Novel t cell receptors targeting melanoma-associated antigen (MAGE) b2 and immune therapy using the same

Abstract

The present invention relates to antigen binding proteins that specifically bind to a tumor expressed melanoma-associated antigen (MAGE) B2 antigenic peptide in a complex with MHC, host cells comprising the antigen binding proteins, pharmaceutical compositions comprising the antigen binding proteins or the host cells comprising the antigen binding proteins, and TCR-T cell therapy employing said antigen binding proteins, host cells and / or pharmaceutical compositions. In particular, TCR-T cell therapy is provided for use in the treatment of MAGEB2-expressing cancers.

Description

[0001] NOVEL T CELL RECEPTORS TARGETING MELANOMA-ASSOCIATED ANTIGEN (MAGE) B2 AND IMMUNE THERAPY USING THE SAME

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to antigen binding proteins that specifically bind to a tumor expressed melanoma-associated antigen (MAGE) B2 antigenic peptide in a complex with MHC, host cells comprising the antigen binding proteins, pharmaceutical compositions comprising the antigen binding proteins or the host cells comprising the antigen binding proteins, and TCR-T cell therapy employing said antigen binding proteins, host cells and / or pharmaceutical compositions. In particular, TCR-T cell therapy is provided for use in the treatment of MAGEB2-expressing cancers.

[0004] BACKGROUND OF THE INVENTION

[0005] 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.

[0006] Cancer-testis antigens (CTA) are attractive targets for cancer immunotherapy; including T cell receptor-engineered T cell (TCR-T) cell therapy; 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 MAGE-B2. 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. Targeting MAGEB2 for immunotherapy was previously disclosed in WO 2016 / 102272 A1 , WO 2017 / 097602 A1 , WO 2017 / 148888, WO 2017 / 174822 A1 and WO 2021 / 236638 A1.

[0007] Many types of cancers, including those in which MAGEB2 is aberrantly expressed, still have a high unmet medical need, with patients needing improved, effective, and specific therapeutics. Accordingly, there exists a need to develop new anti-cancer agents that specifically target intracellular proteins that are highly specific to cancer cells. The present invention addresses that need by providing novel antigen binding proteins specifically binding to MAGEB2, and TCR-T cell therapy employing said novel antigen binding proteins.

[0008] SUMMARY OF THE INVENTION

[0009] 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 a first polypeptide comprising a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, and a second polypeptide comprising a variable domain VB comprising CDRbl , CDRb2, and CDRb3; preferably wherein the VA comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 98, 97, 99, 100, 101 , 102, and 103 or an amino acid sequence having at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 98% or preferably at least 99% identity to SEQ ID NO: 98, 97, 99, 100, 101 , 102, or 103, preferably wherein the B comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 105, 104, 106, 107, 108, 109, and 110 or an amino acid sequence having at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 98% or preferably at least 99% identity to SEQ ID NO: 105, 104, 106, 107, 108, 109, and 110, preferably wherein

[0010] CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0011] CDRal comprises SEQ ID NO: 3, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, and CDRb3 comprises SEQ ID NO: 27;

[0012] CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, and CDRb3 comprises SEQ ID NO: 28;

[0013] CDRal comprises SEQ ID NO: 4, CDRa3 comprises SEQ ID NO: 11 , CDRbl comprises SEQ ID NO: 20, and CDRb3 comprises SEQ ID NO: 29;

[0014] CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21 , and CDRb3 comprises SEQ ID NO: 30;

[0015] CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31 ; or CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal , CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0016] The invention also 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 has the amino acid sequence GVYDGEEHSV (SEQ ID NO: 1), wherein the antigen binding protein has a first polypeptide comprising a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, and a second polypeptide has a variable domain VB comprising CDRbl , CDRb2, and CDRb3; wherein

[0017] CDRal includes SEQ ID NO: 2, CDRa3 includes SEQ ID NO: 7, CDRbl includes SEQ ID NO: 15, and CDRb3 includes SEQ ID NO: 26;

[0018] CDRal includes SEQ ID NO: 3, CDRa3 includes SEQ ID NO: 9, CDRbl includes SEQ ID NO: 18, and CDRb3 includes SEQ ID NO: 27;

[0019] CDRal includes SEQ ID NO: 2, CDRa3 includes SEQ ID NO: 10, CDRbl includes SEQ ID NO: 19, and CDRb3 includes SEQ ID NO: 28;

[0020] CDRal includes SEQ ID NO: 4, CDRa3 includes SEQ ID NO: 11 , CDRbl includes SEQ ID NO: 20, and CDRb3 includes SEQ ID NO: 29;

[0021] CDRal includes SEQ ID NO: 5, CDRa3 includes SEQ ID NO: 12, CDRbl includes SEQ ID NO: 21 , and CDRb3 includes SEQ ID NO: 30;

[0022] CDRal includes SEQ ID NO: 6, CDRa3 includes SEQ ID NO: 13, CDRbl includes SEQ ID NO: 22, and CDRb3 includes SEQ ID NO: 31 ; or

[0023] CDRal includes SEQ ID NO: 5, CDRa3 includes SEQ ID NO: 14, CDRbl includes SEQ ID NO: 25, and CDRb3 includes SEQ ID NO: 52; wherein the CDRal , CDRa3, CDRbl and / or CDRb3 sequence(s) may include one, two or three amino acid mutations.

