mRNA encoding mageb2 TCER molecule

Abstract

Present disclosure provides engineered polynucleotides encoding MAGEB2 binding proteins, including MAGEB2-specific TCER® polypeptides capable of promoting immune targeting of cancer cells expressing MAGEB2. The disclosure also provides pharmaceutical compositions and kits comprising the same, and methods of use and treatment of MAGEB2-positive cancers.

Description

MRNA ENCODING MAGEB2 TCER MOLECULECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 676,116, filed July 26, 2024, the entire contents of which are incorporated herein by reference in their entireties.BACKGROUND

[0002] TCR based immunotherapy targets peptide epitopes derived from tumor-associated or tumor-specific proteins, which are presented by molecules of the major histocompatibility complex (MHC). These tumor associated antigens (TAAs) can be peptides derived from all protein classes, such as enzymes, receptors, transcription factors, etc., which are specifically expressed by cancer cells, and / or upregulated in cancer cells. Unlike chimeric antigen receptor (CAR)-T cell therapy and current antibody-based approaches, which can only target cell surface proteins, TCR based immunotherapy enables the targeting of otherwise inaccessible intracellular proteins and thus significantly increases the number and diversity of targets derived from tumor-associated or tumor-specific proteins.

[0003] Cancer-testis antigens (CTA) are attractive targets for cancer immunotherapy due to their restricted expression in germ cells and aberrant reactivation in various cancers, and their immunogenic properties. The melanoma antigen (MAGE) gene family includes intracellular cancer-testis antigens, such as MAGEB2. MAGEB2 is typically only expressed in normal testis. MAGEB2, which may function to enhance ubiquitin ligase activity of RING-type zinc finger containing E3 ubiquitin protein ligases, has been found to be aberrantly expressed in a variety of human tumors such as lung carcinoma, breast carcinoma, melanoma, and others. Many of these cancers still have a high unmet medical need, with patients needing improved, effective, and specific therapeutics. Accordingly, there exists a need to develop new anticancer agents that specifically target intracellular proteins highly specific to cancer cells.SUMMARY OF THE DISCLOSURE The present disclosure provides antigen binding proteins and polynucleotides encoding the same, as well as pharmaceutical compositions comprising the same. The present disclosure also provides methods of treating cancer in a subject in need thereof comprising administering to a subject a pharmaceutical composition disclosed herein. In one aspect, the present disclosure provides a pharmaceutical composition comprising: a first mRNA encoding a first polypeptide, wherein the first polypeptide comprises a TCR α-chain variable domain (Vα) comprising a CDRa1 comprising SEQ ID NO: 10, a CDRa2 comprising SEQ ID NO: 11, and a CDRa3 comprising SEQ ID NO: 12, and an antibody heavy chain variable domain (VH) comprising a CDRH1 comprising SEQ ID NO: 18, a CDRH2 comprising SEQ ID NO: 19, and a CDRH3 comprising SEQ ID NO: 20; a second mRNA encoding a second polypeptide, wherein the second polypeptide comprises a TCR β-chain variable domain (Vβ) comprising a CDRb1 comprising SEQ ID NO: 13, a CDRb2 comprising SEQ ID NO: 14, and a CDRb3 comprising SEQ ID NO: 15, and an antibody light chain variable domain (VL) comprising a CDRL1 comprising SEQ ID NO: 21, a CDRL2 comprising SEQ ID NO: 22, and CDRL3 comprising SEQ ID NO: 23; or both, wherein at least one of the first mRNA and the second mRNA comprises one or more of the following: a 5’ UTR, a 3’ UTR, a nucleotide cap, a stabilizing domain, and a poly A tail. In some embodiments, the Vα domain comprises the sequence of SEQ ID NO:8. In some embodiments, the Vβ domain comprises the sequence of SEQ ID NO:9. In some embodiments, the VH domain comprises the sequence of SEQ ID NO:16. In some embodiments, the VL domain comprises the sequence of SEQ ID NO:17. In some embodiments, the second polypeptide further comprises an Fc domain comprising the sequence of SEQ ID NO:24. In some embodiments, the first polypeptide further comprises an Fc domain comprising the sequence of SEQ ID NO:25. In some embodiments, the second polypeptide comprises the sequence of SEQ ID NO:6. In some embodiments, the first polypeptide comprises the sequence of SEQ ID NO:7. In some embodiments, the second polypeptide comprises the sequence of SEQ ID NO:4. In some embodiments, the first polypeptide comprises the sequence of SEQ ID NO:5. In some embodiments, the second mRNA comprises the sequence of SEQ ID NO:2. In some embodiments, the first mRNAcomprises the sequence of SEQ ID NO:3. In some embodiments, the pharmaceutical composition comprises both the first mRNA and the second mRNA. In some embodiments, at least one of the first mRNA and the second mRNA comprises one or more of the following: a 5′-UTR comprising the sequence of any one of SEQ ID NOs: 28-58, and a 3′ UTR comprising the sequence of any one of SEQ ID NOs: 59-67. In some embodiments, the pharmaceutical composition further comprises a lipid nanoparticle (LNP). In some embodiments, the LNP comprises an ionizable lipid. In some embodiments, the ionizable lipid has a chemical structure selected from any one of (a)-(p): (a)or a salt thereof, wherein: R1is -OH, -NRN-C4-10cycloalkenyl optionally substituted with one or more oxo or - N(RN’RN’’); RNis H or C1-6alkyl; RN’is H or C1-6alkyl; RN’’is H or C1-6alkyl; o is 1, 2, 3, or 4; n is 4, 5, 6, 7, or 8; m is 4, 5, 6, 7, or 8; M is -C(=O)-O-* or -O-C(=O)-*, wherein * indicates attachment to R2; M’ is -C(=O)-O-* or -O-C(=O)-*, wherein * indicates attachment to R3; R2isor –(C1-6alkylene)-(C3-8cycloalkyl)-C1-6alkyl; R2ais -H or C1-10alkyl; R2bis -H or C1-10alkyl; R2cis C1-8alkyl or C2-8alkenyl;R3isR3ais H or C1-10alkyl; R3bis H or C1-8alkyl; and R3cis C1-10alkyl or C2-8alkenyl, or (b)or a salt thereof, wherein: R1is -OH; o is 2, 3, or 4; n is 4, 5, 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2cis C4-8alkyl; R3ais C7-10alkyl; and R3cis C3-5alkyl, or (c)or a salt thereof, wherein: R1is NRN-C4-10cycloalkenyl optionally substituted with one or more oxo or - N(RN’RN’’); RNis H; RN’is C1-2alkyl; RN’’is H; o is 2, 3, or 4; n is 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2ais C7-10alkyl; R2cis C4-6alkyl; R3ais C1-3alkyl; and R3cis C4-6alkyl, or (d)or a salt thereof, wherein: R1is OH; o is 2, 3, or 4; n is 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3;R2bis C3-5alkyl; R2cis C2-4alkyl; R3ais C7-10alkyl; and R3cis C4-6alkyl, (e)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula I; and R3ais C1-8alkyl. (f)or a salt thereof, wherein: o, M, M’, R2cand R3care as defined for Formula (I); and R3ais C1-8alkyl. (g)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula I; and R3ais C1-8alkyl.(h)or a salt thereof, wherein: o, M, M’, R2cand R3care as defined for Formula (I); and R3ais C1-8alkyl. (i)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula (I); R2ais a C1-8alkyl; and R3ais C1-8alkyl, (j)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for formula I; R2bis a C1-8alkyl; andR3ais C1-8alkyl, or (k)or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or (l)or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or (m)or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or (n)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for formula I; R2bis a C1-8alkyl; and R3ais C1-8alkyl, or (o)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for formula I; R2bis a C1-8alkyl; and R3ais C1-8alkyl, or (p)or a salt thereof, wherein: o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or N-oxides, salts, or isomers of each thereof. In some embodiments, the ionizable lipid is a compound selected from the group consisting of:or N-oxides, salts, or isomers thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the mRNA comprises a 5' terminal cap, optionally wherein the 5' terminal cap comprises a Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino- guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5' methylG cap, or an analog thereof. In some embodiments, the mRNA comprises a poly-A region, optionally wherein the poly-A region is at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90 nucleotides in length, or at least about 100 nucleotides in length, or optionally wherein the poly-A region is about 10 to about 200, about 20 to about 180, about 50 to about 160, about 70 to about 140, or about 80 to about 120 nucleotides in length. In some embodiments, the mRNA comprises at least one chemically modified nucleobase, sugar, backbone, or any combination thereof. In some embodiments, the mRNA comprises at least one chemically modified nucleobase, wherein the at least one chemically modified nucleobase is selected from the group consisting of pseudouracil (ψ), N1-methylpseudouracil (m1ψ), 1- ethylpseudouracil, 2-thiouracil (s2U), 4’-thiouracil, 5-methylcytosine, 5-methyluracil, 5- methoxyuracil, and any combination thereof, optionally wherein at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% of the uracils are N1 methylpseudouracils. In some embodiments, the mRNA comprises a 5’terminal cap comprising Cap1 and a poly-A region 100 nucleotides in length (SEQ ID NO: 101), and wherein all uracils of the polynucleotide are N1-methylpseudouracils. In one aspect, the present disclosure provides a method for treating cancer comprising administering to a subject in need thereof the pharmaceutical composition of any of the aboveembodiments. In some embodiments, the subject is a HLA-A*02-positive subject. In some embodiments, the cancer is a MAGEB2-positive solid tumor. In some embodiments, the MAGEB2-positive solid tumor expresses MAGEB2 peptide GVYDGEEHSV (SEQ ID NO: 1) in a complex with a major histocompatibility complex (MHC) protein on cell surface. In some embodiments, the cancer is selected from the group consisting of: liver cancer, lung cancer, chronic lymphocytic leukemia (CLL), colorectal cancer (CRC), gallbladder cancer (GBC), glioblastoma (GBM), gastric cancer (GC), hepatocellular carcinoma (HCC), head and neck cancer, head and neck squamous cell carcinoma (HNSCC), melanoma (MEL), non- Hodgkin lymphoma (NHL), non-small cell lung cancer adenocarcinoma (NSCLCadeno), non-small cell lung cancer (NSCLC), squamous cell non-small cell lung cancer (NSCLCsquam), ovarian cancer (OC), esophageal cancer (OSCAR), renal cell carcinoma (RCC), small cell lung cancer (SCLC), urinary bladder carcinoma (UBC), and uterine endometrial cancer (UEC). In some embodiments, the cancer is selected from the group consisting of: hepatocellular carcinoma (HCC), melanoma, non-small cell lung cancer (NSCLC), non-Hodgkin lymphoma (NHL), head and neck squamous cell carcinoma (HNSCC), and uterine endometrial cancer (UEC). In some embodiments, the pharmaceutical composition or the lipid nanoparticle is administered to the subject via intravenous (IV), subcutaneous, intramuscular (IM), or intradermal administration. In one aspect, the present disclosure provides a use of the composition of any of the foregoing embodiments in the manufacture of a medicament for the treatment of a MAGEB2- positive solid tumor in a HLA-A*02-positive subject. In one aspect, the present disclosure provides a pharmaceutical composition according to any of the foregoing embodiments, for use in the treatment of a MAGEB2-positive solid tumor in a HLA-A*02-positive subject. In one aspect, the present disclosure provides a kit comprising the pharmaceutical composition of any of the foregoing embodiments and instructions for use. Both the foregoing summary and the following description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the disclosure, but are not to be construed as limiting. Other objects, advantages,and novel features will be readily apparent to those skilled in the art from the following detailed description of the disclosure. It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below are provided as being part of the inventive subject matter disclosed herein and may be employed in any combination to achieve the benefits described herein. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-1C are graphs illustrating a dose-dependent in vitro cytotoxicity profile for MAGEB2-targeting TCER® polypeptides encoded by mRNA. FIG. 1A shows a panel of graphs depicting a dose-response curve depicting cytotoxicity % as a function of TCER® protein concentration against SK-MEL-5 [200 CpCs] cells when co-incubated with healthy donor PBMCs. TCER® protein produced from human 293F cells following mRNA transfection was compared to recombinant control TCER® protein from CHO cells following plasmid transfection. Gray shapes indicate HLA-A*02-positive whole blood donors, with each individual shape representing a separate donor. White shapes indicate HLA-A*02- negative donor. Data from Donor 1 are shown in the left panel; data from Donor 2 are shown in the center panel; and data from Donor 3 are shown in the right panel. FIG. 1B shows a graph depicting a dose-response curve depicting cytotoxicity % as a function of TCER® protein concentration against RPMI7951 [20 CpCs] cells when co-incubated with healthy donor PBMCs. TCER® protein produced from human 293F cells following mRNA transfection was compared to recombinant control TCER® protein from CHO cells following plasmid transfection. Gray shapes indicate HLA-A*02-positive whole blood donors, with each individual shape representing a separate donor. White shapes indicate HLA-A*02- negative donor. Data from Donor 1 are shown in the left panel; data from Donor 2 are shown in the center panel; and data from Donor 3 are shown in the right panel. FIG. 1C shows a graph depicting a dose-response curve depicting cytotoxicity % as a function of TCER® protein concentration against T98G control cells (which did not contain MAGEB2-001) when co-incubated with healthy donor PBMCs. TCER® protein produced from human 293F cells following mRNA transfection was compared to recombinant control TCER® protein fromCHO cells following plasmid transfection. Gray shapes indicate HLA-A*02-positive whole blood donors, with each individual shape representing a separate donor. White shapes indicate HLA-A*02-negative donor. Data from Donor 1 are shown in the left panel; data from Donor 2 are shown in the center panel; and data from Donor 3 are shown in the right panel. FIGS. 2A-2O are graphs illustrating in vitro induction of cytokine release as a function of TCER® protein concentration in whole blood samples from HLA-A*02-positive (gray) and -negative (white) donors. FIG. 2A shows a panel of graphs depicting the release of MCP-1 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2B shows a panel of graphs depicting the release of GM-CSF (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2C shows a panel of graphs depicting the release of IFNγ (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2D shows a panel of graphs depicting the release of IL-10 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2E shows a panel of graphs depicting the release of IL-18 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2F shows a panel of graphs depicting the release of IL-2 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2G shows a panel of graphs depicting the release of IL-3 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2H shows a panel of graphs depicting the release of IL-4 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2I shows a panel of graphs depicting the release of IL-5 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2J shows a panel of graphs depicting the release of IL-6 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left)and recombinant cKIH TCER® control protein concentration (Right). FIG. 2K shows a panel of graphs depicting the release of IL-7 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2L shows a panel of graphs depicting the release of IL-8 (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2M shows a panel of graphs depicting the release of MIP-1α (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2N shows a panel of graphs depicting the release of TNFα (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIG. 2O shows a panel of graphs depicting the release of TNFβ (pg / mL) as a function of mRNA-encoded cKIH TCER® protein concentration (Left) and recombinant cKIH TCER® control protein concentration (Right). FIGS. 3A-3B are graphs illustrating in vivo expression of mRNA-encoded TCER® protein. FIG. 3A shows a graph illustrating a time course of TCER® protein expression in mouse plasma following a single IV administration of an LNP / mRNA comprising mRNA encoding the TCER® protein. FIG. 3B shows a graph illustrating an expanded time course of TCER® protein expression in mouse plasma following a single IV administration of an LNP / mRNA comprising mRNA encoding the TCER® protein. DETAILED DESCRIPTION The present disclosure generally relates to, among other things, compositions and methods for treating cancer comprising administering a polynucleotide encoding one or more antigen binding proteins, particularly one or more antigen binding proteins capable of targeting MAGEB2. Without wishing to be bound by any one theory, it is understood that administration of the polynucleotide encoding one or more of the disclosed antigen binding proteins promote immune targeting of cancer cells expressing the antigen to which the antigen binding protein is directed. In some embodiments, the disclosed antigen binding proteins are TCER® polypeptides specific for MAGEB2 and a T cell antigen, such as CD3.The present disclosure also relates to polynucleotides and compositions and formulations utilized in the methods described herein (e.g., lipid nanoparticle compositions) and kits comprising such polynucleotides and / or compositions and formulations. It is to be appreciated that certain aspects, modes, embodiments, variations and features of the present methods are described below in various levels of detail in order to provide a substantial understanding of the present technology. The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the disclosure. All the various embodiments of the present disclosure will not be described herein. Many modifications and variations of the disclosure can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that the present disclosure is not limited to particular uses, methods, reagents, compounds, compositions or biological systems, which can, 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. In practicing the present methods, many conventional techniques in molecular biology, protein biochemistry, cell biology, microbiology and recombinant DNA are used. See, e.g., Sambrook and Russell eds. (2001) Molecular Cloning: A Laboratory Manual, 3rd edition; the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent No. 4,683,195; Hames andHiggins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); and Herzenberg et al. eds (1996) Weir’s Handbook of Experimental Immunology. I. Definitions This disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. This disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. In this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms “one or more,” and “at least one” can be used interchangeably herein. In certain aspects, the term “a” or “an” means “single.” In other aspects, the term “a” or “an” includes “two or more” or “multiple.” Furthermore, “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: 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). 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 is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo,Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0025] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within this disclosure. Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of this disclosure. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of this disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having a plurality of alternatives, examples of that invention in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of an invention can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.

[0026] Nucleotides are referred to by their commonly accepted single-letter codes. Unless otherwise indicated, nucleic acids are written left to right in 5' to 3' orientation. Nucleobases are referred to herein by their commonly known one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Accordingly, A represents adenine, C represents cytosine, G represents guanine, T represents thymine, U represents uracil.

[0027] Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB BiochemicalNomenclature Commission. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. As used herein, the term “about” as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art, such interval of accuracy is ± 10 %. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of this disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. As used herein, the term “administration” of an agent (e.g., polynucleotides of the disclosure or compositions or formulations comprising such polynucleotides) to a subject (e.g., a subject in need thereof) includes any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self- administration and the administration by another. Administration of a polynucleotide or other agent and compositions containing same can be performed in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician or in the case of animals, by the treating veterinarian. In some embodiments, administering or a grammatical variation thereof also refers to more than one doses with certain interval. In some embodiments, the interval is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year or longer. In some embodiments, one dose is repeated for once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times or more. Suitable dosage formulations and methodsof administering the agents are known in the art. Route of administration can also be determined and method of determining the most effective route of administration are known to those of skill in the art and will vary with the composition used for treatment, the purpose of the treatment, the health condition or disease stage of the subject being treated, and target cell or tissue. Non-limiting examples of route of administration include oral administration, intraperitoneal, infusion (e.g., intravenous administration), nasal administration, inhalation, injection (e.g., intramuscular administration), and topical application. In some embodiments, the administration is an infusion (for example to peripheral blood of a subject) over a certain period of time, such as about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 24 hours or longer.

[0031] As used herein, the term “administered in combination” or “combined administration” or “combination therapy” means that two or more agents are administered to a subject at the same time or within an interval such that there can be an overlap of an effect of each agent on the patient. In some embodiments, they are administered within about 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, they are administered within 1 day, 2, days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4, weeks, 5 weeks, or 6 weeks or more of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved.

[0032] As used herein, the term “amino acid substitution” refers to replacing an amino acid residue present in a parent or reference sequence with another amino acid residue. An amino acid can be substituted in a parent or reference sequence, for example, via chemical peptide synthesis or through recombinant methods known in the art. Accordingly, a reference to a “substitution at position X” refers to the substitution of an amino acid present at position X with an alternative amino acid residue. In some aspects, substitution patterns can be described according to the schema AnY, wherein A is the single letter code corresponding to the amino acid naturally or originally present at position n, and Y is the substituting amino acid residue. In other aspects, substitution patterns can be described according to the schema An(YZ), wherein A is the single letter code corresponding to the amino acid residue substituting theamino acid naturally or originally present at position X, and ¥ and Z are alternative substituting amino acid residue.

[0033] In the context of the present disclosure, substitutions (even when they referred to as amino acid substitution) are conducted at the nucleic acid level, i.e., substituting an amino acid residue with an alternative amino acid residue is conducted by substituting the codon encoding the first amino acid with a codon encoding the second amino acid.

[0034] As used herein, the term “analog” refers to a structurally related polypeptide or nucleic acid molecule having the function of a reference polypeptide or nucleic acid molecule.

[0035] As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans at any stage of development. In some embodiments, “animal” refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, genetically engineered animal, or a clone.

[0036] As used herein, an “antigen” refers to a molecule to which an antibody can selectively bind. A target antigen may be a protein (e.g., an antigenic peptide), carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. An antigen (e.g., a target antigen expressed by a tumor cell) may also be administered to an animal subject to generate an immune response in the subject.

