGGS)n (SEQ ID NO:353), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, e.g., 1, 2, or 3.

[0235] In some cases, the Cys-containing peptide linker between the peptide and the 02M polypeptide comprises the amino acid sequence GGGCS (SEQ ID NO:354). In some cases, the Cys-containingpeptide linker comprises the amino acid sequence GGGCS(GGGGS)n (SEQ ID NO:355), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1, 2, or 3.

[0236] In some cases, the Cys-containing peptide linker between the peptide and the (32M polypeptide comprises the amino acid sequence GGGGC (SEQ ID NO:356). In some cases, the Cys-containing peptide linker comprises the amino acid sequence GGGGC(GGGGS)n (SEQ ID NO:357), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1, 2, or 3.

[0237] Where the TEP comprises a heterodimer, the Cys in the linker can form a disulfide bond with a Cys in the MHC class I heavy chain polypeptide in the second polypeptide. Where the TEP comprises a single-chain polypeptide, the Cys in the linker can form an intrachain disulfide bond with a Cys in the MHC class I heavy chain polypeptide, e.g., with a Cys at position 84 or a Cys at one of positions 135- 143, e.g., at position 139.MULTIMERS OF A TEP

[0238] As discussed above, a TEP can be a dimer of two TEPs. That is, the present disclosure provides a TEP comprising a dimer of two TEPs, which two TEPs can be the same or different. Because dimeric TEPs present two pMHCs to T cells, they can effect crosslinking upon engaging with the TCRs of a T cell, which can trigger intracellular signaling events within the T cell and lead to T cell activation. The covalent linkage of the dimer can be one or more (typically two) disulfide bonds between an Ig Fc polypeptide in the first TEP and an Ig Fc polypeptide in the second TEP. When tire TEP comprises an Ig Fc polypeptide, e.g., an IgGl Fc polypeptide, the TEP typically will self-assemble into a dimer by spontaneously forming one or more (typically two) disulfide bonds with the Ig Fc polypeptide of another TEP. In many cases, the two TEPs will be identical to one another in amino acid sequence and comprise Ig Fc polypeptides that spontaneously form two disulfide bonds, thereby forming a TEP that is a homodimer. Alternatively, the dimeric TEP may comprise two different TEPs. In such case, the Ig Fc polypeptides of each TEP can comprise interspecific dimerization sequences, e.g., ’Knob-in-Holc" sequences that permit the two different TEPs to selectively dimerize. Such interspecific dimerization sequences are disclosed in WO 2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to interspecific dimerization sequences (including but not limited to paragraphs

[0212] -

[0213] ) is expressly incorporated herein by reference. Interspecific dimerization sequences also may be employed to enable TEPs to be linked to non-TEP molecules that can provide additional functionality to the TEP.

[0239] Where the dimeric TEP comprises two different TEPs, the two TEPS may be of any configuration, e.g., one TEP can comprise a single-chain pMHC and the other can comprise a heterodimeric pMHC. As another example, a dimeric TEP can comprise a first TEP that comprises a single-chain pMHC that has a single intrachain disulfide bond (e.g., a body disulfide) and a second TEPthat comprises a single-chain pMHC that has two intrachain disulfide bonds (e.g., both a body disulfide and a linker disulfide). As another example, a dimeric TEP can comprise a first TEP that comprises a heterodimeric or single-chain pMEIC that has a linker disulfide bond that joins a Cys-containing linker to a Y84C amino acid in the MHC heavy chain polypeptide and a second TEP that comprises a heterodimeric or single-chain pMHC that has a linker disulfide bond that joins a Cys-containing linker to an A139C amino acid in the MHC heavy chain polypeptide. As another example, the first TEP can comprise one BCTC (e.g., an anti-CD19 scFv), and the second TEP can comprise a different BCTC (e.g., an anti-BCMA scFv). As another example, the first TEP can comprise one peptide epitope (e.g., a CMV epitope), and the second TEP can comprise a different peptide epitope (e.g., a SARS-CoV-2 epitope). As another example, the first TEP can comprise one BCTC and peptide epitope, and the second TEP can comprise a different BCTC and a different peptide epitope.

[0240] It should be understood that references to TEPs in the sections that follow expressly include dimeric TEPs.FORMULATIONS, DOSAGES, AND ROUTES OF ADMINISTRATION OF THE TEP

[0241] A composition can comprise, in addition to a TEP, one or more pharmaceutically acceptable additives, a variety of which are known in the art and need not be discussed in detail herein. See, for example, the ninth (or latest) edition of Sheskey et al., “Handbook of Pharmaceutical Excipients” (2020), and / or the 23rd(or latest) edition of “Remington: The Science and Practice of Pharmacy”. 23rd Ed. (2020).

[0242] Where a TEP is administered as an injectable (e.g. subcutaneously, intraperitoneally, intramuscularly, and / or intravenously) directly into a tissue or vessel, a formulation can be provided as a ready-to-use dosage form that may be directly injected or infused into the patient or admixed with a saline solution for infusion, or possibly as a non-aqueous form (e.g., a reconstitutable storage -stable powder) or aqueous form, such as liquid composed of pharmaceutically acceptable carriers and excipients. Formulations may also be provided so as to enhance serum half-life of the TEP following administration. For example, the TEP may be provided in a liposome formulation, prepared as a colloid, or other conventional techniques for extending serum half-life. Tire preparations may also be provided in controlled release or slow-rclcasc fonns.

[0243] Tire concentration of a TEP in a liquid composition formulation can vary widely (e.g., from less than about 0.1% to at least about 2% to as much as 20% to 50% or more by weight). Included within this range is a concentration of from about 5 to about 15 mg / mL, from about 8 to about 12 mg / mL, from about 9 to about 11 mg / mL, including about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL,about 14 mg / mL and about 1 mg / mL. The concentration may depend on numerous factors, including the stability of the TEP in the liquid composition.

[0244] In some cases, a TEP is present in a liquid composition. In some cases, a composition comprises: a) a TEP; and b) saline (e.g.. 0.9% NaCl). In some cases, the composition is sterile and suitable for administration to a human subject.

[0245] In some cases, mRNA, DNA, or a recombinant expression vector comprising one or more nucleic acids encoding a TEP (or a cell, e.g., a B cell or other blood cell such as a red blood cell comprising such nucleic acids or recombinant expression vector) may be administered to induce in vivo expression of the TEP instead of directly administering the TEP itself to a patient. When nucleic acids are employed (e.g., mRNA or DNA), they may be fonnulated for delivery’ using known methods. For example, mRNA can be delivered using known lipid nanoparticle technology. DNA can be delivered using known viral and non-viral methods.

[0246] A suitable dose of a TEP can be determined by an attending physician or other qualified medical personnel, based on various clinical factors. As is well known in the medical arts, dosages for any one patient depend upon many factors, including the patient's size, body surface area, age, the particular TEP or nucleic acid to be administered (including the number and type of MOD(s). if present in the TEP). sex of the patient, time, and route of administration, general health, and other drugs being administered concurrently. A pharmaceutical composition comprising a TEP may be administered in amounts between 0.01 mg / kg body weight and 20 mg / kg body weight per dose, e.g. between 0.1 mg / kg body weight to 10 mg / kg body weight, e.g., from 0.5 mg / kg to 1 mg / kg, from 0.5 mg / kg body weight to 5 mg / kg body weight, from 1 mg / kg body weight to 5 mg / kg body weight; from 5 mg / kg body weight to 10 mg / kg body weight; from 10 mg / kg body weight to 15 mg / kg body weight; from 1 mg / kg body weight to 20 mg / kg body weight, however, doses above this exemplary range are envisioned, especially considering the aforementioned factors. If the regimen is a continuous infusion, it can also be in the range of 1 pg to 10 mg per kilogram of body weight per minute.

[0247] Alternatively, a patient may simply be administered a flat amount of a TEP, e.g., in an amount of from 1 mg to 1500 mg, including from 50 to 1000 mg, from 100 to 800 mg, from 200 mg to 600 mg or more, including from 250 mg to 450 mg. from 250 mg to 350 mg, from 450 mg to 600 mg, including specific amounts of 250 mg, 300 mg. 350 mg, 400 mg, 500 mg. or 600 mg or more.

[0248] Persons of ordinary skill in the art can readily estimate repetition rates for dosing based on measured residence times and concentrations of the administered agent in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein a TEP or dimerized TEP is administered in maintenance doses, wherein the maintenance dose level may be different from the dose level used during the treatment phase.

[0249] Those of skill will readily appreciate that dose levels can vary as a function of the specific TEP, the severity of the symptoms and the susceptibility of the subject to side effects. Appropriate dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[0250] In certain embodiments, one or multiple doses of a TEP, a nucleic acid (e.g., mRNA), or a recombinant expression vector (or a cell, e.g., a B cell or other blood cell such as a red blood cell comprising a nucleic acid or recombinant expression vector) are administered. The frequency and duration of administration can vary depending on any of a variety of factors, e.g., severity of unwanted side effects, recurrence of symptoms. For some disorders, one or only a few treatments may be required to effect a therapeutically sufficient depletion of the patient’s B cells, especially in the case of delivery of nucleic acids (mRNA or DNA) encoding the TEP, which can provide a prolonged, in vivo production of the TEP. Additional treatments will depend on recurrence of symptoms for the particular disorder being treated. For some chronic disorders such a GVHD, HVGD, allergies and transplant rejection, periodic treatments may be required to maintain a reduction in tire number of B cells compared to the pretreatment level of B cells, where the reduction is greater than 10%, greater than 20% greater than 30% greater than 40% greater than 50%, greater than 60%. greater than 70%, greater than 80% or greater than 90%, greater than 95%. greater than 98%. or greater than 99%. Periodic treatments can be once per week (qw), once every two weeks, once every three weeks, or once every four weeks, once every month, every two months, every three months, and so on depending on the above factors.DISORDERS SUITABLE FOR TREATMENT

[0251] Disorders that can be treated with a method or composition of this disclosure include autoimmune disorders, immune-mediated inflammation disorders and other B-cell mediated immune disorders. Such disorders include but are not limited to Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune-associated infertility, autoimmune thrombocytopenic purpura (aka, idiopathic thrombocytopenia purpura), bullous pemphigoid, Goodpasture's syndrome, glomerulonephritis (e.g., crescentic glomerulonephritis, proliferative glomerulonephritis), Grave's disease, idiopathic inflammatory myositis, Hashimoto's thyroiditis, a mixed connective tissue disease, systemic sclerosis, multiple sclerosis, Chronic inflammatory demyelinating polyradiculoneuropathy, neuromyelitis optica (NMO) myasthenia gravis (MG), pemphigus (e g., pemphigus vulgaris), pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus (SLE), autoimmune vasculitis, including types of ANCA-vasculitis (e.g., Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA)), celiac disease, type 1 diabetes (T1D). vitiligo,antiphospholipid syndrome, Type-2 diabetes, periodontal disease, pulmonary arterial hypertension (PAH), preeclampsia, dilated cardiomyopathy, discoid lupus, palmoplantar pustulosis, Chagas' disease, Evan's syndrome, autoimmune hypoglycemia, anti-NMDA receptor encephalitis, Anti-CASPR encephalitis, glomerulonephritis associated with SLE), Guillain-Barre disease, autoimmune autonomic ganglionopathy (AAG). autoimmune diseases of specific organs (myocarditis, oophoritis, pancreatitis, gastritis, hepatitis, testicular autoimmunity), inflammatory bowel diseases (including ulcerative colitis, Crohn’s disease and irritable bowel syndrome), acute or chronic graft versus host disease (GVHD), acute, hyperacute or chronic host versus graft disease (HVGD), transplant rejection, eczema (atopic dermatitis), or allergies and allergic reactions to insect venom, peanuts, tree nuts, shellfish, infections, medications such as penicillin, airborne allergens such as pollen, dust mites and pet dander, and allergies that can trigger eczema.METHODS OF TREATMENT

[0252] Methods of treatment comprise administering to a patient having an above-described autoimmune disorder, immune-mediated inflammation disorder or other B-cell mediated immune disorder, a therapeutically effective amount of a pharmaceutical composition comprising (i) a TEP or (ii) a nucleic acid (e.g., DNA or mRNA), recombinant expression vector or other composition that causes in vivo production of the TEP to cause a reduction of, or a substantially complete elimination of, the patient’s B cells, or a reduction of, or a substantially complete elimination of. the patient’s pathogenic B cells. For some disorders such as GVHD. HVGD, transplant rejection, and allergies, where the onset of symptoms is expected, the TEP can be prophylactically administered to reduce or substantially prevent the onset of symptoms associated with the disorder. The amount, duration and frequency of administration, as well as any maintenance administration can be determined by a qualified healthcare provider.

[0253] As mentioned above, methods of treating can include vaccination prior to administration of the TEP. The vaccination will be to elicit / expand the patient’s repertoire of T cells having TCRs specific for the pMHC of the TEP, thereby ensuring that the patient will have an available repertoire of T cells for B-cell depletion. A vaccine typically can be administered from one to four weeks prior to administration of the TEP. In instances where a patient has previously received a vaccine that elicits T cells having TCRs specific for the pMHC of the TEP, it may be desirable to give the patient a booster of the vaccine to ensure a higher titer of T cells that will recognize and bind to the pMHC of the TEP. In the event that the duration of treatment is prolonged, it may be advantageous to re-administer the vaccine to increase the patient’s T cells specific for the TEP.EXAMPLES OF NON-LIMITING ASPECTS OF THE DISCLOSURE

[0254] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below.Aspect Section A

[0255] 1. A method of treating an individual to deplete autorcactivc B cells, the method comprising administering to the individual a therapeutic amount of a T cell engaging protein (“TEP”), wherein the TEP comprises: i) a peptide-major histocompatibility complex ("pMHC”) comprising a peptide epitope, a (32- microglobulin (“|32M”) polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig”) Fc polypeptide; iii) at least one B-cell targeting component; and iv) optionally one or more activating immunomodulatory polypeptides, wherein each of the at least one B-cell targeting components of the TEP binds to a B cell binding partner on a B cell, a plasmablast, and / or a plasma cell.

[0256] 2. The method of aspect 1, wherein the at least one B-cell targeting component comprises:(i) an antibody or antigen-binding portion of an antibody that binds to a binding partner on a B cell, a plasmablast, and / or a plasma cell, and / or(ii) an autoantigen or antigenic portion of an autoantigen.

[0257] 3. The method of aspect 2, wherein the at least one B-cell targeting component comprises:(i) an antibody or antigen-binding portion of an antibody that binds to CD 19, CD20, CD21, CD40, B cell maturation antigen (BCMA), CD38, CD79a, CD79b, CD138, and / or CD139; and / or(ii) an autoantigen or antigenic portion of an autoantigen selected from desmoglein (DSG) proteins (including DSG1 and DSG3), BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO), PR3 (Proteinase-3), aquaporin-4, nicotinic acetylcholine receptor- 1 (nAChR-1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG), Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

[0258] 4. The method of any one of aspects 1-3, wherein the Ig Fc polypeptide is an IgGlFc polypeptide, IgG2 Fc polypeptide, IgG3 Fc polypeptide, or IgG4 polypeptide, optionally wherein the Ig Fc polypeptide is an IgGl Fc polypeptide, and optionally wherein the Ig Fc polypeptide is a variant having one or more substitutions that reduce or substantially eliminate effector function.

[0259] 5. The method of aspect 4, wherein the Ig Fc polypeptide is an IgGl Fc polypeptide having one or more substitutions that reduce or substantially eliminate effector function, optionally wherein tire Ig Fc polypeptide does not include a C -terminal Lys present in a wild-type Ig Fc polypeptide variant.

[0260] 6. The method of any one of aspects 1-5, wherein the pMHC presents an epitope of a pathogen-infected cell, optionally wherein the pMHC presents an epitope of a virus-infected cell or a bacteria-infected cell.

[0261] 7. The method of aspect 6, wherein the pMHC presents an epitope of a cell infected with a virus selected from CMV, influenza, EBV or SARS-CoV2, optionally wherein the pMHC comprises the CMV peptide NLVPMVATV (SEQ ID NO: 141) or the SARS-CoV-2 peptide YLQPRTFLL (SEQ ID NO: 166).

[0262] 8. The method of any one of aspects 1-7, wherein the MHC class I heavy chain is anHLA-A allele heavy chain polypeptide, optionally wherein the HLA-A allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-A amino acid sequence depicted in in any one of FIGS. 7A-7E, 8A- 8E, 9A-9E, 10A-10E. l lA-HE and 12A-12D.

[0263] 9. The method of any one of aspects 1-7, wherein the MHC class I heavy chain is anHLA-B allele heavy chain polypeptide, optionally wherein the HLA-B allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-B amino acid sequence depicted in figs. 13A-13D.

[0264] 10. The method of any one of aspects 1-7, wherein the MHC class I heavy chain is anHLA-C allele heavy chain polypeptide, optionally wherein the HLA-C allele heavy chain polypeptidecomprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-C amino acid sequence depicted in FIGS. 14A-14D.

[0265] 11. The method of any one of aspects 1-7, wherein the MHC class I heavy chain is anHLA-E allele heavy chain polypeptide, optionally wherein the HLA-E allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-E amino acid sequence depicted in FIGS. 15A-15D or 16A-16D.