[0024] The antigen binding proteins of the invention are e.g. characterized by a high functional avidity and high specificity as documented in the Examples. The antigen binding proteins of the invention are thus both more effective and safer than prior art antigen binding proteins as demonstrated in the exemplary part below.

[0025] In a second aspect, the invention provides (a) nucleic acid(s) comprising a sequence encoding the antigen binding protein of the first aspect of the invention.

[0026] In a third aspect, the invention provides (a) vector(s) comprising the nucleic acid(s) of the second aspect of the invention. In a fourth aspect, the invention provides a host cell comprising the antigen binding protein of the first aspect of the invention, the nucleic acid(s) of the second aspect of the invention, and / or the vector(s) of the third aspect of the invention.

[0027] In a fifth aspect, the invention provides methods of making the antigen binding protein according to the first aspect of the invention.

[0028] In a sixth aspect, the invention provides a pharmaceutical composition comprising the antigen binding protein of the first aspect of the invention, the nucleic acid(s) of the second aspect of the invention, the vector(s) of the third aspect of the invention or the host cell of the fourth aspect of the invention, and optionally a pharmaceutically acceptable carrier.

[0029] In a seventh aspect, the invention provides the antigen binding protein of the first aspect of the invention, the nucleic acid(s) of the second aspect of the invention, the vector(s) of the third aspect of the invention, the host cell of the fourth aspect of the invention, or the pharmaceutical composition of the sixth aspect of the invention for use in the treatment of cancer, in particular a MAGEB2-expressing cancer.

[0030] In an eighth aspect, the invention provides a kit comprising the antigen binding protein of the first aspect of the invention, the nucleic acid(s) of the second aspect of the invention, the vector(s) of the third aspect of the invention, and / or the host cell of the fourth aspect of the invention.

[0031] BRIEF DESCRIPTION OF THE FIGURES

[0032] Figure 1. Functional avidity (EC50) as measured by IFN-y release

[0033] Functional avidity (EC50) of TCRs 1-7 (Fig. 1A: TCRs 1-4; Fig. 1 B: TCRs 5-7) was measured by IFN-y release of TCR-transfected T cells after co-culture with T2 cells loaded with increasing amounts of MAGEB2-001 peptide. The assay was repeated 2-3 times with effector cells of different donors as indicated in the individual plots.

[0034] Figure 2. Cross-reactivity check against sequence similar-peptides

[0035] T2-cells were loaded with MAGEB2-001 peptide, 9 different sequence-similar peptides (SEQ ID NOs: 129-137), the irrelevant peptide control NYESG1-001 (SEQ ID NO: 150) or not loaded, respectively. Next, the T2 cells were co-cultivated with CD8 T cells transfected with the specific TCRs (TCRs 1-7). Supernatants were collected 24h after start of co-culture and subjected to an IFN-y ELISA. The assay was performed with CD8 effector cells of one donor.

[0036] Figure 3. Motif determination by a substitution-scan

[0037] T2-cells were loaded with MAGEB2-001 substituted single-amino acid exchange peptide variants, an irrelevant peptide control NYESO1-001 or not loaded, respectively. Next, the T2 cells were co-cultivated with CD8 T cells transfected with the specific TCRs (TCRs 1- 7). Supernatants were collected 24h after start of co-culture and subjected to an IFN-y ELISA. The assay was performed with CD8 effector cells. A position is considered relevant for TCR contact when the exchange leads to a response reduction of >70% (considering the response against wild type MAGEB2-001 peptide as 100% and the response against the irrelevant peptide NYESO1-001 as 0%).

[0038] Figure 4. Target tetramer titration for stabilized scTCR

[0039] Selected clones (TCR-6_scTCR_S (lower right) and TCR-1_scTCR_S (upper right)) from the scTCR conversion library (right) were stained with HLA-A*02 / MAGEB2-001 tetramer at a concentration of 25 nM and compared to the respective parental scTCRs (left).