[0037] The term “antigen binding protein” herein (occasionally abbreviated to “ABP”) refers to a polypeptide or a complex of two or more polypeptides comprising an antigen binding site that specifically binds to a MAGEB2 antigenic peptide that is in a complex with a major histocompatibility complex (MHC) protein, wherein the MAGEB2 antigenic peptide comprises or consists of the amino acid sequence GVYDGEEHSV (SEQ ID NO: 1), and that polypeptide or the two or more polypeptides comprise(s) the CDRs as herein provided, suchas CDRa1, CDRa3, and optionally CDRa2, and CDRb1, CDRb3, and optionally CDRb2. The two or more polypeptides of the antigen binding protein may be covalently or non-covalently linked together. As used in the context of the present specification, the term antigen binding protein includes antigen binding proteins of multiple different formats as described below, including soluble antigen binding proteins, monovalent, bivalent and multivalent antigen binding proteins, monospecific, bispecific and multispecific antigen binding proteins, single chain antigen binding proteins and antigen binding proteins comprising two or more chains, fusion proteins and chimeric proteins. The skilled person is aware that the CDRs provided herein can be included in various formats as disclosed in the prior art, e.g., in Brinkmann U, Kontermann RE. The making of bispecific antibodies (MAbs. 2017 Feb / Mar;9(2):182-212, doi: 10.1080 / 19420862.2016.1268307) or WO 2019 / 012138. The term includes antigen binding proteins having the overall structure of a TCR, an antibody and / or a chimeric antigen receptor (CAR). The antigen binding protein of the present invention comprises the TCR-derived CDRs, in particular a variable domain VAcomprising TCR-derived CDRa1, CDRa3, and optionally CDRa2, and a variable domain VBcomprising TCR-derived CDRb1, CDRb3, and optionally CDRb2. Antigen binding proteins of the invention comprise a variable domain VAcomprising complementarity determining regions (CDRs) CDRa1, CDRa2, and CDRa3, e.g. on a first polypeptide, and a variable domain VBcomprising CDRb1, CDRb2, and CDRb3, e.g. on a second polypeptide, wherein CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 form an “antigen binding domain A”. “Antigen binding domain A” denotes a binding domain that binds to the antigenic peptide (MAGEB2 antigenic peptide in the context of the present invention) that is in a complex with a major histocompatibility complex (MHC) protein. In a particular embodiment, the entire VAdomain and / or the entire VBdomain are TCR-derived and are thus TCR alpha, beta, gamma or delta variable domains (Vα, Vβ, Vγor Vδ). In preferred embodiments, the antigen binding protein is a TCR or functional fragment(s) thereof, e.g. the variable domains VAand VBof the TCR. In particular embodiments, the antigen binding protein of the present invention comprises CDRs and optionally the VAand VBas herein provided, and comprises further (an) additional domain(s) fused directly or indirectly to VAor VB. The further domains may form (an) additional binding domain(s) or (a) binding site(s). For example and in particular embodiments, the additional binding domains may form antigen binding domain B. Furtherbinding domains may be comprised that, e.g., form further antigen binding domains, e.g. antigen binding domain C, etc. The additional / further domains comprised in the antigen binding protein may also be a further protein. Such an antigen binding protein can also be referred to as “fusion protein”. Examples of additional domains comprised in an antigen binding protein of the invention that is a fusion protein are listed below. If the antigen binding protein is a bispecific or multispecific antigen binding protein, it comprises – in addition to VAand VBas herein defined – at least one more binding domain / site, e.g. a variable domain, preferably two variable domains, and optionally a further domain, such as constant domain(s), wherein the variable and / or constant domains may be derived from an antibody or TCR. In this aspect, the antigen binding protein may thus comprise two different antigen binding sites (one formed by VAand VBand one formed by the additional at least one, preferably two, variable domains) and is able to specifically bind to two different antigens. In particular embodiments, the antigen binding protein comprises TCR-derived VAand VBand in addition two antibody-derived variable domains, in particular VLand VH. Such constructs comprising elements of both antibodies and TCRs represent hybrid formats and may be e.g. referred to as bispecific TCR-antibody fusion protein or bispecific TCR molecules / proteins as herein used in the exemplary part. In the bispecific fusion proteins, the variable domains may be included in different formats and may be arranged in various orientations. Techniques to produce such bispecific fusion proteins are known to the skilled in the art as also disclosed herein below, who can thus use the variable domains as herein defined to generate and produce bispecific antigen binding proteins in various formats. The skilled person is capable of selecting suitable linkers to ensure folding in the desired conformation. Antigen binding proteins described herein may take the form of a TCR, an antibody, including engineered TCRs and antibodies, such as single chain fragment variable (scFv), disulfide-stabilized Fv (dsFv), scTVs, Fab, Fab’, F(ab’)2, nanobody, DARPin, Knottin, diabody, single-chain diabody or oligomers thereof. The term “bispecific” in the context of the present invention refers to antigen binding proteins with at least two valences and binding specificities for at least two different antigens(preferably two different antigens) and thus comprises at least two antigen-binding sites. The term “valence” refers to the number of binding sites of an antigen binding protein, e.g. a bivalent antigen binding protein relates to an antigen binding protein that has two binding sites. The binding sites may bind to the same or different targets, i.e. a bivalent antigen binding protein may be monospecific, e.g. binding one target, or bispecific, e.g. binding two different targets. The bispecific antigen-binding molecules of the present invention comprise at least one antigen binding domain A comprising TCR-derived CDRs. In preferred embodiments, the antigen-binding molecules of the present invention comprise at least one TCR-derived antigen-binding site. The bispecific antigen binding proteins of the invention may be referred to as a bispecific TCR, or as a bispecific TCR / mAb diabody. The antigen binding protein of this embodiment may also be referred to as a T cell engaging receptor, or TCER®. Bispecific antigen binding proteins of the invention, such as TCER®, may comprise a VH comprising a CDRH1, a CDRH2 and a CDRH3, and a VL comprising a CDRL1, a CDRL2, and a CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 form an antigen binding domain B. The antigen binding domain B denotes a binding domain that specifically binds to immune cells, preferably T cells or natural killer (NK) cells. “TCER®” are soluble antigen binding proteins comprising two antigen binding domains, a first variable domain (VA) and second variable domain (VB) as defined in the context of the invention and a further antigen binding domain that is formed by the heavy and light chain variable domains of an antibody, also referred to as “recruiter”, such as variable heavy (VH) and variable light (VL) domains directed against a T cell antigen (such as CD3) or directed against TCRα / β or a combination thereof. “VA” or Va in the context of the present invention refers to a TCR variable domain comprising TCR-derived CDR sequences and TCR-derived framework sequences. The CDR and framework sequences may be derived from a variable domain of a TCR α-chain (Vα), β- chain (Vβ), γ-chain (Vγ) or δ-chain (Vδ), preferably from a Vα. The sequences surrounding the CDRs, i.e. the framework sequences, may be derived from a variable domain of a TCR, i.e. a variable domain of a TCR α-chain, β-chain, γ-chain or δ-chain, or from a variabledomain of an antibody, preferably from a variable domain of a TCR α-chain. In the examples, various framework and CDR mutations / substitutions are shown. The CDR and framework sequences of the VAdomain in context of the present invention may not necessarily be derived from the same TCR chain. For example, the CDRs derived from one TCR variable domain (of the donor TCR) could also be grafted onto another TCR variable domain (of the acceptor TCR). For example, the donor TCR may comprise a VAencoded by e.g. TRAV5*01 and TRAJ31*01, and the acceptor TCR may comprise a VAencoded by e.g. TRAV14 and TRAJ33. “VB” or Vb in the context of the present invention refers to a variable domain comprising TCR-derived CDR sequences and TCR-derived framework sequences. The CDR and framework sequences may be derived from a variable domain of a TCR α-chain (Vα), β- chain (Vβ), γ-chain (Vγ) or δ-chain (Vδ), preferably from a Vβ. The sequences surrounding the CDRs, i.e. the framework sequences, may be derived from a variable domain of a TCR, i.e. a variable domain of a TCR α-chain, β-chain, γ-chain or δ-chain, or from a variable domain of an antibody, preferably from a variable domain of a TCR β-chain. In the examples, various framework and CDR mutations / substitutions are shown. The CDR and framework sequences of the VBdomain in context of the present invention may not necessarily be derived from the same TCR. For example, CDRs derived from one TCR variable domain (of the donor TCR) could be grafted onto another TCR variable domain (of the acceptor TCR). For example, the donor TCR may comprise a VBencoded by e.g. TRBV29-1*01 and TRBJ1-2*01, and the acceptor TCR may comprise a VBencoded by e.g. TRBV27 and TRBJ1-5. Vαin the context of the present invention refers to a variable domain of a TCR α- chain. Vβin the context of the present invention refers to a variable domain of a TCR β- chain. Vγin the context of the present invention refers to a variable domain of a TCR γ- chain.Vδin the context of the present invention refers to a variable domain of a TCR δ- chain. VLin the context of the present invention refers to a variable domain of an antibody light chain. VHin the context of the present invention refers to a variable domain of an antibody heavy chain. CLin the context of the present invention may refer to a constant domain of an antibody light chain. CH1, CH2and CH3in the context of the present invention may refer to constant domains of an antibody heavy chain, in particular an IgG heavy chain. The constant domains as herein disclosed may be comprised in the antigen binding protein and may further improve certain characters of the antigen binding protein and thus can be present or absent. For example, the stability or half life of the antigen binding protein may be increased or the purification of the antigen binding protein may be eased. The constant domains may also comprise a further binding domain. Exemplary constant domains may be constant domains, e.g. of an antibody, for example, CLor CH, and / or Fc domains / portions. The constant domains may also be albumin, unstructured polypeptides, and / or Leu-Zipper etc. The term “epitope”, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system. As used herein, the term epitope comprises the terms “structural epitope” and “functional epitope”. The “structural epitope” are those amino acids of the antigen, e.g. peptide-MHC complex, that are covered by the antigen binding protein when bound to the antigen. Typically, all amino acids of the antigen are considered covered that are within 5 Å of any atom of an amino acid of the antigen binding protein. The structural epitope of an antigen may be determined by art known methods including X-ray crystallography or NMR analysis. The structural epitope of an antibody typically comprises 20 to 30 amino acids. The structural epitope of a TCR typically comprises 20 to 30 amino acids. The “functional epitope” as herein defined is a subset of those amino acids forming thestructural epitope and comprises the amino acids of the antigen that are critical for formation of the interface with the antigen binding protein of the invention or functional fragment thereof, either by directly forming non-covalent interactions such as H-bonds, salt bridges, aromatic stacking or hydrophobic interactions or by indirectly stabilizing the binding conformation of the antigen and is, for instance, determined by mutational scanning. In the context of the present invention, the functional epitope is also referred to as “binding motif”. Typically, the functional epitope of an antigen bound by an antibody comprises between 4 and 6 amino acids (see Example 2 herein). Typically, the functional epitope of a peptide- MHC complex comprises between 2 to 6 or 7 amino acids of the peptide and 2 to 7 amino acids of the MHC molecule. Since MHC I presented peptides typically have a length between 8 to 10 amino acids only a subset of amino acids of each given peptide is part of the functional epitope of a peptide-MHC complex. The epitope, in particular the functional epitope, bound by the antigen binding proteins of the present invention comprises or consists of the amino acids of the antigen that are required for formation of the binding interface. The “Major Histocompatibility Complex” (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates, which in turn determines histocompatibility. The main function of MHC molecules is to bind to antigens derived from pathogens and display them on the cell surface for recognition by the appropriate T cells. The human MHC is also called the HLA (human leukocyte antigen) complex (or just HLA). Thus, in a preferred embodiment, MHC is HLA. The MHC gene family is divided into three subgroups: class I, class II, and class III. Complexes of peptide and MHC class I molecules (MHC I) are usually recognized by CD8-positive T cells (CD8+ T cells) bearing the appropriate T cell receptor (TCR), whereas complexes of peptide and MHC class II molecules (MHC II) are usually recognized by CD4-positive helper-T cells (CD4+ T cells) bearing the appropriate TCR. CD4 and CD8 usually function as co-receptors of a TCR in binding to MHC I and MHC II, respectively. In some exceptional cases, complexes of peptide and MHC I are recognized by CD8-negative (in particular CD8- negative, CD4-positive) T cells (Soto et al., 2013, Cancer Immunol Immunother. 2013 Feb; 62(2): 359–369). Since the responses of CD8-positive and CD4-positive T cells contribute jointly and synergistically to the anti-tumor effect, the identification and characterization of tumor-associated antigens and corresponding T cell receptors is important in the developmentof cancer immunotherapies such as vaccines and cell therapies. The HLA-A gene is located on the short arm of chromosome 6 and encodes the larger, α-chain, constituent of HLA-A. Variation of HLA-A α-chain is key to HLA function. This variation promotes genetic diversity in the population. Since each HLA has a different affinity for peptides of certain structures, greater variety of HLAs means greater variety of antigens to be 'presented' on the cell surface. The MHC class I HLA protein in the context of the present disclosure may be an HLA-A, HLA-B or HLA-C protein, suitably HLA-A protein, for example HLA-A*02. In the MHC class I dependent immune reaction, peptides not only have to be able to bind to certain MHC class I molecules expressed by tumor cells, they subsequently also have to be recognized by T cells bearing specific T cell receptors (TCR). “Antigenic peptide in a complex with an MHC protein”, herein refers to an antigenic peptide that is non-covalently bound to an MHC molecule. In particular, the antigenic peptide is located to a “peptide-binding groove” formed by the MHC molecule. A complex of an MHC molecule and an antigenic peptide is herein also referred to as “peptide-MHC complex” or “pMHC complex”. In the case of the MAGEB2 antigenic peptide, the complex is also referred to as “MAGEB2 antigenic peptide-MHC complex” or “MAGEB2:MHC complex”. The term “HLA-A*02” signifies a specific HLA allele, wherein the letter A signifies the allele and “*02” indicates the A2 serotype. The term “TCR” as used herein includes engineered TCRs. A “native TCR” refers to a wildtype TCR that can be isolated from nature. Native TCRs are heterodimeric cell surface proteins of the immunoglobulin super-family, which are associated with invariant proteins of the CD3 complex involved in mediating signal transduction. Native heterodimeric TCRs exist in αβ and γδ forms, which are structurally similar but have distinct locations and probably functions. Native, full-length αβ heterodimeric TCRs consist of an α-chain and a β-chain. The α-chain comprises a variable region (V region) encoded by a TRAV gene, a joining region (J region) encoded by a TRAJ gene, and a constant region (C region) encoded by a TRAC gene. The β-chain comprises a variable region (V region) encoded by a TRBV gene, a joining region (J region) encoded by aTRBJ gene and a constant region (C region) encoded by a TRBC gene, and usually a short diversity region (D region) encoded by a TRBD gene between the V and J regions, although this D region is often considered as part of the J region (Lefranc, (2001), Curr Protoc Immunol Appendix 1: Appendix 10). The genes encoding different α-chain and β-chain variable, joining and constant regions are referred to in IMGT nomenclature by unique numbers (Folch and Lefranc, (2000), Exp Clin Immunogenet 17(1): 42-54; Scaviner and Lefranc, (2000), Exp Clin Immunogenet 17(2): 83-96; LeFranc and LeFranc, (2001), "T cell Receptor Factsbook", Academic Press). Further information on TCR genes can be found in the international ImMunoGeneTics information system®, Lefranc M-P et al., (Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22; and http: / / www.imgt.org / ). The alpha chain TRAC constant domain sequence and the beta chain TRBC1 or TRBC2 constant domain are in the following, also referred to as TCR constant domain sequences. In one embodiment, the TCR constant domain sequences may be derived from any suitable species, such as any mammal, e.g., human, rat, monkey, rabbit, donkey, or mouse, preferably human. In some preferred embodiments, the TCR constant domain sequences may be slightly modified, for example, by the introduction of heterologous sequences, preferably mouse sequences, which may increase TCR expression and stability. Also, further stabilizing mutations as known from the state of the art (e.g. WO 2018 / 104407, PCT / EP2018 / 069151, WO 2011 / 044186, WO 2014 / 018863) may be introduced, such as replacement of unfavorable amino acids in the variable regions and / or the introduction of a disulfide bridge between the TCR C domains and the removal of unpaired cysteine. On the protein level, TCR α-, β-, γ- and δ-chains comprise two immunoglobulin domains, the variable domain and the constant domain. The variable domain corresponds to the V(D)J region. The constant domain corresponds to the C region. The constant domain is the membrane-proximal domain and in the context of the present invention also includes the transmembrane (TM) domain and a short cytoplasmic tail. Each of the constant and variable domains include an intra-chain disulfide bond. The variable domains (Vαand Vβin αβ TCRs and Vγand Vδin γδ TCRs) contain highly polymorphic loops comprising the complementarity determining regions (CDRs).Each TCR variable domain comprises three “TCR complementarity determining regions (CDRs)” embedded in a framework sequence, one being the hypervariable region named CDR3. In the context of the present invention, CDRa1, CDRa2 and CDRa3 denote α- chain CDRs, and CDRb1, CDRb2 and CDRb3 denote β-chain CDRs. The sequences encoding CDRa1 and CDRa2 are comprised in TRAV, the sequences encoding CDRa3 are comprised in TRAV and TRAJ, the sequences encoding CDRb1 and CDRb2 are comprised in TRBV, and the sequences encoding CDRb3 are comprised in TRBV, TRBD and TRBJ. In TCRs, the CDR1 and CDR3 amino acid residues make contact with the antigenic peptide, while the CDR2 amino acid residues mainly contact the HLA molecule (Stadinski et al., J Immunol. 2014 June 15; 192(12): 6071–6082; Cole et al., J Biol Chem.2014 Jan 10;289(2):628-38). The antigen specificity of a TCR is thus defined by the CDR3 and CDR1 sequences. The CDR2 sequences are not required for the determination of antigen specificity, but may play a role in the overall affinity of a TCR towards a peptide:MHC complex. “TCR framework regions” (FRs) refer to amino acid sequences interposed between the CDRs, i.e. to those portions of the variable domains that are to some extent conserved among different TCRs. The α-, β-, γ- and δ-chain variable domains each have four FRs, herein designated FR1-a, FR2-a, FR3-a, FR4-a (for an α- or γ-chain), and FR1-b, FR2-b, FR3-b, FR4-b (for a β- or δ-chain), respectively. Accordingly, an α-chain or γ-chain variable domain may be described as (FR1-a)-(CDRa1)-(FR2-a)-(CDRa2)-(FR3-a)-(CDRa3)-(FR4-a) and a β- or δ-chain variable domain may be described as (FR1-b)-(CDRb1)-(FR2-b)- (CDRb2)-(FR3-b)-(CDRb3)-(FR4-b). In the context of the present invention, the CDR / FR sequences in an α-, β-, γ- or δ-chain variable domain is determined based on IMGT definition (Lefranc et al., Dev. Comp. Immunol., 2003, 27(1):55-77; www.imgt.org). Accordingly, CDR / FR amino acid positions when related to TCR or TCR-derived domains are indicated according to said IMGT definition. Preferably, the IMGT position of the CDR / FR amino acid positions of the variable domain Vα is given in analogy to the IMGT numbering of TRAV5*01 and / or the IMGT position of the CDR / FR amino acid positions of the variable domain Vβ is given in analogy to the IMGT numbering of TRBV29-1*01. An “engineered TCR” may be a protein resembling a native TCR, but comprising modifications in the variable and / or constant domains, e.g. a humanized TCR or a TCR withimproved / altered characteristics (e.g. improved binding, heterodimerization or expression level), or may be a soluble TCR and / or a single-chain TCR, a monovalent, bivalent or multivalent TCR, a monospecific, bispecific or multispecific TCR, and / or a functional fragment of a TCR, or functional fragments of one or more TCRs, or a fusion protein and / or chimeric protein comprising a functional fragment of a TCR or functional fragments of one or more TCRs. The term "Fcdomain" as used in the context of the present invention encompasses native Fcdomains and Fcdomain variants and sequences as also further defined herein below. As with Fcvariants and native Fcmolecules, the term "Fcdomain" includes molecules in monomeric or multimeric form, whether digested from whole antibody or produced by other means. The term "native Fc" as used herein refers to a molecule comprising the sequence of a non-antigen binding fragment resulting from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and may contain the hinge region. The original immunoglobulin source of the native Fcis, in particular, of human origin and can be any of the immunoglobulins, preferably IgG1 or IgG2, most preferably IgG1. Native Fcmolecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fcmolecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, and IgGA2). One example of a native Fcis a disulfide-bonded dimer resulting from papain digestion of an IgG. The term "native Fc" as used herein is generic to the monomeric, dimeric, and multimeric forms. An example of a native Fcamino acid sequence is provided in WO2021023658 (A1). The "hinge" or "hinge region" or "hinge domain" refers typically to the flexible portion of a heavy chain located between the CH1domain and the CH2domain. It is approximately 25 amino acids long, and is divided into an "upper hinge," a "middle hinge" or "core hinge," and a "lower hinge." A "hinge subdomain" refers to the upper hinge, middle (orcore) hinge or the lower hinge. The amino acids sequences of the hinges of an IgG1, IgG2, IgG3 and IgG4 molecule are provided, for example, in WO2021023658 (A1). In the context of the present invention, in case reference is made to amino acid positions in the Fcdomain, these amino acid positions or residues are indicated according to the EU numbering system as described, for example in Edelman, G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969). The term "Fcvariant" as used herein refers to a molecule or sequence that is modified from a native Fcbut still comprises a binding site for the salvage receptor, FcRn (neonatal Fcreceptor). Exemplary Fcvariants, and their interaction with the salvage receptor, are known in the art. Thus, the term "Fcvariant" can comprise a molecule or sequence that is humanized from a non-human native Fc. Furthermore, a native Fccomprises regions that can be removed because they provide structural features or biological activity that are not required for the antigen binding proteins of the invention. Thus, the term "Fcvariant" comprises a molecule or sequence that lacks one or more native Fcsites or residues, or in which one or more Fcsites or residues has be modified, that affect or are involved in: (1) disulfide bond formation, (2) incompatibility with a selected host cell, (3) N-terminal heterogeneity upon expression in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fcreceptor other than a salvage receptor, or (7) antibody-dependent cellular cytotoxicity (ADCC). Accordingly, in one embodiment the Fc-domain, such as Fc1and / or Fc2, comprises a hinge domain. In one embodiment, the Fc-domain is a human IgG Fcdomain, preferably derived from human IgG1, IgG2, IgG3 or IgG4, preferably IgG1 or IgG2, more preferably IgG1. In some embodiments, in particular, when the antigen binding protein comprises two Fcdomains, e.g. in the TCER® format described herein below (such as Fc1and Fc2), the two Fcdomains may be of the same immunoglobulin isotype or isotype subclass or of different immunoglobulin isotype or isotype subclass, preferably of the same. Accordingly, in some embodiments Fc1and Fc2, are of the IgG1 subclass, or of the IgG2 subclass, or of the IgG3subclass, or of the IgG4 subclass, preferably of the IgG1 subclass, or of the IgG2 subclass, more preferably of the IgG1 subclass. In some embodiments, the Fcdomain is a variant Fcdomain and thus comprises one or more of the amino acid substitutions described herein below. In some embodiments, the Fcdomain comprises or further comprise the “RF” and / or “Knob-into-hole” mutation, preferably the “Knob-into-hole”. The “RF mutation” generally refers to the amino acid substitutions of the amino acids HY into RF in the CH3domain of Fcdomains, such as the amino acid substitution H435R and Y436F in CH3domain as described by Jendeberg, L. et al. (1997, J. Immunological Meth., 201: 25-34) and is described as advantageous for purification purposes as it abolishes binding to protein A. In case the antigen binding protein comprises two Fc-domains, the RF mutation may be in one or both, preferably in one Fc-domain. The “Knob-into-Hole” or also called “Knob-into-Hole”-technology refers to amino acid substitutions T366S, L368A and Y407V (Hole) and T366W (Knob) both in the CH3-CH3interface to promote heteromultimer formation. Those knob-into-hole mutations can be further stabilized by the introduction of additional cysteine amino acid substitutions Y349C and S354C. The “Knob-into-Hole” technology together with the stabilizing cysteine amino acid substitutions has been described in patents US5731168 and US8216805. In the context of the present invention, the “Knob” mutation together with the cysteine amino acid substitution S354C is, for example, present in the Fcdomain comprising or consisting of the amino acid sequence of SEQ ID NO: 24 and the “Hole” mutation together with the cysteine amino acid substitutions Y349C is present in the Fcdomain comprising or consisting amino acid sequence of SEQ ID NO: 25. In some embodiments, the Fcdomain of one of the polypeptides, for example Fc1, comprises the amino acid substitution T366W (Knob) in its CH3domain and the Fc domain of the other polypeptide, for example Fc2, comprises the amino acid substitution T366S, L368A and Y407V (Hole) in its CH3domain, or vice versa.In some embodiments, the Fcdomain of one of the polypeptides, for example Fc1, comprises or further comprises the amino acid substitution S354C in its CH3domain and the Fcdomain of the other polypeptide, for example Fc2, comprises or further comprises the amino acid substitution Y349C in its CH3domain, or vice versa. Accordingly, in some embodiments, the Fcdomain of one of the polypeptides, for example Fc1, comprises the amino acid substitutions S354C and T366W (Knob) in its CH3domain and the Fcdomain of the other polypeptide, for example Fc2, comprises the amino acid substitution Y349C, T366S, L368A and Y407V (Hole) in its CH3domain, or vice versa. This set of amino acid substitutions can be further extended by inclusion of the amino acid substitutions K409A on one polypeptide and F405K in the other polypeptide as described by Wei et al. (Structural basis of a novel heterodimeric Fcfor bispecific antibody production, Oncotarget.2017). Accordingly, in some embodiments, the Fcdomain of one of the polypeptides, for example Fc1, comprises or further comprises the amino acid substitution K409A in its CH3domain and the Fcdomain of the other polypeptide, for example Fc2, comprises or further the amino acid substitution F405K in its CH3domain, or vice versa. In some cases, artificially introduced cysteine bridges may improve the stability of the antigen binding proteins, optimally without interfering with the binding characteristics of the antigen binding proteins. Such cysteine bridges can further improve heterodimerization. Further amino acid substitutions, such as charged pair substitutions, have been described in the art, for example in EP2970484 to improve the heterodimerization of the resulting proteins. Accordingly in one embodiment, the Fcdomain of one of the polypeptides, for example Fc1, comprises or further comprises the charge pair substitutions E356K, E356R, D356R, or D356K and D399K or D399R, and the Fcdomain of the other polypeptide, for example Fc2, comprises or further comprises the charge pair substitutions R409D, R409E, K409E, or K409D and N392D, N392E, K392E, or K392D, or vice versa.In a further embodiment, the Fcdomain on one or both, preferably both polypeptide chains can comprise one or more alterations that inhibit Fcgamma receptor (FcyR) binding. Such alterations can include L234A, L235A. With the inclusion of Fc-parts consisting of Hinges, CH2and CH3domains, or parts thereof, into antigen binding proteins, more particularly into bispecific antigen binding proteins the problem of unspecific immobilization of these molecules, induced by Fc:Fc- gamma receptor (FcgR) interactions arose. FcgRs are composed of different cell surface molecules (FcgRI, FcgRIIa, FcgRIIb, FcgRIII) binding with differing affinities to epitopes displayed by Fc-parts of IgG-molecules. As such an unspecific (i.e. not induced by either of the two binding domains of a bispecific molecule) immobilization is unfavorable due to i) influence on pharmacokinetics of a molecule and ii) off-target activation of immune effector cells various Fc-variants and mutations to ablate FcgR-binding have been identified. In this context, Morgan et al. 1995, Immunology (The N-terminal end of the CH2domain of chimeric human IgG1 anti-HLA-DR is necessary for C1q, FcyRI and FcyRIII binding) disclose the exchange of the residues 233-236 of human IgG1 with the corresponding sequence derived from human IgG2, i.e., the residues 233P, 234V and 235A and wherein no amino acid is present at position 236, resulting in abolished FcgRI binding, abolished C1q binding and diminished FcgRIII binding. EP1075496 discloses antibodies and other Fc-containing molecules with variations in the Fcdomain (such as one or more of 233P, 234V, 235A and no residue or G in position 236 and 327G, 330S and 331S) wherein the recombinant antibody is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target. Accordingly, in some embodiments, the Fcdomain comprises or further comprises one or more of the amino acids or deletions selected from the group consisting of 233P, 234V, 235A, 236 (no residue) or G, 327G, 330S, 331S, preferably, the Fcdomain comprises or further comprises the amino acids 233P, 234V, 235A, 236 (no residue) or G and one or more amino acids selected from the group consisting of 327G, 330S, 331S, most preferably, the Fc domain comprises or further comprises the amino acids 233P, 234V, 235A, 236 (no residue) and 331S.In one further embodiment, the Fcdomain comprises or further comprises the amino acid substitution N297Q, N297G or N297A, preferably N297Q. The amino acid substitution “N297Q”, “N297G” or “N297A” refer to amino acid substitutions at position 297 that abrogate the native N-Glycosylation site within the Fc- domain. This amino acid substitution further prevents Fc-gamma-receptor interaction and decreases the variability of the final protein products, i.e. the antigen binding proteins of the present invention, due to sugar residues as described for example in Tao, MH and Morrison, SL (J Immunol. 1989 Oct 15;143(8):2595-601). In one further embodiment, in particular when no light chain, the Fcdomain comprises or further comprises the amino acid substitution S220C. The amino acid substitution "S220C” deletes the cysteine forming the CH1-CLdisulfide-bridge. In some embodiments, the Fcdomain comprises or further comprises at least two additional cysteine residues, for example S354C and Y349C or L242C and K334C, wherein S354C is in the Fc-domain of one polypeptide, such as Fc1, and Y349C is in the Fcdomain of the other polypeptide, such as Fc2, to form a heterodimer and / or wherein L242C and K334C are located in the same Fc-domain, either in the Fc1or Fc2of one or both polypeptides to form a intradomain C-C bridge. Additional substitutions and description may be found in U.S. Patent Application No. 20180162922 the contents of which is incorporated by reference in its entirety. It may be also desirable to modify the antigen binding protein of the present invention with respect to effector function, e.g. so as to enhance or reduce antigen-dependent cell- mediated cytotoxicity (ADCC) and / or complement dependent cytotoxicity (CDC) of the antigen binding protein. This may be achieved by introducing one or more amino acid substitutions in an Fcdomain of the antigen binding protein, herein also called Fc-variants in the context with the antigen binding proteins of the present invention. Alternatively, or additionally, cysteine residue(s) may be introduced in the Fcdomain, thereby allowing inter- chain disulfide bond formation in this region. The heterodimeric antigen binding protein thus generated may have improved or reduced internalization capability and / or increasedcomplement-mediated cell killing and / or antibody-dependent cellular cytotoxicity (ADCC) (Caron PC. et al. 1992; and Shopes B. 1992).

[0097] Another type of amino acid modification of the antigen binding protein of the invention may be useful for altering the original glycosylation pattern of the antigen binding protein, i.e. by deleting one or more carbohydrate moieties found in the antigen binding protein, and / or adding one or more glycosylation sites that are not present in the antigen binding protein. The presence of either of the tripeptide sequences asparagine-X-serine, and asparagine-X-threonine, where X is any amino acid except proline, creates a potential glycosylation site. Addition or deletion of glycosylation sites to the antigen binding protein is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites).

[0098] Another type of modification involves the removal of sequences identified, either in silico or experimentally, as potentially resulting in degradation products or heterogeneity of antigen binding protein preparations. As examples, deamidation of asparagine and glutamine residues can occur depending on factors such as pH and surface exposure. Asparagine residues are particularly susceptible to deamidation, primarily when present in the sequence Asn-Gly, and to a lesser extent in other dipeptide sequences such as Asn-Ala. When such a deamidation site, in particular Asn-Gly, is present in an antigen binding protein of the invention, it may therefore be desirable to remove the site, typically by conservative substitution to remove one of the implicated residues. Such substitutions in a sequence to remove one or more of the implicated residues are also intended to be encompassed by the present invention.