[0266] 12. The method of any one of aspects 1-11, wherein the 02M polypeptide, wherein the02M polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to 21-119 of any one of the amino acid sequences set forth in SEQ ID NOs: 1-3.

[0267] 13. The method of any one of aspect 1-12, wherein at least one of the optional one or more activating immunomodulatory’ polypeptides are selected from a cytokine, a 4-1BBL polypeptide, an ICOS-L polypeptide, an OX-40L polypeptide, a CD80 polypeptide, a CD86 polypeptide, a CD40 polypeptide, a CD70 polypeptide, and combinations thereof.

[0268] 14. The method of aspect 13. wherein the cytokine is an IL-2 polypeptide, and wherein the IL-2 polypeptide is a variant IL-2 polypeptide that exhibits reduced affinity to an IL-2 receptor compared to the affinity of a wild-type IL-2 polypeptide for the IL-2 receptor.

[0269] 15. The method of aspect 14. wherein the variant IL-2 polypeptide has at least 90%, at least 95%, at least 97%. at least 98%. at least 99%, or 100% amino acid sequence identity to the wildtype IL-2 amino acid sequence, and wherein amino acid 16 of the variant IL-2 polypeptide is other than histidine and amino acid 42 is other than phenylalanine, optionally wherein amino acid 16 is Ala, Thr, Asp or Glu and wherein amino acid 42 is Ala, and optionally wherein amino acid 16 is Ala and wherein amino acid 42 is Ala.

[0270] 16. The method of aspect 14 or 15, wherein the TEP comprises two variant IL-2 poly peptides in tandem, optionally connected by a linker.

[0271] 17. The method of any one of aspects 1-16, wherein the TEP comprises a heterodimer, wherein the heterodimer comprises: a) a first polypeptide comprising: i) the peptide; and ii) the 02-microglobulin (02M) polypeptide; and b) a second polypeptide comprising:i) the MHC class I heavy chain polypeptide; and ii) the immunoglobulin (Ig) Fc polypeptide; iii) the at least one B-cell targeting component; and iv) the optional one or more activating immunomodulatory polypeptides, optionally wherein the TEP comprises one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0272] 18. The method of aspect 17. wherein the heterodimer comprises a disulfide bond formed between a Cys residue in the 02M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.

[0273] 19. The method of aspect 17 or 18. wherein the heterodimer comprises a disulfide bond formed between (i) a Cys residue in a Cys-containing linker interposed between the peptide and the 02M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0274] 20. Hie method of aspect 17. wherein the first polypeptide and the second polypeptide are covalently linked to one another by at least a first and second disulfide bond, wherein the first disulfide bond formed between (i) a Cys residue in a Cys-containing linker between the peptide epitope and the 02M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide; and wherein the second disulfide bond is fomied between a Cys residue in the 02M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.

[0275] 21. The method of any one of aspects 17-20, wherein a) the first polypeptide of each heterodimer comprises, in order from N-tenninus to C-terminus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids; ii) a peptide linker; and iii) the [32M polypeptide; b) the second polypeptide of each heterodimer comprises, in order from N-tenninus to C- terminus: i) the optional one or more activating immunomodulatory polypeptides; ii) the MHC class I heavy chain polypeptide; iii) the Ig Fc polypeptide; and iv) the at least one B-cell targeting component, andwherein the second polypeptide optionally comprises independently selected peptide linkers between one or more components of the second polypeptide.

[0276] 22. The method of any one of aspects 17-20. wherein a) the first polypeptide of each heterodimer comprises, in order from N-terminus to C-terminus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids; ii) a peptide linker; and iii) the 02M polypeptide; b) the second polypeptide of each heterodimer comprises, in order from N-terminus to C- terminus: i) the at least one B-cell targeting component; ii) the MHC class I heavy chain polypeptide; and iii) the Ig Fc polypeptide; and wherein the optional one or more activating immunomodulatory polypeptides, if present, may be positioned (i) between tire at least one B-cell targeting component and MHC class I heavy chain polypeptide, (ii) between the MHC class I heavy chain polypeptide and Ig Fc polypeptide, or (iii) at the C terminus of the Ig Fc polypeptide, and wherein the second polypeptide optionally comprises independently selected peptide linkers between one or more components of the second polypeptide.

[0277] 23. The method of any one of aspects 17-22, wherein: i) the 02M polypeptide comprises a Cys at amino acid 12 based on the amino acid numbering of SEQ ID NO: 1; and ii) the MHC class I polypeptide comprises a Cys at residue 236 based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A, and wherein each heterodimer comprises a disulfide bond linking the first polypeptide to the second polypeptide, and wherein the disulfide bond joins the Cys at amino acid 12 of the 02 M polypeptide to the Cys at amino acid 236 of the MHC heavy chain polypeptide, optionally wherein the heterodimer comprises a second disulfide bond formed between (i) a Cys residue in a Cys-containing linker between the peptide and the 02M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0278] 24. The method of any one of aspects 17-23, wherein the TEP comprises a dimer of two heterodimeric TEPs.

[0279] 25. The method of aspect 24. wherein the first polypeptides of each heterodimer have the same amino acid sequence, and the second polypeptide of each heterodimer have the same aminoacid sequences, and wherein the two heterodimers are joined together by one or more disulfide bonds (e.g., two disulfide bonds) formed between the Ig Fc polypeptides of each heterodimer, optionally wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO:90. and the second polypeptide comprises the amino acid sequence of SEQ ID NO:89 or the first polypeptide comprises the amino acid sequence of SEQ ID NO:91, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:89.

[0280] 26. The method of aspect 24. wherein the second polypeptides of each heterodimer have a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second heterodimers comprise interspecific dimerization sequences, optionally wherein the interspecific dimerization sequences are "Knob-in-Holc" sequences that permit the two heterodimers to selectively dimerize.

[0281] 27. The method of aspect 26. wherein(i) the first and second heterodimeric TEPs comprise BCTCs that target different B cell antigens (e.g., different antigens selected from CD19, CD20, CD21, CD40, BCMA, CD38, CD79a, CD79b, CD138, and CD139), wherein the TEP is capable of binding to each target antigen individually and / or simultaneously binding to both target antigens, optionally wherein the different BCTCs comprise a BCTC that targets B cells (e.g., the BCTC targets CD19 or CD20), and a BCTC that targets plasmablasts and plasma cells (e.g., the BCTC targets BCMA or CD38), and / or(ii) the first and second heterodimers comprise different peptide epitopes, optionally wherein the different peptide epitopes comprise a CMV peptide epitope (e.g., NLVPMVATV, SEQ ID NO: 141), a SARS-CoV-2 peptide epitope (e.g., YLQPRTFLL, SEQ ID NO: 166), and / or an EBV peptide epitope.

[0282] 28. The method of aspect 27, wherein one heterodimer comprises a BCTC that targetsCD 19 and the other heterodimer comprises a BCTC that targets BCMA, optionally wherein one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, orone heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360.

[0283] 29. The method of any one of aspects 1-16, wherein the TEP comprises a single-chain polypeptide, and wherein the single-chain polypeptide comprises, from the N-tenninal to C-terminal direction: i) the peptide: ii) the 02M polypeptide; iii) the class I HLA heavy chain polypeptide; iv) the immunoglobulin (Ig) Fc polypeptide; v) the at least one B-cell targeting component; and vi) the optional one or more activating immunomodulatory polypeptides, optionally wherein the TEP comprises one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0284] 30. The method of aspect 29. wherein the TEP comprises a Cys-containing peptide linker between the peptide and the 02M polypeptide, and wherein the TEP comprises an intrachain disulfide bond between the Cys in the Cys-containing peptide linker and a Cys in the class I HLA heavy chain polypeptide.

[0285] 31. The method of aspect 30. wherein the class I HLA heavy chain polypeptide comprises a Cys at any one of amino acids 135-143, based on the numbering ofthe class I HLA heavy chain polypeptide depicted in FIG. 7A, and wherein amino acid 84, based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A, is other than Cys; and wherein the TEP comprises an intrachain disulfide bond between tire Cys present in the Cys- containing peptide linker and the Cys at any one of amino acids 135-143 of the class I HLA heavy chain polypeptide.

[0286] 32. The method of aspect 31, wherein the class I HLA heavy chain polypeptide comprises a Cys at amino acid 138, 139, or 140 based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A, optionally wherein the class I HLA heavy chain polypeptide comprisesa Cys at amino acid 139 based on the numbering of the class I HLA heavy chain polypeptide depicted inFIG. 7A.

[0287] 33. The method of aspect 30. wherein the TEP comprises an intrachain disulfide bond between the Cys present in the Cys-containing peptide linker and the Cys at amino acid 84 of the class I HLA polypeptide.

[0288] 34. The method of any one of aspects 29-33, wherein the peptide linker between the peptide and the (32M polypeptide comprises the sequence CGGGS(GGGGS)n (SEQ ID NO:351). GCGGS(GGGGS)n (SEQ ID NO:348), or GGCGS(GGGGS)n (SEQ ID NO:353), wherein n is an integer from 1-10, optionally wherein n is an integer from 1-3.

[0289] 35. The method of any one of aspects 29-34, wherein the |32M polypeptide comprises a Cys at amino acid 12, wherein tire class I HLA heavy chain polypeptide comprises a Cys at amino acid 236, and wherein the TEP comprises a disulfide bond formed between the Cys at amino acid 12 of the (32M polypeptide and the Cys at amino acid 236 of the class I HLA heavy chain polypeptide.

[0290] 36. The method of any one of aspects 29-35. wherein the TEP comprises a dimer of two single-chain TEPs.

[0291] 37 Hie method of aspect 36. wherein the first and second single-chain TEPs have the same amino acid sequence, and wherein the two single-chain TEPs are joined together by one or more disulfide bonds formed between the 1g Fc polypeptides of each single-chain TEP. optionally wherein the two single-chain TEPs are joined together by two disulfide bonds formed between the Ig Fc polypeptides of each single-chain TEP.

[0292] 38. The method of aspect 36. wherein each single-chain TEP has a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second single-chain TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two singlechain TEPs to selectively dimerize.

[0293] 39. The method of aspect 38, wherein(i) the first and second single-chain TEPs comprise BCTCs that target different B cell antigens (e.g., different antigens selected from CD19, CD20. CD21, CD40, BCMA, CD38, CD79a, CD79b, CD138, and CD139), wherein the TEP is able to bind to each target B cell antigen separately and / or simultaneously, optionally wherein the different BCTCs comprise a BCTC that targets B cells (e.g., the BCTC targets CD19 or CD20), and a BCTC that targets plasmablasts and plasma cells (e.g., the BCTC targets BCMA or CD38), and / or(ii) the first and second single-chain TEPs comprise different peptide epitopes, optionally wherein tire different peptide epitopes comprise a CMV peptide (e.g., NLVPMVATV, SEQ ID NO: 141), a SARS-CoV-2 peptide (e.g., YLQPRTFLL, SEQ ID NO: 166), and / or an EBV peptide epitope.

[0294] 40. The method of any one of aspects 1-16, wherein the TEP comprises a chemical conjugation site, wherein the peptide of the pMHC is chemically conjugated to the TEP through the chemical conjugation site, and wherein the peptide is positioned in the pMHC for presentation to a cell bearing a T-cell receptor specific for the epitope presented by the pMHC.

[0295] 41. The method of aspect 40, wherein the chemical conjugation site is present in the[32M polypeptide or MHC class I heavy chain polypeptide.

[0296] 42. The method of aspect 41 or 42. wherein the TEP presents an epitope associated with a viral infection.

[0297] 43. The method of aspect 42, wherein the viral epitope is an epitope of influenza,CMV, SARS-Cov-2 or EBV, optionally wherein the CMV peptide epitope is NLVPMVATV (SEQ ID NO: 141) or the SARS-CoV-2 peptide epitope is YLQPRTFLL (SEQ ID NO: 166).

[0298] 44. The method of any one of aspects 40-43, wherein the chemical conjugation site is present in the [32M polypeptide.

[0299] 45. The method of aspect 44, wherein the chemical conjugation site is a cysteine present in the [32M polypeptide.

[0300] 46. The method of aspect 45. wherein the peptide is conjugated to the TEP by the reaction of a maleimide group and the cysteine of the chemical conjugation site.

[0301] 47. The method of any one of aspects 40-46, wherein the TEP comprises a heterodimer, wherein the heterodimer comprises: a) a first polypeptide comprising the (32M polypeptide; b) a second polypeptide comprising,(i) the MHC class I heavy chain polypeptide;(ii) the Ig Fc polypeptide;(iii) the at least one B-cell targeting component; and(iv) the optional one or more activating immuno odulatory polypeptides.

[0302] 48. The method of aspect 47. wherein the TEP comprises a dimer of two heterodimeric TEPs.

[0303] 49. Hie method of aspect 48. wherein the first polypeptides of each heterodimer have the same amino acid sequence, and the second polypeptide of each heterodimer have the same amino acid sequences, optionally wherein the second polypeptide of each heterodimer has the amino acid sequence of SEQ ID NO:359 or SEQ ID NO:360, and wherein the two heterodimers are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each heterodimer, optionally wherein the two heterodimers are joined together by two disulfide bonds fomied between the Ig Fc polypeptides of each heterodimer.

[0304] 50. The method of aspect 48, wherein the second polypeptides of each heterodimer have a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second heterodimers comprise interspecific dimerization sequences, optionally “Knob-in-Hole'’ sequences that permit the two heterodimers to selectively dimerize.

[0305] 51. The method of aspect 50, wherein(i) the first and second heterodimeric TEPs comprise BCTCs that target different B cell antigens (e.g., different antigens selected from CD19, CD20, CD21, CD40, BCMA, CD38, CD79a, CD79b, CD138, and CD139), wherein the TEP is able to bind to each target B cell antigen separately and / or simultaneously, optionally wherein the different BCTCs comprise a BCTC that targets B cells (e.g., the BCTC targets CD19 or CD20), and a BCTC that targets plasmablasts and plasma cells (e.g., the BCTC targets BCMA or CD38), e.g., wherein the second polypeptide of one heterodimer has the amino acid sequence of SEQ ID NO:359 and the second polypeptide of the other heterodimer has the amino acid sequence of SEQ ID NO:360, and / or(ii) the first and second heterodimers comprise different peptide epitopes, optionally wherein the different peptide epitopes comprise a CMV peptide epitope (e.g., NLVPMVATV; SEQ ID NO: 141), a SARS-CoV-2 peptide epitope (e.g., YLQPRTFLL; SEQ ID NO: 166), and / or an EBV peptide epitope.

[0306] 52. The method of any one of aspects 40-46, wherein the TEP comprises a singlechain polypeptide, wherein the single-chain polypeptide comprises: a) the [32M polypeptide; b) the MHC class I heavy chain polypeptide; c) the Ig Fc polypeptide; d) the at least one B-cell targeting component; and e) the optional one or more activating immunomodulatory polypeptides.

[0307] 53. The method of aspect 52. wherein the TEP comprises a dimer of t o single-chainTEPs.

[0308] 54. The method of aspect 53, wherein the first and second single-chain TEPs have the same amino acid sequence, and wherein the two single-chain TEPs are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each single-chain TEP. optionally wherein the two single-chain TEPs are joined together by two disulfide bonds formed between the Ig Fc polypeptides of each single-chain TEP.

[0309] 55. The method of aspect 53, wherein each single-chain TEP has a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second single-chain TEPs comprise interspecific dimerization sequences, optionally 'Knob-in-Holc’’ sequences that permit the two heterodimers to selectively dimerize.

[0310] 56. Dre method of aspect 55. wherein(i) the first and second single-chain TEPs comprise BCTCs that target different B cell antigens (e.g., different antigens selected from CD19, CD20, CD21, CD40, BCMA, CD38, CD79a, CD79b, CD138, and CD139), wherein the TEP is able to bind to each target B cell antigen separately and / or simultaneously, optionally wherein the different BCTCs comprise a BCTC that targets B cells (e.g.. the BCTC targets CD19 or CD20), and a BCTC that targets plasmablasts and plasma cells (e.g., the BCTC targets BCMA or CD38), and / or(ii) the first and second single-chain TEPs comprise different peptide epitopes, optionally wherein the different peptide epitopes comprise a CMV peptide epitope, a SARS-CoV-2 peptide epitope and / or an EBV peptide epitope.

[0311] 57. The method of any one of aspects 1-16, wherein the TEP comprises a multimeric antigen-presenting polypeptide (MAPP), wherein the MAPP comprises:(i) a framework polypeptide comprising a dimerization sequence and a multimerization sequence;(ii) a dimerization polypeptide comprising a counterpart dimerization sequence complementary to the dimerization sequence of the framework polypeptide, the dimerization sequence and counterpart dimerization sequence dimerizing through covalent and / or non-covalent interactions to form a heterodimer;(iii) the pMHC, wherein the pMHC comprises at least one presenting sequence and / or presenting complex;(iv) the at least one B-cell targeting component;(v) the optional one or more activating immunomodulatory polypeptides.

[0312] 58 The method of aspect 57, wherein the pMHC comprises a heterodimeric presenting complex.

[0313] 59. The method of aspect 57, wherein the pMHC comprises a single-chain presenting sequence.

[0314] 60. The method of any one of aspects 57-59. wherein the TEP comprises a dimer of two MAPP TEPs, wherein the MAPP TEPs are covalently attached through the binding of interspecific multimerization sequences in the MAPPs.