[0099] Another type of covalent modification involves chemically or enzymatically coupling glycosides to the antigen binding protein. These procedures are advantageous in that they do not require production of antigen binding protein in a host cell that has glycosylation capabilities for N-or O-linked glycosylation. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine,or tryptophan, or (f) the amide group of glutamine. For example, such methods are described in WO 87 / 05330. Removal of any carbohydrate moieties present on the antigen binding protein may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the antigen binding protein to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), while leaving the antigen binding protein intact. Chemical deglycosylation is described by Sojahr H. et al. (1987) and by Edge, AS. et al. (1981). Enzymatic cleavage of carbohydrate moieties on antibodies can be achieved by the use of a variety of endo-and exo-glycosidases as described by Thotakura, NR. et al. (1987). Another type of covalent modification of the antigen binding protein comprises linking the antigen binding protein to one of a variety of non-proteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in US Patent Nos. 4,640, 835; 4,496, 689; 4,301, 144; 4,670, 417; 4,791, 192 or 4,179,337. “Functional fragment of a TCR” refers to a fragment of a TCR that retains or substantially retains the affinity, functional avidity and / or specificity of the TCR from which it is derived for a target antigen. Exemplary functional fragments, e.g. VAand VB, are herein demonstrated in the examples below. As binding to the target antigenic peptide is defined by the CDR1 and CDR3 sequences, and binding to the target antigenic peptide MHC complex is defined by CDR1, CDR2 and CDR3, antigen binding proteins comprising the CDR1 and CDR3 and optionally CDR2 sequences of a TCR retain the affinity, functional avidity and / or specificity of the parental TCR for a target antigen. The person skilled in the art is aware that the CDRs are usually interspersed with framework regions (FRs), however the specific amino acid sequences of the framework regions may not directly be involved in target antigen specificity. Examples of functional TCR fragments include the variable domains, such as TCR alpha, beta, gamma or delta variable domains, or fragments of the α, β, δ or γ chain, such as an α, β, δ or γ chain without transmembrane domain and short cytoplasmic tail. The term “fragment” as used herein refers to naturally occurring fragments (e.g. splice variants orpeptide fragments) as well as artificially constructed fragments, in particular to those obtained by gene-technological means. The functional fragments of the TCRs may be comprised in various formats in the antigen binding protein of the invention. A functional fragment of a TCR may have retained or substantially retained the affinity for a target antigen, if, for example, the KD for binding to the target antigen measured as outlined below is identical to the KD of the TCR or is increased or reduced, preferably reduced, no more than 10x, 5x, 3x, or 2x. The functional fragments as herein provided in the examples have improved affinity for the target antigen, e.g. by at least 100x, at least 500x or at least 1000x fold, compared to the variable domains as comprised in the naturally occurring TCR from which they were derived. A functional fragment of a TCR is considered to have retained or substantially retained the functional avidity for a target antigen, if, for example, the functional avidity for the target antigen is identical to that of the TCR or is increased or reduced, preferably reduced, no more than 50%, 40%, 30%, 20%, 15%, 10%, 8%, 5%, 3%, 2% or 1%. In particular, a functional fragment of a TCR is considered to have retained or substantially retained the functional avidity for a target antigen, if, for example, its cytotoxic activity in response to the target of the parent protein measured in a cytotoxicity assay is identical to the cytotoxic activity of the TCR or is increased or reduced, preferably reduced, no more than 50%, 40%, 30%, 20%, 15%, 10%, 8%, 5%, 3%, 2% or 1%, preferably 10%, 8%, 5%, 3%, 2% or 1%. A functional fragment of a TCR is considered to have retained or substantially retained the specificity for a target antigen (i.e. the ability to specifically bind to a target antigen), if it does not significantly bind to peptides other than the target antigenic peptide of the TCR. “Does not significantly bind” in the context of antigenic peptide variants and in the context of antigen binding proteins of the invention, in particular soluble antigen binding proteins of the invention, denotes, typically in a binding assay, for example biolayer interferometry, a relative response signal was determined for antigenic peptide variants that is not higher than 30%, not higher than 25%, not higher than 20%, not higher than 15%,preferably not higher than 20% of the signal obtained for binding to the MAGEB2 peptide consisting of the amino acid sequence of SEQ ID NO: 1, preferably in the same experimental conditions. The terms “α / β TCR” or a ”γ / δ TCR” refer to a TCR comprising an α-chain and a β- chain as described above, or a γ-chain and a δ-chain, respectively. Such a TCR may also be described as “full length TCR” or “conventional TCR”. An α / β TCR or a γ / δ TCR may be a native TCR or may be an engineered TCR that retains the structure of a native TCR, i.e. an engineered TCR comprising minor modifications in the variable and / or constant domains as described above, such as a humanized TCR. “Single chain TCR (scTCR)” as used herein denotes a TCR in which the variable domains of the TCR are located on a single polypeptide. Typically, the variable domains in scTCRs are separated by a linker, wherein said linker typically comprises 10 to 30 amino acids, such as 25 amino acids. A “chimeric protein” herein refers to a protein comprising sequences from multiple species. A “chimeric TCR” herein refers to a TCR comprising sequences from multiple species. Preferably, a chimeric TCR in the context of the invention may comprise an α-chain comprising at least one domain from a human and one domain from mouse. More preferably, a chimeric TCR in the context of the invention may comprise an α-chain comprising a variable domain of a human α-chain and, for example, a constant domain of a murine TCR α- chain. The term “antibody” as used herein is meant to include native and engineered antibodies. The term “engineered antibody includes functional antibody fragments, single chain antibodies, single domain antibodies, bispecific or multispecific antibodies. A “native antibody” comprises two heavy and two light chains, wherein the heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (λ) and kappa (κ). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct domains (alsoreferred to as regions). The light chain includes two domains, a variable domain (VL) and a constant domain (CL). The heavy chain includes four or five domains depending on the antibody isotype; a variable domain (VH) and three or four constant domains (CH1, CH2and CH3, and optionally CH4, collectively referred to as CH). The variable domains of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The specificity of the antibody resides in the structural complementarity between the antibody binding site and the antigenic determinant. Antibody binding sites are made up of residues that are primarily from the “antibody complementarity determining regions” (CDRs) or hypervariable regions. Occasionally, residues from non-hypervariable or framework regions (FR) influence the overall domain structure and hence the binding site. CDRs refer to amino acid sequences that together define the binding affinity and specificity of the natural Fv region of a native antibody binding site. The light and heavy chains of an antibody each have three CDRs, designated CDRL1, CDRL2, CDRL3, and CDRH1, CDRH2, and CDRH3, respectively. An antibody antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. “Antibody framework regions” (FRs) refer to amino acid sequences interposed between CDRs, i.e. to those portions of antibody light and heavy chain variable regions that are relatively conserved among different antibodies in a single species. The light and heavy chains of an antibody each have four FRs, designated FR1-L, FR2-L, FR3-L, FR4-L, and FR1-H, FR2-H, FR3-H, FR4-H, respectively. Accordingly, the light chain variable domain may be described as (FR1-L)-(CDRL1)-(FR2- L)-(CDRL2)-(FR3-L)-(CDRL3)-(FR4-L) and the heavy chain variable domain may be described as (FR1-H)-(CDRH1)-(FR2-H)-(CDRH2)-(FR3-H)-(CDRH3)-(FR4-H). As used herein, a "human framework region" is a framework region that is substantially identical (about 85%, or more, in particular 90%, 95%, 97%, 99% or 100%) to the framework region of a naturally occurring human antibody. In the context of the invention, CDR / FR definition in an antibody light or heavy chain variable domain is determined based on Kabat definition (Kabat et al., U.S. Dept. of Health and Human Services, "Sequences of proteins of immunological interest", 1991). Accordingly, amino acid sequences of the CDR1, CDR2 andCDR3 of a given variable chain and the amino acid sequences of the framework regions (e.g. FR1, FR2, FR3, and FR4) are indicated according to said Kabat definition in the herein provided disclosure. Knowing the amino acid sequence of the CDRs of an antibody, a TCR or an antigen binding protein of the invention, one skilled in the art can easily determine the framework regions, such as the TCR framework regions or antibody framework regions. In cases where the CDRs are not indicated, the skilled in the art can first determine the CDR amino acid sequences based on the IMGT definition for TCRs or the Kabat definition for antibodies and then determine the amino acid sequences of the framework regions. Engineered antibody formats include functional antibody fragments, single chain antibodies, single domain antibodies, and Fc- and / or hinge-engineered, effector function- silenced, -augmented or -altered antibodies, chimeric, humanized, bispecific or multispecific antibodies. Engineered antibody formats further include constructs in which the light chain variable domain of an antibody may be replaced with the α-chain variable domain of a TCR and the heavy chain variable domain may be replaced with the β-chain variable domain of a TCR, or vice versa. A “functional antibody fragment” refers to a portion of a full-length antibody that retains the ability to bind to its target antigen, in particular the affinity and / or specificity for its target antigen. Preferably, a functional antibody fragment comprises the antigen binding region or variable region of the full-length antibody. Examples of functional antibody fragments include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, nanobodies, DARPins, Knottins and diabodies. A functional antibody fragment may also be a single domain antibody, such as a heavy chain antibody. The term “Fab” denotes an antibody fragment having a molecular weight of about 50,000 Daltons and antigen binding activity, in which about a half of the N-terminal side of H chain and the entire L chain, among fragments obtained by treating IgG with a protease, e.g. papain, are bound together through a disulfide bond. The Fv fragment is the N-terminal part of the Fab fragment of an antibody and consists of the variable portions of one light chain and one heavy chain.The antigen binding protein and the CDRs as provided herein can be incorporated in various formats as herein disclosed above. Further exemplary antigen binding proteins comprising the inventive CDRs in different formats are herein provided below. The antigen binding protein may be a “diabody” or the herein provided binding sites may be comprised in the “diabody format”. These terms refer to bivalent molecules composed of two polypeptide chains, each comprising two variable domains connected by a linker (e.g. LDb1and LDb2), wherein two of the domains may be first and second variable domains as defined herein (e.g. V1 and V2) and the other two domains may be TCR derived or antibody derived variable domains (e.g. V3 and V4). Particularly, the V1and V2domains may be located on two different polypeptides and the V3and V4domains may be located on two different polypeptides and the domains dimerize in a cross-over confirmation. The domains may also be located on further polypeptide chains, e.g. four polypeptide chains. The LDb1and LDb1,can be identical or different and may be short linkers. A short linker is a linker that is typically between 2 to 12, 3 to 13, such as 3, 4, 5, 6, 7, 8, 9 amino acids long, for example 4, 5 (Brinkmann U. and Kontermann R.E. (MAbs. 2017 Feb-Mar; 9(2): 182–212) or 8 amino acids long, such as ‘GGGSGGGG’ of SEQ ID NO: 26. A further format of the antigen binding protein may be the “dual-variable-domain immunoglobulin (DVD-Ig™)” format as described in 2007 by Wu C. et al. (Nat Biotechnol. 2007 Nov; 25(11):1290-7). The DVD-Ig™ as described in the art, is thus typically composed of two polypeptide chains, one heavy chain comprising V-L-V-CH1-CH2-CH3and one light chain comprising V-L-V-CL. The domain pairs V / V and V / V are thus pairing in parallel. The herein provided CDRs and variable domains may be incorporated into this exemplary format. The “dual-variable-domain Ig format” (or “DVD-Ig format”) refers to a protein comprising two polypeptide chains, each comprising two variable domains connected by a linker (L1, L3), wherein two of the variable domains are first and second variable domains as defined in the context of the present invention (VAand VB) and the other two domains are antibody or TCR derived. As used herein, a “format” of an antigen binding protein specifies a defined spatial arrangement of domains, in particular of variable and optionally constant domains.Characteristics of such antigen binding protein formats are the number of polypeptide chains (single chain, double chain or multiple chains), the type and length of linkers connecting different domains, the number of variable domains (and thus the number of valences), the number of different variable domains (and thus the number of specificities for different antigens, e.g. bispecific, multispecific), and the order and orientation of variable domains (e.g. cross-over, parallel). As indicated herein above and as shown in the examples, the inventive antigen binding domains, e.g. specified by the CDRs as provided herein, may be comprised in various formats. The term "humanized” in the context of an antigen binding protein or antibody refers to an antibody which is completely or partially of non-human origin and which has been modified by replacing certain amino acids, in particular in the framework regions of the heavy and light chains, in order to avoid or minimize an immune response in humans. The constant domains of a humanized antibody are mainly human CHand CLdomains. Numerous methods for humanization of an antibody sequence are known in the art. For example, a “humanized” antibody can be made by the introduction of conservative substitutions, consensus sequence substitutions, germline substitutions and / or back mutations, see, e.g., Teng et al., Proc. Natl. Acad. Sci. U.S.A., 80: 7308-7312, 1983; Kozbor et al., Immunology Today, 4: 7279, 1983; Olsson et al., Meth. Enzymol., 92: 3-16, 1982, and the review by Almagro & Fransson (2008) Front Biosci. 13: 1619-1633. One commonly used method is CDR grafting, or antibody reshaping, which involves grafting of the CDR sequences of a donor antibody, generally a mouse antibody, into the framework scaffold of a human antibody of different specificity. Since CDR grafting may reduce the binding specificity and affinity, and thus the biological activity, of a CDR grafted non-human antibody, back mutations may be introduced at selected positions of the CDR grafted antibody in order to retain the binding specificity and affinity of the parent antibody. Identification of positions for possible back mutations can be performed using information available in the literature and in antibody databases. An alternative humanization technique to CDR grafting and back mutation is resurfacing, in which non-surface exposed residues of non-human origin are retained, while surface residues are altered to human residues. Another alternative technique is known as “guided selection” (Jespers et al. (1994) Biotechnology 12, 899) and can be used to derive from for example a murine or rat antibody a fully human antibody conserving theepitope and binding characteristics of the parental antibody. A further method of humanization is the so-called 4D humanization. The 4D humanization protocol is described in the patent application US20110027266 Al (W02009032661 Al) and is exemplified in the following applying the 4D humanization to humanize the rat antibody variable light (VL) and heavy (VH) domains.

[0121] For chimeric antibodies, humanization typically involves modification of the framework regions of the variable region sequences.

[0122] The term "linker" as used herein refers to one or more amino acid residues inserted between domains or a domain and an agent to provide sufficient mobility for the domains or elements, for example the variable domains of bispecific antigen binding to fold correctly to form the antigen binding sites.

[0123] In some embodiments, a linker consists of 0 amino acid meaning that the linker is absent. A linker is inserted at the transition between variable domains or between variable domains and constant domains (or dimerization domains), respectively, at the amino acid sequence level. The transition between domains can be identified because the approximate size of the antibody domains as well as of the TCR domains is well understood. The precise location of a domain transition can be determined by locating peptide stretches that do not form secondary structural elements such as beta-sheets or alpha-helices as demonstrated by experimental data or as can be assumed by techniques of modelling or secondary structure prediction.

[0124] A linker, as long as it is not specified otherwise in the respective context, can be from at least 1 to 30 amino acids in length. In some embodiments, a linker can be 2-25, 2-20, or 3- 18 amino acids long. In some embodiments, a linker can be a peptide of a length of no more than 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 amino acids. In other embodiments, a linker can be 5- 25, 5-15, 4-11, 10-20, or 20-30 amino acids long. In other embodiments, a linker can be about, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids long. In a particular embodiment, a linker can be less than 24, less than 20, less than 16, is less than 12, less than 10, for example from 5 to 24, 10 to 24 or 5-10 amino acid residues in length. In some embodiments, said linker is equal to 1 or more aminoacid residues in length, such as more than 1, more than 2, more than 5, more than 10, more than 20 amino acid residues in length, more than 22 amino acid residues in length. In preferred embodiments, the linker is a glycine / serine linker, i.e. a linker consisting of or essentially consisting of glycine and serine residues. The antigen binding protein of the present disclosure can be synthetic, recombinant, isolated, engineered and / or purified. In particular aspects, the antigen binding protein is a non-naturally occurring antigen binding protein, e.g. if the antigen binding protein is a soluble bispecific antigen binding protein, such as a TCER®. An “engineered” antigen binding protein, in particular an engineered TCR in the context of the present invention refers to a protein that is not naturally occurring or that has been modified by biotechnological methods, in particular by introducing amino acid mutations / substitutions into the native protein sequence. Such biotechnological methods are well known to the skilled in the art. The term “isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated”. An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. An isolated antigen binding protein is substantially free of other antigen binding proteins having different antigenic specificities (e.g., an antigen binding protein that specifically binds MAGEB2 is substantially free of antigen binding proteins that specifically bind antigens other than MAGEB2). Moreover, an isolated antigen binding protein may be substantially free of other cellular material and / or chemicals. Accordingly, “isolated” may refer to a protein that is removed from cell culture and separated from cell culture components, e.g., it may have been separated from at least 90%, preferably at least 95%, of cell culture components. The term “E:T ratio” refers to the ratio of effector cells (i.e. immune cells,) to target cells. In some embodiments, the E:T ratio corresponds to the seeding ratio, i.e. the ratio of the total number of immune cells to target cells.In an example of a lactate dehydrogenase (LDH)-release assay, the effector cells are immune cells. These effector cells are co-cultured with tumor cells endogenously expressing and presenting the MAGEB2 antigenic peptide and optionally additionally loaded with the MAGEB2 antigenic peptide. In some embodiments, the tumor cells are SKMEL-5 cells, RPMI7951 cells or SCC25 cells. In some embodiments of the LDH-release assay, the seeding ratio of total immune cells and target cells is 10:1. The efficacy of an antigen binding protein is considered high if in a LDH-release assay as defined above, killing of tumor cells (as determined LDH release) is observed at an E:T ratio of 10:1. Alternatively, the efficacy of an antigen binding protein is considered high, if in a cytotoxicity assay, preferably a LDH- release assay as defined above, the cytotoxic activity of the effector cells against the target cells at the highest concentration of the antigen binding protein tested is at least 50%, at least 60%, at least 70%, at least 75%, preferably at least 80%, at least 85%, at least 90%, or at least 95% of the cytotoxic activity of a control toxic reagent. The skilled in the art is aware that the cytotoxic activity can be higher than 100%. This is due to the fact that 100% cytotoxic activity is defined by a “maximum lysis control”, which refers to incubation of the target cells with the toxic reagent. In some embodiments, the toxic reagent is a detergent, e.g. Triton- X100, Tween-20, Tween-80 or NP-40, that effects lysis of the target cells. In some specific examples, the maximum lysis control comprises adding a 0.9% Triton-X100 solution to the target cell culture. The cytotoxic activity of the toxic reagent, i.e. the number of target cells killed by the toxic reagent is defined as 100%. Since the target cells can still proliferate during the co-culture, the effector cells may eventually kill an even higher number of target cells during the cytotoxicity assay than the toxic reagent killed during the maximum lysis control. In such instances, the calculated cytotoxic activity will be higher than 100%. “Half maximal effective concentration” also called “EC50”, typically refers to the concentration of a molecule which induces a response halfway between the baseline and maximum after a specified exposure time. EC50 and affinity are inversely related, the lower the EC50 value the higher the affinity of the molecule. In one example, the “EC50” refers to the concentration of the antigen binding protein of the invention which induces a response halfway between the baseline and maximum after a specified exposure time, more particularly, refers to the concentration of the antigen binding protein of the invention which induces a response halfway between the baseline and maximum after a specified exposuretime. EC50 values can be experimentally assessed by a variety of known methods, using for example binding assays such as ELISA or flow cytometry, or functional assays such as cytokine release assay or lactate dehydrogenase (LDH) release assay. In particular embodiments, the “EC50” refers to the concentration of the antigen binding protein, which induces a response halfway between the baseline and maximum, when target cells are co- cultured with effector cells in a LDH-release assay as defined above. The functional avidity of an antigen binding protein is considered high, if the EC50determined in a cytotoxicity assay, preferably a LDH-release assay as defined above, is less than about 500 pM, preferably less than about 200 pM, more preferably less than about 100 pM, or most preferably less than about 30 pM, determined using a co-culture assays with MAGEB2- expressing tumor cells having MAGEB2 copy number per cell of less than 200. The term “specificity” in the context of the present invention denotes the capacity of an antigen binding protein to discriminate its target peptide from peptides having a different amino acid sequence, e.g. similar peptides as defined below. An antigen binding protein is considered specific for a target peptide, if binding to the target peptide presented in an MHC molecule occurs with a significantly higher affinity and / or higher functional avidity than the binding to similar peptides. The specificity of the antigen binding protein is determined by the amino acid sequences CDRa1, CDRa3, CDRb1 and CDRb3. The amino acid sequences of CDRa2 and CDRb2 contact the MHC molecule and are not required for antigen specificity. As used herein, the term “approximately,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). As used herein with respect to a disease, the term “associated with” means that the symptom, measurement, characteristic, or status in question is linked to the diagnosis, development, presence, or progression of that disease. As association can, but need not, becausatively linked to the disease. For example, symptoms, sequelae, or any effects causing a decrease in the quality of life of a patient having cancer are considered associated with the cancer and in some embodiments of the present invention can be treated, ameliorated, or prevented by administering the polynucleotides of the present invention to a subject in need thereof.

[0134] When used with respect to two or more moieties, the terms “associated with,” “conjugated,” “linked,” “attached,” and “tethered,” when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An “association” need not be strictly through direct covalent chemical bonding. It can also suggest ionic or hydrogen bonding or a hybridization-based connectivity sufficiently stable such that the “associated” entities remain physically associated.

[0135] As used herein, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.

[0136] As used herein, the term “biodegradable” means capable of being broken down into innocuous products by the action of living things.

[0137] As used herein, the term “binding affinity” refers to the strength of the total noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Without wishing to be bound by theory, affinity depends on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, and on the distribution of charged and hydrophobic groups. Affinity also includes the term “avidity,” which refers to the strength of the antigen-antibody bond after formation of reversible complexes (e.g., either monovalent or multivalent). Methods for calculating the affinity of an antibody for an antigen are known in the art, comprising use of binding experiments to calculate affinity.The affinity of a molecule X for its partner Y can generally be represented by the dissociationconstant (Kd). A low-affinity complex contains an antibody that generally tends to dissociate readily from the antigen, whereas a high-affinity complex contains an antibody that generally tends to remain bound to the antigen for a longer duration. Antibody activity in functional assays (e.g., flow cytometry assay) is also reflective of antibody affinity. Antibodies and affinities can be phenotypically characterized and compared using functional assays (e.g., flow cytometry assay). As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a biological system and / or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular embodiments, a polynucleotide of the present invention can be considered biologically active if even a portion of the polynucleotide is biologically active or mimics an activity considered biologically relevant. As used herein, the terms “codon substitution” or “codon replacement” in the context of sequence optimization refer to replacing a codon present in a reference nucleic acid sequence with another codon. A codon can be substituted in a reference nucleic acid sequence, for example, via chemical peptide synthesis or through recombinant methods known in the art. Accordingly, references to a "substitution" or "replacement" at a certain location in a nucleic acid sequence (e.g., an mRNA) or within a certain region or subsequence of a nucleic acid sequence (e.g., an mRNA) refer to the substitution of a codon at such location or region with an alternative codon. As used herein, a "CpG site" refers to a region of DNA in which cytosine nucleotides follow a guanine nucleotide in a linear order of bases in the 5 'to 3' direction. CpG sites occur at high frequency in regions of the genome called CpG islands (or CG islands). Cytosine in CpG dinucleotides can be methylated to form 5-methylcytosine. In mammals, 70% to 80% of CpG cytosines are methylated. Methylation of cytosine within a gene can alter its expression. As used herein, the terms “coding region” and “region encoding” and grammatical variants thereof, refer to an Open Reading Frame (ORF) in a polynucleotide that upon expression yields a polypeptide or protein.

[0142] As used herein, the term “comprising” is intended to mean that the compounds, compositions and methods include the recited elements, but not exclude others. “Consisting essentially of" when used to define compounds, compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants, e.g., from the isolation and purification method and pharmaceutically acceptable carriers, preservatives, and the like. “Consisting of" shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this technology.

[0143] As used herein, “complementary” sequences refer to two nucleotide sequences which, when aligned anti-parallel to each other, contain multiple individual nucleotide bases which pair with each other. Paring of nucleotide bases forms hydrogen bonds and thus stabilizes the double strand structure formed by the complementary sequences. It is not necessary for every nucleotide base in two sequences to pair with each other for sequences to be considered “complementary”. Sequences may be considered complementary, for example, if at least 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% of the nucleotide bases in two sequences pair with each other. In some embodiments, the term complementary refers to 100% of the nucleotide bases in two sequences pair with each other. In addition, sequences may still be considered “complementary” when the total lengths of the two sequences are significantly different from each other. For example, a primer of 15 nucleotides may be considered “complementary” to a longer polynucleotide containing hundreds of nucleotides if multiple individual nucleotide bases of the primer pair with nucleotide bases in the longer polynucleotide when the primer is aligned anti-parallel to a particular region of the longer polynucleotide. Nucleotide bases paring is known in the field, such as in DNA, the purine adenine (A) pairs with the pyrimidine thymine (T) and the pyrimidine cytosine (C) always pairs with the purine guanine (G); while in RNA, adenine (A) pairs with uracil (U) and guanine (G) pairs with cytosine (C). Further, the nucleotide bases aligned anti-parallel to each other in two complementary sequences, but not a pair, are referred to herein as a mismatch.

[0144] As used herein, the term “composition” is intended to mean a combination of active agent and another compound or composition, inert (for example, a nanoparticle, detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include carriers, such as pharmaceutically acceptable carriers. In some embodiments, the carrier (such as the pharmaceutically acceptable carrier) comprises, or consists essentially of, or yet further consists of a nanoparticle, such as an polymeric nanoparticle carrier or an lipid nanoparticle that can be used alone or in combination with another carrier, such as an adjuvant or solvent. Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri, tetraoligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid components, which can also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D- mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol. A composition as disclosed herein can be a pharmaceutical composition. A “pharmaceutical composition” is intended to include the combination of an active agent with a carrier, inert or active, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[0145] As used herein, the term “compound,” is meant to include all stereoisomers and isotopes of the structure depicted. As used herein, the term “stereoisomer” means any geometric isomer (e.g., cis- and trans- isomer), enantiomer, or diastereomer of a compound. The present disclosure encompasses any and all stereoisomers of the compounds describedherein, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereomeric mixtures of compounds and means of resolving them into their component enantiomers or stereoisomers are well-known. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. Further, a compound, salt, or complex of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.

[0146] As used herein, the term “contacting” means establishing a physical connection between two or more entities. For example, contacting a mammalian cell with a nanoparticle composition means that the mammalian cell and a nanoparticle are made to share a physical connection. Methods of contacting cells with external entities both in vivo and ex vivo are well known in the biological arts. For example, contacting a nanoparticle composition and a mammalian cell disposed within a mammal can be performed by varied routes of administration (e.g., intravenous, intramuscular, intradermal, and subcutaneous) and can involve varied amounts of nanoparticle compositions. Moreover, more than one mammalian cell can be contacted by a nanoparticle composition.

[0147] As used herein, the term “conservative amino acid substitution” is one in which the amino acid residue in a protein sequence is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, or histidine), acidic side chains (e.g., aspartic acid or glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, or cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, or tryptophan), betabranched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, or histidine). Thus, if an amino acid in a polypeptide is replaced with another amino acid from the same side chain family, the amino acid substitution is considered to be conservative. In another aspect, a string of amino acids can beconservatively replaced with a structurally similar string that differs in order and / or composition of side chain family members. Non-conservative amino acid substitution: Non-conservative amino acid substitutions include those in which (i) a residue having an electropositive side chain (e.g., Arg, His or Lys) is substituted for, or by, an electronegative residue (e.g., Glu or Asp), (ii) a hydrophilic residue (e.g., Ser or Thr) is substituted for, or by, a hydrophobic residue (e.g., Ala, Leu, Ile, Phe or Val), (iii) a cysteine or proline is substituted for, or by, any other residue, or (iv) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, His, Ile or Trp) is substituted for, or by, one having a smaller side chain (e.g., Ala or Ser) or no side chain (e.g., Gly). Other amino acid substitutions can be readily identified by workers of ordinary skill. For example, for the amino acid alanine, a substitution can be taken from any one of D- alanine, glycine, beta-alanine, L-cysteine and D-cysteine. For lysine, a replacement can be any one of D-lysine, arginine, D-arginine, homo-arginine, methionine, D-methionine, ornithine, or D- ornithine. Generally, substitutions in functionally important regions that can be expected to induce changes in the properties of isolated polypeptides are those in which (i) a polar residue, e.g., serine or threonine, is substituted for (or by) a hydrophobic residue, e.g., leucine, isoleucine, phenylalanine, or alanine; (ii) a cysteine residue is substituted for (or by) any other residue; (iii) a residue having an electropositive side chain, e.g., lysine, arginine or histidine, is substituted for (or by) a residue having an electronegative side chain, e.g., glutamic acid or aspartic acid; or (iv) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having such a side chain, e.g., glycine. The likelihood that one of the foregoing non-conservative substitutions can alter functional properties of the protein is also correlated to the position of the substitution with respect to functionally important regions of the protein: some non-conservative substitutions can accordingly have little or no effect on biological properties. As used herein, the term "conserved" refers to nucleotides or amino acid residues of a polynucleotide sequence or polypeptide sequence, respectively, that are those that occur unaltered in the same position of two or more sequences being compared. Nucleotides oramino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences. In some embodiments, two or more sequences are said to be “completely conserved” if they are 100% identical to one another. In some embodiments, two or more sequences are said to be "highly conserved" if they are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be "highly conserved" if they are about 70% identical, about 80% identical, about 90% identical, about 95%, about 98%, or about 99% identical to one another. In some embodiments, two or more sequences are said to be "conserved" if they are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be "conserved" if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. Conservation of sequence can apply to the entire length of an polynucleotide or polypeptide or can apply to a portion, region or feature thereof. As used herein, a “control” is an alternative sample used in an experiment for comparison purpose. A control can be “positive” or “negative.” For example, where the purpose of the experiment is to determine a correlation of the efficacy of a therapeutic agent for the treatment for a particular type of disease, a positive control (a composition known to exhibit the desired therapeutic effect) and a negative control (a subject or a sample that does not receive the therapy or receives a placebo) are typically employed. As used herein, the term “delivering” means providing an entity to a destination. For example, delivering a polynucleotide to a subject can involve administering a nanoparticle composition including the polynucleotide to the subject (e.g., by an intravenous, intramuscular, intradermal, or subcutaneous route). Administration of a nanoparticle composition to a mammal or mammalian cell can involve contacting one or more cells with the nanoparticle composition.As used herein, when referring to polypeptides, the term "domain" refers to a motif of a polypeptide having one or more identifiable structural or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions). As used herein, a "dosing regimen" or a "dosing regimen" is a schedule of administration or physician determined regimen of treatment, prophylaxis, or palliative care. As used herein, the term “encapsulate” means to enclose, surround, or encase. As used herein, the term “effective amount” or “therapeutically effective amount” refers to a quantity of an agent (e.g., a polynucleotide as described herein) sufficient to achieve a beneficial or desired clinical result upon treatment. In the context of therapeutic applications, the amount of a therapeutic agent administered to the subject can depend on the type and severity of the disease or condition and on the characteristics of the individual, such as general health, age, sex, body weight, effective concentration of the polynucleotide(s) administered, and tolerance to drugs. It can also depend on the degree, severity, and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. An effective amount can be administered to a subject in one or more doses. In terms of treatment, an effective amount is an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of the disease, or otherwise reduce the pathological consequences of the disease. The effective amount is generally determined by the physician on a case-by-case basis and is within the skill of one in the art. The terms “effective amount” or “therapeutically effective amount,” can be used interchangeably with “effective dose” or “therapeutically effective dose.” As used herein, “encapsulation efficiency” refers to the amount of a therapeutic and / or prophylactic (e.g., polynucleotide) that becomes part of a nanoparticle composition, relative to the initial total amount of therapeutic and / or prophylactic used in the preparation of an LNP. For example, if 97 mg of therapeutic and / or prophylactic are encapsulated in an LNP out of a total 100 mg of therapeutic and / or prophylactic initially provided to the composition, the encapsulation efficiency may be given as 97%. As used herein, “encapsulation” may refer to complete, substantial, or partial enclosure, confinement, surrounding, or encasement.