[0315] 61. The method of any one of aspects 57-59, wherein the TEP comprises a dimer of two MAPP TEPs. wherein the MAPP TEPs are covalently attached through the binding of non- interspecific multimerization sequences in the MAPPs.

[0316] 62. lire method of aspect 60 or 61, wherein each MAPP TEP comprises the same B- cell targeting component.

[0317] 63. The method of aspect 60 or 61, wherein(i) each MAPP TEP comprises a BCTC that targets a different B cell antigen (e.g., different antigens selected from CD19, CD20, CD21, CD40, BCMA, CD38, CD79a, CD79b, CD138, and CD 139), wherein the dimeric TEP is able to bind to each target B cell antigen separately and / or simultaneously, optionally wherein the different BCTCs comprise a BCTC that targets B cells (e.g.. the BCTC targets CD19 or CD20), and a BCTC that targets plasmablasts and plasma cells (e.g., the BCTC targets BCMA or CD38), and / or and / or(ii) each MAPP TEP comprises a different peptide epitope, optionally wherein the different peptide epitopes comprise a CMV peptide epitope, a SARS-CoV-2 peptide epitope and / or an EBV peptide epitope.

[0318] 64. The method of any one of aspects 1-63, wherein the MAPP TEP does not comprise an activating immunomodulatory polypeptide.

[0319] 65. A T cell engaging protein (“TEP"). wherein the TEP comprises: i) a peptide-major histocompatibility complex (“pMHC") comprising a peptide epitope, a (32- microglobulin (“(32M") polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig") Fc polypeptide; iii) at least one B-cell targeting component, wherein the B-cell targeting component comprises a protein or an antigenic portion of a protein that is an autoantigen; and iv) optionally one or more activating immunomodulatory polypeptides.

[0320] 66. The TEP of aspect 65, wherein at least one of the one B-cell targeting component comprises an autoantigenic protein or an antigenic portion of an autoantigenic protein selected from desmoglein (DSG) proteins (including DSG1 and DSG3). BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65). myeloperoxidase (MPO). PR3 (Proteinase-3), aquaporin-4. nicotinic acetylcholine receptor-1 (nAChR-1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG), Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

[0321] 67. The TEP of aspect 65 or 66, wherein the Ig Fc polypeptide is an IgGl Fc polypeptide, IgG2 Fc polypeptide, IgG3 Fc polypeptide, or IgG4 polypeptide, optionally wherein the Ig Fc polypeptide is an IgGl Fc polypeptide.

[0322] 68. The TEP of any one of aspects 65-67, wherein the Ig Fc polypeptide is a variant having one or more substitutions that reduce or substantially eliminate effector function.

[0323] 69. The TEP of aspect 68, wherein the Ig Fc polypeptide is an IgGl Fc polypeptide having one or more substitutions that reduce or substantially eliminate effector function, optionally wherein tire Ig Fc polypeptide does not include a C -terminal Lys present in a wild-type Ig Fc polypeptide variant.

[0324] 70. The TEP of any one of aspects 65-69, wherein the pMHC presents an epitope of a pathogen-infected cell, optionally wherein the pMHC presents an epitope of a virus-infected cell or a bacteria-infected cell.

[0325] 71. The TEP of aspect 70, wherein the pMHC presents an epitope of a cell infected with a virus selected from CMV, influenza (flu) or SARS-CoV2 and EBV.

[0326] 72. The TEP of any one of aspects 65-71, wherein the MHC class I heavy chain is anHLA-A allele heavy chain polypeptide, optionally wherein the HLA-A allele heavy chain polypeptide comprises an amino acid sequence having at least 90%. at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-A amino acid sequence depicted in any one of FIGS. 7A-7E, 8A-8E, 9A-9E, 10A-10E, HA-HE and 12A-12D.

[0327] 73. The TEP of any one of aspects 65-71, wherein the MHC class I heavy chain is anHLA-B allele heavy chain polypeptide, optionally wherein the E1LA-B allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the EILA-B amino acid sequence depicted in FIGS. 13A-13D.

[0328] 74. The TEP of any one of aspects 65-71, wherein the MHC class I heavy chain is anHLA-C allele heavy chain polypeptide, optionally wherein the HLA-C allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-C amino acid sequence depicted in FIGS. 14A-14D.

[0329] 75. The TEP of any one of aspects 65-71, wherein the MHC class I heavy chain is anHLA-E allele heavy chain polypeptide, optionally wherein the HLA-E allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-E amino acid sequence depicted in FIGS 15A-15D.

[0330] 76. The TEP of any one of aspects 65-75, wherein the P2M polypeptide, wherein theP2M polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to 21-119 of any one of the amino acid sequences set forth in SEQ ID NOs: 1-3.

[0331] 77. The of any one of aspect 65-76, wherein at least one of the optional one or more activating immunomodulatory polypeptides are selected from a cytokine, a 4-1 BBL polypeptide, an ICOS-L polypeptide, an OX-40L polypeptide, a CD80 polypeptide, a CD86 polypeptide, a CD40 polypeptide, a CD70 polypeptide, and combinations thereof.

[0332] 78. The TEP of aspect 77, wherein the cytokine is an TL-2 polypeptide, and wherein the IL-2 polypeptide is a variant IL-2 polypeptide that exhibits reduced affinity to an IL-2 receptor compared to the affinity of a wild-type IL-2 polypeptide for the IL-2 receptor.

[0333] 79. The TEP of aspect 78, wherein the variant IL-2 polypeptide has at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the wildtype IL-2 amino acid sequence, and wherein amino acid 16 of the variant IL-2 polypeptide is other than histidine and amino acid 42 is other than phenylalanine, optionally wherein amino acid 16 is Ala, Thr, Asp or Glu and wherein amino acid 42 is Ala, and optionally wherein amino acid 16 is Ala and wherein amino acid 42 is Ala.

[0334] 80. The TEP of aspect 78 or 79, wherein the TEP comprises two variant IL-2 polypeptides in tandem, optionally connected by a linker.

[0335] 81 . The TEP of any one of aspects 65-80, wherein the TEP comprises a heterodimer, wherein tire heterodimer comprises: a) a first polypeptide comprising: i) the peptide; and ii) the (32-microglobulin (|32M) polypeptide; and b) a second polypeptide comprising: i) the MHC class I heavy chain polypeptide; and ii) the immunoglobulin (Ig) Fc polypeptide; iii) the at least one B-ccll targeting component; and iv) the optional one or more activating immunomodulatory polypeptides, optionally wherein the TEP comprises one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0336] 82. The TEP of aspect 81, wherein each heterodimeric TEP comprises a disulfide bond formed between a Cys residue in the [32M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.

[0337] 83. The TEP of aspect 81 or 82, wherein the heterodimeric TEP comprises a disulfide bond formed between (i) a Cys residue in a Cys-containing linker interposed between the peptide and the [32M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0338] 84. The TEP of aspect 81, wherein the first polypeptide and the second polypeptide are covalently linked to one another by at least a first and second disulfide bond, wherein the first disulfide bond formed between (i) a Cys residue in a Cys-containing linker between the peptide epitope and the [32M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide; and wherein tire second disulfide bond is formed between a Cys residue in the [32 M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.

[0339] 85. The TEP of any one of aspects 81-84, wherein a) the first polypeptide of the heterodimeric TEP comprises, in order from N-terminus to C- terminus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids; ii) a peptide linker; and iii) the [32M polypeptide; b) the second polypeptide of each heterodimeric TEP comprises, in order from N-terminus to C- terminus: i) the optional one or more activating immunomodulatory polypeptides; ii) the MHC class I heavy chain polypeptide; iii) the Ig Fc polypeptide; and iv) the at least one B-cell targeting component, and wherein the second polypeptide optionally comprises independently selected peptide linkers between one or more components of the second polypeptide.

[0340] 86. The TEP of any one of aspects 81-84, wherein a) tire first polypeptide of tire heterodimeric TEP comprises, in order from N-terminus to C- te minus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids; ii) a peptide linker; andiii) the P2M polypeptide; b) the second polypeptide of each heterodimeric TEP comprises, in order from N-temrinus to C- terminus: i) at least one B-cell targeting component; ii) the MHC class I heavy chain polypeptide; iii) the Ig Fc polypeptide; and iv) the optional one or more activating immunomodulatory polypeptides, wherein the second polypeptide optionally comprises independently selected peptide linkers between one or more components of the second polypeptide.

[0341] 87. The TEP of any one of aspects 81-86, wherein: i) the [32M polypeptide comprises a Cys at amino acid 12 based on the amino acid numbering of SEQ ID NO: 1; and ii) the MHC class I polypeptide comprises a Cys at residue 236 based on the amino acid numbering of FIG. 7A, and wherein the heterodimeric TEP comprises a disulfide bond linking the first polypeptide to the second polypeptide, and wherein the disulfide bond joins the Cys at amino acid 12 of the P2M polypeptide to the Cys at amino acid 236 of the MHC heavy chain polypeptide, optionally wherein the hctcrodimcr comprises a second disulfide bond fonned between (i) a Cys residue in a Cys-containing linker between the peptide and the P2M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0342] 88. A dimeric TEP comprising two heterodimeric TEPs according to any one of aspects 81-87, wherein the first polypeptides of each heterodimeric TEP have the same amino acid sequence, and the second polypeptide of each heterodimeric TEP have the same amino acid sequences, and wherein the two heterodimeric TEPs are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each heterodimeric TEP, optionally wherein the two heterodimeric TEPs are joined together by two disulfide bonds formed between the Ig Fc polypeptides of each heterodimeric TEP.

[0343] 89. A dimeric TEP comprising two heterodimeric TEPs according to any one of aspects 81-87, wherein the first and / or second polypeptides of each heterodimeric TEP have a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second heterodimeric TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two heterodimeric TEPs to selectively dimerize, optionally wherein each TEP of the dimeric TEP comprises a BCTC that targets a different protein or antigenic portion of a protein that is an autoantigen.

[0344] 90. The TEP of any one of aspects 65-80, wherein the TEP is a single-chain TEP comprising from the N-terminal to C -terminal direction: i) the peptide; ii) the [32M polypeptide; iii) the class I HLA heavy chain polypeptide; iv) the immunoglobulin (Ig) Fc polypeptide; v) the at least one B-cell targeting component; and vi) the optional one or more activating immunomodulatory polypeptides, optionally wherein the TEP comprises one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0345] 91. Hie TEP of aspect 90, wherein the single-chain TEP comprises a Cys-containing peptide linker between the peptide and the (32M polypeptide, and wherein the single-chain TEP comprises an intrachain disulfide bond between the Cys in the Cys-containing peptide linker and a Cys in the class I HLA heavy chain polypeptide.

[0346] 92. Hie TEP of aspect 91, wherein the class I HLA heavy chain polypeptide comprises a Cys at any one of amino acids 135-143, based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG 7A, and wherein amino acid 84, based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A is other than Cys; and wherein the TEP comprises an intrachain disulfide bond between the Cys present in the Cys- containing peptide linker and the Cys at any one of amino acids 135-143 of the class I HLA heavy chain polypeptide.

[0347] 93. The TEP of aspect 92, wherein the class I HLA heavy chain polypeptide comprises a Cys at amino acid 138, 139, or 140 based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A.

[0348] 94. The TEP of aspect 93, wherein the class I HLA heavy chain polypeptide comprises a Cys at amino acid 139 based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A.

[0349] 95. The TEP of aspect 91, wherein the single-chain TEP comprises an intrachain disulfide bond between the Cys present in the Cys-containing peptide linker and the Cys at amino acid 84 of the class I HLA polypeptide.

[0350] 96. The TEP of any one of aspects 91-95, wherein the peptide linker between the peptide and the [32M polypeptide in the single-chain TEP comprises the sequence CGGGS(GGGGS)n (SEQ ID NO:351), GCGGS(GGGGS)n (SEQ ID NO:348), or GGCGS(GGGGS)n (SEQ ID NO:353), wherein n is an integer from 1-10, optionally wherein n is an integer from 1-3.

[0351] 97. The TEP of any one of aspects 90-96, wherein the P2M polypeptide comprises aCys at amino acid 12, wherein the class I HLA heavy chain polypeptide comprises a Cys at amino acid 236, and wherein the single-chain TEP comprises a disulfide bond fonned between the Cys at amino acid 12 of the (32M polypeptide and the Cys at amino acid 236 of the class I HLA heavy chain polypeptide.

[0352] 98. A dimeric TEP comprising two single-chain TEPs according to any one of aspects91-97, wherein the two single-chain TEPs have the same amino acid sequence, and wherein the two single-chain TEPs are joined together by one or more disulfide bonds formed between tire Ig Fc polypeptides of each single-chain TEP, optionally wherein the two single-chain TEPs are joined together by two disulfide bonds formed between the Ig Fc polypeptides of each single-chain TEP.

[0353] 99. A dimeric TEP comprising two single-chain TEPs according to any one of aspects91-97, wherein each single-chain TEP has a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second single-chain TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two single-chain TEPs to selectively dimerize, optionally wherein each TEP of the dimeric TEP comprises a BCTC that targets a different protein or antigenic portion of a protein that is an autoantigen.

[0354] 100. The TEP of any one of aspects 65-80, wherein the TEP comprises a chemical conjugation site, wherein the peptide of the pMHC of the TEP is chemically conjugated to the constituent TEP through the chemical conjugation site, and wherein the peptide is positioned in the pMHC of the constituent TEP for presentation to a cell bearing a T-cell receptor specific for the epitope presented by tire pMHC.

[0355] 101. The TEP of aspect 100, wherein the chemical conjugation site is present in the[32M polypeptide or MHC lass I heavy chain polypeptide.

[0356] 102. The TEP of aspect 100 or 101, wherein the TEP presents a viral epitope.

[0357] 103. The TEP of aspect 102, wherein the viral epitope is an influenza (flu), CMV (e.g., comprising the peptide epitope NLVPMVATV, SEQ ID NO: 141), EBV or SARS-Cov-2 epitope (e.g., comprising the peptide epitope YLQPRTFLL, SEQ ID NO: 166).

[0358] 104. The TEP of any one of aspects 100-103, wherein the chemical conjugation site is present in the [32M polypeptide.

[0359] 105. The TEP of aspect 104, wherein the chemical conjugation site is a cysteine present in the [32M polypeptide.

[0360] 106. Hie TEP of aspect 105, wherein tire peptide is conjugated to the TEP by the reaction of a maleimide group and the cysteine of the chemical conjugation site.

[0361] 107. A TEP according to any one of aspects 100-106, wherein the TEP comprises: a) a first polypeptide comprising the |32M polypeptide; b) a second polypeptide comprising,(i) the MHC class I heavy chain polypeptide;(ii) the Ig Fc polypeptide;(iii) at least one B-cell targeting component; and(iv) the optional one or more activating immunomodulatory polypeptides.

[0362] 108. A dimeric TEP comprising two heterodimeric TEPs according to aspect 107. wherein:(i) the first polypeptides of the heterodimeric TEPs have the same amino acid sequence, and the second polypeptides of the heterodimeric TEPs have the same amino acid sequences, and wherein the two heterodimeric TEPs are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each heterodimeric TEP, optionally wherein the two heterodimeric TEPs are joined together by two disulfide bonds formed between the Ig Fc polypeptides of each heterodimeric TEP; or(ii) the first or second polypeptide of one heterodimeric TEP has a different amino acid sequence from tire second polypeptide of the other heterodimeric TEP, and wherein the Ig Fc polypeptides of the two heterodimeric TEPs comprise interspecific dimerization sequences, optionally ”Knob-in-Hole” sequences that permit the two heterodimeric TEPs to selectively dimerize, optionally wherein each TEP of the dimeric TEP comprises a BCTC that targets a different protein or antigenic portion of a protein that is an autoantigen.

[0363] 109. The TEP of any one of aspects 100-106, wherein the TEP is a single-chain TEP comprising: a) the [32M polypeptide; b) the MHC class I heavy chain polypeptide; c) the Ig Fc polypeptide;d) at least one B-cell targeting component; and e) the optional one or more activating immunomodulatory polypeptides.

[0364] 110. A dimeric TEP comprising two single-chain TEPs according to aspect 109, wherein:(i) the single-chain TEPs have the same amino acid sequence, and wherein the two singlechain TEPs are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each TEP, optionally wherein the two TEPs are joined together by two disulfide bonds formed between the Ig Fc polypeptides of each TEP; or(ii) each single-chain TEP has a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second single-chain TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two heterodimers to selectively dimerize.

[0365] 111. The TEP of any one of aspects 65-80, wherein the TEP comprises a MAPP, wherein the MAPP comprises:(i) a framework polypeptide comprising a dimerization sequence and a multimerization sequence;(ii) a dimerization polypeptide comprising a counterpart dimerization sequence complementary to the dimerization sequence of the framework polypeptide, the dimerization sequence and counterpart dimerization sequence dimerizing through covalent and / or non-covalent interactions to form a heterodimer;(iii) the pMHC, wherein the pMHC comprises at least one presenting sequence and / or presenting complex;(iv) at least one B-cell targeting component;(v) the optional one or more activating immunomodulatory polypeptides.

[0366] 112. The TEP of aspect 111, wherein the pMFIC comprises a heterodimeric presenting complex or a single-chain presenting sequence.

[0367] 113. A dimeric TEP comprising two TEPs according to aspect 111 or 112, wherein theMAPPs are covalently attached through the binding of non-interspecific multimerization sequences in the MAPPs.