[0159] As used herein, the term “enhanced delivery” means delivery of more (e.g., at least 1.5 fold more, at least 2 -fold more, at least 3-fold more, at least 4-fold more, at least 5-fold more, at least 6-fold more, at least 7 -fold more, at least 8-fold more, at least 9-fold more, at least 10-fold more) of a polynucleotide by a nanoparticle to a target tissue of interest (e.g., mammalian liver) compared to the level of delivery of a polynucleotide by a control nanoparticle to a target tissue of interest (e.g., MC3, KC2, or DLinDMA). The level of delivery of a nanoparticle to a particular tissue can be measured by comparing the amount of protein produced in a tissue to the weight of said tissue, comparing the amount of polynucleotide in a tissue to the weight of said tissue, comparing the amount of protein produced in a tissue to the amount of total protein in said tissue, or comparing the amount of polynucleotide in a tissue to the amount of total polynucleotide in said tissue. It will be understood that the enhanced delivery of a nanoparticle to a target tissue need not be determined in a subject being treated, it can be determined in a surrogate such as an animal model (e.g., a mouse model).

[0160] As used herein, the term “excipient” refers to a natural or synthetic substance formulated alongside the active ingredient of a medication, included for the purpose of longterm stabilization, bulking up solid formulations, or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility.

[0161] As used herein, an “expression vector” includes vectors capable of expressing DNA that is operably linked with regulatory sequences, such as promoter regions, that are capable of effecting expression of such DNA fragments. Such additional segments can include promoter and terminator sequences, and optionally can include one or more origins of replication, one or more selectable markers, an enhancer, a polyadenylation signal, and the like. Expression vectors are generally derived from plasmid or viral DNA, or can contain elements of both. Thus, an expression vector refers to a recombinant DNA or RNA construct, such as a plasmid, a phage, recombinant virus or other vector that, upon introduction into an appropriate host cell, results in expression of the cloned DNA. Appropriate expression vectors are well known to those of skill in the art and include thosethat are replicable in eukaryotic cells and / or prokaryotic cells and those that remain episomal or those which integrate into the host cell genome.

[0162] As used herein, a "formulation" includes at least a polynucleotide and one or more of a carrier and an excipient.

[0163] A "fragment," as used herein, refers to a portion. For example, fragments of proteins can comprise polypeptides obtained by digesting full-length protein isolated from cultured cells. In some embodiments, a fragment is a subsequence of a full-length protein wherein N- terminal, and / or C-terminal, and / or internal subsequences have been deleted. In some preferred aspects of the present invention, the fragments of a protein of the present invention are functional fragments.

[0164] As used herein, the term “helper lipid” refers to a compound or molecule that includes a lipidic moiety (for insertion into a lipid layer, e.g., lipid bilayer) and a polar moiety (for interaction with physiologic solution at the surface of the lipid layer). In some embodiments, the helper lipid is a phospholipid. A function of the helper lipid is to “complement” the amino lipid and increase the fusogenicity of the bilayer and / or to help facilitate endosomal escape, e.g., of nucleic acid delivered to cells. Helper lipids are also believed to be a key structural component to the surface of the LNP.

[0165] As used herein, the term "homology" refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. Generally, the term "homology" implies an evolutionary relationship between two molecules. Thus, two molecules that are homologous will have a common evolutionary ancestor. In the context of the present disclosure, the term homology encompasses both to identity and similarity.

[0166] In some embodiments, polymeric molecules are considered to be "homologous" to one another if at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the monomers in the molecule are identical (exactly the same monomer) or are similar (conservative substitutions). The term "homologous" necessarilyrefers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). As used herein, the term "identity" refers to the overall monomer conservation between polymeric molecules, e.g., between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. When comparing DNA and RNA, thymine (T) and uracil (U) can be considered equivalent. In certain aspects, the percentage identity "%ID" of a first amino acid sequence (or nucleic acid sequence) to a second amino acid sequence (or nucleic acid sequence) is calculated as %ID = 100 x (Y / Z), where Y is the number of amino acid residues (or nucleobases) scored as identical matches in the alignment of the first and second sequences (as aligned by visual inspection or a particular sequence alignment program) and Z is the total number of residues in the second sequence. If the length of a first sequence is longer than the second sequence, the percent identity of the first sequence to the second sequence will be higher than the percent identity of the second sequence to the first sequence.One skilled in the art will appreciate that the generation of a sequence alignment for the calculation of a percent sequence identity is not limited to binary sequence-sequence comparisons exclusively driven by primary sequence data. It will also be appreciated that sequence alignments can be generated by integrating sequence data with data from heterogeneous sources such as structural data (e.g., crystallographic protein structures), functional data (e.g., location of mutations), or phylogenetic data. A suitable program that integrates heterogeneous data to generate a multiple sequence alignment is T-Coffee, available at www.tcoffee.org, and alternatively available, e.g., from the EBI. It will also be appreciated that the final alignment used to calculate percent sequence identity can be curated either automatically or manually. As used herein, the term “insertional variants”, when referring to polypeptides are those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a native or starting sequence. "Immediately adjacent" to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid. "Deletional variants" when referring to polypeptides are those with one or more amino acids in the native or starting amino acid sequence removed. In some embodiments, deletional variants will have one or more amino acids deleted in a particular region of the molecule. As used herein, the term “ionizable lipid” or “ionizable amino lipid” includes those lipids having one, two, three, or more fatty acid or fatty alkyl chains and a pH-titratable amino head group (e.g., an alkylamino or dialkylamino head group). An ionizable amino lipid is typically protonated (i.e., positively charged) at a pH below the pKa of the amino head group and is substantially not charged at a pH above the pKa. Such ionizable amino lipids include, but are not limited to DLin-MC3-DMA (MC3), (13Z,165Z)-N,N-dimethyl-3- nonydocosa-13-16-dien-1-amine (L608), and a compound of any one of Formula I-XVI described herein. As used herein, the term “increase” or “enhance” means to alter positively by at least about 5%, including, but not limited to, alter positively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.As used herein, the term “isolated,” “purified,” or “biologically pure” refers to material that is free to varying degrees from components which normally accompany it as found in its native state. “Isolate” denotes a degree of separation from original source or surroundings. “Purify” denotes a degree of separation that is higher than isolation. A “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or polypeptide of the presently disclosed subject matter is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography (HPLC). The term “purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified. As used herein, the term “lipoplex” refers to a nucleic acid-liposome complex, where nucleic acid can be DNA, siRNA or mRNA. As used herein, the term “lymphocyte” refers to all immature, mature, undifferentiated, and differentiated white blood cell populations that are derived from lymphoid progenitors including tissue specific and specialized varieties, and encompasses, by way of non-limiting example, B cells, T cells, NKT cells, and NK cells. In some embodiments, lymphocytes include all B cell lineages including pre-B cells, progenitor B cells, early pro-B cells, late pro-B cells, large pre-B cells, small pre-B cells, immature B cells, mature B cells, plasma B cells, memory B cells, B-1 cells, B-2 cells, and anergic AN1 / T3 cell populations. As used herein, “methods of administration” can include intravenous, intramuscular, intradermal, subcutaneous, or other methods of delivering a composition to a subject. Amethod of administration can be selected to target delivery (e.g., to specifically deliver) to a specific region or system of a body. As used herein, the term “messenger RNA” or “mRNA” refers to any polynucleotide (a ribonucleic acid) which encodes a polypeptide of interest and which is capable of being translated to produce the encoded polypeptide of interest in vitro, in vivo, in situ, or ex vivo. Traditionally, the basic components of an mRNA molecule include a coding region, a 5’UTR, a 3’UTR, a 5’ cap, and a poly-A tail. As used herein, the term “modified messenger RNA” or “modified mRNA” refers to mRNA polynucleotides that include naturally occurring and / or non-naturally occurring modifications, for example, of a sugar, a nucleobase, or an internucleoside linkage (e.g., to a linking phosphate, to a phosphodiester linkage, or to the phosphodiester backbone). Non- natural modified nucleotides may be introduced during synthesis of post-synthesis of the polynucleotides to achieve desired functions or properties. The modifications may be present on an internucleoside linkage, purine or pyrimidine base, or sugar. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a polynucleotide may be chemically modified. As used herein, a “nanoparticle composition” is a composition comprising one or more lipids. Nanoparticle compositions are typically sized on the order of micrometers or smaller and can include a lipid bilayer. Nanoparticle compositions encompass lipid nanoparticles (LNPs), liposomes (e.g., lipid vesicles), and lipoplexes. For example, a nanoparticle composition can be a liposome having a lipid bilayer with a diameter of 500 nm or less. As used herein, the term “nucleoside” refers to a compound containing a sugar molecule (e.g., a ribose in RNA or a deoxyribose in DNA), or derivative or analog thereof, covalently linked to a nucleobase (e.g., a purine or pyrimidine), or a derivative or analog thereof (also referred to herein as “nucleobase”), but lacking an internucleoside linking group (e.g., a phosphate group). As used herein, the term “nucleotide” refers to a nucleoside covalently bonded to an internucleoside linking group (e.g., a phosphate group), or anyderivative, analog, or modification thereof that confers improved chemical and / or functional properties (e.g., binding affinity, nuclease resistance, chemical stability) to a nucleic acid or a portion or segment thereof. As used herein, the term “open reading frame”, abbreviated as “ORF”, refers to a segment or region of an mRNA molecule that encodes a polypeptide. The ORF comprises a continuous stretch of non-overlapping, in-frame codons, beginning with the initiation codon and ending with a stop codon, and is translated by the ribosome. As used herein, “operably linked” with reference to nucleic acid sequences, regions, elements or domains means that the nucleic acid regions are functionally related to each other. For example, a nucleic acid encoding a leader peptide can be operably linked to a nucleic acid encoding a polypeptide, whereby the nucleic acids can be transcribed and translated to express a functional fusion protein, wherein the leader peptide affects secretion of the fusion polypeptide. In some instances, the nucleic acid encoding a first polypeptide (e.g., a leader peptide) is operably linked to nucleic acid encoding a second polypeptide and the nucleic acids are transcribed as a single mRNA transcript, but translation of the mRNA transcript can result in one of two polypeptides being expressed. For example, an amber stop codon can be located between the nucleic acid encoding the first polypeptide and the nucleic acid encoding the second polypeptide, such that, when introduced into a partial amber suppressor cell, the resulting single mRNA transcript can be translated to produce either a fusion protein containing the first and second polypeptides, or can be translated to produce only the first polypeptide. In another example, a promoter can be operably linked to nucleic acid encoding a polypeptide, whereby the promoter regulates or mediates the transcription of the nucleic acid. Herein a phrase of the form "optionally substituted X" (e.g., optionally substituted alkyl) is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein said alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) per se is optional. As used herein, a "part" or "region" of a polynucleotide is defined as any portion of the polynucleotide that is less than the entire length of the polynucleotide.

[0185] As used herein, "patient" refers to a subject who can seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition. In some embodiments, the treatment is needed, required, or received to prevent or decrease the risk of developing acute disease, i.e., it is a prophylactic treatment.

[0186] As used herein, the term “pharmaceutically acceptable carriers” refers to any diluents, excipients, or carriers that may be used in the compositions disclosed herein. In some embodiments, a pharmaceutically acceptable carrier comprises, or consists essentially of, or yet further consists of a nanoparticle, such as an polymeric nanoparticle carrier or an lipid nanoparticle (LNP). Additionally or alternatively, pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They can be selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[0187] The terms “polynucleotide”, “nucleic acid” and “oligonucleotide” are used interchangeably and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides can have any three-dimensional structure and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of anysequence, nucleic acid probes and primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The term also refers to both double and single stranded molecules. Unless otherwise specified or required, any embodiment of this disclosure that is a polynucleotide encompasses both the double stranded form and each of two complementary single stranded forms known or predicted to make up the double stranded form. A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching.

[0188] As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer can comprise modified amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids such as homocysteine, ornithine, p- acetylphenylalanine, D-amino acids, and creatine), as well as other modifications known in the art. Polypeptides include encoded polynucleotide products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing. A polypeptide can be a monomer or can be a multi-molecular complex such as a dimer, trimer or tetramer. They can also comprise single chain or multichain polypeptides. Most commonly disulfide linkages are found in multichain polypeptides. The term polypeptide can also apply to amino acid polymers inwhich one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid. As used herein, the term "preventing" refers to partially or completely delaying onset of an infection, disease, disorder and / or condition; partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular infection, disease, disorder, and / or condition; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular infection, disease, disorder, and / or condition; partially or completely delaying progression from an infection, a particular disease, disorder and / or condition; and / or decreasing the risk of developing pathology associated with the infection, the disease, disorder, and / or condition. As used herein, "prophylactic" refers to a therapeutic or course of action used to prevent the spread of disease. As used herein, a "prophylaxis" refers to a measure taken to maintain health and prevent the spread of disease. An "immune prophylaxis" refers to a measure to produce active or passive immunity to prevent the spread of disease. As used herein, pseudouridine (ψ) refers to the C-glycoside isomer of the nucleoside uridine. A "pseudouridine analog" is any modification, variant, isoform or derivative of pseudouridine. For example, pseudouridine analogs include but are not limited to 1- carboxymethyl-pseudouridine, 1-propynyl-pseudouridine, 1-taurinomethyl-pseudouridine, 1- taurinomethyl-4-thio-pseudouridine, 1-methylpseudouridine (m1ψ) (also known as N1- methyl-pseudouridine), 1-methyl-4-thio-pseudouridine (m1s4ψ), 4-thio-1-methyl- pseudouridine, 3-methyl-pseudouridine (m3ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydropseudouridine, 2-thio- dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy- pseudouridine, 4-methoxy-2-thio-pseudouridine, 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine (acp3 ψ), and 2′-O-methyl-pseudouridine (ψm). As used herein, "purify," "purified," "purification" means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection.

[0194] As used herein, the term “reduce” means to alter negatively by at least about 5%, including, but not limited to, alter negatively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.

[0195] The term "reference nucleic acid sequence" or “reference nucleic acid” or “reference nucleotide sequence” or “reference sequence” refers to a starting nucleic acid sequence (e.g., a RNA, e.g., an mRNA sequence) that can be sequence optimized. In some embodiments, the reference nucleic acid sequence is a wild-type nucleic acid sequence, a fragment or a variant thereof. In some embodiments, the reference nucleic acid sequence is a previously sequence optimized nucleic acid sequence.

[0196] As used herein, “regulatory sequence” of a nucleic acid molecule means a cis- acting nucleotide sequence that influences expression, positively or negatively, of an operably linked gene. Regulatory regions include sequences of nucleotides that confer inducible (i.e., require a substance or stimulus for increased transcription) expression of a gene. When an inducer is present or at increased concentration, gene expression can be increased.Regulatory regions also include sequences that confer repression of gene expression (i.e., a substance or stimulus decreases transcription). When a repressor is present or at increased concentration, gene expression can be decreased. Regulatory regions are known to influence, modulate or control many in vivo biological activities including cell proliferation, cell growth and death, cell differentiation and immune modulation. Regulatory regions typically bind to one or more trans-acting proteins, which results in either increased or decreased transcription of the gene.

[0197] Particular examples of gene regulatory regions are promoters and enhancers.Promoters are sequences located around the transcription or translation start site, typically positioned 5' of the translation start site. Promoters usually are located within 1 Kb of the translation start site, but can be located further away, for example, 2 Kb, 3 Kb, 4 Kb, 5 Kb or more, up to and including 10 Kb. Polymerase II and HI are examples of promoters. A polymerase II or “pol II” promoter catalyzes the transcription of DNA to synthesize precursors of mRNA, and most shRNA and microRNA. Examples of pol II promoters are known in the art and include without limitation, the phosphoglycerate kinase (“PGK”)promoter; EF1-alpha; CMV (minimal cytomegalovirus promoter); and LTRs from retroviral and lentiviral vectors. In some embodiments, the promoter is a constitutive promoter. As used herein, the term “constitutive promoter” refers to a promoter that allows for continual transcription of the coding sequence or gene under its control in all or most tissues of a subject at all or most developing stages. Non-limiting examples of the constitutive promoters include a CMV promoter, a simian virus 40 (SV40) promoter, a polyubiquitin C (UBC) promoter, an EF1-alpha promoter, a PGK promoter and a CAG promoter. In some embodiments, the promoter is a conditional promoter, which allows for continual transcription of the coding sequence or gene under certain conditions. In further embodiments, the conditional promoter is an immune cell specific promoter, which allows for continual transcription of the coding sequence or gene in an immune cell. Non-limiting examples of the immune cell specific promoters include a promoter of a B29 gene promoter, a CD14 gene promoter, a CD43 gene promoter, a CD45 gene promoter, a CD68 gene promoter, a IFN-β gene promoter, a WASP gene promoter, a T-cell receptor β-chain gene promoter, a V9 γ (TRGV9) gene promoter, a V2 δ (TRDV2) gene promoter, and the like. Enhancers are known to influence gene expression when positioned 5' or 3' of the gene, or when positioned in or a part of an exon or an intron. Enhancers also can function at a significant distance from the gene, for example, at a distance from about 3 Kb, 5 Kb, 7 Kb, 10 Kb, 15 Kb or more. Regulatory regions also include, but are not limited to, in addition to promoter regions, sequences that facilitate translation, splicing signals for introns, maintenance of the correct reading frame of the gene to permit in-frame translation of mRNA and, stop codons, leader sequences and fusion partner sequences, internal ribosome binding site (IRES) elements for the creation of multigene, or polycistronic, messages, polyadenylation signals to provide proper polyadenylation of the transcript of a gene of interest and stop codons, and can be optionally included in an expression vector. As used herein, the term "sample" or "biological sample" refers to a subset of its tissues, cells or component parts (e.g., body fluids, including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cordblood, urine, vaginal fluid and semen). A sample further can include a homogenate, lysate or extract prepared from a whole organism or a subset of its tissues, cells or component parts, or a fraction or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, organs. A sample further refers to a medium, such as a nutrient broth or gel, which can contain cellular components, such as proteins or nucleic acid molecule.

[0201] As used herein, the term “separate” therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes.

[0202] As used herein, the term “sequential” therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.

[0203] As used herein, the term “sequence optimization” refers to a process or series of processes by which nucleobases in a reference nucleic acid sequence are replaced with alternative nucleobases, resulting in a nucleic acid sequence with improved properties, e.g., improved protein expression or decreased immunogenicity of the nucleic acid itself.

[0204] In general, the goal in sequence optimization is to produce a synonymous nucleotide sequence than encodes the same polypeptide sequence encoded by the reference nucleotide sequence. Thus, there are no amino acid substitutions (as a result of codon optimization) in the polypeptide encoded by the codon optimized nucleotide sequence with respect to the polypeptide encoded by the reference nucleotide sequence. In some embodiments, codon optimization is achieved by modification of a coding sequence according to at least one of the following; (i) replacing the naturally occurring codon sequence with an alternative codon that retains the amino acid sequence encoding the protein but alters the composition and / orstructure of the encoding RNA; (ii) adjusting the guanosine cytosine content of the coding sequence relative to the naturally occurring guanosine cytosine content of the coding sequence; (iii) adjusting the number of CpG sites of the coding sequence relative to the number of CpG sites in the naturally occurring coding sequence; (iv) substituting the naturally occurring codon sequence with an alternative codon relative to (ii) guanosine cytosine content and / or (iii) number of CpG sites. Codon optimization may include adjusting codons in the context of tRNA expression in a particular tissue and / or may include methods for evading the effects of natural, tissue-specific shRNAs or miRNAs. As used herein, the phrases "signal sequence," "signal peptide," and "transit peptide" are used interchangeably and refer to a sequence that can direct the transport or localization of a protein to a certain organelle, cell compartment, or extracellular export. The term encompasses both the signal sequence polypeptide and the nucleic acid sequence encoding the signal sequence. Thus, references to a signal sequence in the context of a nucleic acid refer in fact to the nucleic acid sequence encoding the signal sequence polypeptide. As used herein, the term "similarity" refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. Calculation of percent similarity of polymeric molecules to one another can be performed in the same manner as a calculation of percent identity, except that calculation of percent similarity takes into account conservative substitutions as is understood in the art. As used herein, the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time. As used herein, a "single unit dose" is a dose of any therapeutic administered in one dose / at one time / single route / single point of contact, i.e., single administration event. As used herein, the term “specifically binds” or “specifically binds to” or “specifically target” refers to a molecule (e.g., a polypeptide or fragment thereof) that recognizes and binds a molecule of interest (e.g., an antigen), but which does not substantially recognize and bindother molecules. The terms “specific binding,” “specifically binds to,” or is “specific for” a particular molecule (e.g., an antigen), as used herein, can be exhibited, for example, by a molecule having a Kd for the molecule to which it binds to of about 10−4M, 10−5M, 10−6M, 10−7M, 10−8M, 10−9M, 10−10M, 10−11M, or 10−12M. As used herein, the term “specific delivery,” “specifically deliver,” or “specifically delivering” means delivery of more (e.g., at least 1.5 fold more, at least 2-fold more, at least 3-fold more, at least 4-fold more, at least 5-fold more, at least 6-fold more, at least 7-fold more, at least 8-fold more, at least 9-fold more, at least 10-fold more) of a polynucleotide by a nanoparticle to a target tissue of interest (e.g., mammalian liver) compared to an off-target tissue (e.g., mammalian spleen). The level of delivery of a nanoparticle to a particular tissue can be measured by comparing the amount of protein produced in a tissue to the weight of said tissue, comparing the amount of polynucleotide in a tissue to the weight of said tissue, comparing the amount of protein produced in a tissue to the amount of total protein in said tissue, or comparing the amount of polynucleotide in a tissue to the amount of total polynucleotide in said tissue. For example, for renovascular targeting, a polynucleotide is specifically provided to a mammalian kidney as compared to the liver and spleen if 1.5, 2- fold, 3-fold, 5-fold, 10-fold, 15 fold, or 20 fold more polynucleotide per 1 g of tissue is delivered to a kidney compared to that delivered to the liver or spleen following systemic administration of the polynucleotide. It will be understood that the ability of a nanoparticle to specifically deliver to a target tissue need not be determined in a subject being treated, it can be determined in a surrogate such as an animal model (e.g., a rat model). As used herein "stable" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and in some cases capable of Formulation into an efficacious therapeutic agent. As used herein, the term "stabilize," "stabilized," "stabilized region" means to make or become stable. As used herein, by "subject" or "individual" or "animal" or "patient" or "mammal," is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, but are not limited to, humans, domesticanimals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; bears, food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on. In certain embodiments, the mammal is a human subject. In other embodiments, a subject is a human patient. In a particular embodiment, a subject is a human patient in need of treatment.

[0214] As used herein, the term "substantially" refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical characteristics rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term "substantially" is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical characteristics.

[0215] As used herein, the term “substantially equal” as it relates to time differences between doses, the term means plus / minus 2%.

[0216] As used herein, the term “sub-therapeutic dose” refers to a dose of an agent that does not achieve a particular therapeutic effect (e.g., wherein the particular therapeutic effect is achieved using a therapeutically effective amount). Typically, a sub-therapeutic dose of an agent is an amount of a therapeutic dose that is less than a therapeutically effective amount of the agent.

[0217] As used herein, the term “suffering from” refers to an individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with or displays one or more symptoms of the disease, disorder, and / or condition.

[0218] An individual who is "susceptible to" a disease, disorder, and / or condition has not been diagnosed with and / or cannot exhibit symptoms of the disease, disorder, and / or condition but harbors a propensity to develop a disease or its symptoms. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition (forexample, cancer) can be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and / or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and / or condition; (3) increased and / or decreased expression and / or activity of a protein and / or nucleic acid associated with the disease, disorder, and / or condition; (4) habits and / or lifestyles associated with development of the disease, disorder, and / or condition; (5) a family history of the disease, disorder, and / or condition; and (6) exposure to and / or infection with a microbe associated with development of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0219] The presence of a therapeutic agent in an off-target tissue can be the result of: (i) leakage of a polynucleotide from the administration site to peripheral tissue or distant off- target tissue via diffusion or through the bloodstream (e.g., a polynucleotide intended to express a polypeptide in a certain tissue would reach the off-target tissue and the polypeptide would be expressed in the off-target tissue); or (ii) leakage of an polypeptide after administration of a polynucleotide encoding such polypeptide to peripheral tissue or distant off-target tissue via diffusion or through the bloodstream (e.g., a polynucleotide would expressed a polypeptide in the target tissue, and the polypeptide would diffuse to peripheral tissue).

[0220] As used herein, the phrase "targeting sequence" refers to a sequence that can direct the transport or localization of a protein or polypeptide.

[0221] The term "therapeutic agent" refers to an agent that, when administered to a subject, has a therapeutic, diagnostic, and / or prophylactic effect and / or elicits a desired biological and / or pharmacological effect. For example, in some embodiments, an mRNA encoding a antigen binding protein can be a therapeutic agent.

[0222] As used herein, the term "therapeutically effective outcome" means an outcome that is sufficient in a subject suffering from or susceptible to an infection, disease, disorder, and / orcondition, to treat, improve symptoms of, diagnose, prevent, and / or delay the onset of the infection, disease, disorder, and / or condition. As used herein, the term "transcription" refers to methods to produce mRNA (e.g., an mRNA sequence or template) from DNA (e.g., a DNA template or sequence). As used herein, the term "treating" or "treatment" or "therapy" refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a disease, e.g., cancer. For example, "treating" cancer can refer to diminishing symptoms associate with the disease, prolong the lifespan (increase the survival rate) of patients, reducing the severity of the disease, preventing or delaying the onset of the disease, etc. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. Therapeutic effects of treatment include, without limitation, inhibiting recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. By “treating cancer” is meant that the symptoms associated with the cancer are, e.g., alleviated, reduced, cured, or placed in a state of remission. As used herein, “unmodified” refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the “unmodified” starting molecule for a subsequent modification. Uracil is one of the four nucleobases in the nucleic acid of RNA, and it is represented by the letter U. Uracil can be attached to a ribose ring, or more specifically, a ribofuranose via a b-N1-glycosidic bond to yield the nucleoside uridine. The nucleoside uridine is also commonly abbreviated according to the one letter code of its nucleobase, i.e., U. Thus, in thecontext of the present disclosure, when a monomer in a polynucleotide sequence is U, such U is designated interchangeably as a "uracil" or a "uridine."

[0227] The terms "uridine content" or "uracil content" are interchangeable and refer to the amount of uracil or uridine present in a certain nucleic acid sequence. Uridine content or uracil content can be expressed as an absolute value (total number of uridine or uracil in the sequence) or relative (uridine or uracil percentage respect to the total number of nucleobases in the nucleic acid sequence).

[0228] The terms "uridine-modified sequence" refers to a sequence optimized nucleic acid (e.g., a synthetic mRNA sequence) with a different overall or local uridine content (higher or lower uridine content) or with different uridine patterns (e.g., gradient distribution or clustering) with respect to the uridine content and / or uridine patterns of a candidate nucleic acid sequence. In the content of the present disclosure, the terms "uridine-modified sequence" and "uracil-modified sequence" are considered equivalent and interchangeable.

[0229] A "high uridine codon" is defined as a codon comprising two or three uridines, a "low uridine codon" is defined as a codon comprising one uridine, and a "no uridine codon" is a codon without any uridines. In some embodiments, a uridine-modified sequence comprises substitutions of high uridine codons with low uridine codons, substitutions of high uridine codons with no uridine codons, substitutions of low uridine codons with high uridine codons, substitutions of low uridine codons with no uridine codons, substitution of no uridine codons with low uridine codons, substitutions of no uridine codons with high uridine codons, and combinations thereof. In some embodiments, a high uridine codon can be replaced with another high uridine codon. In some embodiments, a low uridine codon can be replaced with another low uridine codon. In some embodiments, a no uridine codon can be replaced with another no uridine codon. A uridine-modified sequence can be uridine enriched or uridine rarefied.

[0230] As used herein, the terms "uridine enriched" and grammatical variants refer to the increase in uridine content (expressed in absolute value or as a percentage value) in a sequence optimized nucleic acid (e.g., a synthetic mRNA sequence) with respect to the uridine content of the corresponding candidate nucleic acid sequence. Uridine enrichment canbe implemented by substituting codons in the candidate nucleic acid sequence with synonymous codons containing less uridine nucleobases. Uridine enrichment can be global (i.e., relative to the entire length of a candidate nucleic acid sequence) or local (i.e., relative to a subsequence or region of a candidate nucleic acid sequence).

[0231] As used herein, the terms "uridine rarefied" and grammatical variants refer to a decrease in uridine content (expressed in absolute value or as a percentage value) in a sequence optimized nucleic acid (e.g., a synthetic mRNA sequence) with respect to the uridine content of the corresponding candidate nucleic acid sequence. Uridine rarefication can be implemented by substituting codons in the candidate nucleic acid sequence with synonymous codons containing less uridine nucleobases. Uridine rarefication can be global (i.e., relative to the entire length of a candidate nucleic acid sequence) or local (i.e., relative to a subsequence or region of a candidate nucleic acid sequence).(0232] As used herein, the term “variant” refers to both natural variants (e.g., polymorphisms, isoforms, etc.) and artificial variants in which at least one amino acid residue in a native or starting sequence (e.g., a wild type sequence) has been removed and a different amino acid inserted in its place at the same position. These variants can be described as “substitutional variants.” The substitutions can be single, where only one amino acid in the molecule has been substituted, or they can be multiple, where two or more amino acids have been substituted in the same molecule. If amino acids are inserted or deleted, the resulting variant would be an “insertional variant” or a “deletional variant” respectively.