[0368] 114. The TEP of any one of aspects 65-113. wherein the TEP does not comprise an activating immunomodulatory polypeptide.

[0369] 115. A dimeric T cell engaging protein (“TEP”), wherein the TEP comprises first and second constituent TEPs, wherein each constituent TEP comprises: i) a peptide-major histocompatibility complex (“pMHC”) comprising a peptide epitope, a [32- microglobulin (“J32M”) polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig”) Fc polypeptide: iii) at least one B-cell targeting component; and iv) optionally one or more activating immunomodulatory polypeptides, wherein(i) the first constituent TEP and second constituent TEP comprise BCTCs that target different B cell antigens (e.g., different antigens selected from CD19, CD20, CD21, CD40, BCMA. CD38, CD79a, CD79b, CD138. and CD139). wherein tire TEP is able to bind to each target B cell antigen separately and / or simultaneously, optionally wherein one of the different BCTCs comprises a BCTC that targets B cells (e.g., the BCTC targets CD19 or CD20), and the other BCTC targets plasmablasts and plasma cells (e.g., the BCTC targets BCMA or CD38), and / or(ii) the first constituent TEP comprises a peptide epitope that is different from the peptide epitope of the second constituent TEP, optionally wherein both peptide epitopes are viral peptide epitopes.

[0370] 116. The dimeric TEP of aspect 115, wherein at least one of the one B-ccll targeting component of each TEP comprises an antigen-binding portion of an antibody that binds to CD 19, CD20, CD21, CD40. BCMA, CD79a, CD79b, CD38, CD138, or CD139, optionally wherein one constituent TEP comprises a B-cell targeting component that comprises antigen-binding portion of an antibody that binds to CD 19 and the other constituent TEP comprises a B-cell targeting component that comprises an antigen-binding portion of an antibody that binds to BCMA.

[0371] 117. The dimeric TEP of aspect 115 or 116. wherein at least one of the one B-cell targeting component comprises an autoantigenic protein or an antigenic portion of an autoantigenic protein selected from desmoglein (DSG) proteins (including DSG1 and DSG3), BP 180, BP230, insulin. Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO), PR3 (Proteinase-3), aquaporin-4, nicotinic acetylcholine receptor-1 (nAChR-1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG). Myelin-Associated Glycoprotein (MAG), Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA. La / SSB, and Centromere Protein B (CENP-B).

[0372] 118. The dimeric TEP of any one of aspects 115-117, wherein the Ig Fc polypeptide is an IgGl Fc polypeptide, IgG2 Fc polypeptide, IgG3 Fc polypeptide, or IgG4 polypeptide, optionallywherein the Ig Fc polypeptide is an IgGl Fc polypeptide, and optionally wherein the Ig Fc polypeptide is a variant having one or more substitutions that reduce or substantially eliminate effector function.

[0373] 119. The dimeric TEP of aspect 118, wherein the Ig Fc polypeptide is an IgGl Fc polypeptide having one or more substitutions that reduce or substantially eliminate effector function, optionally wherein the Ig Fc polypeptide does not include a C-terminal Lys present in a wild-type Ig Fc polypeptide variant.

[0374] 120. The dimeric TEP of any one of aspects 115-119. wherein the pMHC presents an epitope of a pathogen-infected cell, optionally wherein the pMHC presents an epitope of a virus-infected cell or a bacteria-infected cell.

[0375] 121. The dimeric TEP of aspect 120, wherein the pMFIC presents an epitope of a cell infected with a virus selected from CMV (e.g., comprising the peptide epitope NLVPMVATV, SEQ ID NO: 141), influenza (flu), SARS-CoV2 (e g., comprising the peptide epitope YLQPRTFLL, SEQ ID NO: 166), and EBV.

[0376] 122. The dimeric TEP of any one of aspects 115-121, wherein the MEIC class I heavy chain is an HLA-A allele heavy chain polypeptide, optionally wherein the HLA-A allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-A amino acid sequence depicted in any one of FIGS. 7A- 7E, 8A-8E, 9A-9E, 10A-10E, HA-l lE and 12A-12D.

[0377] 123. The dimeric TEP of any one of aspects 1 15-121, wherein the MHC class I heavy chain is an HLA-B allele heavy chain polypeptide, optionally wherein the HLA-B allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-B amino acid sequence depicted in FIGS. 13A-13D.

[0378] 124. The dimeric TEP of any one of aspects 115-121, wherein the MHC class I heavy chain is an HLA-C allele heavy chain polypeptide, optionally wherein the HLA-C allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-C amino acid sequence depicted in FIGS. 14A-14D.

[0379] 125. The dimeric TEP of any one of aspects 115-121, wherein the MHC class I heavy chain is an HLA-E allele heavy chain polypeptide, optionally wherein the HLA-E allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-E amino acid sequence depicted in FIGS 15A-15D.

[0380] 126. The dimeric TEP of any one of aspects 115-125, wherein the [32M polypeptide, wherein tire [32M polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to 21-119 of any one of the amino acid sequences set forth in SEQ ID NOs: 1-3.

[0381] 127. The dimeric TEP of any one of aspect 115-126, wherein at least one of the optional one or more activating immunomodulatory polypeptides are selected from a cytokine, a 4-1BBL polypeptide, an ICOS-L polypeptide, an OX-40L polypeptide, a CD80 polypeptide, a CD86 polypeptide, a CD40 polypeptide, a CD70 polypeptide, and combinations thereof.

[0382] 128. The dimeric TEP of aspect 127, wherein the cytokine is an IL-2 polypeptide, and wherein tire IL-2 polypeptide is a variant IL-2 polypeptide that exhibits reduced affinity to an IL-2 receptor compared to the affinity of a wild-type IL-2 polypeptide for the IL-2 receptor.

[0383] 129. The dimeric TEP of aspect 128, wherein the variant IL-2 polypeptide has at least90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the wild-type IL-2 amino acid sequence, and wherein amino acid 16 of the variant IL-2 polypeptide is other than histidine and amino acid 42 is other than phenylalanine, optionally wherein amino acid 16 is Ala, Thr, Asp or Glu and wherein amino acid 42 is Ala, and optionally wherein amino acid 16 is Ala and wherein amino acid 42 is Ala.

[0384] 130. The dimeric TEP of aspect 128 or 129, wherein the TEP comprises two variant IL-2 polypeptides in tandem, optionally connected by a linker.

[0385] 131 . The dimeric TEP of any one of aspects 1 15-130, wherein the two constituent TEPs are each a heterodimeric TEP, wherein each heterodimeric TEP comprises: a) a first polypeptide comprising: i) the peptide; and ii) the (32-microglobulin (|32M) polypeptide; and b) a second polypeptide comprising: i) the MHC class I heavy chain polypeptide; and ii) the immunoglobulin (Ig) Fc polypeptide; iii) the at least one B-ccll targeting component; and iv) the optional one or more activating immunomodulatory polypeptides, optionally wherein the TEP comprises one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0386] 132. The dimeric TEP of aspect 131, wherein each heterodimeric TEP comprises a disulfide bond formed between a Cys residue in tire [32M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.

[0387] 133. The dimeric TEP of aspect 131 or 132, wherein the heterodimeric TEP comprises a disulfide bond formed between (i) a Cys residue in a Cys-containing linker interposed between the peptide and the [32M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0388] 134. The dimeric TEP of aspect 131, wherein the first polypeptide and the second polypeptide of each heterodimeric TEP are covalently linked to one another by at least a first and second disulfide bond, wherein the first disulfide bond formed between (i) a Cys residue in a Cys-containing linker between the peptide epitope and the [32M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide; and wherein tire second disulfide bond is formed between a Cys residue in the (32M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.

[0389] 135. Hie dimeric TEP of any one of aspects 131-134, wherein a) the first polypeptide of each heterodimeric TEP comprises, in order from N-terminus to C- terminus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids; ii) a peptide linker; and iii) the P2M polypeptide; b) the second polypeptide of each heterodimeric TEP comprises, in order from N-terminus to C- terminus: i) the optional one or more activating immunomodulatory polypeptides: ii) the MHC class I heavy chain polypeptide; iii) the Ig Fc polypeptide; and iv) the at least one B-cell targeting component, and wherein the second polypeptide optionally comprises independently selected peptide linkers between one or more components of the second polypeptide.

[0390] 136. The dimeric TEP of any one of aspects 131-134, wherein a) the first polypeptide of each heterodimeric TEP comprises, in order from N-terminus to C- terminus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids:ii) a peptide linker; and iii) the P2M polypeptide; b) the second polypeptide of each heterodimeric TEP comprises, in order from N-tenninus to C- terminus: i) at least one B-cell targeting component; ii) the MHC class I heavy chain polypeptide; iii) the Ig Fc polypeptide; and iv) the optional one or more activating immunomodulatory polypeptides, wherein the second polypeptide optionally comprises independently selected peptide linkers between one or more components of the second polypeptide.

[0391] 137. The dimeric TEP of any one of aspects 131-136, wherein: i) the [32M polypeptide comprises a Cys at amino acid 12 based on the amino acid numbering of SEQ ID NO: 1; and ii) the MHC class I polypeptide comprises a Cys at residue 236 based on the amino acid numbering of FIG. 7A, and wherein each heterodimeric TEP comprises a disulfide bond linking the first polypeptide to the second polypeptide, and wherein the disulfide bond joins the Cys at amino acid 12 of the [32M polypeptide to the Cys at amino acid 236 of the MHC heavy chain polypeptide, optionally wherein the heterodimer comprises a second disulfide bond fomied between (i) a Cys residue in a Cys-containing linker between the peptide and the [32M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0392] 138. The dimeric TEP of any one of aspects 131-137, wherein the second polypeptides of each heterodimeric TEP have a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second heterodimeric TEPs comprise interspecific dimerization sequences, optionally ■‘Knob-in -Hole” sequences that permit the two heterodimeric TEPs to selectively dimerize.

[0393] 139. The dimeric TEP of any one of aspects 131-137, wherein one heterodimer comprises a BCTC that targets CD 19 and the other heterodimer comprises a BCTC that targets BCMA. optionally wherein one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, orone heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360.

[0394] 140. The dimeric TEP of any one of aspects 115-130, wherein the two constituent TEPs are each single-chain TEPs, wherein each single-chain TEP comprises, from the N-terminal to C- terminal direction: i) the peptide; ii) the [32 M polypeptide; iii) the class I HLA heavy chain polypeptide; iv) the immunoglobulin (Ig) Fc polypeptide; v) the at least one B-cell targeting component; and vi) the optional one or more activating immunomodulatory polypeptides, optionally wherein the TEP comprises one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0395] 141. The dimeric TEP of aspect 140, w herein each single-chain TEP comprises a Cys- containing peptide linker between the peptide and the (32M polypeptide, and wherein each single-chain TEP comprises an intrachain disulfide bond between the Cys in the Cys-containing peptide linker and a Cys in the class I HLA heavy chain polypeptide.

[0396] 142. The dimeric TEP of aspect 141, wherein the class I HLA heavy chain polypeptide comprises a Cys at any one of amino acids 135-143, based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG 7A, and wherein amino acid 84, based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A is other than Cys; and wherein the TEP comprises an intrachain disulfide bond between the Cys present in the Cys- containing peptide linker and the Cys at any one of amino acids 135-143 of the class I HLA heavy chain polypeptide.

[0397] 143. The dimeric TEP of aspect 142, wherein the class I HLA heavy chain polypeptide comprises a Cys at amino acid 138, 139, or 140 based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A.

[0398] 144. The dimeric TEP of aspect 143, wherein the class I HLA heavy chain polypeptide comprises a Cys at amino acid 139 based on the numbering of the class I HLA heavy chain polypeptide depicted in FIG. 7A.

[0399] 145. The dimeric TEP of aspect 141, wherein each single-chain TEP comprises an intrachain disulfide bond between the Cys present in the Cys-containing peptide linker and the Cys at amino acid 84 of the class I HLA polypeptide.

[0400] 146. The dimeric TEP of any one of aspects 141-145, wherein the peptide linker between the peptide and the [32M polypeptide in each single-chain TEP comprises the sequence CGGGS(GGGGS)n (SEQ ID NO:351), GCGGS(GGGGS)n (SEQ ID NO:348), or GGCGS(GGGGS)n (SEQ ID NO:353), wherein n is an integer from 1-10, optionally wherein n is an integer from 1-3.

[0401] 147. The dimeric TEP of any one of aspects 140-146, wherein the [32M polypeptide comprises a Cys at amino acid 12, wherein the class I HLA heavy chain polypeptide comprises a Cys at amino acid 236, and wherein each single-chain TEP comprises a disulfide bond formed between the Cys at amino acid 12 of the P2M polypeptide and the Cys at amino acid 236 of the class I HLA heavy chain polypeptide.

[0402] 148. The dimeric TEP of any one of aspects 141-147, wherein the two single-chainTEPs have the same amino acid sequence, and wherein the two single-chain TEPs are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each single-chain TEP, optionally wherein the two single-chain TEPs are joined together by two disulfide bonds fonned between the Ig Fc polypeptides of each single-chain TEP.

[0403] 149. The dimeric TEP of any one of aspects 141-147, wherein each single-chain TEP has a different amino acid sequence, and wherein the Ig Fc poly peptides of the first and second singlechain TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two single-chain TEPs to selectively dimerize.

[0404] 150. The dimeric TEP of any one of aspects 115-130, wherein each constituent TEP comprises a chemical conjugation site, wherein the peptide of the pMHC of each constituent TEP is chemically conjugated to the constituent TEP through the chemical conjugation site, and wherein thepeptide is positioned in the pMHC of the constituent TEP for presentation to a cell bearing a T-cell receptor specific for the epitope presented by the pMHC.

[0405] 151. The dimeric TEP of aspect 150, wherein the chemical conjugation site is present in the [32M polypeptide or MHC lass I heavy chain polypeptide.

[0406] 152. Hie dimeric TEP of aspect 150 or 151, wherein the TEP presents a viral epitope.

[0407] 153. The dimeric TEP of aspect 152, wherein the viral epitope is an influenza (flu),CMV (e.g., comprising the peptide epitope NLVPMVATV, SEQ ID NO: 141), EBV or SARS-Cov-2 epitope (e.g., comprising the peptide epitope YLQPRTFLL, SEQ ID NO: 166).

[0408] 154. The dimeric TEP of any one of aspects 150-153, wherein the chemical conjugation site is present in the (32M polypeptide.

[0409] 155. The dimeric TEP of aspect 154, wherein the chemical conjugation site is a cysteine present in the 02M polypeptide.

[0410] 156. The dimeric TEP of aspect 155, wherein the peptide is conjugated to the TEP by the reaction of a maleimide group and the cysteine of the chemical conjugation site.

[0411] 157. The dimeric TEP of any one of aspects 150-156, wherein the two constituent TEPs are each heterodimeric TEPs, wherein each heterodimeric TEP comprises: a) a first polypeptide comprising the |32M polypeptide; b) a second polypeptide comprising,(i) the MHC class I heavy chain polypeptide;(ii) the Ig Fc polypeptide;(iii) at least one B-cell targeting component; and(iv) the optional one or more activating immunomodulatory polypeptides.

[0412] 158. The dimeric TEP of aspect 157, wherein the first polypeptides of each heterodimeric TEP have the same amino acid sequence, and the second polypeptide of each heterodimeric TEP have the same amino acid sequences, and wherein the two heterodimeric TEPs are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each heterodimeric TEP, optionally wherein the two heterodimeric TEPs are joined together by two disulfide bonds formed between the Ig Fc polypeptides of each heterodimeric TEP.

[0413] 159. The dimeric TEP of aspect 157, wherein the second polypeptide of one heterodimeric TEP has a different amino acid sequence from the second polypeptide of the other heterodimeric TEP, and wherein the Ig Fc polypeptides of the two heterodimeric TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that pennit the two heterodimeric TEPs to selectively dimerize.

[0414] 160. The dimeric TEP of any one of aspects 150-156, wherein the two constituent TEPs are each single-chain TEPs, wherein each single-chain TEP comprises: a) the [32M polypeptide: b) the MHC class I heavy chain polypeptide; c) the Ig Fc polypeptide; d) at least one B-cell targeting component; and e) the optional one or more activating immunomodulatory polypeptides.

[0415] 161. The dimeric TEP of aspect 160, wherein each single-chain TEP has a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second single-chain TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two heterodimers to selectively dimerize.

[0416] 162. The dimeric TEP of any one of aspects 115-130, wherein each of the constituentTEPs comprises a MAPP, wherein the MAPP comprises:(i) a framework polypeptide comprising a dimerization sequence and a multimerization sequence;(ii) a dimerization polypeptide comprising a counterpart dimerization sequence complementary to the dimerization sequence of the framework polypeptide, the dimerization sequence and counterpart dimerization sequence dimerizing through covalent and / or non-covalent interactions to form a heterodimer;(iii) the pMHC, wherein the pMHC comprises at least one presenting sequence and / or presenting complex;(iv) at least one B-cell targeting component;(v) the optional one or more activating immunomodulatory polypeptides.

[0417] 163. The dimeric TEP of aspect 162, wherein each pMHC comprises a heterodimeric presenting complex.

[0418] 164. The dimeric TEP of aspect 162, wherein each pMHC comprises a single-chain presenting sequence.