[0233] As used herein, the term “initiation codon”, used interchangeably with the term “start codon”, refers to the first codon of an open reading frame that is translated by the ribosome and is comprised of a triplet of linked adenine-uracil-guanine nucleobases. The initiation codon is depicted by the first letter codes of adenine (A), uracil (U), and guanine (G) and is often written simply as “AUG”. Although natural mRNAs may use codons other than AUG as the initiation codon, which are referred to herein as “alternative initiation codons”, the initiation codons of polynucleotides described herein use the AUG codon. During the process of translation initiation, the sequence comprising the initiation codon is recognized via complementary base-pairing to the anticodon of an initiator tRNA (Met-tRNAiMet) bound bythe ribosome. Open reading frames may contain more than one AUG initiation codon, which are referred to herein as “alternate initiation codons”. As used herein, the term “lipid nanoparticle” or “LNP” refers to a nanoparticle comprising one or more lipids. In some embodiments, the LNP has a size of about 500 nm or less, about 450 nm or less, about 400 nm or less, about 350 nm or less, about 300 nm or less, about 250 nm or less, about 200 nm or less, about 150 nm or less, or about 100 nm or less. In some embodiments, the LNP has a size ranging from about 1 nm to about 100 nm. As used herein, the term “liposome” refers to a composite having at least one lipid bilayer. In some embodiments, the liposome has a size of about 500 nm or less, about 450 nm or less, about 400 nm or less, about 350 nm or less, about 300 nm or less, about 250 nm or less, about 200 nm or less, about 150 nm or less, or about 100 nm or less. In some embodiments, the liposome has a size ranging from about 1 nm to about 100 nm. As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe). As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof). As used herein, the term “ex vivo” refers to events that occur outside of an organism (e.g., animal, plant, or microbe or cell or tissue thereof). Ex vivo events may take place in an environment minimally altered from a natural (e.g., in vivo) environment. As used herein, the “N:P ratio” is the molar ratio of ionizable (in the physiological pH range) nitrogen atoms in a lipid to phosphate groups in an RNA, e.g., in a TLA including a lipid component and an RNA. As used herein, a “PEG lipid” or “PEGylated lipid” refers to a lipid comprising a polyethylene glycol component. As used herein, a “polymeric lipid” refers to a lipid comprising repeating subunits in its chemical structure. In some embodiments, the polymeric lipid is a lipid comprising apolymer component. In some embodiments, the polymeric lipid is a PEG lipid. In some embodiments, the polymeric lipid is not a PEG lipid. In some embodiments, the polymeric lipid is Brij or OH-PEG-stearate. The term “free of”, as used herein, means not comprising the referenced component. For example, when a population, solution, or formulation is described as being “free of PEG lipid”, the population, solution, or formulation does not comprise PEG lipid (e.g., does not comprise a PEG lipid described herein (e.g., does not comprise PEG-DMG)). The compositions used in accordance with the disclosure can be packaged in dosage unit form for ease of administration and uniformity of dosage. The term "unit dose" or "dosage" refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the composition calculated to produce the desired responses in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the result and / or protection desired. Precise amounts of the composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition. Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described herein. As used herein, “phosphomimic substitution” or “phosphomimetic substitution” refers to an amino acid substitution that mimic a phosphorylated amino acid. In some embodiments, a phosphomimic substitution comprises a glutamic acid (E) substitution. In some embodiments, a phosphomimic substitution comprises an aspartic acid (D) substitution. In some embodiments, a phosphomimic substitution mimics a phosphorylated tyrosine (Y) residue, a phosphorylated serine (S) residue, a phosphorylated threonine (T) residue, a phosphorylated arginine (R) residue, a phosphorylated histidine (H) residue, or a phosphorylated cysteine (C) residue.As used herein, “a mutation that prevents phosphorylation” refers to a mutation where the resulting amino acid cannot be phosphorylated. In some embodiments, a mutation that prevents phosphorylation comprises an alanine (A) substitution, a glutamine substitution (Q) or a phenylalanine (F) substitution. As used herein, an “Intrinsically Disordered Region” or “IDR” refers to a polypeptide segment of a protein that does not form a defined three-dimensional structure. IDRs can be found as flexible linkers or loops. IDRs are typically rich in polar uncharged amino acids. IDRs can be found bioinformatically from a given amino acid sequence, as shown in Tang, Yi-Jun, et al. "(BMC biology 21.1 (2023): 188) which is incorporated herein in its entirety. II. Detailed Description MAGE-B2 Antigen Binding Proteins In a first aspect, the invention provides an antigen binding protein specifically binding to a MAGEB2 antigenic peptide that is in a complex with a major histocompatibility complex (MHC) protein, wherein the MAGEB2 antigenic peptide comprises or consists of the amino acid sequence GVYDGEEHSV (SEQ ID NO: 1), wherein the antigen binding protein comprises the complementarity determining regions (CDRs) CDRa1, CDRa2, and CDRa3 as provided herein, and comprises the CDRb1, CDRb2, and CDRb3 as provided herein, and wherein CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 form an antigen-binding domain A. For example, in one embodiment of the invention, the antigen binding protein comprises CDRa1 comprising an amino acid sequence of SEQ ID NO: 10, CDRa3 comprising an amino acid sequence of SEQ ID NO: 12, CDRb1 comprising an amino acid sequence of SEQ ID NO: 13, and CDRb3 comprising an amino acid sequence of SEQ ID NO: 15; wherein the CDRa1, CDRa3, CDRb1 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations. In another embodiment, the CDRa1, CDRa3, CDRb1 and / or CDRb3 sequence(s) may each comprise at most one, at most two or at most three amino acid mutations. In some embodiments of the antigen binding protein, CDRa2 comprises an amino acid sequence of SEQ ID NO: 11, and CDRb2 comprises an amino acid sequence ofSEQ ID NO: 14; wherein the CDRa2 and / or CDRb2 sequence(s) may comprise one, two or three amino acid mutations. In another embodiment, the CDRa2 and / or CDRb2 sequence(s) may each comprise at most one, at most two or at most three amino acid mutations. In another aspect, the invention provides an antigen binding protein specifically binding to a MAGEB2 antigenic peptide that is in a complex with an MHC protein, wherein the MAGEB2 antigenic peptide comprises or consists of the amino acid sequence GVYDGEEHSV (SEQ ID NO: 1), wherein the antigen binding protein comprises a first polypeptide comprising a variable domain VAcomprising complementarity determining regions (CDRs) CDRa1, CDRa2, and CDRa3, and a second polypeptide comprising a variable domain VBcomprising CDRb1, CDRb2, and CDRb3, wherein CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 form an antigen-binding domain A; wherein CDRa1 comprises SEQ ID NO: 10, CDRa3 comprises SEQ ID NO: 12, CDRb1 comprises SEQ ID NO: 13, and CDRb3 comprises SEQ ID NO: 15; wherein the CDRa1, CDRa3, CDRb1 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations. In some embodiments, the invention provides an antigen binding protein specifically binding to a MAGEB2 antigenic peptide that is in a complex with an MHC protein, wherein the MAGEB2 antigenic peptide comprises or consists of the amino acid sequence GVYDGEEHSV (SEQ ID NO: 1), wherein the antigen binding protein comprises a first polypeptide comprising a variable domain VAcomprising complementarity determining regions (CDRs) CDRa1, CDRa2, and CDRa3, and a second polypeptide comprising a variable domain VBcomprising CDRb1, CDRb2, and CDRb3, wherein CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 form an antigen-binding domain A; wherein CDRa1 comprises SEQ ID NO: 10, CDRa2 comprises SEQ ID NO: 11, CDRa3 comprises SEQ ID NO: 12, CDRb1 comprises SEQ ID NO: 13, CDRb2 comprises SEQ ID NO: 14, and CDRb3 comprises SEQ ID NO: 15; wherein the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2, and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations. In another aspect, the invention provides an antigen binding protein comprising a variable domain VAcomprising complementarity determining regions (CDRs) CDRa1, CDRa2, and CDRa3, and comprising a variable domain VBcomprising CDRb1, CDRb2, and CDRb3, wherein CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 form an antigen-binding domain A; wherein CDRa1 comprises SEQ ID NO: 10, CDRa3 comprises SEQ ID NO: 12, CDRb1 comprises SEQ ID NO: 13, and CDRb3 comprises SEQ ID NO: 15. In some embodiments, the invention provides an antigen binding protein comprising a variable domain VAcomprising complementarity determining regions (CDRs) CDRa1, CDRa2, and CDRa3, and comprising a variable domain VBcomprising CDRb1, CDRb2, and CDRb3, wherein CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 form an antigen- binding domain A; wherein CDRa1 comprises SEQ ID NO: 10, CDRa2 comprises SEQ ID NO: 11, CDRa3 comprises SEQ ID NO: 12, CDRb1 comprises SEQ ID NO: 13, CDRb2 comprises SEQ ID NO: 14, and CDRb3 comprises SEQ ID NO: 15. In some embodiments of the antigen binding protein, the CDRa1, CDRa3, CDRb1 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRa1, CDRa3, CDRb1 and CDRb3. In some embodiments of the antigen binding protein, the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2, and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRa1, CDRa2, CDRa3, CDRb1, CDR2b, and CDRb3. In some embodiments of the antigen binding protein, CDRa1 comprises SEQ ID NO: 10, CDRa2 comprises SEQ ID NO: 11, CDRa3 comprises SEQ ID NO: 12, CDRb1 comprises SEQ ID NO: 13, CDRb2 comprises SEQ ID NO: 14, and CDRb3 comprises SEQ ID NO: 15, wherein the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations. In another embodiment, the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and / or CDRb3 sequence(s) may each comprise at most one, at most two or at most three amino acid mutations. In some embodiments of the antigen binding protein, CDRa1 comprises SEQ ID NO: 10, CDRa2 comprises SEQ ID NO: 11, CDRa3 comprises SEQ ID NO: 12, CDRb1 comprises SEQ ID NO: 13, CDRb2 comprises SEQ ID NO: 14, and CDRb3 comprises SEQ ID NO: 15, wherein the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and / or CDRb3 sequence(s) may have one, two, or three amino acid mutations. In some embodiments of the antigen binding protein, the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3.In some embodiments of the antigen binding protein, the VAcomprises an amino acid sequence of SEQ ID NO: 11, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 11, and comprising the CDRa1, CDRa2, and CDRa3 of SEQ ID NOs: 10, 11, and 12, respectively; and the VBcomprises an amino acid sequence of SEQ ID NOs: 9, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 9, and comprising the CDRb1, CDRb2, and CDRb3 of SEQ ID NOs: 13, 14, and 15, respectively, wherein optionally the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2, and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions. In some embodiments of the antigen binding protein, the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3. In some embodiments of the antigen binding protein, the VAcomprises an amino acid sequence of SEQ ID NO: 8 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 8, and comprising the CDRa1, CDRa2, and CDRa3 of SEQ ID NOs: 10, 11, and 12, respectively, and the VBcomprises an amino acid sequence of SEQ ID NO: 9 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 9, and comprising the CDRb1, CDRb2, and CDRb3 of SEQ ID NOs: 13, 14, and 15, respectively, wherein optionally said CDRa1, CDRa2, CDRa3, CDRb1, CDRb2, and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions. In some embodiments of the antigen binding protein, the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3. In all embodiments of the antigen binding protein of the invention, amino acid mutations within the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 sequences – if present – are preferably amino acid substitutions, more preferably conservative amino acid substitutions. It is preferred that the CDR sequences comprise not more than two, preferably not more than one, amino acid mutation(s). It is further preferred that the amino acidmutation(s) – if present – are at the first or last position of the respective CDR sequence. In most preferred embodiments, the CDR sequences do not comprise any amino acid mutation. In some embodiments of the antigen binding protein, the first and the last two positions of the CDR1, CDR2 and / or CDR3 of the VA and / or the VB comprise a conservative substitution, and preferably when the CDRa1, CDRa3, CDRb1 and / or CDRb3 may comprise one, two or three amino acid mutations. In particular embodiments of the antigen binding protein, the first and the last two positions of the CDR3 of the VA and / or the VB domain comprise a conservative substitution, and preferably when the CDRa3 and / or CDRb3 may comprise one, two or three amino acid mutations. Introducing a mutation into a known amino acid sequence is standard procedure well- known in the art and routine work for the skilled person. Respective methods are known in the field (e.g. Stratagene’s QuikChange Site Directed Mutagenesis Kit since 2007). The skilled person is thus very well capable of introducing specific mutations such as substitutions into an amino acid sequence in general and into a CDR sequence in particular. Screening of variants of a given CDR for binding to its target is also a procedure applied by the skilled person. The present application describes functional assays, including cytokine production assays to determine binding of an antigen binding protein of the invention to the MAGEB2 antigenic peptide. Binding of an antigen binding protein of the invention to the MAGEB2 antigenic peptide can also be determined by peptide MHC multimer staining or biolayer interferometry. While the outcome of an amino acid mutation in a CDR may not be readily predictable, the skilled person would be well capable of generating and screening multiple mutants without undue burden. The skilled person would thus be able to generate antigen binding proteins carrying one, two or three amino acid mutations within their CDRs and subsequently identify antigen binding proteins having the same binding characteristics as an antigen binding protein comprising the CDR sequences of Table 7. In some embodiments of the antigen binding protein, the VAcomprises an amino acid sequence of SEQ ID NO: 8; and the VBcomprises an amino acid sequence of SEQ ID NO: 9.In preferred embodiments of the antigen binding protein, the VAcomprises an amino acid sequence of SEQ ID NO: 8 and the VBcomprises an amino acid sequence of SEQ ID NO: 9, optionally wherein the framework region(s) comprise(s) at least one amino acid substitution selected from the group of amino acid substitutions consisting of: an amino acid substitution at position 19 in FR1-a, wherein said amino acid substitution is a hydrophobic amino acid selected from the group consisting of A, G, F, L, I, Y, W, V, M and P, preferably A, F, I, L, V and M, such as S19A, S19I, S19L, or S19V, more preferably S19A, or S19V, even more preferably S19A, an amino acid substitution at position 39 in FR2-a, wherein said amino acid substitution is L39F, L39I, or L39V, most preferably L39F, an amino acid substitution at position 13 in FR1-b, wherein said amino acid substitution is C13V, C13G, C13T, C13S, or C13A, preferably C13V, amino acid substitutions at positions 94 and / or 95 in FR3-b, wherein said amino acid substitution at position 94 is M94V, and / or said amino acid substitution at position 95 is S95E, or S95D, preferably S95E, respectively; and wherein the positions of the substitutions are given according to the IMGT nomenclature. In some embodiments, the antigen binding protein further comprises a constant domain, wherein the constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 and 25, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 24 and 25; and / or comprises a linker, wherein the linker comprises an amino acid sequence of SEQ ID NO: 26, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 26. In some embodiments of the antigen binding protein, the first polypeptide comprises an amino acid sequence of SEQ ID NO: 7, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 7 and comprising the CDRa1, CDRa2, and CDRa3 of SEQ ID NO: 10, 11, and 12, respectively; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 6 and comprising the CDRb1, CDRb2, and CDRb3 of SEQ ID NO: 13, 14, and 15, respectively, wherein optionally said CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.In some embodiments of the antigen binding protein, the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3. In particular embodiments of the antigen binding protein, the first polypeptide comprises an amino acid sequence of SEQ ID NO: 7, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 7 and comprising the CDRa1, CDRa2, and CDRa3 of SEQ ID NO: 10, 11, and 12, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 6 and comprising the CDRb1, CDRb2, and CDRb3 of SEQ ID NO: 13, 14, and 15, respectively. In some embodiments of the antigen binding protein, the CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRa1, CDRa2, CDRa3, CDRb1, CDRb2 and CDRb3. In some embodiments of the antigen binding protein, the first polypeptide comprises an amino acid sequence of SEQ ID NO: 7 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6. In some embodiments, the antigen-binding domain A is derived from a TCR, or is a TCR or fragment(s) thereof. In a preferred embodiment, the TCR is selected from the group consisting of an α / β TCR, a γ / δ TCR, functional fragments of a TCR, and a fusion protein or chimeric protein comprising a functional fragment of a TCR. In some embodiments, VAand VBare TCR variable domains, in particular TCR alpha, beta, gamma or delta variable domains. In some embodiments, VAis a TCR alpha, gamma or delta variable domain and VBis a TCR beta, gamma or delta variable domain. Preferably, VAis a TCR alpha variable domain and VBis a TCR beta variable domain, or VAis a TCR gamma variable domain and VBis a TCR delta variable domain, or VAis a TCR alpha variable domain and VBis a TCR gamma variable domain, or VAis a TCR delta variable domain and VBis a TCR beta variable domain. In preferred embodiments, VAand VBare TCRα and TCRβ domains, respectively. In someembodiments, VAis a TCR gamma variable domain comprising CDR1 and CDR3 and optionally CDR2 derived from a TCR alpha variable domain, and / or VBis a TCR delta variable domain comprising CDR1 and CDR3 and optionally CDR2 derived from a TCR beta variable domain. In some embodiments, the MHC protein is an HLA protein, preferably HLA-A, more preferably HLA-A*02. The antigen binding proteins of the invention have a high specificity for the MAGEB2 antigenic peptide (SEQ ID NO: 1), in particular an increased specificity in comparison to a reference protein when measured under similar, preferably identical experimental conditions. In preferred embodiments, the antigen binding protein is a soluble protein. In some embodiments, the antigen binding protein is a multispecific antigen binding protein, in particular a bispecific antigen binding protein. In particular embodiments, the antigen binding protein comprises a further antigen- binding domain or site B. In further embodiments, the antigen binding protein may comprise further antigen binding sites / domains, e.g. C, D, E, etc. The further binding domain may for example be a recruiter that concentrates or recruits further binding moieties in spatial proximity to the antigen binding protein, e.g. T cells. In some embodiments, the antigen binding protein further comprises a variable domain VHcomprising a CDRH1, a CDRH2 and a CDRH3, and a VLcomprising a CDRL1, a CDRL2, and a CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 form an antigen-binding domain B. The VH and VL may be derived from an antibody. The antigen binding domain B may also be a further TCR derived binding domain, or be a further binding domain, such as an Fc domain. In particular embodiments, the antigen-binding domain B specifically binds to immune cells, preferably T cells or natural killer (NK) cells.In some embodiments, the antigen-binding domain B specifically binds to an antigen selected from the group consisting of CD2, CD3, in particular CD3γ, CD3δ, and / or CD3ε, CD4, CD5, CD7, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18, CD22, CD25, CD28, CD32a, CD32b, CD33, CD41, CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD55, CD56, CD61, CD64, CD68, CD69, CD89, CD90, CD94, CD95, CD117, CD123, CD125, CD134, CD137, CD152, CD163, CD193, CD203c, CD235a, CD278, CD279, CD287, Ly- 6.2C, Mel14, Nkp46, NKG2D, GITR, FcεRI, TCRα / β, TCRγ / δ, HLA-DR and 4-1 BB, or combinations thereof. An example of a receptor molecule that is present on the surface of both T cells and natural killer (NK) cells is CD2 and further members of the CD2-superfamily. CD2 is able to act as a co-stimulatory molecule on T and NK cells. In preferred embodiments, the antigen-binding domain B specifically binds to the antigen CD3. In more preferred embodiments, the antigen-binding domain B specifically binds to an α / β T cell receptor (TCR) / CD3 complex. In some embodiments, the CDRH3 comprises the amino acid sequence of GSYYDYEGFVY [SEQ ID NO: 20], and optionally the CDRH3 comprises up to three amino acid mutations, preferably amino acid substitutions. In preferred embodiments of an antibody-binding protein comprising a binding domain B, the VHcomprises (a) a CDRH1 comprising the amino acid sequence of SYVMH [SEQ ID NO: 18], (b) a CDRH2 comprising the amino acid sequence of YINPRNDVTKYAEKFQG [SEQ ID NO: 19], and (c) a CDRH3 comprising the amino acid sequence of GSYYDYEGFVY [SEQ ID NO: 20], and the VLcomprises (a) a CDRL1 comprising the amino acid sequence of SATSSVSYMH [SEQ ID NO: 21], (b) a CDRL2 comprising the amino acid sequence of DTSKLAS [SEQ ID NO: 22], and (c) a CDRL3 comprising the amino acid sequence of QQWSSNPLT [SEQ ID NO: 23]; and optionally wherein each of the CDRH1, the CDRH2 and the CDRH3, and the CDRL1, CDRL2, and CDRL3 comprises up to three amino acid substitutions.In some embodiments, the antigen binding protein comprises a variable domain VHcomprising a CDRH1, a CDRH2 and a CDRH3 of SEQ ID NOs: 18, 19, and 20, respectively, and a VLcomprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NOs: 21, 22, and 23, respectively, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 form an antigen binding domain B. In some embodiments of the antigen binding protein, the VHcomprises an amino acid sequence of SEQ ID NO: 16, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 16 and preferably comprising the CDRH1, CDRH2, and CDRH3 as disclosed hereinabove; and the VLcomprises an amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 17, and preferably comprising the CDRL1, CDRL2, and CDRL3 as disclosed hereinabove; and optionally wherein each of said CDRH1, CDRH2 and CDRH3, and said CDRL1, CDRL2 and CDRL3 comprises up to three amino acid substitutions. In preferred embodiments, the antigen-binding site B comprises (i) a VHthat comprises an amino acid sequence of SEQ ID NO: 16, or an antigen-binding fragment(s) thereof, and (ii) a VLthat comprises an amino acid sequence of SEQ ID NO: 17, or an antigen-binding fragment(s) thereof. In some embodiments, the antigen binding protein comprises a variable domain VHcomprising an amino acid sequence of SEQ ID NO: 16 and a variable domain VLcomprising an amino acid sequence of SEQ ID NO: 17. Other recruiters may also be used in the antigen binding proteins of the invention as e.g. disclosed in WO 2022 / 233957, Zhu et al. (J lmmunol, 1995, 155, 1903-101910), Shearman et al. (J lmmunol, 1991, 147, 4366-73), WO 2021 / 023657, Liu et al. (mAbs, 2023 Structure-based engineering of a novel CD3ε-targeting antibody for reduced polyreactivity, mAbs, 15:1, 2189974). In some embodiments, the antigen binding protein comprises a VAcomprising: CDRa1 comprising or consisting of SEQ ID NO: 10, CDRa2 comprising or consisting of SEQ ID NO: 11, and CDRa3 comprising or consisting of SEQ ID NO: 12; a VBcomprising:CDRb1 comprising or consisting of SEQ ID NO: 13, CDRb2 comprising or consisting of SEQ ID NO: 14, and CDRb3 comprising or consisting of SEQ ID NO: 15; a VHcomprising: CDRH1 comprising or consisting of SEQ ID NO: 18, CDRH2 comprising or consisting of SEQ ID NO: 19, and CDRH3 comprising or consisting of SEQ ID NO: 20; and a VLcomprising: CDRL1 comprising or consisting of SEQ ID NO: 21, CDRL2 comprising or consisting of SEQ ID NO: 22, and CDRL3 comprising or consisting of SEQ ID NO: 23. In these embodiments, the CDRa1, CDRa3, CDRb1, CDRb3, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 sequence(s) may comprise one, two or three amino acid mutations. In some embodiments, the first polypeptide and the second polypeptide of the antigen binding protein are covalently linked together, e.g., directly or via a cleavable or non- cleavable linker. In some embodiments, the first polypeptide and the second polypeptide of the antigen binding protein are non-covalently linked together. In some embodiments, the binding domains A and / or B are in the format selected from the group consisting of an antibody, a single chain fragment variable (scFv), disulfide- stabilized Fv (dsFv), Fab, Fab’, F(ab’)2, a nanobody, a DARPin, a Knottin, a diabody or oligomers thereof. The single chain fragment variable (scFv) may also include single chain fragment(s) of the TCR, e.g. scTvs. In some embodiments, the binding domains A and B are in the format of an scFv. The antigen binding protein may also comprise the binding domains A and B on two scFvs, e.g. on two polypeptide chains. In some embodiments, the antigen binding protein comprises a single chain TCR (scTCR) and / or a single-chain bispecific antibody. In the following, further particular formats of the antigen binding protein are exemplified wherein the antigen binding site A and antigen binding site B are in a particular configuration, e.g., on a particular polypeptide chain. Such formats / configuration only have an exemplary character and the antigen binding sites (e.g. A and B) may for example be on one, two, three, four or more polypeptide chains. For example, the variable domains V1 to V4are each present on one polypeptide chain, i.e. on four polypeptide chains; or V1 and V2 are present on a polypeptide chain and V3 and V4 are present on a polypeptide chain, e.g. two polypeptide chains; or V1, V2, and V3 are present on a polypeptide chain, and V4 is present on a polypeptide chain, e.g. two polypeptide chains. As a further example, VB, VA and VH may be on a polypeptide chain and VL may be on a further polypeptide chain (or any other further configuration) as long as VA and VB are able to form antigen binding site A and VH and VL are able to form antigen binding site B, or any further binding site that may be comprised in the antigen binding protein. Alternatively, VB, VA and VH and a dimerizing protein may be on a polypeptide chain and VL may be on a further polypeptide chain, and the other part of the dimerizing protein may be on a third polypeptide chain. The herein provided examples exemplify further antigen binding proteins, such as the TCER format. Thus, the further indicated formulae have no limiting character but are merely examples. The indicated formulae V1-V4 comprise the herein provided inventive CDR regions. For example, Vα comprise the herein provided CDRs of the alpha variable domain and Vβ comprise the herein provided CDRs of the beta variable domain. In some embodiments, the antigen binding protein comprises two antigen-binding sites A and B, wherein a polypeptide chain comprises a structure represented by formula [I]: V1-L1-V2 [I] wherein V1 is a first variable domain; V2 is a second variable domain; L1 is a linker domain, that is present or absent; and wherein a further polypeptide chain comprises a structure represented by formula [II]: V3-L3-V4 [II] wherein V3 is a third variable domain; V4 is a fourth variable domain; L3 is a linker, that is present or absent; optionally wherein V1 and V2 form the antigen-binding site A and V3 and V4 form the antigen-binding site B, or V1 and V2 form the antigen-binding site B and V3 and V4 form the antigen-binding site A, or V1 and V3 form the antigen-binding site A andV2 and V4 form the antigen-binding site B, or V1 and V3 form the antigen-binding site B and V2 and V4 form the antigen-binding site A, or V1 and V4 form the antigen-binding site A and V2 and V3 form the antigen-binding site B, or V1 and V4 form the antigen-binding site B and V2 and V3 form the antigen-binding site A, and optionally, wherein the first polypeptide and the second polypeptide are covalently or non-covalently linked together. As also disclosed above, V1 and V2 do not necessarily have be on the same polypeptide chain, or V2 and V3 do not necessarily have be on the same polypeptide chain. For example, in some embodiments, the antigen binding protein comprises two antigen- binding sites A and B, wherein a polypeptide chain comprises a structure represented by formula [I]: V1-L1-V2-L2-V3 [I] wherein V1 is a first variable domain; V2 is a second variable domain; V3 is a third variable domain; L1 and L2 are (a) linker domain(s) that is present or absent; and wherein a further polypeptide chain comprises a structure represented by formula [II]: V4 [II] wherein V4 is a fourth variable domain; optionally wherein V1 and V2 form the antigen- binding site A and V3 and V4 form the antigen-binding site B, or V1 and V2 form the antigen-binding site B and V3 and V4 form the antigen-binding site A, or V1 and V3 form the antigen-binding site A and V2 and V4 form the antigen-binding site B, or V1 and V3 form the antigen-binding site B and V2 and V4 form the antigen-binding site A, or V1 and V4 form the antigen-binding site A and V2 and V3 form the antigen-binding site B, or V1 and V4 form the antigen-binding site B and V2 and V3 form the antigen-binding site A, and optionally, wherein the first polypeptide and the second polypeptide are covalently or non- covalently linked together. Such antigen binding proteins, or the polypeptide chains of the antigen binding protein may further be covalently or non-covalently linked to further proteins / domains, e.g. constant domains of antibodies or TCRs, e.g., Fc domains, or albumin, dimerizing proteins orfragments thereof, or further binding domains, e.g. to further improve stability or include further binding sites. In some embodiments, the antigen binding protein comprises one polypeptide chain that forms the antigen-binding sites A and B, wherein for example, this polypeptide chain comprises a structure represented by any of the formulae [I] to [VIII]: V1-L1-V4-L2-V2-L3-V3-C [I], V4-L1-V1-L2-V2-L3-V3-C [II], V1-L1-V4-L2-V3-L3-V2-C [III], V4-L1-V1-L2-V3-L3-V2-C [IV], V2-L1-V3-L2-V1-L3-V4-C [V], V3-L1-V2-L2-V1-L3-V4-C [VI], V2-L1-V3-L2-V4-L3-V1-C [VII], V3-L1-V2-L2-V4-L3-V1-C [VIII], wherein V1 is a first variable domain; V2 is a second variable domain; V3 is a third variable domain; V4 is a fourth variable domain; L1, L2 and L3 are linkers; C is a constant domain, which might be present or absent. In one preferable embodiment, V1 and V4 may form the antigen-binding site A and V2 and V3 may form the antigen-binding site B. In some embodiments, the antigen binding protein comprises one polypeptide chain that forms the antigen-binding sites A and B, wherein this polypeptide chain comprises a structure represented by any of the formulae [I] to [VIII]: V1-L1-V2-L2-V3-L3-V4-C [I], V1-L1-V3-L2-V2-L3-V4-C [II],V2-L1-V1-L2-V4-L3-V3-C [III], V2-L1-V4-L2-V1-L3-V3-C [IV], V3-L1-V1-L2-V4-L3-V2-C [V], V3-L1-V4-L2-V1-L3-V2-C [VI], V4-L1-V2-L2-V3-L3-V1-C [VII], V4-L1-V3-L2-V2-L3-V1-C [VIII], wherein V1 is a first variable domain; V2 is a second variable domain; V3 is a third variable domain; V4 is a fourth variable domain; L1, L2 and L3 are linker domains; C is a constant domain, which might be present or absent. As indicated above, in a preferable embodiment, V1 and V4 may form the antigen- binding site A and V2 and V3 may form the antigen-binding site B. In some embodiments, the antigen binding protein comprises two polypeptide chains that form the antigen-binding sites A and B, wherein a polypeptide chain comprises a structure represented by one of the formulae [I] to [IV]: V2-L1-V3-L2-V1-C1 [I] V2-L1-V3-L2-V4-C1 [II] V3-L1-V2-L2-V1-C1 [III] V3-L1-V2-L2-V4-C1 [IV] wherein V1 is a first variable domain; V2 is a second variable domain; V3 is a third variable domain; V4 is a fourth variable domain; C1 and C2 are constant domains; L1 and L2 are linker domains; and wherein a further polypeptide chain comprises a structure represented by formulae [V] and [VI]: V4-C2 [V]V1-C2 [VI] wherein [I] or [III] bind to [VI] and [II] or [IV] bind to [VI]. In a preferred embodiment, V1 and V4 may form the antigen-binding site A and V2 and V3 may form the antigen-binding site B. In some embodiments, the antigen binding protein comprises two polypeptide chains that together form the antigen-binding sites A and B, wherein a first polypeptide chain comprises a structure represented by formula [III]: V1-L1-V2-L2-C1 [III] wherein V1 is a first variable domain; V2 is a second variable domain; L1 and L2 are linkers; L2 may be present or absent; C1 may be a constant domain or a dimerizing portion thereof (e.g. CL) or another dimerizing protein or fragment thereof and present or absent, or in particular a light chain constant domain or a dimerizing portion thereof and present or absent; and wherein a second polypeptide chain comprises a structure represented by formula [IV]: V3-L3-V4-L4-C2 [IV] wherein V3 is a third variable domain; V4 is a fourth variable domain; L3 and L4 are linkers; L4 may be present or absent; C2 may be a constant domain or a dimerizing portion thereof (e.g. CH) or another dimerizing protein or fragment thereof and present or absent, or in particular a heavy chain constant domain 1 or a dimerizing portion thereof and is present or absent; and wherein V1 and V2 form the antigen-binding site A and V3 and V4 form the antigen-binding site B, or V1 and V2 form the antigen-binding site B and V3 and V4 form the antigen-binding site A, or V1 and V3 form the antigen-binding site A and V2 and V4 form the antigen-binding site B, orV1 and V3 form the antigen-binding site B and V2 and V4 form the antigen-binding site A, or V1 and V4 form the antigen-binding site A and V2 and V3 form the antigen-binding site B, or V1 and V4 form the antigen-binding site B and V2 and V3 form the antigen-binding site A, and optionally, wherein the first polypeptide and the second polypeptide are covalently or non-covalently linked together. In a particular aspect, the antigen binding comprises - a first polypeptide of formula V1–L1-V2-L2–C1-L5-FC1wherein L2, C1, L5may be absent, and - a second polypeptide of formula V3-L3-V4-L4–C2-L6-FC2wherein L4, C2, L6 may be absent, wherein L2, L4, L5 and L6 are linkers, C1 may be CL a light chain constant domain or a dimerizing portion thereof, or CH a heavy chain constant domain or a dimerizing portion thereof; and C2 may be a CH heavy chain constant domain or a dimerizing portion thereof if C1 is CL, and C2 may be a CL or dimerizing portion thereof if C1 is CH. In some embodiments, the first polypeptide chain has a structure represented by the formula [V]: V1–L1-V2-L2–C1-L5-FC1[V] and the second polypeptide chain has a structure represented by the formula [VI]: V3-L3-V4-L4-C2-L6-FC2[VI] wherein V1-V4, L1-L4, C1 and C2 are as defined hereinabove, and wherein L2, C1, L5, L4, C2, and C6 may be present or absent and FC1, and FC2may be Fc-domains and wherein FC1and FC2are the same or different.In particular embodiments as herein provided above, V1 comprises CDRa1, CDRa2 and CDRa3 as defined hereinabove, V2comprises CDRH1, CDRH2, and CDRH3 as defined hereinabove, V3 comprises CDRL1, CDRL2, and CDRL3 as defined hereinabove, V4comprises CDRb1, CDRb2 and / or CDRb3 as defined hereinabove. For example, the antigen binding protein may comprise V1comprising: CDRa1 comprising or consisting of SEQ ID NO: 10, CDRa2 comprising or consisting of SEQ ID NO: 11, and CDRa3 comprising or consisting of SEQ ID NO: 12, V2comprising: CDRH1 comprising or consisting of SEQ ID NO: 18, CDRH2 comprising or consisting of SEQ ID NO: 19, and CDRH3 comprising or consisting of SEQ ID NO: 20, V3 comprising: CDRL1 comprising or consisting of SEQ ID NO: 21, CDRL2 comprising or consisting of SEQ ID NO: 22, and CDRL3 comprising or consisting of SEQ ID NO: 23, V4comprising: CDRb1 comprising or consisting of SEQ ID NO: 13, CDRb2 comprising or consisting of SEQ ID NO: 14, and / orCDRb3 comprising or consisting of SEQ ID NO: 15. In a particular aspect, the antigen binding protein comprises - a polypeptide of formula V1–L1-V2, and - a further polypeptide of formula V3-L3-V4wherein V1 is a first variable domain; V2 is a second variable domain; V3 is a third variable domain; V4 is a fourth variable domain, and L1 and L3 are linkers, and wherein V1 is Vα, V2 is VH, V3 is VL, V4 is Vβ; V1 is VL, V2 is Vα, V3 is Vβ, V4 is VH; V1 is Vβ, V2 is VL, V3 is VH, V4 is Vα; V1 is VH, V2 is Vα, V3 is Vβ, V4 is VL; V1 is Vα, V2 is VL, V3 is VH, V4 is Vβ; V1 is VL, V2 is Vβ, V3 is Vα, V4 is VH; V1 is Vβ, V2 is VH, V3 is VL, V4 is Vα; or V1 is VH, V2 is Vβ, V3 is Vα, V4 is VL. In more preferred aspects, V1 is Vα, V2 is VH, V3 is VL, V4 is Vβ. In an even more preferred aspect, the antigen binding is a TCER as exemplified in the Examples and comprises - a polypeptide of formula V1–L1-V2-FC1, and - a polypeptide of formula V3-L3-V4-FC2wherein V1 is a first variable domain; V2 is a second variable domain; V3 is a third variable domain; V4 is a fourth variable domain, and L1 and L3 are linkers, and wherein Fc1 and Fc2are Fc-domains and wherein FC1and FC2are the same or preferably different, and wherein V1 and V4 form the antigen-binding site A and V2 and V3 form the antigen-binding site B, or V1 and V4 form the antigen-binding site B and V2 and V3 form the antigen-binding site A. In this preferred aspect, V1 is Vα, V2 is VH, V3 is VL, V4 is Vβ; V1 is VL, V2 is Vα, V3 is Vβ, V4 is VH; V1 is Vβ, V2 is VL, V3 is VH, V4 is Vα; V1 is VH, V2 is Vα, V3 is Vβ, V4 is VL; V1 is Vα, V2 is VL, V3 is VH, V4 is Vβ; V1 is VL, V2 is Vβ, V3 is Vα, V4 is VH; V1 is Vβ, V2 is VH, V3 is VL, V4 is Vα; or V1 is VH, V2 is Vβ, V3 is Vα, V4 is VL. In more preferred aspects, V1 is Vα, V2 is VH, V3 is VL, V4 is Vβ. In other exemplary embodiments, the antigen binding protein comprises - a polypeptide of formula V1–L1-V2, and - a further polypeptide of formula V3-L3-V4, and wherein V1 comprises CDRa1, CDRa2 and CDRa3 as defined hereinabove, V2comprises CDRH1, CDRH2, and CDRH3 as defined hereinabove, V3comprises CDRL1, CDRL2, and CDRL3 as defined hereinabove, V4comprises CDRb1, CDRb2 and / or CDRb3 as defined hereinabove.For example, the antigen binding protein may comprise V1 comprising: CDRa1 comprising or consisting of SEQ ID NO: 10, CDRa2 comprising or consisting of SEQ ID NO: 11, and CDRa3 comprising or consisting of SEQ ID NO: 12, V2comprising: CDRH1 comprising or consisting of SEQ ID NO: 18, CDRH2 comprising or consisting of SEQ ID NO: 19, and CDRH3 comprising or consisting of SEQ ID NO: 20, V3comprising: CDRL1 comprising or consisting of SEQ ID NO: 21, CDRL2 comprising or consisting of SEQ ID NO: 22, and CDRL3 comprising or consisting of SEQ ID NO: 23, V4comprising: CDRb1 comprising or consisting of SEQ ID NO: 13, CDRb2 comprising or consisting of SEQ ID NO: 14, and / or CDRb3 comprising or consisting of SEQ ID NO: 15. In preferred aspects of the invention, FC1and / or FC2comprises or consists of the amino acid sequence SEQ ID NO: 24 [Fc knob] and / or SEQ ID NO: 25 [Fc hole]; and / or L1and L3comprise or consist of the amino acid sequence GGGSGGGG of SEQ ID NO: 26. In these embodiments, optionally the following may further be comprised:L1and L3comprise or consist of the amino acid sequence GGGSGGGG of SEQ ID NO: 26, and L2, L4, L5 and L6 are absent, and optionally wherein FC1comprises or consists of the amino acid sequence SEQ ID NO: 25 [Fc hole], and, FC2comprises or consists of the amino acid sequence SEQ ID NO: 24 [Fc knob], or FC1comprises or consists of the amino acid sequence SEQ ID NO: 24 [Fc knob], and FC2comprises or consists of the amino acid sequence SEQ ID NO: 25 [Fc hole]. Preferably, the antigen binding protein of the invention has the variable domain orientations for Vα, Vβ, VL and VH according to orientation D of Figure 8. In a preferred embodiment, the antigen binding protein of the invention comprises the following CDR amino acid sequences: CDRa1 comprising or consisting of SEQ ID NO: 10, CDRa2 comprising or consisting of SEQ ID NO: 11, CDRa3 comprising or consisting of SEQ ID NO: 12, CDRb1 comprising or consisting of SEQ ID NO: 13, CDRb2 comprising or consisting of SEQ ID NO: 14, CDRb3 comprising or consisting of SEQ ID NO: 15, CDRH1 comprising or consisting of SEQ ID NO: 18, CDRH2 comprising or consisting of SEQ ID NO: 19, CDRH3 comprising or consisting of SEQ ID NO: 20, CDRL1 comprising or consisting of SEQ ID NO: 21, CDRL2 comprising or consisting of SEQ ID NO: 22, and CDRL3 comprising or consisting of SEQ ID NO: 23;optionally wherein the CDRa1, CDRa3, CDRb1, CDRb3, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 sequence(s) may comprise one, two or three amino acid mutations. In the following, the formats of the exemplary provided sequences are explained. The skilled person is well aware that the binding domains may also be included in other formats. In a preferred embodiment, the antigen binding protein of the invention comprises: a first polypeptide of formula V1–L1-V2-L2–C1-L5-FC1[V] of the amino acid sequence (SEQ ID NO: 7): EDVEQSSFLSVREGDSAVINCTYTDASSTYFYWYKQEPGAGLQLLTYIYSNMDMKQ DQRLTVLLNKKDKHLSLRIADTQTGDSAIYFCAVKDNARLLFGDVTQLVVKPGGGS GGGGEVQLVQSGAEVKKPGASVKVSCKASGYKFTSYVMHWVRQAPGQGLEWMG YINPRNDVTKYAEKFQGRVTLTSDTSTSTAYMELSSLRSEDTAVYYCARGSYYDYE GFVYWGQGTLVTVSSEPKSSDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSP wherein L2, C1, L5 are absent and which comprises V1 (maturated TCR derived alpha variable domain) of sequence SEQ ID NO: 8 (with the CDRa1, CDRa2, CDRa3 of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; in bold), L1(TCER linker; underlined) of sequence SEQ ID NO: 26, V2 (BMhanced T cell Recruiter VHwith the CDRH1, CDRH2, CDRH3 of SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, respectively; in bold) of sequence SEQ ID NO: 16, and FC1(fc hole; in italic and underlined) of sequence SEQ ID NO: 25; and a second polypeptide of formula V3-L3-V4-L4–C2-L6-FC2[VI] of the amino acid sequence (SEQ ID NO: 6):QIQMTQSPSSLSASVGDRVTITCSATSSVSYMHWYQQKPGKAPKRWIYDTSKLASG VPSRFSGSGSGTDYTLTISSLQPEDAATYYCQQWSSNPLTFGGGTKVEIKGGGSGGG GAVISQKPSRVIVQRGTSVTIQCQVDRPVTMMYWYRQQPGQSLTLIATAYDEGSAT YESGFDIDKFPISRPNLTFSTLTVSNVEPEDSSIYLCSVLGAYGYTFGSGTRLTVVEPK SSDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAK GQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP wherein L4, C2, L6are absent and which comprises V3(BMhanced T cell recruiter VL with the CDRL1, CDRL2, CDRL3 of SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23, respectively; in bold) of sequence SEQ ID NO: 17, L3(TCER linker; underlined) of sequence SEQ ID NO: 26, V4(TCR derived beta variable domain) of sequence SEQ ID NO: 9 (with the CDRb1, CDRb2, CDRb3 of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively in bold), and FC2(fc knob; in italic and underlined) of sequence SEQ ID NO: 24, wherein the FC1and FC2sequence comprise a cysteine to serine amino acid substitution (S indicated in bold) since no light chain needs to be connected via said cysteine, amino acid substitutions of the IgG1 hinge region to resemble the IgG2 hinge to abrogate Fc-gamma receptor interaction (PVA indicated in bold in positions 233 to 235 and 331S, and the removal of G236), a N297Q amino acid substitution (Q in bold) to remove the N- Glycosylation site within the Fc-part to abrogate Fc-gamma-receptor interaction and in addition the hole mutation (Y349C, T366S, L368A and Y407V in bold) in case of FC1and the knob mutation (S354C and T366W in bold) in case of FC2. Furthermore, the C-terminal glycine-lysine (G446, K447) residues of human IgG1 heavy chains may be deleted to decrease C-terminal heterogeneity. In some embodiments, the amino acid sequences of the binding domains A and B are chimeric, humanized, or human. In some embodiments, the N-terminal or the C-terminal amino acid(s) of the polypeptide chains of the antigen binding protein comprise(s) (a) modification(s), e.g. a post-translational modification. Preferably, the N-terminal amino acid(s) of the polypeptide chains of the antigen binding protein comprise(s) a modification. In one embodiment, the N-terminal or the C-terminal amino acid(s) of the polypeptide chains of the antigen binding protein comprise(s) (a) modification(s), such as a naturally- occurring modification in aqueous solution, preferably a pyro-glutamate modification. In one embodiment, the N-terminal amino acid(s) of the polypeptide chains, e.g. in the VL, of the antigen binding protein comprise a modification, preferably a pyro-glutamate modification. In some embodiments, a soluble antigen binding protein according to the present invention is capable of activating a CD4+ T cell, preferably a CD4+ CD8- T cell, and / or a CD8+ T cell, preferably a CD8+ CD4-T cell. In some embodiments, the antigen binding protein binds the MAGEB2 antigenic peptide of SEQ ID NO: 1 with a KDof less than 50 nM, preferably less than 20 nM, more preferably less than 5 nM, as measured by biolayer interferometry. In one embodiment, the antigen binding protein of the invention specifically binds to the MAGEB2 antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1 and a HLA molecule, preferably HLA-A*02, with a KD which is ≤ 100 µM, ≤ 50 µM, ≤ 30 µM, ≤ 25 µM, ≤ 1 µM, ≤ 500 nM, ≤ 100 nM, ≤ 50 nM, ≤ 10 nM, preferably ≤ 5 nM, for example, 50 pM to 100 µM, 50 pM to 10 µM, 50 pM to 1 µM, more particularly, 50 pM to 500 nM, 50 pM to 100 nM, 50 pM to 50 nM, 50 pM to 10 nM, 50 pM to 5 nM. “KD” and “affinity” are as defined herein above in the section “Definitions”. Accordingly, in one example, the antigen binding proteins of the invention are expressed, for instance, as soluble TCER® described herein above and are analyzed for their binding affinity towards the HLA-A*02 / MAGEB2 antigenic peptide complex. General conditions for biolayer interferometry are provided above. Typically, measurements are performed, for instance, on an Octet RED384 system using, typically, settings recommended by the manufacturer. Briefly, binding kinetics are, typically, measured at 30°C and, for instance, 1000 rpm shake speed using, for example, PBS, 0.05% Tween-20, 0.1% BSA asbuffer. The antigen binding proteins can be either loaded onto biosensors, such as FAB2G or AHC, or analyzed in solution. In some embodiments, the antigen binding protein is capable of killing MAGEB2- expressing tumor cells in an in vitro cytotoxicity assay, wherein the MAGEB2-expressing tumor cells have a MAGEB2 copy number per cell of less than 200, preferably less than 100, more preferably less than 50. In a preferred embodiment, the MAGEB2-expressing tumor cells have a MAGEB2 copy number per cell is determined by AbsQuant® (e.g. as disclosed in PCT / EP2015 / 079873). In some embodiments, the antigen binding protein is capable of killing MAGEB2- expressing tumor cells in an in vitro cytotoxicity assay, wherein the MAGEB2-expressing tumor cells have a MAGEB2 copy number per cell of less than 200, with an EC50 of less than 200 pM, preferably less than 100 pM, more preferably less than 30 pM. Engineered polynucleotides encoding MAGEB2-targetting TCER® polypeptides An aspect of the disclosure is directed to an engineered, non-naturally-occurring polynucleotide encoding one or more antigen binding polypeptides. In some embodiments, the polynucleotide comprises at least one non-naturally modified nucleotide. In some embodiments, the polynucleotide is codon optimized for expressing in mammalian cells. In some embodiments, the polynucleotide is an mRNA. The instant invention features mRNAs for use in treating cancer. The mRNAs featured for use in this disclosure are administered to subjects and encode MAGEB2- targeting binding proteins in vivo. Accordingly, this disclosure relates to polynucleotides, e.g., mRNA, comprising an open reading frame of linked nucleosides encoding MAGEB2- targeting binding proteins. Specifically, this disclosure provides sequence-optimized polynucleotides comprising nucleotides encoding one or more polypeptide sequences of MAGEB2-targeting binding proteins, or sequence having high sequence identity with those sequence optimized polynucleotides.An exemplary polynucleotide encoding MAGEB2-targeting binding protein is set forth in SEQ ID NO: 2: ATGGAGACACCCGCCCAGCTGCTGTTCCTGCTGTTGCTGTGGCTGCCCGACACCA CCGGACAGATCCAGATGACCCAGTCCCCGAGCTCCCTGAGCGCCAGCGTCGGCG ACCGAGTGACCATCACCTGCAGCGCCACCAGCAGCGTGAGCTACATGCACTGGT ATCAGCAGAAGCCTGGCAAGGCCCCTAAGCGGTGGATCTACGACACCTCTAAGC TCGCCAGCGGCGTGCCCTCTCGGTTCAGCGGGTCAGGGTCCGGCACCGACTATAC CTTGACCATAAGCAGCCTGCAGCCTGAGGACGCCGCCACCTACTACTGCCAGCA GTGGAGCAGCAACCCTCTGACCTTTGGCGGCGGCACCAAGGTGGAGATCAAGGG AGGTGGGAGTGGAGGCGGCGGAGCTGTGATCAGCCAGAAGCCCAGCCGGGTGA TCGTGCAGCGGGGCACCAGCGTGACTATCCAGTGCCAGGTGGACCGGCCCGTGA CCATGATGTACTGGTACCGGCAGCAGCCCGGCCAGAGCCTGACCCTGATCGCCA CCGCCTACGACGAGGGCAGCGCTACCTACGAGAGCGGCTTCGACATCGACAAGT TCCCCATCAGCCGGCCCAACCTGACCTTCAGCACCCTGACTGTGTCTAACGTGGA GCCCGAGGACAGCAGCATCTACCTGTGCAGCGTACTGGGCGCCTACGGCTACAC CTTCGGCAGCGGCACCCGGTTGACCGTGGTGGAACCCAAGAGCAGCGACAAGAC CCACACCTGCCCTCCCTGTCCCGCTCCACCAGTCGCGGGTCCAAGCGTGTTCCTG TTCCCACCAAAGCCCAAGGACACCCTGATGATCTCTCGGACCCCAGAGGTGACCT GCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGGTGAAGTTCAACTGGTACG TGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTAC CAGAGCACCTACCGGGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGAGCAACAAAGCCCTGCCCGCCAGCATC GAGAAGACCATCAGCAAGGCCAAGGGCCAACCCAGAGAGCCCCAAGTGTACAC CCTGCCACCTTGCCGGGACGAGCTGACCAAGAACCAGGTGAGCCTGTGGTGCCT GGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCA GCCCGAGAACAACTACAAGACCACCCCTCCCGTGCTGGACAGCGACGGCAGCTT CTTCCTGTACAGCAAGCTGACAGTGGACAAGAGCCGGTGGCAGCAGGGCAACGT GTTCAGCTGCTCGGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAG CCTGTCACTGAGCCCC (SEQ ID NO: 2) An exemplary polynucleotide encoding MAGEB2-targeting binding protein is set forth in SEQ ID NO: 3:ATGGAGACACCCGCCCAGTTGCTGTTCCTGCTGTTGCTGTGGCTGCCCGACACCA CCGGAGAGGACGTGGAGCAGTCCAGCTTCCTGAGTGTGCGGGAGGGCGACTCCG CAGTGATCAACTGCACCTACACCGACGCCAGCAGCACGTACTTCTACTGGTATAA GCAGGAGCCTGGCGCTGGCCTGCAACTGTTAACCTACATCTACTCTAACATGGAC ATGAAGCAGGACCAGAGGCTAACCGTTCTCCTGAACAAGAAGGACAAGCACCTG AGCTTGCGGATAGCCGACACACAGACCGGCGACAGCGCCATCTACTTCTGCGCT GTGAAAGACAACGCCCGGCTGCTGTTTGGCGACGTCACCCAGCTGGTGGTGAAG CCTGGAGGTGGGAGTGGAGGCGGCGGAGAGGTGCAGCTGGTTCAGAGCGGCGC CGAGGTTAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAAGCCAGCGGCTA CAAGTTCACCAGCTACGTGATGCATTGGGTGCGGCAGGCCCCAGGTCAGGGCCT GGAGTGGATGGGCTACATCAACCCACGGAACGACGTGACCAAGTACGCCGAGAA GTTCCAGGGCCGGGTGACCCTGACCAGTGACACCAGCACTAGCACCGCCTACAT GGAGCTGTCTAGCCTGCGGAGCGAGGACACCGCCGTGTACTACTGCGCCCGGGG CAGCTACTACGACTACGAGGGCTTCGTGTACTGGGGCCAGGGCACCCTGGTGAC CGTGTCTAGCGAACCCAAGAGCAGCGACAAGACCCACACCTGCCCTCCCTGTCC CGCTCCACCAGTCGCGGGTCCAAGCGTGTTCCTGTTCCCACCAAAGCCCAAGGAC ACCCTGATGATCTCTCGGACCCCAGAGGTGACCTGCGTGGTGGTGGACGTGAGC CACGAGGACCCCGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCAC AACGCCAAGACCAAGCCCCGGGAGGAGCAGTACCAGAGCACCTACCGGGTGGT GAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTCAGCAACAAAGCCCTGCCCGCCAGCATCGAGAAGACCATCAGCAAGGC CAAGGGCCAACCCAGAGAGCCCCAAGTGTGCACCCTGCCACCTAGCCGGGACGA GCTGACCAAGAACCAGGTGAGCCTGAGCTGCGCCGTGAAGGGCTTCTACCCCAG CGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGA CCACCCCTCCCGTGCTGGACAGCGACGGCAGCTTCTTCCTGGTGAGCAAGCTGAC AGTGGACAAGAGCCGGTGGCAGCAGGGCAACGTGTTCAGCTGCTCGGTGATGCA CGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGTCACTGAGCCCC This disclosure relates to polynucleotides, e.g., mRNA, comprising an open reading frame of linked nucleosides encoding MAGEB2-binding proteins, variants thereof, functional fragments thereof, and fusion proteins comprising the same. Specifically, this disclosure provides sequence-optimized polynucleotides comprising nucleotides encoding thepolypeptide sequence of a MAGEB2-binding protein, or sequence having high sequence identity with those sequence optimized polynucleotides. In certain aspects, this disclosure provides polynucleotides (e.g., a RNA such as an mRNA) that comprise a nucleotide sequence (e.g., an ORF) encoding one or more antigen binding proteins. In some embodiments, this disclosure provides polynucleotides (e.g., a RNA such as an mRNA) that comprise a nucleotide sequence (e.g., an ORF) encoding any of the antigen binding proteins disclosed herein. In some embodiments, the encoded antigen binding protein can comprise an amino acid sequence selected from the group consisting of be selected from SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ IDNO: 9, SEQ ID NO: 16, and SEQ ID NO: 17. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence has at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO:2 or SEQ ID NO: 3. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence has 65% to 100%, 70% to 100%, 75% to 100%, 80% to 100%, 85% to 100%, 90% to 100%, 95% to 100%, 97% to 100%, 98% to 100%, 99% to 10)%, 90% to 95%, 90% to 97%, 90% to 98%, 95% to 97%, 95% to 98%, or 95% to 99% sequence identity to the sequence SEQ ID NO: 2 or SEQ ID NO: 3. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence is at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 2 or SEQ ID NO: 3. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence is 65% to 100%, 70% to 100%, 75% to 100%, 80% to 100%, 85% to 100%, 90% to 100%, 95% to 100%, 97% to 100%, 98% to 100%, 99% to 100%, 90% to 95%, 90% to 97%, 90% to 98%, 95% to 97%, 95% to 98%, or 95% to 99% identical to the sequence of SEQ ID NO: 2 or SEQ ID NO: 3. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence encodes an amino acid sequence that is at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of any of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ IDNO: 9, SEQ ID NO: 16, and SEQ ID NO: 17. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence has 90% to 100%, 95% to 100%, 97% to 100%, 98% to 100%, 90% to 95%, 90% to 97%, 90% to 98%, 95% to 97%, 95% to 98%, or 95% to 99% sequence identity to the sequence of any of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ IDNO: 9, SEQ ID NO: 16, and SEQ ID NO: 17. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., aMAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence has at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of any of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ IDNO: 9, SEQ ID NO: 16, and SEQ ID NO: 17. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence has 90% to 100%, 95% to 100%, 97% to 100%, 98% to 100%, 90% to 95%, 90% to 97%, 90% to 98%, 95% to 97%, 95% to 98%, or 95% to 99%, sequence identity to the sequence of any of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ IDNO: 9, SEQ ID NO: 16, and SEQ ID NO: 17. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., a MAGEB2-binding protein, functional fragment, or variant thereof, e.g., a MAGEB2 / αCD3 TCER® polypeptide), wherein the nucleotide sequence is between 90% and 100% identical; between 91% and 99% identical; between 92% and 98% identical; between 93% and 97% identical, or between 94% and 96% identical to the sequence of any of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ IDNO: 9, SEQ ID NO: 16, and SEQ ID NO: 17. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises from about 1,000 to about 100,000 nucleotides (e.g., from 1,000 to 2,500, from 1,000 to 2,600, from 1,000 to 2,700, from 1,000 to 2,800, from 1,000 to 2,900, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 10,000, from 1,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, or from 1,000 to 100,000). In some embodiments, the polynucleotide of this disclosure (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., the wild-type sequence, functional fragment, or variant thereof), wherein the length of the nucleotide sequence (e.g., an ORF) is at least 500 nucleotides in length (e.g., at least orgreater than about 500, 600, 700, 800, 900, 1,000, 1,050, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,635, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides). In some embodiments, the polynucleotide of this disclosure (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence encoding an antigen binding protein (e.g., the wild- type sequence, functional fragment, or variant thereof) further comprises a 5′-UTR and / or a 3′-UTR. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises the sequence of SEQ ID NO: 2 or SEQ ID NO: 3. In a further embodiment, the polynucleotide (e.g., a RNA, e.g., an mRNA) comprises a 5′ terminal cap (e.g., m7Gp-ppGm-A, Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′-fluoro- guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, 2- azidoguanosine, Cap2, Cap4, 5′ methylG cap, or an analog thereof) and a poly-A-tail region (e.g., about 100 nucleotides in length). In some embodiments, the mRNA comprises a polyA tail. In some instances, the poly A tail is 50-150 (SEQ ID NO: 103), 75-150 (SEQ ID NO: 104), 85-150 (SEQ ID NO: 105), 90-120 (SEQ ID NO: 106), 90-130 (SEQ ID NO: 107), or 90-150 (SEQ ID NO: 108) nucleotides in length. In some instances, the poly A tail is 100 nucleotides in length (SEQ ID NO: 101). In some instances, the poly A tail is protected (e.g., with an inverted deoxy-thymidine). In some instances, the poly A tail comprises A100- UCUAG-A20-inverted deoxy-thymidine. In some instances, the poly A tail is A100- UCUAG-A20-inverted deoxy-thymidine. In some embodiments, the polynucleotide of this disclosure (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., the wild-type sequence, functional fragment, or variant thereof) further comprises at least one nucleic acid sequence that is noncoding, e.g., a microRNA binding site. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure further comprises a 5′-UTR and / or a 3′ UTR. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of this disclosure comprises the sequence of SEQ ID NO: 2 or SEQ ID NO:3. In a further embodiment, the polynucleotide (e.g., a RNA, e.g., an mRNA) comprises a 5′ terminal cap (e.g., m7Gp-ppGm-A, Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′- fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5′ methylG cap, or an analog thereof) and a poly-A-tail region (e.g., about 100 nucleotides in length, e.g., A100-UCUAG-A20-inverted deoxy- thymidine). In some embodiments, the mRNA comprises a polyA tail. In some instances, the poly A tail is 50-150 (SEQ ID NO: 103), 75-150 (SEQ ID NO: 104), 85-150 (SEQ ID NO: 105), 90-120 (SEQ ID NO: 106), 90-130 (SEQ ID NO: 107), or 90-150 (SEQ ID NO: 108) nucleotides in length. In some instances, the poly A tail is 100 nucleotides in length (SEQ ID NO: 101). In some instances, the poly A tail is protected (e.g., with an inverted deoxy- thymidine). In some instances, the poly A tail comprises A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO: 109). In some instances, the poly A tail is A100-UCUAG- A20-inverted deoxy-thymidine (SEQ ID NO: 109). In some embodiments, the polynucleotide of this disclosure (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein is single stranded or double stranded. In some embodiments, the polynucleotide of this disclosure comprising a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., the wild-type sequence, functional fragment, or variant thereof) is DNA or RNA. In some embodiments, the polynucleotide of this disclosure is RNA. In some embodiments, the polynucleotide of this disclosure is, or functions as, a mRNA. In some embodiments, the mRNA comprises a nucleotide sequence (e.g., an ORF) that encodes at least one antigen binding polypeptide, and is capable of being translated to produce the encoded antigen binding polypeptide in vitro, in vivo, in situ or ex vivo. In some embodiments, the polynucleotide of this disclosure (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF) encoding an antigen binding protein (e.g., the wild-type sequence, functional fragment, or variant thereof), wherein the polynucleotide comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil. In certain embodiments, all uracils in thepolynucleotide are N1 -methylpseudouracils. In other embodiments, all uracils in the polynucleotide are 5 -methoxyuracils. In some embodiments, the polynucleotide further comprises a miRNA binding site, e.g., a miRNA binding site that binds to miR-142 and / or a miRNA binding site that binds to miR-126.Features of polynucleotides encoding TCER® polypeptides

[0360] In some embodiments, the polynucleotides of the disclosure comprise one or more of the following features: i. Optimization of Nucleic Acid Sequence Intrinsic Properties

[0361] In some embodiments of this disclosure, the desired property of the polynucleotide is an intrinsic property of the nucleic acid sequence. For example, the nucleotide sequence (e.g., a RNA, e.g., an mRNA) can be sequence optimized for in vivo or in vitro stability. In some embodiments, the nucleotide sequence can be sequence optimized for expression in a given target tissue or cell. In some embodiments, the nucleic acid sequence is sequence optimized to increase its plasma half-life by preventing its degradation by endo and exonucleases.

[0362] In other embodiments, the nucleic acid sequence is sequence optimized to increase its resistance to hydrolysis in solution, for example, to lengthen the time that the sequence optimized nucleic acid or a pharmaceutical composition comprising the sequence optimized nucleic acid can be stored under aqueous conditions with minimal degradation.

[0363] In other embodiments, the sequence optimized nucleic acid can be optimized to increase its resistance to hydrolysis in dry storage conditions, for example, to lengthen the time that the sequence optimized nucleic acid can be stored after lyophilization with minimal degradation. ii. Nucleic Acid Sequences Optimized for Protein Expression

[0364] In some embodiments of this disclosure, the desired property of the polynucleotide is the level of expression of one or more antigen binding proteins encoded by a codon optimized sequence. Protein expression levels can be measured using one or more expression systems. In some embodiments, expression can be measured in cell culture systems, e.g.,CHO cells or HEK293 cells. In some embodiments, expression can be measured using in vitro expression systems prepared from extracts of living cells, e.g., rabbit reticulocyte lysates, or in vitro expression systems prepared by assembly of purified individual components. In other embodiments, the protein expression is measured in an in vivo system, e.g., mouse, rabbit, monkey, etc.

[0365] In some embodiments, protein expression in solution form can be desirable.Accordingly, in some embodiments, a reference sequence can be sequence optimized to yield a sequence optimized nucleic acid sequence having optimized levels of expressed proteins in soluble form. Levels of protein expression and other properties such as solubility, levels of aggregation, and the presence of truncation products (i.e., fragments due to proteolysis, hydrolysis, or defective translation) can be measured according to methods known in the art, for example, using electrophoresis (e.g., native or SDS-PAGE) or chromatographic methods (e.g., HPLC, size exclusion chromatography, etc.). iii. Optimization of Target Tissue or Target Cell Viability

[0366] In some embodiments, the expression of heterologous proteins (e.g., therapeutic proteins) encoded by a nucleic acid sequence can have deleterious effects in the target tissue or cell, reducing protein yield, or reducing the quality of the expressed product (e.g., due to the presence of protein fragments or precipitation of the expressed protein in inclusion bodies), or causing toxicity.

[0367] Accordingly, in some embodiments of this disclosure, the sequence optimization of a nucleic acid sequence disclosed herein, e.g., a nucleic acid sequence encoding one or more antigen binding proteins, can be used to increase the viability of target cells expressing the protein encoded by the sequence optimized nucleic acid.

[0368] Heterologous protein expression can also be deleterious to cells transfected with a nucleic acid sequence for autologous or heterologous transplantation. Accordingly, in some embodiments of the present disclosure the sequence optimization of a nucleic acid sequence disclosed herein can be used to increase the viability of target cells expressing the protein encoded by the sequence optimized nucleic acid sequence. Changes in cell or tissue viability,toxicity, and other physiological reaction can be measured according to methods known in the art. iv.Reduction of an Undesired Immune and / or Inflammatory Response In some cases, the administration of a sequence optimized nucleic acid encoding a one or more antigen binding proteins can trigger an undesired immune response, which could be caused by the therapeutic agent itself (e.g., an mRNA). Accordingly, in some embodiments of the present disclosure the sequence optimization of nucleic acid sequence (e.g., RNA, e.g., an mRNA) disclosed herein can be used to decrease an immune or inflammatory response triggered by the administration of such a nucleic acid (e.g., the immune or inflammatory response caused by the nucleic acid itself). In some cases, an undesired inflammatory response can be measured by detecting increased levels of one or more inflammatory cytokines using methods known in the art, e.g., ELISA. The term "inflammatory cytokine" refers to cytokines that are elevated in an inflammatory response. Examples of inflammatory cytokines include interleukin-6 (IL-6), CXCL1 (chemokine (C-X-C motif) ligand 1; also known as GROa, interferon-g (IFNg), tumor necrosis factor a (TNFa), interferon g-induced protein 10 (IP-10), or granulocyte- colony stimulating factor (G-CSF). The term “inflammatory cytokines” includes also other cytokines associated with inflammatory responses known in the art, e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-13 (Il-13), interferon α (IFN-α). a. Untranslated Regions Untranslated regions (UTRs) are nucleic acid sections of a polynucleotide before a start codon (5′ UTR) and after a stop codon (3′ UTR) that are not translated. In some embodiments, a polynucleotide (e.g., a ribonucleic acid (RNA), e.g., a messenger RNA (mRNA)) of this disclosure comprising an open reading frame (ORF) encoding one or more antigen binding proteins further comprises a UTR (e.g., a 5′ UTR or functional fragment thereof, a 3′ UTR or functional fragment thereof, or a combination thereof). A UTR (e.g., 5′ UTR or 3′ UTR) can be homologous or heterologous to the coding region in a polynucleotide. In some embodiments, the UTR is homologous to the ORFencoding the one or more antigen binding proteins. In some embodiments, the UTR is heterologous to the ORF encoding the one or more antigen binding proteins. In some embodiments, the polynucleotide comprises two or more 5′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the polynucleotide comprises two or more 3′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the 5′ UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof is sequence optimized. In some embodiments, the 5′UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil. UTRs can have features that provide a regulatory role, e.g., increased or decreased stability, localization and / or translation efficiency. A polynucleotide comprising a UTR can be administered to a cell, tissue, or organism, and one or more regulatory features can be measured using routine methods. In some embodiments, a functional fragment of a 5′ UTR or 3′ UTR comprises one or more regulatory features of a full length 5′ or 3′ UTR, respectively. Natural 5′UTRs bear features that play roles in translation initiation. They harbor signatures like Kozak sequences that are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A / G)CCAUGG (SEQ ID NO: 27), where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’. 5′ UTRs also have been known to form secondary structures that are involved in elongation factor binding. By engineering the features typically found in abundantly expressed genes of specific target organs, one can enhance the stability and protein production of a polynucleotide. For example, introduction of 5′ UTR of liver-expressed mRNA, such as albumin, serum amyloid A, Apolipoprotein A / B / E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII, can enhance expression of polynucleotides in hepatic cell lines or liver. Likewise, use of 5′UTRfrom other tissue-specific mRNA to improve expression in that tissue is possible for muscle (e.g., MyoD, Myosin, Myoglobin, Myogenin, Herculin), for endothelial cells (e.g., Tie-1, CD36), for myeloid cells (e.g., C / EBP, AML1, G-CSF, GM-CSF, CD11b, MSR, Fr-1, i- NOS), for leukocytes (e.g., CD45, CD18), for adipose tissue (e.g., CD36, GLUT4, ACRP30, adiponectin) and for lung epithelial cells (e.g., SP-A / B / C / D). In some embodiments, UTRs are selected from a family of transcripts whose proteins share a common function, structure, feature or property. For example, an encoded polypeptide can belong to a family of proteins (i.e., that share at least one function, structure, feature, localization, origin, or expression pattern), which are expressed in a particular cell, tissue or at some time during development. The UTRs from any of the genes or mRNA can be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide. In some embodiments, the 5′ UTR and the 3′ UTR can be heterologous. In some embodiments, the 5′ UTR can be derived from a different species than the 3′ UTR. Co-owned International Patent Application No. PCT / US2014 / 021522 (Publ. No. WO / 2014 / 164253, incorporated herein by reference in its entirety) provides a listing of exemplary UTRs that can be utilized in the polynucleotide of the present invention as flanking regions to an ORF. Additional exemplary UTRs of the application include, but are not limited to, one or more 5′UTR and / or 3′UTR derived from the nucleic acid sequence of: a globin, such as an α- or β-globin (e.g., a Xenopus, mouse, rabbit, or human globin); a strong Kozak translational initiation signal; a CYBA (e.g., human cytochrome b-245 α polypeptide); an albumin (e.g., human albumin7); a HSD17B4 (hydroxysteroid (17-β) dehydrogenase); a virus (e.g., a tobacco etch virus (TEV), a Venezuelan equine encephalitis virus (VEEV), a Dengue virus, a cytomegalovirus (CMV) (e.g., CMV immediate early 1 (IE1)), a hepatitis virus (e.g., hepatitis B virus), a sindbis virus, or a PAV barley yellow dwarf virus); a heat shock protein (e.g., hsp70); a translation initiation factor (e.g., elF4G); a glucose transporter (e.g., hGLUT1 (human glucose transporter 1)); an actin (e.g., human α or β actin); a GAPDH; a tubulin; a histone; a citric acid cycle enzyme; a topoisomerase (e.g., a 5′UTR of a TOP gene lacking the5′ TOP motif (the oligopyrimidine tract)); a ribosomal protein Large 32 (L32); a ribosomal protein (e.g., human or mouse ribosomal protein, such as, for example, rps9); an ATP synthase (e.g., ATP5A1 or the β subunit of mitochondrial H+-ATP synthase); a growth hormone e (e.g., bovine (bGH) or human (hGH)); an elongation factor (e.g., elongation factor 1 α1 (EEF1A1)); a manganese superoxide dismutase (MnSOD); a myocyte enhancer factor 2A (MEF2A); a β-F1-ATPase, a creatine kinase, a myoglobin, a granulocyte-colony stimulating factor (G-CSF); a collagen (e.g., collagen type I, alpha 2 (Col1A2), collagen type I, alpha 1 (Col1A1), collagen type VI, alpha 2 (Col6A2), collagen type VI, alpha 1 (Col6A1)); a ribophorin (e.g., ribophorin I (RPNI)); a low density lipoprotein receptor-related protein (e.g., LRP1); a cardiotrophin-like cytokine factor (e.g., Nnt1); calreticulin (Calr); a procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (Plod1); and a nucleobindin (e.g., Nucb1). In some embodiments, the 5′ UTR is selected from the group consisting of a βglobin 5′ UTR; a 5′UTR containing a strong Kozak translational initiation signal; a cytochrome b- 245 α polypeptide (CYBA) 5′ UTR; a hydroxysteroid (17-β) dehydrogenase (HSD17B4) 5′ UTR; a Tobacco etch virus (TEV) 5′ UTR; a Venezuelen equine encephalitis virus (TEEV) 5′ UTR; a 5′ proximal open reading frame of rubella virus (RV) RNA encoding nonstructural proteins; a Dengue virus (DEN) 5′ UTR; a heat shock protein 70 (Hsp70) 5′ UTR; a eIF4G 5′ UTR; a GLUT15′ UTR; functional fragments thereof and any combination thereof. Wild-type UTRs derived from any gene or mRNA can be incorporated into the polynucleotides of this disclosure. In some embodiments, a UTR can be altered relative to a wild type or native UTR to produce a variant UTR, e.g., by changing the orientation or location of the UTR relative to the ORF; or by inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. In some embodiments, variants of 5′ or 3′ UTRs can be utilized, for example, mutants of wild type UTRs, or variants wherein one or more nucleotides are added to or removed from a terminus of the UTR. Additionally, one or more synthetic UTRs can be used in combination with one or more non-synthetic UTRs. See, e.g., Mandal and Rossi, Nat. Protoc. 20138(3):568-82, the contents of which are incorporated herein by reference in their entirety.UTRs or portions thereof can be placed in the same orientation as in the transcript from which they were selected or can be altered in orientation or location. Hence, a 5′ and / or 3′ UTR can be inverted, shortened, lengthened, or combined with one or more other 5′ UTRs or 3′ UTRs. In some embodiments, the polynucleotide comprises multiple UTRs, e.g., a double, a triple or a quadruple 5′ UTR or 3′ UTR. For example, a double UTR comprises two copies of the same UTR either in series or substantially in series. For example, a double beta-globin 3′UTR can be used (see US2010 / 0129877, the contents of which are incorporated herein by reference in its entirety). The polynucleotides of this disclosure can comprise combinations of features. For example, the ORF can be flanked by a 5′UTR that comprises a strong Kozak translational initiation signal and / or a 3′UTR comprising an oligo(dT) sequence for templated addition of a poly-A tail. A 5′UTR can comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and / or different UTRs (see, e.g., US2010 / 0293625, herein incorporated by reference in its entirety). Other non-UTR sequences can be used as regions or subregions within the polynucleotides of this disclosure. For example, introns or portions of intron sequences can be incorporated into the polynucleotides of this disclosure. Incorporation of intronic sequences can increase protein production as well as polynucleotide expression levels. In some embodiments, the polynucleotide of this disclosure comprises an internal ribosome entry site (IRES) instead of or in addition to a UTR (see, e.g., Yakubov et al., Biochem. Biophys. Res. Commun. 2010394(1):189-193, the contents of which are incorporated herein by reference in their entirety). In some embodiments, the polynucleotide comprises an IRES instead of a 5′ UTR sequence. In some embodiments, the polynucleotide comprises an ORF and a viral capsid sequence. In some embodiments, the polynucleotide comprises a synthetic 5′ UTR in combination with a non-synthetic 3′ UTR. In some embodiments, the UTR can also include at least one translation enhancer polynucleotide, translation enhancer element, or translational enhancer elements (collectively, “TEE,” which refers to nucleic acid sequences that increase the amount ofpolypeptide or protein produced from a polynucleotide. As a non-limiting example, the TEE can be located between the transcription promoter and the start codon. In some embodiments, the 5′ UTR comprises a TEE. In one aspect, a TEE is a conserved element in a UTR that can promote translational activity of a nucleic acid such as, but not limited to, cap-dependent or cap-independent translation. i. 5’-UTR Sequences 5′ UTR sequences are important for ribosome recruitment to the mRNA and have been reported to play a role in translation (Hinnebusch A, et al., (2016) Science, 352:6292: 1413-6). Disclosed herein, inter alia, is a polynucleotide, e.g., mRNA, comprising an open reading frame encoding one or more antigen binding proteins, comprising, inter alia, a 5’ UTR. In an embodiment, the polynucleotide comprises: (a) a 5′-UTR (e.g., as provided in Table 1 or a variant or fragment thereof); (b) a coding region; and (c) a stop element and a 3′- UTR (e.g., as described herein), and LNP compositions comprising the same. In an embodiment, the polynucleotide comprises a 5′-UTR comprising a sequence provided in Table 1 or a variant or fragment thereof (e.g., a functional variant or fragment thereof). It will be understood that such 5’UTRs are incorporated into constructs not found in nature, e.g., such 5’ UTRs are synthetic, are altered in sequence from naturally occurring 5’UTRs, are truncated or lengthened versions of those found in nature, comprise chemically modified bases, are 5’ of ORF sequences different from those which they may be found in nature, or the like. In an embodiment, the 5′ UTR comprises a sequence provided in Table 1 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 5′ UTR sequence provided in Table 1, or a variant or a fragment thereof. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 28. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or100% identity to SEQ ID NO: 29. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 30. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 31. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 32. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 33. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 34. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 35. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 36. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 37. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 38. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 39. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 40. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 41. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 42. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 43. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 44. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 45. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 46. In an embodiment, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 47. In an embodiment, the 5′ UTR comprises a sequence with at least80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 48. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 49. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 50. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 51. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 52. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 53. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 54. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 55. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 56. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 57. In an embodiment, the 5' UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 58.

[0396] In an embodiment, the 5' UTR comprises the sequence of any one of SEQ ID NOs:28-58. In an embodiment, the 5' UTR consists of the sequence of any one of SEQ ID NOs:28- 58.

[0397] In an embodiment, a 5' UTR sequence provided in Table 1 has a first nucleotide which is an A. In an embodiment, a 5' UTR sequence provided in Table 1 has a first nucleotide which is a G. In an embodiment, a 5' UTR sequence provided in Table 1 has two first nucleotides which are an AG. In an embodiment, a 5' UTR sequence provided in Table 1 has two first nucleotides which are a GA.Table 1: S' UTR sequencesIn an embodiment, the 5′ UTR comprises a variant of SEQ ID NO: 28. In an embodiment, the variant of SEQ ID NO: 28 comprises a nucleic acid sequence of: G G A A A U C G C A A A A (N2)X (N3)X C U (N4)X (N5)X C G C G U U A G A U U U C U U U U A G U U U U C U N6 N7 C A A C U A G C A A G C U U U U U G U U C U C G C C (N8 C C)x (SEQ ID NO: 37), wherein: (N2)x is a uracil and x is an integer from 0 to 5, e.g., wherein x =3 or 4; (N3)x is a guanine and x is an integer from 0 to 1;(N4)x is a cytosine and x is an integer from 0 to 1; (N5)x is a uracil and x is an integer from 0 to 5, e.g., wherein x =2 or 3; N6 is a uracil or cytosine; N7 is a uracil or guanine; N8 is adenine or guanine and x is an integer from 0 to 1. In an embodiment (N2)x is a uracil and x is 0. In an embodiment (N2)x is a uracil and x is 1. In an embodiment (N2)x is a uracil and x is 2. In an embodiment (N2)x is a uracil and x is 3. In an embodiment, (N2)x is a uracil and x is 4. In an embodiment (N2)x is a uracil and x is 5. In an embodiment, (N3)x is a guanine and x is 0. In an embodiment, (N3)x is a guanine and x is 1. In an embodiment, (N4)x is a cytosine and x is 0. In an embodiment, (N4)x is a cytosine and x is 1. In an embodiment (N5)x is a uracil and x is 0. In an embodiment (N5)x is a uracil and x is 1. In an embodiment (N5)x is a uracil and x is 2. In an embodiment (N5)x is a uracil and x is 3. In an embodiment, (N5)x is a uracil and x is 4. In an embodiment (N5)x is a uracil and x is 5. In an embodiment, N6 is a uracil. In an embodiment, N6 is a cytosine. In an embodiment, N7 is a uracil. In an embodiment, N7 is a guanine. In an embodiment, N8 is an adenine and x is 0. In an embodiment, N8 is an adenine and x is 1. In an embodiment, N8 is a guanine and x is 0. In an embodiment, N8 is a guanine and x is 1. In an embodiment, the 5′ UTR comprises a variant of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to thecorresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 50% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 60% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28- 58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 70% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 80% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 90% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 95% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 96% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 97% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 98% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28-58. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a sequence with at least 99% identity to the corresponding non-variant sequence of any one of SEQ ID NOs: 28- 58.