[0419] 165. The dimeric TEP of any one of aspects 162-164, wherein the TEP comprises a dimer of two MAPPs, wherein the MAPPs are covalently attached through the binding of non- interspecific multimerization sequences in the MAPPs.

[0420] 166. The dimeric TEP of any one of aspects 115-165, wherein the TEP does not comprise an activating immunomodulatory polypeptide.

[0421] 167. The method of any one of aspects 1-64, wherein the individual has an autoimmune disorder or immune-mediated inflammation disorder.

[0422] 168. The method of aspect 167, wherein tire individual has Addison’s disease, alopecia areata, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune-associated infertility, autoimmune thrombocytopenic purpura, bullous pemphigoid. Goodpasture’s syndrome, glomerulonephritis (e.g., crescentic glomerulonephritis, proliferative glomerulonephritis), Grave’s disease, idiopathic inflammatory myositis, Hashimoto’s thyroiditis, a mixed connective tissue disease, systemic sclerosis, multiple sclerosis, Chronic inflammatory demyelinating polyradiculoneuropathy, NMO)myasthenia gravis (MG), pemphigus (e.g., pemphigus vulgaris), pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, systemic lupus erythematosus (SLE), autoimmune vasculitis, including types of ANCA-vasculitis (e.g., Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA)), celiac disease, type 1 diabetes (T1D), vitiligo, antiphospholipid syndrome, Type-2 diabetes, periodontal disease, pulmonary arterial hypertension (PAH), preeclampsia, dilated cardiomyopathy, discoid lupus, palmoplantar pustulosis, Chagas’ disease. Evan’s syndrome, autoimmune hypoglycemia, anti-NMDA receptor encephalitis, Anti-CASPR encephalitis, glomerulonephritis associated with SLE). Guillain-Barre disease, agammaglobulinemia, autoimmune autonomic ganglionopathy (AAG), or an autoimmune diseases of a specific organ (e.g., myocarditis, oophoritis, pancreatitis, gastritis, hepatitis, or testicular autoimmunity).

[0423] 169. The method of aspect 167, wherein the autoimmune disorder is an inflammatory bowel disease including ulcerative colitis. Crohn’s disease and irritable bowel syndrome.

[0424] 170. The method of aspect 167, wherein tire autoimmune disorder is SLE, idiopathic inflammatory myositis, or systemic sclerosis.

[0425] 171. The method of any one of aspects 1-64, wherein the individual has acute or chronic graft versus host disease (GVHD), acute, hyperacute or chronic host versus graft disease (HVGD), or transplant rejection, or wherein the individual is administered the TEP to prophylacticallyreduce or substantially prevent acute or chronic graft versus host disease (GVHD) or acute, hyperacute or chronic host versus graft disease (HVGD), or transplant rejection.

[0426] 172. The method of any one of aspects 1-64, wherein the individual is administered theTEP to reduce or substantially prevent an allergic reaction, or wherein the individual is administered the TEP to prophylactically reduce or substantially prevent an allergic reaction.

[0427] 173. The method of any one of aspects 1-64, wherein the individual has an autoimmune disorder selected from: a pemphigus disorder associated with autoantibodies to DSG1 and / or DSG3 (e.g.. pemphigus vulgaris, pemphigus vegetans, pemphigus erythematosus and pemphigus follaceus); bullous pemphigoid; type 1 diabetes; (ANCA)-associated vasculitis (AAV) (including microscopic polyangiitis (MPA)); multiple sclerosis; rheumatoid arthritis; granulomatosis with polyangiitis (GPA), Neuromyelitis Optica (NMO) (or Devic's Disease); or Myasthenia Gravis.

[0428] 174. The method of any one of aspects 167-173, wherein the TEP comprises a homodimer of two heterodimeric TEPs, wherein the first polypeptide of each heterodimer comprises the amino acid sequence of SEQ ID NO:90, and a second polypeptide of each heterodimer comprises the amino acid sequence of SEQ ID NO: 89.

[0429] 175. The method of any one of aspects 167-173, wherein the TEP comprises a homodimer of two heterodimeric TEPs, wherein the first polypeptide of each heterodimer comprises the amino acid sequence of SEQ ID NO:91, and the second polypeptide of each heterodimer comprises the amino acid sequence of SEQ ID NO: 89.

[0430] 176. The method of aspect 167, wherein the individual has autoantibodies to one or more of DSG1, DSG3, BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), Myeloperoxidase (MPO), PR3 (Proteinase-3), Aquaporin-4, Nicotinic acetylcholine receptor- 1 (nAChR- 1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG). Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF). Ro / SSA. Ea / SSB, and Centromere Protein B (CENP-B).

[0431] 177. A pharmaceutical composition comprising a TEP or dimeric TEP of any one of aspects 65-166.

[0432] 178. A method of treating an individual to deplete autoreactive B cells, the method comprising administering to the individual a therapeutic amount of a pharmaceutical composition of aspect 177.

[0433] 179. The method of aspect 178, wherein the individual has an autoimmune disorder or an immune-mediated inflammation disorder.

[0434] 180. The method of aspect 179, wherein the autoimmune disorder is Addison’s disease, alopecia areata, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune-associated infertility, autoimmune thrombocytopenic purpura, bullous pemphigoid, Goodpasture’s syndrome, glomerulonephritis (e.g., crescentic glomerulonephritis, proliferative glomerulonephritis), Grave’s disease, idiopathic inflammatory myositis, Hashimoto's thyroiditis, a mixed connective tissue disease, systemic sclerosis, multiple sclerosis, Chronic inflammatory demyelinating polyradiculoneuropathy. NMO)myasthenia gravis (MG), pemphigus (e.g.. pemphigus vulgaris), pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, systemic lupus erythematosus (SLE), autoimmune vasculitis, including types of ANCA-vasculitis (e.g., Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA)), celiac disease, type 1 diabetes (T1D), vitiligo, antiphospholipid syndrome, Type-2 diabetes, periodontal disease, pulmonary arterial hypertension (PAH), preeclampsia, dilated cardiomyopathy, discoid lupus, palmoplantar pustulosis, Chagas' disease, Evan's syndrome, autoimmune hypoglycemia, anti-NMDA receptor encephalitis, Anti-CASPR encephalitis, glomerulonephritis associated with SLE), Guillain-Barre disease, agammaglobulinemia, autoimmune autonomic ganglionopathy (AAG), or an autoimmune disease of a specific organ (e.g., myocarditis, oophoritis, pancreatitis, gastritis, hepatitis, testicular autoimmunity).

[0435] 181. The method of aspect 179, wherein the autoimmune disorder is an inflammatory bowel disease including ulcerative colitis, Crohn’s disease and irritable bowel syndrome.

[0436] 182. The method of aspect 179, wherein the autoimmune disorder is SLE. idiopathic inflammatory myositis, or systemic sclerosis.

[0437] 183. Hie method of aspect 179, wherein the immune-mediated inflammation disorder is acute or chronic graft versus host disease (GVHD), acute, hyperacute or chronic host versus graft disease (HVGD). or transplant rejection, or wherein the individual is administered the pharmacal composition to prophylactically reduce or substantially prevent acute or chronic graft versus host disease (GVHD), acute, hyperacute or chronic host versus graft disease (HVGD), or transplant rejection.

[0438] 184. The method of aspect 178, wherein the individual is administered the TEP to reduce an allergic reaction.

[0439] 185. The method of aspect 178, wherein the individual is prophylactically administered the TEP to reduce or substantially prevent an allergic reaction.

[0440] 186. The method of aspect 178, wherein the individual has an autoimmune disorder selected from: a pemphigus disorder associated with autoantibodies to DSG1 and / or DSG3 (e.g., pemphigus vulgaris, pemphigus vegetans, pemphigus erythematosus and pemphigus follaceus); bullous pemphigoid; type 1 diabetes; (ANCA)-associated vasculitis (AAV) (including microscopic polyangiitis (MPA)); multiple sclerosis; rheumatoid arthritis; granulomatosis with polyangiitis (GPA), Neuromyelitis Optica (NMO) (or Devic’s Disease); or Myasthenia Gravis.

[0441] 187. The method of aspect 186, wherein tire individual has autoantibodies to one or more of DSG1, DSG3, BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), Myeloperoxidase (MPO), PR3 (Proteinase-3), Aquaporin-4, Nicotinic acetylcholine receptor- 1 (nAChR- 1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG). Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF). Ro / SSA. Ea / SSB, and Centromere Protein B (CENP-B).

[0442] 188. Hie method of any one of aspects 167-187, further comprising the step of administering a vaccine to the patient to cause the production of T cells specific for the pMHC of the TEP, optionally wherein the vaccine is an influenza (flu) vaccine, tetanus vaccine, CMV vaccine, EBV vaccine or a SARS-CoV-2 vaccine.

[0443] 189. One or more nucleic acids encoding the first and second polypeptide of the heterodimeric TEPs of any one of aspects 81-89 or 131-139.

[0444] 190. One or more nucleic acids encoding the single -chain TEPs of any one of aspects90-99 or 140-149.

[0445] 191. One or more nucleic acids encoding the MAPPs of any one of aspects 111-113.

[0446] 192. The nucleic acids of any of aspects 189-191, wherein the nucleic acids are mRNA.

[0447] 193. One or more expression vectors comprising the one or more nucleic acids of any one of aspects 189-192.

[0448] 194. An in vitro composition of host cells comprising the one or more nucleic acids of any one of aspects 189- 192 or an expression vector of aspect 193.

[0449] 195. A method of making a TEP comprising culturing the in vitro composition of host cells of aspect 194 under conditions in which the host cells produce the TEP.

[0450] 196. Use of a TEP capable of binding to an autoreactive B cell in the manufacture of a medicament for use in a method according to any one of aspects 1-64, or a TEP for use in a method according to any one of aspects 1-64.

[0451] 197. Use of a TEP in the manufacture of a medicament according to aspect 196. or aTEP for use in a method according to aspect 196. for the treatment of an individual having an autoimmune disorder or immune-mediated inflammation disorder.

[0452] 198. Use of a TEP in the manufacture of a medicament according to aspect 197. or aTEP for use in a method according to aspect 197, wherein the individual has Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune-associated infertility, autoimmune thrombocytopenic purpura, bullous pemphigoid, Goodpasture’s syndrome, glomerulonephritis (e.g., crescentic glomerulonephritis, proliferative glomerulonephritis), Grave’s disease, idiopathic inflammatory myositis, Hashimoto's thyroiditis, a mixed connective tissue disease, systemic sclerosis, multiple sclerosis, Chronic inflammatory demyelinating polyradiculoneuropathy. NMO)myasthenia gravis (MG), pemphigus (e.g.. pemphigus vulgaris), pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, systemic lupus erythematosus (SLE), autoimmune vasculitis, including types of ANCA-vasculitis (e.g., Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA)), celiac disease, type 1 diabetes (T1D), vitiligo, antiphospholipid syndrome, Type-2 diabetes, periodontal disease, pulmonary arterial hypertension (PAH), preeclampsia, dilated cardiomyopathy, discoid lupus, palmoplantar pustulosis, Chagas’ disease, Evan’s syndrome, autoimmune hypoglycemia, anti-NMDA receptor encephalitis, Anti-CASPR encephalitis, glomerulonephritis associated with SLE), Guillain-Barre disease, agammaglobulinemia, autoimmune autonomic ganglionopathy (AAG), or an autoimmune diseases of a specific organ (e.g., myocarditis, oophoritis, pancreatitis, gastritis, hepatitis, or testicular autoimmunity).

[0453] 199. Use of a TEP in the manufacture of a medicament according to aspect 197, or aTEP for use in a method according to aspect 197, wherein the autoimmune disorder is an inflammatory bowel disease including ulcerative colitis, Crohn’s disease and irritable bowel syndrome.

[0454] 200. Use of a TEP in the manufacture of a medicament according to aspect 197, or aTEP for use in a method according to aspect 197, wherein the autoimmune disorder is SLE, idiopathic inflammatory' myositis, or systemic sclerosis.

[0455] 201. Use of a TEP in the manufacture of a medicament according to aspect 197, or aTEP for use in a method according to aspect 197, wherein the individual has acute or chronic graft versus host disease (GVEID), acute, hyperacute or chronic host versus graft disease (HVGD), or transplant rejection.

[0456] 202. Use of a TEP in the manufacture of a medicament according to aspect 197, or aTEP for use in a method according to aspect 197, wherein the individual is administered the TEP to prophylactically reduce or substantially prevent acute or chronic graft versus host disease (GVHD) or acute, hyperacute or chronic host versus graft disease (HVGD), or transplant rejection.

[0457] 203. Use of a TEP in the manufacture of a medicament according to aspect 197, or aTEP for use in a method according to aspect 197, wherein the individual is administered the TEP to reduce or substantially prevent an allergic reaction, or wherein the individual is administered the TEP to prophylactically reduce or substantially prevent an allergic reaction.

[0458] 204. Use of a TEP in the manufacture of a medicament according to aspect 197, or aTEP for use in a method according to aspect 197, wherein the individual has an autoimmune disorder selected from: a pemphigus disorder associated with autoantibodies to DSG1 and / or DSG3 (e.g., pemphigus vulgaris, pemphigus vegetans, pemphigus erythematosus and pemphigus follaceus); bullous pemphigoid: type 1 diabetes; (ANCA)-associated vasculitis (AAV) (including microscopic polyangiitis (MPA)); multiple sclerosis; rheumatoid arthritis; granulomatosis with polyangiitis (GPA), Neuromyelitis Optica (NMO) (or Devic’s Disease); or Myasthenia Gravis.

[0459] 205. Use of a TEP in the manufacture of a medicament according to aspect 197. or aTEP for use in a method according to aspect 197, wherein the individual has autoantibodies to one or more of DSG1, DSG3, BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), Myeloperoxidase (MPO), PR3 (Proteinase-3), Aquaporin-4, Nicotinic acetycholine receptor- 1 (nAChR- 1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG). Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).Aspect Section B

[0460] 1. A method of treating an individual to deplete autoreactive B cells, the method comprising administering to the individual a therapeutic amount of a T cell engaging protein (“TEP”), wherein tire TEP comprises:i) a peptide-major histocompatibility complex f‘pMHC”) comprising a peptide epitope, a (32- microglobulin (' [32 M") polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig”) Fc polypeptide; iii) at least one B-cell targeting component; and iv) optionally one or more activating immunomodulatory polypeptides. wherein each of the at least one B-cell targeting components of the TEP binds to a B cell binding partner on a B cell, a plasmablast, and / or a plasma cell.

[0461] 2. The method of aspect 1, wherein the at least one B-cell targeting component comprises:(i) an antibody or antigen-binding portion of an antibody that binds to a binding partner on a B cell, a plasmablast, and / or a plasma cell, and / or(ii) an autoantigen or antigenic portion of an autoantigen.

[0462] 3. The method of aspect 1 or 2. wherein the at least one B-cell targeting component comprises:(i) an antibody or antigen-binding portion of an antibody that binds to CD 19, CD20, CD21, CD40, B cell maturation antigen (BCMA), CD38, CD79a, CD79b, CD138, and / or CD139; and / or(ii) an autoantigen or antigenic portion of an autoantigen selected from desmoglein (DSG) proteins (including DSG1 and DSG3), BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO), PR3 (Proteinase-3), aquaporin-4, nicotinic acetylcholine receptor- 1 (nAChR- 1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG). Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF). Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

[0463] 4. The method of any one of aspects 1-3, wherein the Ig Fc polypeptide is an IgGlFc polypeptide, optionally wherein the Ig Fc polypeptide is a variant having one or more substitutions that reduce or substantially eliminate effector function.

[0464] 5. The method of any one of aspects 1-4, wherein the pMHC presents an epitope of a pathogcn-infcctcd cell, optionally wherein the pMHC presents an epitope of a virus-infcctcd cell or a bacteria-infected cell.

[0465] 6. The method of any? one of aspects 1-5, wherein the pMHC presents an epitope of a cell infected with a virus selected from CMV (e.g., comprising the peptide epitope NLVPMVATV, SEQID NO: 141), influenza, EBV or SARS-CoV2 (e.g., comprising the peptide epitope YLQPRTFLL, SEQ ID NO: 166).

[0466] 7. The method of any one of aspects 1-6, wherein the [32M polypeptide, wherein the(32M polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to 21-119 of any one of the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein the MHC class I heavy chain is selected from:(i) an HLA-A allele heavy chain polypeptide, optionally wherein the HLA-A allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%. at least 98%, or at least 99%, amino acid sequence identity to the HLA-A amino acid sequence depicted in in any one of FIGS. 7A-7E, 8A-8E, 9A-9E, 10A-10E, HA-l lE and 12A-I2D;(ii) an HLA-B allele heavy chain polypeptide, optionally wherein the HLA-B allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-B amino acid sequence depicted in figs. 13A- 13D;(iii) an HLA-C allele heavy chain polypeptide, optionally wherein the HLA-C allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-C amino acid sequence depicted in FIGS. 14A- 14D; or(iv) an HLA-E allele heavy chain polypeptide, optionally wherein the HLA-E allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%. at least 98%, or at least 99%, amino acid sequence identity to the HLA-E amino acid sequence depicted in FIGS. 15A- L5D or 16A-16D.