[0408] In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 5%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 10%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 20%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 30%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 40%. In an embodiment, thevariant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 50%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 60%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 70%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises a uridine content of at least 80%. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises at least 2, 3, 4, 5, 6 or 7 consecutive uridines (e.g., a polyuridine tract). In an embodiment, the polyuridine tract in the variant of any one of SEQ ID NOs: 28-58 comprises at least 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, or 3-5 consecutive uridines. In an embodiment, the polyuridine tract in the variant of any one of SEQ ID NOs: 28-58 comprises 4 consecutive uridines. In an embodiment, the polyuridine tract in the variant any one of SEQ ID NOs: 28- 58 comprises 5 consecutive uridines. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 polyuridine tracts. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises 3 polyuridine tracts. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises 4 polyuridine tracts. In an embodiment, the variant of any one of SEQ ID NOs: 28-58 comprises 5 polyuridine tracts. In an embodiment, one or more of the polyuridine tracts are adjacent to a different polyuridine tract. In an embodiment, each of, e.g., all, the polyuridine tracts are adjacent to each other, e.g., all of the polyuridine tracts are contiguous. In an embodiment, one or more of the polyuridine tracts are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18. 19, 20, 30, 40, 50 or 60 nucleotides. In an embodiment, each of, e.g., all of, the polyuridine tracts are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18. 19, 20, 30, 40, 50 or 60 nucleotides. In an embodiment, a first polyuridine tract and a second polyuridine tract are adjacent to each other. In an embodiment, a subsequent, e.g., third, fourth, fifth, sixth or seventh, eighth, ninth, or tenth, polyuridine tract is separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15,16, 17, 18. 19, 20, 30, 40, 50 or 60 nucleotides from the first polyuridine tract, the second polyuridine tract, or any one of the subsequent polyuridine tracts. In an embodiment, a first polyuridine tract is separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18. 19, 20, 30, 40, 50 or 60 nucleotides from a subsequent polyuridine tract, e.g., a second, third, fourth, fifth, sixth or seventh, eighth, ninth, or tenth polyuridine tract. In an embodiment, one or more of the subsequent polyuridine tracts are adjacent to a different polyuridine tract. In an embodiment, the 5′ UTR comprises a Kozak sequence, e.g., a GCCRCC nucleotide sequence (SEQ ID NO: 57) wherein R is an adenine or guanine. In an embodiment, the Kozak sequence is disposed at the 3′ end of the 5′UTR sequence. In an embodiment, the polynucleotide comprising a 5’ UTR sequence disclosed herein comprises a coding region which encodes for a payload, e.g., a therapeutic or prophylactic payload (e.g., one or more Antigen binding proteins). In an aspect, the polynucleotide (e.g., mRNA) comprising a 5’ UTR sequence disclosed herein is formulated as an LNP. In an embodiment, the LNP composition comprises: (i) an ionizable lipid, e.g., an amino lipid; (ii) a sterol or other structural lipid; (iii) a non-cationic helper lipid or phospholipid; and (iv) a PEG-lipid. In another aspect, the LNP compositions of the disclosure are used in a method of treating a disease or disorder. In an aspect, an LNP composition comprising a polynucleotide disclosed herein encoding a therapeutic payload or prophylactic payload, e.g., one or more target antigen binding proteins, can be administered with one or more other therapeutic agents, e.g., as described herein. ii.Stop elements and 3’-UTRs Translational stop codons, UAA, UAG, and UGA, are an important component of the genetic code and signal the termination of translation of an mRNA. During protein synthesis, stop codons interact with protein release factors and this interaction can modulate ribosomalactivity thus having an impact translation (Tate WP, et al., (2018) Biochem Soc Trans, 46(6):1615-162). 3′ UTR sequences have been shown to influence translation, half-life, and subcellular localization of mRNAs (Mayr C., Cold Spring Harb Persp Biol 2019 Oct 1;11(10):a034728). Disclosed herein, inter alia, is a polynucleotide, e.g., mRNA, comprising an open reading frame encoding one or more antigen binding proteins, which polynucleotide has a stop element in combination with a 3′ UTR that confers an increased half-life, increased expression and / or increased activity of the one or more antigen binding proteins encoded by said polynucleotide, or of the polynucleotide itself. In an embodiment, a polynucleotide disclosed herein comprises: (a) a 5′-UTR; (b) a coding region; and (c) a stop element and 3′- UTR (e.g., as described herein), and LNP compositions comprising the same. Disclosed herein, inter alia, is a polynucleotide encoding a polypeptide comprising, inter alia, a 3’ UTR. In an embodiment, a polynucleotide disclosed herein comprises: (a) a 5’-UTR (e.g., as provided in Table 1 or a variant or fragment thereof); (b) a coding region; and (c) a stop element and 3’-UTR (e.g., as provided in Table 2 or a variant or fragment thereof), and LNP compositions comprising the same. In an embodiment, the polynucleotide comprises a 3’-UTR comprising a sequence provided in Table 2 or a variant or fragment thereof (e.g., a functional variant or fragment thereof). It will be understood that such 3’UTRs are incorporated into constructs not found in nature, e.g., such 3’ UTRs are synthetic, are altered in sequence from naturally occurring 3’UTRs, are truncated or lengthened versions of those found in nature, comprise chemically modified bases, are 3’ of ORF sequences different from those which they may be found in nature, or the like. In an embodiment, the 3′ UTR comprises a sequence provided in Table 2 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in Table 2, or a variant or a fragment thereof. In an embodiment, the 3′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of SEQ ID NO: 59-67. Table 2: 3′ UTR sequences (stop cassette is italicized; miR binding sites are boldened)In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAAGCUCCCCGGGGGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCC CAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUC UGAGUGGGCGGC (SEQ ID NO: 59) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 59). In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 59 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life isabout 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 59 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 59 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO:105 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 59. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAGUCUAAGCUGGAGCCUCCUGAGAGACCUGUGUGAACUAUUGAGAAGAUCG GAACAGCUCCUUACUCUGAGGAAGUUGGUACCCCCGUGGUCUUUGAAUAAAG UCUGAGUGGGCGGC (SEQ ID NO: 60) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 60). In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 60 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life isabout 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 60 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 60 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 60 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 60. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAAGCUCCCCGGGGCAAACACCAUUGUCACACUCCAGCCUCGGUGGCCUAGCU UCUUGCCCCUUGGGCCCAAACACCAUUGUCACACUCCAUCCCCCCAGCCCCUCC UCCCCUUCCUGCACCCGUACCCCCCAAACACCAUUGUCACACUCCAGUGGUCU UUGAAUAAAGUCUGAGUGGGCGGC (SEQ ID NO: 61) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 61). In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 61 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, theincrease in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 61 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 61 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 61 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 61. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAAGCUCCCCGGGGUCCAUAAAGUAGGAAACACUACAGCUGGAGCCUCGGUG GCCUAGCUUCUUGCCCCUUGGGCCCAAACACCAUUGUCACACUCCAUCCCCCC AGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCU GAGUGGGCGGC (SEQ ID NO: 62) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 62. In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 62 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. Inan embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 62 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 62 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 62 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 62. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAAGCUCCCCGGGGGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCC CAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCCAAACACCAUUGUCACACUC CAGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC (SEQ ID NO:109) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 63. In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 63 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. Inan embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 63 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 63 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 63 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 63. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAGCCCCUCCGGGGCAAACACCAUUGUCACACUCCAGCCUCGGUGGCCUAGC UUCUUGCCCCUUGGGCCCAAACACCAUUGUCACACUCCAUCCCCCCAGCCCCUC CUCCCCUUCCUGCACCCGUACCCCCCAAACACCAUUGUCACACUCCAGUGGUCU UUGAAUAAAGUCUGAGUGGGCGGC (SEQ ID NO: 64) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 64. In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 64 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In anembodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 64 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 64 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 64 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 64. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAGCCCCUCCGGGGUCCAUAAAGUAGGAAACACUACAGCCUCGGUGGCCUAG CUUCUUGCCCCUUGGGCCUCCAUAAAGUAGGAAACACUACAUCCCCCCAGCCC CUCCUCCCCUUCCUGCACCCGUACCCCCCGCAUUAUUACUCACGGUACGAGUG GUCUUUGAAUAAAGUCUGAGUGGGCGGC (SEQ ID NO: 65) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 65). In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 65 or a variant or fragment thereof, results in an increased half-life of thepolynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 65 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 65 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 65 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 65. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAGCCCCUCCGGGGUCCAUAAAGUAGGAAACACUACAGCUGGAGCCUCGGUG GCCUAGCUUCUUGCCCCUUGGGCCCAAACACCAUUGUCACACUCCAUCCCCCC AGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCU GAGUGGGCGGC (SEQ ID NO: 66) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 66.In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 66 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 66 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 66 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 66 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 66. In an embodiment, the polynucleotide comprises a stop element and 3’-UTR, wherein the sequence is (stop element is italicized): UAAGCCCCUCCGGGGGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCC CAGCCCCUCCUCCCCUUCCUGCACCCGUACCCCCCAAACACCAUUGUCACACUC CAGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC (SEQ ID NO:113) or a variant or fragment thereof (e.g., a fragment that lacks the first one, two, three, four, five, six, or more nucleotides of nucleotides of SEQ ID NO: 67.In an embodiment, the polynucleotide having a 3’ UTR sequence provided in SEQ ID NO: 67 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In an embodiment, the increase in half-life is about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold, or more. In an embodiment, the increase in half-life is about 1.5-fold or more. In an embodiment, the increase in half-life is about 2-fold or more. In an embodiment, the increase in half-life is about 3-fold or more. In an embodiment, the increase in half-life is about 4-fold or more. In an embodiment, the increase in half-life is about 5-fold or more. In an embodiment, the increase in half-life is about 6-fold or more. In an embodiment, the increase in half-life is about 7-fold or more. In an embodiment, the increase in half-life is about 8-fold. In an embodiment, the increase in half-life is about 9-fold or more. In an embodiment, the increase in half-life is about 10-fold or more. In an embodiment, the polynucleotide having a 3′ UTR sequence provided in SEQ ID NO: 67 or a variant or fragment thereof, results in an increased level and / or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In an embodiment, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of SEQ ID NO: 67 or a variant or fragment thereof. In an embodiment, the polynucleotide comprises a 3′ UTR sequence provided in SEQ ID NO: 67 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in SEQ ID NO: 67. b. 3’ stabilizing region Disclosed herein, inter alia, is a polynucleotide encoding a polypeptide (e.g., one or more antigen binding proteins), wherein the polynucleotide comprises: (a) a 5’-UTR (e.g., as described herein); (b) a coding region comprising a stop element (e.g., as described herein); (c) a 3’-UTR (e.g., as described herein), and (d) a 3’ stabilizing region. Also disclosed herein are LNP compositions comprising the same.In an embodiment, the polynucleotide comprises a 3’ stabilizing region, e.g., a stabilized tail e.g., as described herein. A polynucleotide containing a 3’-stabilizing region (e.g., a 3’-stabilizing region including an alternative nucleobase, sugar, and / or backbone) may be particularly effective for use in therapeutic compositions, because they may benefit from increased stability, high expression levels. In an embodiment, the 3’ stabilizing region comprises a poly A tail, e.g., a poly A tail comprising 80-150, e.g., 120, adenines. In an embodiment, the poly A tail comprises one or more non-adenosine residues, e.g., one or more guanosines, e.g., as described herein. In an embodiment, the poly A tail comprises a UCUAG sequence (SEQ ID NO: 100). In an embodiment, the poly A tail comprises about 80-120, e.g., 100, adenines upstream of SEQ ID NO: 100. In an embodiment, the poly A tail comprises about 1-40, e.g., 20, adenines downstream of SEQ ID NO: 100. In an embodiment, the 3’ stabilizing region comprises at least one alternative nucleoside. In an embodiment, the alternative nucleoside is an inverted thymidine (idT). In an embodiment, the alternative nucleoside is disposed at the 3’ end of the 3’ stabilizing region. In an embodiment, the 3’ stabilizing region comprises a structure of:or a salt thereof, wherein each X is independently O or S, and A represents adenine and T represents thymine. In an aspect, disclosed herein is a polynucleotide encoding a polypeptide, wherein the polynucleotide comprises: (a) a 5’-UTR, e.g., as described herein; (b) a coding regioncomprising a stop element (e.g., as described herein); (c) a 3’-UTR (e.g., as described herein) and; (d) a 3’ stabilizing region, e.g., as described herein. In an aspect, an LNP composition comprising a polynucleotide comprising a stabilizing region disclosed herein comprises: (i) an ionizable lipid, e.g., an amino lipid; (ii) a sterol or other structural lipid; (iii) a non-cationic helper lipid or phospholipid; and (iv) a PEG-lipid. In another aspect, the LNP compositions of the disclosure are used in a method of treating a disease or disorder. In an aspect, an LNP composition comprising a polynucleotide disclosed herein encoding a therapeutic payload or prophylactic payload, e.g., a polynucleotide encoding one or more antigen binding proteins, can be administered with one or more other therapeutic agents, e.g., as described herein. c. MicroRNA (miRNA) Binding Sites Polynucleotides of this disclosure can include regulatory elements, for example, microRNA (miRNA) binding sites, transcription factor binding sites, structured mRNA sequences and / or motifs, artificial binding sites engineered to act as pseudo-receptors for endogenous nucleic acid binding molecules, and combinations thereof. In some embodiments, a polynucleotide (e.g., a ribonucleic acid (RNA), e.g., a messenger RNA (mRNA)) of this disclosure comprises an open reading frame (ORF) encoding a polypeptide of interest and further comprises one or more miRNA binding site(s). Inclusion or incorporation of miRNA binding site(s) provides for regulation of polynucleotides of this disclosure, and in turn, of the polypeptides encoded therefrom, based on tissue-specific and / or cell-type specific expression of naturally occurring miRNAs. A miRNA, e.g., a natural occurring miRNA, is a 19-25 nucleotide long noncoding RNA that binds to a polynucleotide (e.g., RNA, e.g., mRNA) and down-regulates gene expression either by reducing stability or by inhibiting translation of the polynucleotide. A miRNA sequence comprises a “seed” region, i.e., a sequence in the region of positions 2-8 ofthe mature miRNA. A miRNA seed can comprise positions 2-8 or 2-7 of the mature miRNA. In some embodiments, a miRNA seed can comprise 7 nucleotides (e.g., nucleotides 2-8 of the mature miRNA), wherein the seed-complementary site in the corresponding miRNA binding site is flanked by an adenosine (A) opposed to miRNA position 1. In some embodiments, a miRNA seed can comprise 6 nucleotides (e.g., nucleotides 2-7 of the mature miRNA), wherein the seed-complementary site in the corresponding miRNA binding site is flanked by an adenosine (A) opposed to miRNA position 1. See, for example, Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP; Mol Cell. 2007 Jul 6;27(1):91-105. miRNA profiling of the target cells or tissues can be conducted to determine the presence or absence of miRNA in the cells or tissues. In some embodiments, a nucleic acid molecule (e.g., RNA, e.g., mRNA) of the disclosure comprises one or more microRNA binding sites, microRNA target sequences, microRNA complementary sequences, or microRNA seed complementary sequences. Such sequences can correspond to, e.g., have complementarity to, any known microRNA such as those taught in US Publication US2005 / 0261218 and US Publication US2005 / 0059005, the contents of each of which are incorporated herein by reference in their entirety. As used herein, the term “microRNA (miRNA or miR) binding site” refers to a sequence within a polynucleotide, e.g., within a DNA or within an RNA transcript, including in the 5′UTR and / or 3′UTR, that has sufficient complementarity to all or a region of a miRNA to interact with, associate with or bind to the miRNA. In some embodiments, a polynucleotide of this disclosure comprising an ORF encoding a polypeptide of interest and further comprises one or more miRNA binding site(s). In exemplary embodiments, a 5′ UTR and / or 3′ UTR of the polynucleotide (e.g., a ribonucleic acid (RNA), e.g., a messenger RNA (mRNA)) comprises the one or more miRNA binding site(s). A miRNA binding site having sufficient complementarity to a miRNA refers to a degree of complementarity sufficient to facilitate miRNA-mediated regulation of a polynucleotide, e.g., miRNA-mediated translational repression or degradation of the polynucleotide. In exemplary aspects of this disclosure, a miRNA binding site having sufficient complementarity to the miRNA refers to a degree of complementarity sufficient to facilitate miRNA-mediated degradation of the polynucleotide, e.g., miRNA-guided RNA-induced silencing complex (RlSC)-mediated cleavage of mRNA. The miRNA binding site can have complementarity to, for example, a 19-25 nucleotide long miRNA sequence, to a 19-23 nucleotide long miRNA sequence, or to a 22-nucleotide long miRNA sequence. A miRNA binding site can be complementary to only a portion of a miRNA, e.g., to a portion less than 1, 2, 3, or 4 nucleotides of the full length of a naturally occurring miRNA sequence. Full or complete complementarity (e.g., full complementarity or complete complementarity over all or a significant portion of the length of a naturally occurring miRNA) is preferred when the desired regulation is mRNA degradation.

[0485] In some embodiments, a miRNA binding site includes a sequence that has complementarity (e.g., partial or complete complementarity) with an miRNA seed sequence. In some embodiments, the miRNA binding site includes a sequence that has complete complementarity with a miRNA seed sequence. In some embodiments, a miRNA binding site includes a sequence that has complementarity (e.g., partial or complete complementarity) with a miRNA sequence. In some embodiments, the miRNA binding site includes a sequence that has complete complementarity with a miRNA sequence. In some embodiments, a miRNA binding site has complete complementarity with a miRNA sequence but for 1, 2, or 3 nucleotide substitutions, terminal additions, and / or truncations.

[0486] In some embodiments, the miRNA binding site is the same length as the corresponding miRNA. In other embodiments, the miRNA binding site is one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve nucleotide(s) shorter than the corresponding miRNA at the 5' terminus, the 3' terminus, or both. In still other embodiments, the microRNA binding site is two nucleotides shorter than the corresponding microRNA at the 5' terminus, the 3' terminus, or both. The miRNA binding sites that are shorter than the corresponding miRNAs are still capable of degrading the mRNA incorporating one or more of the miRNA binding sites or preventing the mRNA from translation.

[0487] In some embodiments, the miRNA binding site binds the corresponding mature miRNA that is part of an active RISC containing Dicer. In another embodiment, binding of the miRNA binding site to the corresponding miRNA in RISC degrades the mRNA containing the miRNA binding site or prevents the mRNA from being translated. In someembodiments, the miRNA binding site has sufficient complementarity to miRNA so that a RISC complex comprising the miRNA cleaves the polynucleotide comprising the miRNA binding site. In other embodiments, the miRNA binding site has imperfect complementarity so that a RISC complex comprising the miRNA induces instability in the polynucleotide comprising the miRNA binding site. In another embodiment, the miRNA binding site has imperfect complementarity so that a RISC complex comprising the miRNA represses transcription of the polynucleotide comprising the miRNA binding site.

[0488] In some embodiments, the miRNA binding site has one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve mismatch(es) from the corresponding miRNA.

[0489] In some embodiments, the miRNA binding site has at least about ten, at least about eleven, at least about twelve, at least about thirteen, at least about fourteen, at least about fifteen, at least about sixteen, at least about seventeen, at least about eighteen, at least about nineteen, at least about twenty, or at least about twenty-one contiguous nucleotides complementary to at least about ten, at least about eleven, at least about twelve, at least about thirteen, at least about fourteen, at least about fifteen, at least about sixteen, at least about seventeen, at least about eighteen, at least about nineteen, at least about twenty, or at least about twenty-one, respectively, contiguous nucleotides of the corresponding miRNA.

[0490] By engineering one or more miRNA binding sites into a polynucleotide of this disclosure, the polynucleotide can be targeted for degradation or reduced translation, provided the miRNA in question is available. This can reduce off-target effects upon delivery of the polynucleotide. For example, if a polynucleotide of this disclosure is not intended to be delivered to a tissue or cell but ends up is said tissue or cell, then a miRNA abundant in the tissue or cell can inhibit the expression of the gene of interest if one or multiple binding sites of the miRNA are engineered into the 5' UTR and / or 3' UTR of the polynucleotide.

[0491] For example, one of skill in the art would understand that one or more miR binding sites can be included in a polynucleotide (e.g., RNA, e.g., mRNA) to minimize expression in certain cell types. In one embodiment, a miR122 binding site can be used. In another embodiment, multiple copies of these miR binding sites or combinations may be used.Conversely, miRNA binding sites can be removed from polynucleotide sequences in which they naturally occur to increase protein expression in specific tissues. For example, a binding site for a specific miRNA can be removed from a polynucleotide to improve protein expression in tissues or cells containing the miRNA. Regulation of expression in multiple tissues can be accomplished through introduction or removal of one or more miRNA binding sites, e.g., one or more distinct miRNA binding sites. The decision whether to remove or insert a miRNA binding site can be made based on miRNA expression patterns and / or their profilings in tissues and / or cells in development and / or disease. Identification of miRNAs, miRNA binding sites, and their expression patterns and role in biology have been rep...

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising: a first mRNA encoding a first polypeptide, wherein the first polypeptide comprises a TCR α-chain variable domain (Vα) comprising a CDRa1 comprising SEQ ID NO: 10, a CDRa2 comprising SEQ ID NO: 11, and a CDRa3 comprising SEQ ID NO: 12, and an antibody heavy chain variable domain (VH) comprising a CDRH1 comprising SEQ ID NO: 18, a CDRH2 comprising SEQ ID NO: 19, and a CDRH3 comprising SEQ ID NO: 20; a second mRNA encoding a second polypeptide, wherein the second polypeptide comprises a TCR β-chain variable domain (Vβ) comprising a CDRb1 comprising SEQ ID NO: 13, a CDRb2 comprising SEQ ID NO: 14, and a CDRb3 comprising SEQ ID NO: 15, and an antibody light chain variable domain (VL) comprising a CDRL1 comprising SEQ ID NO: 21, a CDRL2 comprising SEQ ID NO: 22, and CDRL3 comprising SEQ ID NO: 23; or both, wherein at least one of the first mRNA and the second mRNA comprises one or more of the following: a 5’ UTR, a 3’ UTR, a nucleotide cap, a stabilizing domain, and a poly A tail.

2. The pharmaceutical composition of claim 1, wherein the Vα domain comprises the sequence of SEQ ID NO:

8.

3. The pharmaceutical composition of any of the preceding claims, wherein the Vβ domain comprises the sequence of SEQ ID NO:

9.

4. The pharmaceutical composition of any of the preceding claims, wherein the VH domain comprises the sequence of SEQ ID NO:

16.

5. The pharmaceutical composition of any of the preceding claims, wherein the VL domain comprises the sequence of SEQ ID NO:17.

6. The pharmaceutical composition of any of the preceding claims, wherein the second polypeptide further comprises an Fc domain comprising the sequence of SEQ ID NO:24.

7. The pharmaceutical composition of any of the preceding claims, wherein the first polypeptide further comprises an Fc domain comprising the sequence of SEQ ID NO:25.

8. The pharmaceutical composition of any of the preceding claims, wherein the second polypeptide comprises the sequence of SEQ ID NO:6.

9. The pharmaceutical composition of any of the preceding claims, wherein the first polypeptide comprises the sequence of SEQ ID NO:7.

10. The pharmaceutical composition of any of the preceding claims, wherein the second polypeptide comprises the sequence of SEQ ID NO:4.

11. The pharmaceutical composition of any of the preceding claims, wherein the first polypeptide comprises the sequence of SEQ ID NO:5.

12. The pharmaceutical composition of any of the preceding claims, wherein the second mRNA comprises the sequence of SEQ ID NO:2.

13. The pharmaceutical composition of any of the preceding claims, wherein the first mRNA comprises the sequence of SEQ ID NO:3.

14. The pharmaceutical composition of any of the preceding claims, wherein the pharmaceutical composition comprises both the first mRNA and the second mRNA.

15. The pharmaceutical composition of any of the preceding claims, wherein at least one of the first mRNA and the second mRNA comprises one or more of the following: a 5'-UTR comprising the sequence of any one of SEQ ID NOs: 28-58, and a 3' UTR comprising the sequence of any one of SEQ ID NOs: 59-67.

16. The pharmaceutical composition of any of the preceding claims, further comprising a lipid nanoparticle (LNP).

17. The pharmaceutical composition of claim 16, wherein the LNP comprises an ionizable lipid.

18. The pharmaceutical composition of claim 17, wherein the ionizable lipid has a chemical structure selected from any one of (a)-(p): (a)or a salt thereof, wherein: R1is -OH, -NRN-C4-10cycloalkenyl optionally substituted with one or more oxo or - N(RN’RN’’); RNis H or C1-6alkyl; RN’is H or C1-6alkyl; RN’’is H or C1-6alkyl; o is 1, 2, 3, or 4; n is 4, 5, 6, 7, or 8; m is 4, 5, 6, 7, or 8; M is -C(=O)-O-* or -O-C(=O)-*, wherein * indicates attachment to R2; M’ is -C(=O)-O-* or -O-C(=O)-*, wherein * indicates attachment to R3; R2isor –(C1-6alkylene)-(C3-8cycloalkyl)-C1-6alkyl; R2ais -H or C1-10alkyl; R2bis -H or C1-10alkyl; R2cis C1-8alkyl or C2-8alkenyl; R3isR3ais H or C1-10alkyl; R3bis H or C1-8alkyl; andR3cis C1-10alkyl or C2-8alkenyl, oror a salt thereof, wherein: R1is -OH; o is 2, 3, or 4; n is 4, 5, 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2cis C4-8alkyl; R3ais C7-10alkyl; and R3cis C3-5alkyl, oror a salt thereof, wherein:R1is NRN-C4-10cycloalkenyl optionally substituted with one or more oxo or -N(RN’RN’’); RNis H; RN’is C1-2alkyl; RN’’is H; o is 2, 3, or 4; n is 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2ais C7-10alkyl; R2cis C4-6alkyl; R3ais C1-3alkyl; and R3cis C4-6alkyl, or (d)or a salt thereof, wherein: R1is OH; o is 2, 3, or 4; n is 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2bis C3-5alkyl;R2cis C2-4alkyl; R3ais C7-10alkyl; and R3cis C4-6alkyl, (e)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula I; and R3ais C1-8alkyl. (f)or a salt thereof, wherein: o, M, M’, R2cand R3care as defined for Formula (I); and R3ais C1-8alkyl. (g)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula I; andR3ais C1-8alkyl. (h)or a salt thereof, wherein: o, M, M’, R2cand R3care as defined for Formula (I); and R3ais C1-8alkyl. (i)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula (I); R2ais a C1-8alkyl; and R3ais C1-8alkyl, (j)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for formula I; R2bis a C1-8alkyl; and R3ais C1-8alkyl, or (k)or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or (l)or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or(m)or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or (n)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for formula I; R2bis a C1-8alkyl; and R3ais C1-8alkyl, or (o)or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for formula I; R2bis a C1-8alkyl; and R3ais C1-8alkyl, or (p)or a salt thereof, wherein: o, M, M’, R2c, and R3care as defined for formula I; R2ais a C1-8alkyl; and R3ais C1-8alkyl, or N-oxides, salts, or isomers of each thereof.

19. The pharmaceutical composition of claim 17 or claim 18, wherein the ionizable lipid is a compound selected from the group consisting of:or N-oxides, salts, or isomers thereof.

20. The pharmaceutical composition of any of the preceding claims, further comprising a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of any of the preceding claims, wherein the mRNA comprises a 5' terminal cap, optionally wherein the 5' terminal cap comprises a CapO, Capl, ARC A, inosine, N1 -methyl -guanosine, 2 -fluoro-guanosine, 7-deaza-guanosine, 8-oxo- guanosine, 2-amino-guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5' methylG cap, or an analog thereof.

22. The pharmaceutical composition of any of the preceding claims, wherein the mRNA comprises a poly- A region, optionally wherein the poly- A region is at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90 nucleotides in length, or at least about 100 nucleotides in length, or optionally wherein the poly-A region is about 10 to about 200, about 20 to about 180, about 50 to about 160, about 70 to about 140, or about 80 to about 120 nucleotides in length.

23. The pharmaceutical composition of any of the preceding claims, wherein the mRNA comprises at least one chemically modified nucleobase, sugar, backbone, or any combination thereof.

24. The pharmaceutical composition of any of the preceding claims, wherein the mRNA comprises at least one chemically modified nucleobase, wherein the at least one chemically modified nucleobase is selected from the group consisting of pseudouracil (ψ), N1- methylpseudouracil (m1ψ), 1-ethylpseudouracil, 2-thiouracil (s2U), 4’-thiouracil, 5- methylcytosine, 5-methyluracil, 5-methoxyuracil, and any combination thereof, optionally wherein at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% of the uracils are N1 methylpseudouracils.

25. The pharmaceutical composition of any of the preceding claims, wherein the mRNA comprises a 5’terminal cap comprising Cap1 and a poly-A region 100 nucleotides in length (SEQ ID NO: 101), and wherein all uracils of the polynucleotide are N1-methylpseudouracils.

26. A method for treating cancer comprising administering to a subject in need thereof the pharmaceutical composition of any of claims 1-25.

27. The method of claim 26, wherein the subject is a HLA-A*02-positive subject.

28. The method of claim 26 or 27, wherein the cancer is a MAGEB2-positive solid tumor.

29. The method of claim 28, wherein the MAGEB2-positive solid tumor expresses MAGEB2 peptide GVYDGEEHSV (SEQ ID NO: 1) in a complex with a major histocompatibility complex (MHC) protein on cell surface.

30. The method of any of claims 26-29, wherein the cancer is selected from the group consisting of: liver cancer, lung cancer, chronic lymphocytic leukemia (CLL), colorectal cancer (CRC), gallbladder cancer (GBC), glioblastoma (GBM), gastric cancer (GC), hepatocellular carcinoma (HCC), head and neck cancer, head and neck squamous cell carcinoma (HNSCC), melanoma (MEL), non-Hodgkin lymphoma (NHL), non-small cell lung cancer adenocarcinoma (NSCLCadeno), non-small cell lung cancer (NSCLC), squamous cell non-small cell lung cancer(NSCLCsquam), ovarian cancer (OC), esophageal cancer (OSCAR), renal cell carcinoma (RCC), small cell lung cancer (SCLC), urinary bladder carcinoma (UBC), and uterine endometrial cancer (UEC).

31. The method of any of claims 26-30, wherein the cancer is selected from the group consisting of: hepatocellular carcinoma (HCC), melanoma, non-small cell lung cancer (NSCLC), non-Hodgkin lymphoma (NHL), head and neck squamous cell carcinoma (HNSCC), and uterine endometrial cancer (UEC).

32. The method of any of claims 26-31, wherein the pharmaceutical composition or the lipid nanoparticle is administered to the subject via intravenous (IV), subcutaneous, intramuscular (IM), or intradermal administration.

33. Use of the pharmaceutical composition of any of claims 1-25, in the manufacture of a medicament for the treatment of a MAGEB2-positive solid tumor in a HL A- A* 02-positive subject.

34. The pharmaceutical composition of any of claims 1-25 for use in the treatment of a MAGEB2-positive solid tumor in a HLA-A*02-positive subject.

35. A kit comprising: the pharmaceutical composition of any of claims 1-25 and instructions for use.

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