[0467] 8 Hie method of any one of aspects 1-7, wherein the TEP comprises a heterodimer, wherein the heterodimer comprises: a) a first polypeptide comprising: i) the peptide: and ii) the p2-microglobulin (]32M) polypeptide: and b) a second polypeptide comprising: i) the MHC class I heavy chain polypeptide; and ii) the immunoglobulin (Ig) Fc polypeptide; iii) the at least one B-cell targeting component; and iv) the optional one or more activating immunomodulatory polypeptides,wherein the TEP may comprise one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0468] 9. The method of aspect 8, wherein the heterodimer comprises a disulfide bond formed between a Cys residue in the |32M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide, and / or wherein tire heterodimer comprises a disulfide bond fonned between (i) a Cys residue in a Cys- containing linker interposed between the peptide and the [>2M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0469] 10. Hie method of aspect 8 or 9, wherein a) the first polypeptide of each heterodimer comprises, in order from N-terminus to C-tenninus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids: ii) a peptide linker; and iii) the P2M polypeptide; b) the second polypeptide of each heterodimer comprises, in order from N-terminus to C- terminus: i) the at least one B-cell targeting component; ii) the MHC class I heavy chain polypeptide; and iii) the Ig Fc polypeptide; and wherein the optional one or more activating immunomodulatory polypeptides, if present, may be positioned (i) between the at least one B-cell targeting component and MHC class I heavy chain polypeptide, (ii) between the MHC class I heavy chain polypeptide and Ig Fc polypeptide, or (iii) at the C terminus of the Ig Fc polypeptide, and wherein the second polypeptide may comprise independently selected peptide linkers between one or more components of the second polypeptide.

[0470] 11. The method of any one of aspects 8-10, wherein the TEP comprises a dimer of two heterodimeric TEPs.

[0471] 12. The method of aspect 11, wherein the first polypeptides of each heterodimer have the same amino acid sequence, and the second polypeptide of each heterodimer have the same amino acid sequences, and wherein the two heterodimers are joined together by one or more disulfide bonds (e.g., two disulfide bonds) formed between the Ig Fc polypeptides of each heterodimer.

[0472] 13. The method of aspect 11 or 12, wherein the TEP does not comprise an immunomodulatory polypeptide.

[0473] 14. The method of aspect 13. wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO:90, and a second polypeptide comprises the amino acid sequence of SEQ ID NO:89.

[0474] 15. The method of aspect 13. wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO:91, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:89.

[0475] 16. Hie method of aspect 11. wherein the first and / or second polypeptides of each heterodimer have a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second heterodimers comprise interspecific dimerization sequences that permit the two heterodimers to selectively dimerize.

[0476] 17. The method of aspect 16. wherein the TEP does not comprise an immunomodulatory polypeptide.

[0477] 18. The method of aspect 16 or 17, wherein the first and second heterodimeric TEPs comprise BCTCs that target different B cell antigens, wherein the TEP is capable of binding to each target antigen individually and / or simultaneously binding to both target antigens.

[0478] 19. The method of aspect 18, wherein one heterodimer of the TEP comprises a BCTC that targets B cells, and the other heterodimer of the TEP comprises a BCTC that targets plasmablasts and plasma cells.

[0479] 20. The method of aspect 19, wherein one heterodimer of the TEP comprises a BCTC that targets CD 19, and the other heterodimer of the TEP comprises a BCTC that targets BCMA.

[0480] 21. The method of aspect 20. wherein one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising tire amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the otherheterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360.

[0481] 22. Tire method of any one of aspectsl-13 or 16-18, wherein at least one of the one B- cell targeting component comprises an autoantigenic protein or an antigenic portion of an autoantigenic protein selected from desmoglein (DSG) proteins (including DSG1 and DSG3). BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO), PR3 (Proteinase-3), aquaporin-4, nicotinic acetylcholine receptor-1 (nAChR-1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG), Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

[0482] 23. The method of any one of aspects 1-22, wherein the individual has an autoimmune disorder or an immune -mediated inflammation disorder.

[0483] 24. The method of aspect 23. wherein the autoimmune disorder is an inflammatory bowel disease including ulcerative colitis, Crohn’s disease and irritable bowel syndrome, SLE, idiopathic inflammatory myositis, or systemic sclerosis.

[0484] 25. The method of aspect 23. wherein the immune -mediated inflammation disorder is acute or chronic graft versus host disease (GVHD), acute, hyperacute or chronic host versus graft disease (HVGD), or transplant rejection.

[0485] 26. Hie method of any one of aspects 23-25, further comprising the step of administering a vaccine to the patient to cause the production of T cells specific for the pMHC of the TEP.

[0486] 27. A T cell engaging protein (“TEP”), wherein the TEP comprises: i) a peptide-major histocompatibility complex (“pMHC”) comprising a peptide epitope, a [32- microglobulin (“|32M”) polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig”) Fc polypeptide; iii) at least one B-cell targeting component, wherein the B-cell targeting component comprises a protein or an antigenic portion of a protein that is an autoantigen; and iv) optionally one or more activating immunomodulatory polypeptides.

[0487] 28. The TEP of aspect 27, wherein at least one of the one B-cell targeting component comprises an autoantigenic protein or an antigenic portion of an autoantigenic protein selected from desmoglein (DSG) proteins (including DSG1 and DSG3), BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO). PR3 (Proteinase-3), aquaporin-4, nicotinic acetylcholine receptor-1 (nAChR-1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG), Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

[0488] 29. A dimeric T cell engaging protein (“TEP”), wherein the TEP comprises first and second constituent TEPs, wherein each constituent TEP comprises: i) a peptide-major histocompatibility complex (“pMHC”) comprising a peptide epitope, a [12- microglobulin (“|32M”) polypeptide, and an MEIC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig”) Fc polypeptide; iii) at least one B-cell targeting component; and iv) optionally one or more activating immunomodulatory polypeptides. wherein(i) the first constituent TEP and second constituent TEP comprise BCTCs that target different B cell antigens, wherein the TEP is able to bind to each target B cell antigen separately and / or simultaneously, optionally wherein one of the different BCTCs comprises a BCTC that targets B cells, and the other BCTC targets plasmablasts and plasma cells, and / or(ii) the first constituent TEP comprises a peptide epitope that is different from the peptide epitope of the second constituent TEP, wherein the Ig Fc polypeptides of the first and second heterodimeric TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two heterodimeric TEPs to selectively dimerize.

[0489] 30. The dimeric TEP of aspect 29, wherein each constituent TEP is a heterodimer that comprises: a) a first polypeptide comprising the peptide epitope and P2M polypeptide; b) a second polypeptide comprising,(i) the MHC class I heavy chain polypeptide;(ii) the Ig Fc polypeptide;(iii) at least one B-cell targeting component; and(iv) the optional one or more activating immunomodulatory polypeptides, wherein the TEP may comprise one or more independently selected peptide linkers between anytwo of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

[0490] 31. The dimeric TEP of aspect 29 or 30, wherein the B-cell targeting component of one constituent TEP binds to CD 19 and the B-cell targeting component of the other TEP binds to BCMA.

[0491] 32. The dimeric TEP of any one of aspects 28-31, wherein the dimeric TEP does not comprise an immunomodulatory polypeptide.

[0492] 33. Hie dimeric TEP of aspect 32, wherein one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360.

[0493] 34. A pharmaceutical composition comprising a TEP of aspects 27 or 28.

[0494] 35. A pharmaceutical composition comprising a dimeric TEP of any one of aspects29-33.

[0495] 36. A method of treating an individual to deplete autoreactive B cells, the method comprising administering to the individual a therapeutic amount of the pharmacal composition of aspect 34.

[0496] 37. A method according to aspect 36, wherein the individual has an autoimmune disorder or immune-mediated inflammation disorder.

[0497] 38. A method of treating an individual to deplete autoreactive B cells, the method comprising administering to the individual a therapeutic amount of the pharmaceutical composition of aspect 35.

[0498] 39. A method according to aspect 38, wherein the individual has an autoimmune disorder or immune-mediated inflammation disorder.EXAMPLES

[0499] Hie following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure and are not intended to limit the scope of the disclosure, nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pl. picoliter(s): s or sec, second(s): min, minute(s): h or hr. hour(s): aa. amino acid(s); kb, kilobase(s); bp, base pair(s): nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c., subcutaneous(ly); and the like.EXAMPLE 1: Production, Stability and Purity of T-cell Engaging Proteins (TEPs)

[0500] Plasmids containing nucleic acids for two TEPs of interest (see Table 3) were transfected into ExpiCHO cells and cultured for product expression. Upon harvest and media clarification, TEPs were purified through a standard two-step chromatography process and dialyzed into final product buffer prior to use. Tire first TEP comprised two heterodimeric TEPS, each comprising heavy chain 4656 (FIG. 17A) and light chain 1717 (FIG. 17B), and the second TEP comprised two heterodimeric TEPS, each comprising heavy chain 4656 (FIG. 17A) and light chain 4700 (FIG. 17C). Each heterodimeric TEP included: a heterodimeric pMHC. a body disulfide and linker disulfide, a scaffold component (an IgGl Fc polypeptide), an anti-CD19 scFv as the BCTC, and either a CMV peptide (pp65 95-503) or a SARS- CoV-2 (“SCV2”) peptide (YLQPRTFLL; SEQ ID NO: 166) as the peptide epitope. As shown in Table 3, both the dimeric CMV epitope TEP and the dimeric SCV2 epitope TEP exhibited good production, purity, and stability to frcczc-thaw. See also FIGS. 18A-18B (discussed below).Table 3

[0501] Polyacrylamide gel electrophoresis (SDS-PAGE) analysis was performed for the production of the dimeric TEP comprising two TEPs having a CMV peptide epitope (each 4656-1717), and the dimeric TEP comprising two TEPs having a SCV2 peptide epitope (each 4656-4700). Protein was loaded at 2.0 pg / lane under non-reducing (NR) and reducing (R) conditions. A protein standard (with molecular weights labeled) was loaded in a neighboring lane. Protein was visualized by Coomasie blue staining. Both dimeric TEPs show protein bands at the expected molecular weights under NR and R conditions (FIG. 18A). Analytical size-exclusion chromatography (SEC) shows good purity of the dimeric TEPs (FIG. 18B)Example 2: TEPs Specifically Bind to Target B Cell Antigen CD19

[0502] Three different dimeric TEPs were assayed to determine binding affinity to, and specificity for, the target B cell antigen CD 19, using Biolayer Interferometry (BLI). Each dimeric TEP comprised tw o TEPs. each TEP including: a heterodimeric pMHC with an HLA-A*02 allele MHC Class I heavy chain, a body disulfide and a linker disulfide, a scaffold component (an IgGl Fc polypeptide), a human or murine anti-CD19 BCTC, and a peptide epitope. Each dimeric TEP was tested at three different concentrations 200nM, lOOnM, and 50nM. The binding data for each TEP at each concentration was used to fit an equilibrium dissociation constant (KD).

[0503] The first dimeric TEP comprised two TEPs, each a 2X (4656-4700) construct (discussed above), including an anti -human CD 19 scFv as the BCTC and a SCV2 peptide as the peptide epitope (FIG. 19 top row, left). This dimeric TEP exhibited high binding affinity to target human CD 19 (FIG. 19 top row. middle: AD= 7.1xl0loM; R2= 0.98) and no detectable binding to mouse CD19 (FIG. 19 top row, right).

[0504] The second dimeric TEP comprised two TEPs, each a 2X (4656-1717) construct, discussed above, including an anti-human CD 19 scFv as the BCTC and a CMV peptide as the peptide epitope (FIG. 19 middle row, left). Tire dimeric TEP exhibited high binding affinity to target human CD 19 (FIG. 19 middle row, center: AD = 6.3xlOluM; R2= 0.98) and no detectable binding to mouse CD19 (FIG. 19 middle row. right).

[0505] The third dimeric TEP comprised two TEPs, each a construct comprising heavy chain 4720 (FIG. 17D) and light chain 4700 (FIG. 17C), including an anti -murine CD19 scFv as the BCTC and a SCV2 peptide as the peptide epitope (FIG. 19 bottom row', left). Tire dimeric TEP exhibited high binding affinity to target mouse CD19 (FIG. 19 bottom row', middle: AD = 1.4xlO’9M; R2= 0.95) and no detectable binding to human CD 19 (FIG. 19 bottom row, right).

[0506] Together, the results demonstrate that dimeric anti-CD19 TEPs can specifically bind to their respective target CD 19 antigen with high affinity.Example 3: TTEPs Specifically Bind to Target B Cell Antigen BCMA

[0507] Tire binding affinity of two dimeric anti-BCMA TEPs to target biotinylated human BCMA, biotinylated mouse BCMA. and control biotinylated human IL2J3R ligands was assayed using Biolayer Interferometry (BLI). Each TEP comprised a heterodimeric pMHC with an HLA-A*02 allele MHC Class I heavy chain, a body disulfide and a linker disulfide, a scaffold component (an IgGl Fc polypeptide), an anti-BCMA scFv that is cross-reactive to both human and murine BCMA as the BCTC, and a CMV peptide as the peptide epitope. Each dimeric TEP w'as tested at three different concentrations 200nM, lOOnM, and 50nM. The binding data for each TEP at each concentration was used to fit an equilibrium dissociation constant (AD).

[0508] The first dimeric TEP comprised two heterodimeric TEPS, each comprising heavy chain 4964 (FIG. 17E) and light chain 1717 (FIG. 17B). The second dimeric TEP comprised two heterodimeric TEPS, each comprising heavy chain 4965 (FIG. 17F) and light chain 1717 (FIG. 17B).

[0509] Hie first dimeric TEP (FIG. 20 top row) exhibited high binding affinity to target human BCMA (XD = 1.5xl0‘10M; R2= 0.99), high binding affinity to target murine BCMA ( D = 1. lxlOloM; R2= 0.99). but no detectable binding to human IL2[3R. The second dimeric TEP (FIG. 20 bottom row) exhibited high binding affinity to target human BCMA (XD= 1.2x1 OloM; R = 0.99), high binding affinity to target murine BCMA (XD= 2.5xlOloM; X2= 0.99), but no detectable binding to human IL2pR. Together, the results demonstrate that dimeric anti-BCMA TEPs can specifically bind to a target BCMA antigen with high affinity.Example 4: Dimeric TEPs Deplete CD19-Positive B Cells via Antigen-Specific CD8+T Cells

[0510] HLA-A*02:01-restricted Cytomegalovirus (CMV) pp65495-503-specific CD8+T cells were expanded using pp65495.503 peptide NLVPMVATV (SEQ ID NO: 141) (Elim Biopharma) from human peripheral blood mononuclear cells (PBMCs) of CMV-seropositive and HIV-seronegative healthy donors for 10 days in the presence of recombinant Interleukin-2 (IL-2), and negatively purified by EasySep™ Human CD8+T Cell Isolation Kit (STEMCELL Technologies). B cells were negatively purified by EasySep™ Human B Cell Isolation Kit (STEMCELL Technologies) from the same donors, and then labelled by CellTrace™ Violet (Thermo Fisher) dye. Purified CMV-specific CD8+T cells were mixed with purified and labelled B cells in ratio of 20 to 1 and incubated for 24 hours in the presence of various proteins at various concentrations.

[0511] Hie first dimeric TEP comprised two heterodimeric TEPS, each comprising heavy chain 4 18 (FIG. 17G) and light chain 1717 (FIG. 17B). Each heterodimeric TEP comprised a heterodimeric pMHC with an HLA-A*02 allele MHC Class I heavy chain, a body disulfide and a linker disulfide, a scaffold component (an IgGl Fc polypeptide), a human anti-CD19 BCTC, a CMV peptide epitope, and a reduced affinity MOD (an IL-2 polypeptide having H16A, F42A substitutions). The killing of B cells by this dimeric TEP is shown in empty circles in FIG. 21.

[0512] Hie second dimeric TEP comprised two heterodimeric TEPS, each comprising heavy chain 4518 (FIG. 17G) and light chain 3598 (FIG. 17H). Each heterodimeric TEP comprised a heterodimeric pMHC with an HLA-A*02 allele MHC Class I heavy chain, a body disulfide and a linker disulfide, a scaffold component (an IgGl Fc polypeptide), a human anti-CD19 BCTC, an HIV peptide epitope, and a reduced affinity MOD (an IL-2 polypeptide having H16A, F42A substitutions). The killing of B cells by this dimeric TEP is shown in filled squares in FIG. 21.

[0513] Hie third dimeric TEP comprised two heterodimeric TEPS. each comprising heavy chain 4656 (FIG. 17A) and light chain 1717 (FIG. 17B), as discussed above. Each heterodimeric TEP comprised aheterodimeric pMHC with an HLA-A*02 allele MHC Class I heavy chain, a body disulfide and a linker disulfide, a scaffold component (an IgGl Fc polypeptide), a human anti-CD19 BCTC, and a CMV peptide epitope. The third dimeric TEP did not include a MOD. Tire killing of B cells by this dimeric TEP is shown in filled triangles in FIG. 21.

[0514] Tire fourth dimeric TEP comprised two heterodimeric TEPS, each comprising heavy chain 4656 (FIG. 17A) and light chain 3598 (FIG. 17H). Each heterodimeric TEP comprised a heterodimeric pMHC with an HLA-A*02 allele MHC Class I heavy chain, a body disulfide and a linker disulfide, a scaffold component (an IgGl Fc polypeptide), a human anti-CD19 BCTC, and an HIV peptide epitope. Tire fourth dimeric TEP did not include a MOD. Tire killing of B cells by this dimeric TEP is shown in inverted filled triangles in FIG. 21.

[0515] Tire experiment included killing of B cells by an anti-CD19 / anti-CD3 BiTE shown in empty squares (InvivoGen, catalog No. bimab-hcdl9cd3) as a positive control and no observed killing by anti- (3-Gal / anti-CD3 BiTE shown in filled circles (InvivoGen, catalog No. bimab-bgalhcd3) as a negative control.

[0516] After 24 hours, cells were harvested, stained and analyzed by flow cytometry. Dimeric anti- CD19 TEPs with CMV peptide-MHC, both with IL-2 and without IL-2, exhibited effective killing of CD 19-positive B cells. Dimeric anti-CD19 TEPs with HIV peptide-MHC without IL-2 demonstrated no killing at all concentrations tested, while dimeric anti-CD19 TEPs with HIV peptide-MHC with IL-2 showed modest killing at higher concentrations, likely due to the increased concentration of IL-2. These experiments indicate that dimeric TEPs can mediate substantial depletion of CD 19-positive B cells via killing by antigen-specific CD8+ T cells.Example 5: Anti-CD19 TEPs Mediate Redirected Killing of CD19+Cells with Reduced Production of Proinflammatory Cytokines

[0517] The cell culture supernatants from the corresponding wells of the cytotoxicity assay in Example 4 were collected and the concentrations of the proinflammatory cytokines IFN-gamma and TNF-alpha were measured by MesoScale Discovery (MSD) assay (FIG. 22). The anti-CD19 / anti-CD3 BiTE Blinatumomab (InvivoGen, catalog No. bimab-hcdl9cd3) caused significantly increased secretion of IFN-gamma and TNF-alpha relative to the dimeric anti-CD19 TEP with a CMV pMHC, i.e., 2X (4656- 1717). A dimeric anti-CD19 TEP with an HIV pMHC, i.e.. 2X (4656-3598), demonstrated no secretion of these proinflammatory cytokines at all concentrations tested. Anti-CD19 TEPs are thus able to mediate similar redirected killing of B cells but with far less inflammatory cytokine production than a BiTE molecule.Example 6: Redirected Killing of B Cells by Anti-CD19 TEPs Occurs at Low Frequencies of Antigen-Specific T Cells

[0518] HLA-A*02:01-restricted Cytomegalovirus (CMV) pp65495-503” specific CD8 T cells were expanded using pp65495.503 peptide NLVPMVATV (SEQ ID NO: 141) from human peripheral blood mononuclear cells (PBMCs) of CMV-seropositive and HIV-seronegative healthy donors for 10 days in the presence of recombinant Interleukin-2 (IL-2). Expanded CD8+T cells were then negatively purified by EasySep™ Human CD8+T Cell Isolation Kit (STEMCELL Technologies). Additional non-expanded CD8+T cells were also directly negatively purified from freshly thawed autologous PBMCs, and B cells were negatively purified from freshly thawed autologous PBMCs and then labelled with CellTrace™ Violet (CTV) dye. The purified CD8+T cells expanded by the CMV peptide / IL-2 were mixed with both the non-expanded CD8+T cells and the CTV -labelled purified B cells to obtain different ratios of effector CMV-specific CD8+T cells to target B cells (i.e.. ratios of 0.1: 1, 0.04: 1 and 0.08: 1) and incubated for 48 hours in the presence of an anti-CD19 TEP with a CMV pMHC. i.e.. 2X (4656-1717). at a range of concentrations (FIG. 23). At 48 hours the cells were harvested and analyzed by flow cytometry. Efficient dose-dependent killing of B cells was observed at all three effector-to-target ratios, highlighting the effective redirected killing by anti-CD19 TEPs at extremely low ratios of the effector cells to the target cells.Example 7: Anti-CD19 TEPs Specifically Bind B Cells via Anti-CD19 BCTC

[0519] Freshly thawed PBMCs from healthy human donors were treated with serially diluted proteins of a dimeric anti-CD19 TEP with a CMV pMHC, i.e., 2X (4656-1717), a dimeric anti-CD19 TEP with a SARS-CoV-2 pMHC. i.e., 2X (4656-4700). and a construct having a CMV pMHC but no anti-CD19 BCTC (IST-3438- 1717) for 30 minutes on ice. The amino acid sequence for construct 3438 is provided as FIG. 34A. After incubation, unbound protein was washed off. Anti-Human IgG secondary antibody conjugated to AF488 (Jackson Immunoresearch) was added to detect the Fc region of bound TEPs. Cells were then fixed to preserve binding and permeabilized to enable antibody detection of intracellular and extracellular marker antigens and samples were acquired by flow cytometry. At the range of the concentrations tested, only the molecules with anti-CD19 TEPs, both the dimeric anti-CD19 TEPs with a CMV pMHC, 2X (4656-1717), and the dimeric anti-CD19 TEPs with a SARS-CoV-2 pMHC, 2X (4656- 4700), show a dose-dependent binding to only the B cells, but not other cells in the PBMCs, including NK cells, CD8+T cells, total CD4+T cells and FOXP3+CD4+regulatory T cells (Treg) (FIG. 24). The construct having a CMV pMHC but no anti-CD19 BCTC, i.e., 2X (3438-1717), shows no binding to any of these five cell populations. Hie data indicates that the selective binding of TEPs to B cells occurs via the anti-CD19 BCTC.Example 8: Anti-CD19 TEPs Redirect Unstimulated CMV-Specific T Cells to Selectively Kill B Cells among PBMCs

[0520] PBMCs from CMV-seropositive and HIV-seronegative healthy donors with preexisting CMV- specific CD8+T cells were thawed from frozen vials and treated with a range of concentrations of the dimeric anti-CD19 TEP with CMV pMHC, i.e.. 2X (4656-1717) or the dimeric anti-CD19 TEP with HIV pMHC, i.e., 2X (4656-3598). Cells were harvested following 72, 96 and 120 hours of incubation and stained and analyzed by flow cytometry. While no killing of B cells was observed by either tested TEP following 72 to 96 hours, the dimeric anti-CD19 TEP with CMV pMHC, 2X (4656-1717), demonstrated concentration -dependent killing of B cells at 120 hours, while the dimeric anti-CD19 TEP with HIV pMHC, 2X (4656-3598) did not affect the number of B cells (FIG. 25). An anti-CD19 / anti- CD3 BiTE Blinatumomab (InvivoGen, catalog No. bimab-hcdl9cd3) served as a positive control for B- cell killing in all conditions, while no killing of B cells was observed with an anti-(3-Gal / anti-CD3 BiTE (InvivoGen, catalog No. bimab-bgalhcd3). These experiments provide evidence that dimeric TEPs can mediate substantial killing of CD 19-positive B cells by unstimulated antigen-specific CD8+T cells in PBMCs.

[0521] At the 120-hour time point, the relative frequency of other major lineages in PBMCs, including the CD8+T cells, the CD4+T cells and NK cells, are generally unchanged following exposure to the dimeric anti-CD19 TEP with CMV pMHC. 2X (4656-1717), further demonstrating the selectivity of the TEPs toward B cells without disturbing other major immune cell subsets in the PBMCs (FIG. 26).Example 9: Single-Dose PK Assessment of Murine Surrogate Anti-CD19 TEP 2X (4720-4700)

[0522] A surrogate anti-CD19 TEP comprising a human IgGl Fc, bivalent human HLA, a peptide from SARS-CoV2. and bivalent anti-murine CD19 scFv. i.e.. 2X (4720-4700) was tested in a single intravenous dose pharmacokinetics study in Albino C57B1 / 6 female mice at dose levels of 3 or 10 mg / kg. Serum samples were harvested at scheduled timepoints of 5 minutes, 2 hours, 6 hours, and 24 hours post- dosc to measure scrum exposure levels of TEP 2X (4720-4700). A ligand binding assay was performed to quantify TEP 2X (4720-4700) concentrations in serum at each timepoint by capturing with an antihuman beta-2 -microglobulin antibody and detecting via an anti -human IgG antibody (FIG. 27). The mean (+ / - SD) serum concentration over time results show that TEP 2X (4720-4700) remains detectable in mouse serum for at least 24 hours post-dose with a dose-dependent increase in measurable test article when escalating from 3 to 10 mg / kg.I l lExample 10: Murine Surrogate Anti-CD19 TEP 2X (4720-4700) Displays Durable CD19 Target Engagement In Vivo

[0523] Target engagement of murine CD 19 on B cells in vivo was measured following a single dose of the surrogate anti-CD19, TEP 2X (4720-4700). Albino C57B1 / 6 mice received a single intravenous dose of either 3 mg / kg or 10 mg / kg of TEP 2X (4720-4700) and binding to B cells was monitored in peripheral blood mononuclear cells (PBMCs) at 24, 96, 192, 240, and 336 hours post-dose. PBMCs were isolated at each timepoint and simultaneous fluorescent staining of CD 19 and CD20 on B cells were measured using flow cytometry (FIG. 28). Since the CD 19 antibody clone used for flow staining is the same as the scFv of TEP 2X (4720-4700), in vivo binding of TEP 2X (4720-4700) to CD19 on B cells will result in reduced binding of the fluorescent anti-CD19 flow detection antibody. Thus, quantitating the reduction in geometric mean fluorescent (gMFI) intensity of anti-CD19 staining on B cells provides a measure of CD19 target engagement by TEP 2X (4720-4700). The gMFI of CD19 and CD20 staining was nonnalized at each timepoint by calculating the gMFI of CD 19 or CD20 staining on B cells relative to the average of the gMFI of CD 19 or CD20 staining on B cells from vehicle-treated animals. As shown in FIG. 28. both 3 mg / kg and 10 mg / kg dose levels of TEP 2X (4720-4700) exhibited binding to CD19 in vivo, with complete engagement of CD 19 target on the surface of B cells for at least 96 hours following a 3 mg / kg dose and for at least 240 hours following a 10 mg / kg dose. The relative gMFI of CD20 was unchanged over all the time points, confinning the specificity of this detection method.Example 11: Murine Surrogate Anti-CD19 TEP 2X (4720-4700) Selectively Depletes CD19+ B Cells via Antigen-Specific CD8+ T Cells In Vivo

[0524] HLA-A2 transgenic mice were first immunized with SARS-CoV2 peptide, a CD4 helper peptide, and CpG adjuvant to expand a population of SARS-CoV2-specific CD8+ T cells that the human pMHC of TEP 2X (4720-4700) could subsequently stimulate. The ability of TEP 2X (4720-4700) to redirect SARS-CoV2 antigen-specific CD8+ T cells to kill CD19+ B cells was tested by measuring lymphocyte counts in the spleens of immunized mice that had been treated with Vehicle or with 3 mg / kg of TEP 2X (4720-4700). As shown, seven days following the second dose the total number of B cells was significantly reduced in the spleens of SARS-CoV2 immunized animals that received TEP 2X (4720- 4700) compared to Vehicle treated mice (FIG. 29). In contrast, there was no difference in total numbers of either CD3+ T cells or CD1 lb+ monocytes, neither of which express CD19, following treatment in this study. Importantly, mice that were not immunized with SARS-CoV2 peptide also did not demonstrate reduced numbers of B cells in their spleens following treatment with TEP 2X (4720-4700). Together, these results support a conclusion that TEP 2X (4720-4700) redirected SARS-CoV2-specific CD8+ T cells to selectively kill CD 19+ B cells while not impacting numbers of other immune cell types that do not express CD 19.Example 12: Anti-BCMA TEPs Redirect Killing of BCMA-Positive B Cells by Antigen-Specific CD8+T Cells

[0525] HLA-A* 02: 01 -restricted Cytomegalovirus (CMV) pp65495-503” specific CD8 T cells were expanded using pp65 95.503 peptide NLVPMVATV (SEQ ID NO: 141) from human peripheral blood mononuclear cells (PBMCs) of CMV-seropositive and HIV-seronegative healthy donors for 10 days in the presence of recombinant Interleukin-2 (IL-2). Expanded CD8+T cells were then negatively purified by EasySep™ Human CD8+T Cell Isolation Kit (STEMCELL Technologies). A BCMA+immortalized multiple myeloma B cell line (RPMI-8226 cells; ATCC) was labelled with CellTrace™ Violet dye. and the purified CD8+T cells expanded by the CMV peptide / IL-2 were mixed with the labelled RPMI-8226 cells at a ratio of 20 to 1 and incubated for 48 hours in the presence of various proteins at a range of concentrations (FIG. 30). Anti-BCMA / anti-CD3 BiTE Pacanalotamab (InvivoGen, catalog No. bimab- bcmacd3-05) served as a positive control for BCMA+B-cell killing, while the anti-p-Gal / anti-CD3 BiTE (InvivoGen, catalog No. bimab-bgalhcd3) served as the negative control and demonstrated an absence of BCMA+B cell killing. Anti-BCMA TEP with CMV pMHC (TEP 2X (4964-1717)) demonstrated potent redirected killing of B cells in a dose-dependent manner while anti-BCMA TEP with HIV pMHC (TEP 2X (4964-3598)) showed no killing at the tested concentrations, confirming the TEP induced selective redirected killing of BCMA+B cells by CMV-specific CD8 T cells.Example 13: Redirected Killing of BCMA-Positive B Cells by Anti-BCMA TEPs Occurs at Low Frequencies of Antigen-Specific T Cells

[0526] HLA-A* 02: 01 -restricted Cytomegalovirus (CMV) pp65495-503-specific CD8+T cells were expanded using pp65495.503 peptide NLVPMVATV (SEQ ID NO: 141) from human peripheral blood mononuclear cells (PBMCs) of CMV-seropositive and HIV-seronegative healthy donors for 10 days in the presence of recombinant Interleukin-2 (IL-2). Expanded CD8+T cells were then negatively purified by EasySep™ Human CD8+T Cell Isolation Kit (STEMCELL Technologies). Additional non-expanded CD8+T cells were also directly negatively purified from freshly thawed autologous PBMCs and mixed with both the purified CD8+T cells expanded by the CMV peptide / IL-2 and CTV-labelled BCMA+RPMI-8226 B cells to obtain different ratios of effector CMV-specific CD8+T cells to target RPMI-8226 B cells (i.e. ratios of 2.3: 1, 0.6: 1 and 0.3: 1) and incubated for 72 hours in the presence of anti-BCMA TEP with CMV pMHC, TEP 2X (4964-1717), at a range of concentrations. At 72 hours the cells were harvested and analyzed by flow cytometry. Efficient dose-dependent killing of BCMA+RPMI-8226 B cells was observed at all three effector-to-target ratios, highlighting the effective killing in vitro by anti- BCMA TEPs at extremely low ratios of the effector cells to the target cells (FIG. 31).EXAMPLE 14: Production, Stability and Purity of a Dual-Targeting TEP Having Two Different BCTCs

[0527] Using a three-chain transfection, a TEP having an anti-CD19 BCTC and an anti-BCMA BCTC was prepared in ExpiCHO cells and cultured for product expression. Upon harvest and media clarification, TEPs were purified through a standard two-step chromatography process and dialyzed into final product buffer prior to use. See Table 4. The TEP comprises a heterodimer of two different heterodimeric TEPs, i.e., TEP 5026-1717 and TEP 5027-1717, which are joined together through “Knobin-Hole” interspecific dimerization sequences (discussed above). Hie amino acid sequence of the heavy chain 5026 is provided as FIG. 32B and the amino acid sequence of tlie heavy chain 5027 is provided as FIG. 32C. Each heterodimeric TEP included: a heterodimeric pMHC, a body disulfide and linker disulfide, a scaffold component (an IgGl Fc polypeptide), an anti-BCMA scFv BCTC (in TEP 5026- 1717) or an anti-CD19 scFv BCTC (in TEP 5027-1717), and a CMV peptide (pp65495-503) as the peptide epitope. As shown in Table 4, the TEP exhibited good production, purity, and stability to frcczc-thaw.Table 4

[0528] Polyacrylamide gel electrophoresis (SDS-PAGE) analysis as described in Example 1 was performed for the production of TEP (5026-5027-1717). Protein was loaded at 2.0 pg / lane under nonreducing (NR) and reducing (R) conditions. A protein standard (with molecular weights labeled) was loaded in a neighboring lane. Protein was visualized by Coomasie blue staining. Both dimeric TEPs show protein bands at the expected molecular weights under NR and R conditions (FIG. 33 A).Analytical size-exclusion chromatography (SEC) shows good purity of the dimeric TEPs (FIG. 33B).Example 15: TEPs Specifically Bind to Target B Cell Antigens CD19 and BCMA

[0529] Two different dimeric TEPs, i.e., 2X (4656-1717) and 2X (4964-1717). both discussed above, and dual-targeting TEP (5026-5027-1717), were assayed to determine binding affinity to, and specificity for, the target B cell antigens CD 19 and BCMA, using Biolayer Interferometry (BLI). Each dimeric TEP was tested at three different concentrations 200nM, lOOnM, and 50nM. The binding data for each TEP at each concentration was used to fit an equilibrium dissociation constant (XD).

[0530] The first dimeric TEP, 2X (4656-4700), exhibited high binding affinity to target human CD 19 (FIG. 34 top row, left; D = 5.3xl010M; R2= 0.97). and no detectable binding to human BCMA (FIG. 34 top row, right).

[0531] Tire second dimeric TEP. 2X (4656-1717), exhibited high binding affinity to target human BCMA (FIG. 34 middle row, left; XD = 1. lxlOloM; X2= 0.99) and no detectable binding to human CD 19 (FIG. 34 middle row, right).

[0532] The dual -targeting TEP (5026-5027-1717) exhibited high binding affinity to target human CD 19 (FIG. 34 bottom row, left; XD = 8.4xlOloM; R = 0.99), and high binding affinity to human BCMA (FIG. 34 bottom row. right; XD= 1.2xlQ-9M; R2= 0.99).

[0533] Together, the results demonstrate that a TEP comprising two different BCTCs (here, anti-CD19 and anti-BCMA) can specifically bind to both of its target B cell antigens with high affinity, and without interfering with the binding to either target B cell antigen.Example 16: Dual-Targeting TEPs Can Bind to both Target B Cell Antigens Simultaneously

[0534] An MSD assay was developed to detect the dual binding of the dual -targeting TEP (5026-5027- 1717). Human CD19 was coated onto the QuickPlex® 96-Well High Bind Plate (MSD) at 100 nM. After blocking with the blocking buffer (StartingBlock from ThermoFisher), 0, 10, 50, 100 nM of the three TEPs from Example 15 were added to the plate and the plate was incubated on a room -temperature shaker (750 rpm) for 1 hour. Unbound TEPs were washed using the PBST buffer (PBS supplemented with 0.05% Tween 20). Then 100 nM of biotinylated-BCMA was added to the plate and the plate was incubated on a shaker for 1 hour. After washing, Streptavidin SULFO-TAG was added to the plate and the plate was incubated on a shaker for 1 hour. After washing, 2x reading buffer was added to the plateand the plate was immediately read on the plate reader (MESO QuickPlex SQ 120). The results were analyzed based on the MSD signal (FIG. 35). The dual -targeting TEP (5026-5027-1717) showed a strong MSD signal with 10, 50, and 100 nM. As expected, the other two TEPs, i.e.. 2X (4656-1717) and 2X (4964-1717), both gave weak or no signal. The results demonstrate that TEPs comprising two different BCTCs (here again, anti-CD19 and anti-BCMA) can simultaneously specifically bind to two different B cell antigens with high affinity, and without interfering with the binding to either target B cell antigen.Example 17: Dual-Targeting Anti-CD19 / anti-BCMA TEPs Redirect Killing of Both CD19- Positive Cells and BCMA-Positive Cells by Antigen-Specific CD8+T Cells

[0535] The cell line K-562 (ATCC), which is negative for the expression of CD19 and BCMA, was engineered to express either human CD 19 or human BCMA via lentiviral transduction. The lentivirus was generated by transfection of Lcnti-X 293T cells (Takara) with the lentiviral transfer plasmids pLVX- EFlalpha-IRES-Puro containing either human CD19 transgene (i.e., K-562 / CD19+) or human BCMA transgene (i.e., K562 / BCMA1) (Azenta).

[0536] HLA-A* 02: 01 -restricted Cytomegalovirus (CMV) pp65495-503-specific CD8+T cells were expanded using pp65t, _503 peptide NLVPMVATV (SEQ ID NO: 141) from human peripheral blood mononuclear cells (PBMCs) of CMV-seropositive and HIV-seronegative healthy donors for 10 days in the presence of recombinant Interleukin-2 (IL-2). Expanded CD8+ T cells were then negatively purified by EasySep™ Human CD8+T Cell Isolation Kit (STEMCELL Technologies). The K-562 / CD 19 and K562 / BCMA+cells were independently labelled with CellTrace™ Violet dye. The purified CD8 T cells expanded by the CMV peptide / IL-2 were mixed with either the labelled K-562 / CD 19+cells or the labelled K562 / BCMA+cells at a ratio of 20 to 1 and incubated for 48 hours in the presence of various proteins at a range of concentrations. Cells were harvested at 48 hours and analyzed by flow cytometry (FIG. 36). As seen in FIG. 36, dual-targeting anti-CD19 / anti-BCMA TEP with CMV pMHC, i.e., TEP (5026-5027-1717) discussed above, demonstrated dose-dependent killing of both the K-562 / CD194cells and the K562 / BCMA cells, while a dual-targeting anti-CD19 / anti-BCMA TEP with an HIV pMHC, i.e.. TEP (5026-5027-3598), failed to kill either the K-562 / CD19+cells or the K562 / BCMA+cells.

[0537] As controls, the dimeric anti-CD19 TEP with a CMV pMHC, i.e., 2X (4656-1717) was only able to kill the K-562 / CD 19 cells but not K562 / BCMA+cells, and the dimeric anti-BCMA TEP with a CMV pMHC, i.e., 2X (4964-1717), was only able to kill the K562 / BCMA+cells but not K-562 / CD19+cells. Due to the absence of HIV-specific CD8+T cells in healthy donors, both the dimeric anti-CD19 TEP with an HIV pMHC, i.e., 2X (4656-3598), and the dimeric anti-BCMA TEP with an HIV pMHC. i.e., 2X (4964-3598) did not cause significant killing of either the K-562 / CD19+cells or the K562 / BCMA+cells. Additional experimental controls included the killing of only the K562 / BCMA+cells but not the K-562 / CD19+cells by an anti-BCMA / anti-CD3 BiTE Pacanalotamab (InvivoGen, catalog No. bimab- bcmacd3-05) and the killing of only the K-562 / CD19+cells but not the K562 / BCMA+cells by an anti- CD19 / anti-CD3 BiTE Blinatumomab (InvivoGen, catalog No. bimab-hcdl9cd3). Together, these results demonstrated that the dual-targeting anti-CD19 / anti-BCMA TEP with a CMV pMHC, TEP (5026-5027- 1717), is capable of redirecting CMV-specific CD8+T cells to kill both CD 19-positive target cells and BCMA -positive target cells, thus demonstrating that dual -targeting TEPs can broaden the scope of the targetable B cell lineage.

[0538] While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

1. CLAIMSWhat is claimed is:

1. A method of treating an individual to deplete autoreactive B cells, the method comprising administering to the individual a therapeutic amount of a T cell engaging protein (“TEP”), wherein the TEP comprises: i) a peptide-major histocompatibility complex (“pMHC”) comprising a peptide epitope, a P2- microglobulin (“P2M”) polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin C‘Ig”) Fc polypeptide; iii) at least one B-cell targeting component; and iv) optionally one or more activating immunomodulatory polypeptides, wherein each of the at least one B-cell targeting components of the TEP binds to a B cell binding partner on a B cell, a plasmablast, and / or a plasma cell.

2. The method of claim 1, wherein the at least one B-cell targeting component comprises:(i) an antibody or antigen-binding portion of an antibody that binds to a binding partner on a B cell, a plasmablast, and / or a plasma cell, and / or(ii) an autoantigen or antigenic portion of an autoantigen.

3. The method of claim 2, wherein the at least one B-cell targeting component comprises:(i) an antibody or antigen-binding portion of an antibody that binds to CD 19, CD20, CD21, CD40, B cell maturation antigen (BCMA), CD38, CD79a, CD79b, CD138, and / or CD139; and / or(ii) an autoantigen or antigenic portion of an autoantigen selected from desmoglein (DSG) proteins (including DSG1 and DSG3), BP 180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO), PR3 (Proteinase-3), aquaporin-4, nicotinic acetylcholine receptor- 1 (nAChR- 1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Gly coprotein (MAG), Proteolipid Protein (PLP), Thy roglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

4. The method of claim 3, wherein the Ig Fc polypeptide is an IgGl Fc polypeptide, optionally wherein the Ig Fc polypeptide is a variant having one or more substitutions that reduce or substantially eliminate effector function.

5. The method of claim 4, wherein the pMHC presents an epitope of a pathogen-infected cell, optionally wherein the pMHC presents an epitope of a virus-infected cell or a bacteria-infected cell.

6. The method of claim 5, wherein the pMHC presents an epitope of a cell infected with a virus selected from CMV, influenza, EBV or SARS-CoV2.

7. The method of claim 5. wherein the P2M polypeptide, wherein the P2M polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to 21-119 of any one of the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein the MHC class I heavy chain is selected from:(i) an HLA-A allele heavy chain polypeptide, optionally wherein the HLA-A allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%. at least 98%, or at least 99%, amino acid sequence identity to the HLA-A amino acid sequence depicted in in any one of FIGS. 7A-7E, 8A-8E, 9A-9E, 10A-10E, 11A-11E and 12A-12D;(ii) an HLA-B allele heavy chain polypeptide, optionally wherein the HLA-B allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-B amino acid sequence depicted in figs. 13A- 13D;(iii) an HLA-C allele heavy chain polypeptide, optionally wherein the HLA-C allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the HLA-C amino acid sequence depicted in FIGS. 14A- 14D; or(iv) an HLA-E allele heavy chain polypeptide, optionally wherein the HLA-E allele heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%. at least 98%, or at least 99%, amino acid sequence identity to the HLA-E amino acid sequence depicted in FIGS. 15A- L5D or 16A-16D.

8. The method of claim 7. wherein the TEP comprises a heterodimer, wherein the heterodimer comprises: a) a first polypeptide comprising: i) the peptide: and ii) the P2 -microglobulin (P2M) polypeptide; and b) a second polypeptide comprising: i) the MHC class I heavy chain polypeptide; and ii) the immunoglobulin (Ig) Fc polypeptide; iii) the at least one B-cell targeting component; and iv) the optional one or more activating immunomodulatory polypeptides,wherein the TEP may comprise one or more independently selected peptide linkers between any two of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides optionally may be connected by one or more independently selected peptide linkers.

9. The method of claim 8, wherein the heterodimer comprises a disulfide bond formed between a Cys residue in the f)2M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide, and / or wherein the heterodimer comprises a disulfide bond fonned between (i) a Cys residue in a Cys- containing linker interposed between the peptide and the 2M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.

10. The method of claim 9, wherein a) the first polypeptide of each heterodimer comprises, in order from N-terminus to C-tenninus: i) the peptide, optionally wherein the peptide epitope has a length of 8-12 amino acids: ii) a peptide linker; and iii) the P2M polypeptide; b) the second polypeptide of each heterodimer comprises, in order from N-terminus to C- terminus: i) the at least one B-cell targeting component; ii) the MHC class I heavy chain polypeptide; and iii) the Ig Fc polypeptide; and wherein the optional one or more activating immunomodulatory polypeptides, if present, may be positioned (i) between the at least one B-cell targeting component and MHC class I heavy chain polypeptide, (ii) between the MHC class I heavy chain polypeptide and Ig Fc polypeptide, or (iii) at the C terminus of the Ig Fc polypeptide, and wherein tire second polypeptide may comprise independently selected peptide linkers between one or more components of the second polypeptide.

11. Hie method of claim 10, wherein the TEP comprises a dimer of two heterodimeric TEPs.

12. The method of claim 11, wherein the first polypeptides of each heterodimer have the same amino acid sequence, and the second polypeptide of each heterodimer have the same amino acid sequences, and wherein the two heterodimers are joined together by one or more disulfide bonds formed between the Ig Fc polypeptides of each heterodimer.

13. The method of claim 12, wherein the TEP does not comprise an immunomodulatory polypeptide.

14. The method of claim 13, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO:90, and a second polypeptide comprises the amino acid sequence of SEQ ID NO:89.

15. Hie method of claim 13, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 91, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:89.

16. The method of claim 11, wherein the first and / or second polypeptides of each heterodimer have a different amino acid sequence, and wherein the Ig Fc polypeptides of the first and second heterodimers comprise interspecific dimerization sequences that permit the two heterodimers to selectively dimerize.

17. The method of claim 16, wherein the TEP does not comprise an immunomodulatory polypeptide.

18. The method of claim 17, wherein the first and second heterodimeric TEPs comprise BCTCs that target different B cell antigens, wherein the TEP is capable of binding to each target antigen individually and / or simultaneously binding to both target antigens.

19. Hie method of claim 18, wherein one heterodimer of the TEP comprises a BCTC that targets B cells, and the other heterodimer of the BCTC targets plasmablasts and plasma cells.

20. Hie method of claim 19, wherein one heterodimer of the TEP comprises a BCTC that targets CD 19. and the other heterodimer of the TEP comprises a BCTC that targets BCMA.

21. The method of claim 20, wherein one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NQ:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, orone heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360.

22. The method of claim 10, wherein at least one of the one B-cell targeting component comprises an autoantigenic protein or an antigenic portion of an autoantigenic protein selected from desmoglein (DSG) proteins (including DSG1 and DSG3). BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO). PR3 (Proteinase-3), aquaporin-4. nicotinic acetylcholine receptor-1 (nAChR-1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG), Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

23. Tire method of claim 14 or 15, wherein the individual has an autoimmune disorder or an immune-mediated inflammation disorder.

24. The method of claim 23, wherein the autoimmune disorder is an inflammatory bowel disease including ulcerative colitis, Crohn’s disease and irritable bowel syndrome, SLE, idiopathic inflammatory myositis, or systemic sclerosis.

25. The method of claim 23, wherein the immune-mediated inflammation disorder is acute or chronic graft versus host disease (GVHD), acute, hyperacute or chronic host versus graft disease (HVGD), or transplant rejection.

26. The method of claim 23, further comprising the step of administering a vaccine to the patient to cause the production of T cells specific for the pMHC of the TEP.

27. A T cell engaging protein ("TEP"). wherein the TEP comprises: i) a peptide-major histocompatibility complex f‘pMHC”) comprising a peptide epitope, a P2- microglobulin (“P2M’’) polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig”) Fc polypeptide; iii) at least one B-cell targeting component, wherein the B-cell targeting component comprises a protein or an antigenic portion of a protein that is an autoantigen; and iv) optionally one or more activating immunomodulatory polypeptides.

28. The TEP of claim 27, wherein at least one of the one B-cell targeting component comprises an autoantigenic protein or an antigenic portion of an autoantigenic protein selected from desmoglein (DSG) proteins (including DSG1 and DSG3), BP180, BP230, insulin, Glutamic Acid Decarboxylase (GAD65), myeloperoxidase (MPO). PR3 (Proteinase-3), aquaporin-4, nicotinic acetylcholine receptor-1 (nAChR-1), Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Myelin-Associated Glycoprotein (MAG), Proteolipid Protein (PLP), Thyroglobulin, Rheumatoid factor (RF), Ro / SSA, La / SSB, and Centromere Protein B (CENP-B).

29. A dimeric T cell engaging protein (“TEP”), wherein the TEP comprises first and second constituent TEPs. wherein each constituent TEP comprises: i) a peptide-major histocompatibility complex (“pMHC”) comprising a peptide epitope, a 2- microglobulin (“02M”) polypeptide, and an MHC class I heavy chain polypeptide; ii) an immunoglobulin (“Ig”) Fc polypeptide; iii) at least one B-cell targeting component; and iv) optionally one or more activating immunomodulatory polypeptides. wherein(i) the first constituent TEP and second constituent TEP comprise BCTCs that target different B cell antigens, wherein the TEP is able to bind to each target B cell antigen separately and / or simultaneously, optionally wherein one of the different BCTCs comprises a BCTC that targets B cells, and the other BCTC targets plasmablasts and plasma cells, and / or(ii) the first constituent TEP comprises a peptide epitope that is different from the peptide epitope of the second constituent TEP, wherein the Ig Fc polypeptides of the first and second heterodimeric TEPs comprise interspecific dimerization sequences, optionally “Knob-in-Hole” sequences that permit the two heterodimeric TEPs to selectively dimerize.

30. The dimeric TEP of claim 29, wherein each constituent TEP is a heterodimer that comprises: a) a first polypeptide comprising the peptide epitope and 02M polypeptide; b) a second polypeptide comprising,(i) the MHC class I heavy chain polypeptide;(ii) the Ig Fc polypeptide;(iii) at least one B-cell targeting component; and(iv) the optional one or more activating immunomodulatory polypeptides, wherein the TEP may comprise one or more independently selected peptide linkers between anytwo of the components, and wherein when the TEP comprises more than one activating immunomodulatory polypeptide, the activating immunomodulatory polypeptides may be connected by one or more independently selected peptide linkers.

31. The dimeric TEP of claim 30, wherein the B-cell targeting component of one constituent TEP binds to CD 19 and the B-cell targeting component of the other TEP binds to BCMA.

32. Hie dimeric TEP of claim 30, wherein the dimeric TEP does not comprise an immunomodulatory polypeptide.

33. The dimeric TEP of claim 32, wherein one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360, or one heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:90 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:359, and the other heterodimer comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO:96 and a second polypeptide comprising the amino acid sequence of SEQ ID NO:360.

34. A pharmaceutical composition comprising a TEP of claims 27 or 28.

35. A pharmaceutical composition comprising a dimeric TEP of any one of claims 29-33.

36. A method of treating an individual to deplete autoreactive B cells, the method comprising administering to the individual a therapeutic amount of the pharmaceutical composition of claim 34.

37. A method according to claim 36, wherein the individual has an autoimmune disorder or immune-mediated inflammation disorder.

38. A method of treating an individual to deplete autoreactive B cells, the method comprising administering to the individual a therapeutic amount of the pharmaceutical composition of claim 35.

39. A method according to claim 38, wherein the individual has an autoimmune disorder or immune-mediated inflammation disorder.

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