[0040] Figure 5. Target binding and specificity analysis

[0041] Figure 5A. Target binding and specificity analysis on affinity matured TCR-6 scTCRs. Selected yeast clones with scTCRs from the TCR-6 CDRbl library were analyzed for target and similar peptide binding. The parental library clone TCR-6_scTCR_S was included in the analysis (left). CDRbl clones were analyzed with HLA-A*02 / MAGEB2-001 monomers at a concentration of 100 nM (staining on X-axis). Specificity was addressed using a mix of 9 similar peptides together with HLA-A*02 as peptide-HLA tetramer at a concentration of 25 nM each (staining on Y-axis). Figure 5B. Selected yeast clones with scTCRs from the TCR-1 CDRa3 (top middle) and CDRbl library (bottom middle and bottom right) were analyzed for target and similar peptide binding. The parental library clone TCR-1_scTCR_S was included in the analysis (left). CDRa3 clones were analyzed with HLA-A*02 / MAGEB2-001 dimers at a concentration of 10 nM (staining on X-axis), CDRbl clones with dimers at a concentration of 2 nM. Specificity was addressed using a mix of 9 similar peptides together with HLA-A*02 as peptide-HLA tetramer at a concentration of 25 nM each (staining on Y-axis).

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] In order for the present invention to be readily understood, several definitions of terms used in the course of the invention are set forth below.

[0044] As used herein, the term “amino acid” refers to one of the 20 naturally occurring amino acids or any non-natural analogues. Preferably, the term “amino acid” refers to one of the 20 naturally occurring amino acids.

[0045] As used herein, the terms “polypeptide” or “protein” mean a macromolecule composed of one or more sequence(s) of amino acids. A protein can be a native protein, that is, a protein produced by a naturally-occurring and non-recombinant cell; or it can be produced by a genetically-engineered or recombinant cell, and comprise molecules having the amino acid sequence of the native protein, or molecules having deletions from, additions to, and / or substitutions of one or more amino acids of the native sequence.

[0046] As used herein, a “domain” may be any region of a protein, generally defined on the basis of sequence homologies and often referring to a specific structural or functional entity. In the context of variable domains of an antibody or a TCR, the domain comprises the antibody or TCR-derived CDR sequences as also disclosed below.

[0047] The term "antigen" or "target antigen" as used herein refers to a molecule or a portion of a molecule or complex that is capable of being bound by an antigen binding site, wherein said antigen binding site is present in an antigen binding protein, preferably an antigen binding protein of the present invention. The antigen in the context of the present invention is melanoma-associated antigen (MAGE) B2 antigenic peptide, more particularly a MAGEB2 antigenic peptide that comprises or consists of the amino acid sequence GVYDGEEHSV (SEQ ID NO:1), in a complex with a MHC protein, such as an HLA protein, for instance HLA- A*02. The peptide GVYDGEEHSV (SEQ ID NO: 1) corresponds to amino acid residue numbers 231-241 of the known MAGEB2 protein. In instances where the MAGEB2 antigenic peptide comprises further amino acids in addition to the amino acid sequence GVYDGEEHSV (SEQ ID NO: 1), it is preferred that the overall length of the MAGEB2 antigenic peptide does not exceed 30 or 20 amino acids, more preferably does not exceed 15 amino acids, even more preferably does not exceed 12 amino acids. In instances where the MAGEB2 antigenic peptide comprises further amino acids in addition to SEQ ID NO: 1 , the amino acids of SEQ ID NO: 1 are preferably located within the peptide binding groove of the MHC protein when the antigenic peptide is in a complex with an MHC protein. The person skilled in the art is aware that antigenic peptides presented on MHC I are usually no longer than 12 amino acids.

[0048] A “MAGEB2:MHC complex presenting cell” herein refers to a cell that presents on its surface the MAGEB2 antigenic peptide in a complex with an MHC molecule. In preferred embodiments, the MAGEB2:MHC complex presenting cell is a tumor cell, wherein the tumor is preferably a cancer as defined herein below in the section ‘Therapeutic Methods and Uses’. In the context of the present invention, the MAGEB2:MHC complex is over-presented on the cell surface of a MAGEB2:MHC complex presenting cell, compared to levels of said complex on the surface of cells in normal (healthy) tissue (also referred to as “healthy cells”) or on the surface of control cells loaded with a different antigen presenting peptide or no peptide. By "over-presented" is meant that the MAGEB2:MHC complex is present at a level at least 2- fold, preferably between 5-fold to 10-fold of the level present in healthy tissue or control cells. For example, GVYDGEEHSV (SEQ ID NO: 1) was found over-presented in cancers, as disclosed in US20160250307, US20170165337, and US20170253633, respectively; the contents of which are hereby incorporated by reference in their entireties).

[0049] The term “immunoglobulin (Ig) domain” in the context of the present invention refers to a protein domain that consists of a 2-layer sandwich of 7-9 antiparallel p-strands arranged in two p-sheets with a Greek key topology. Proteins containing Ig domains are subsumed into the immunoglobulin superfamily, including e.g. antibodies, T cell receptors (TCRs) and cell adhesion molecules. Examples of Ig domains are the variable and constant domains of antibodies and TCRs.

[0050] 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 seguence GVYDGEEHSV (SEQ ID NO: 1), and that polypeptide or the two or more polypeptides comprise(s) the CDRs as herein provided, such as CDRal , CDRa3, and optionally CDRa2, and CDRbl , 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 that comprise fragment(s) of the herein provided TCRs. The herein provided antigen binding proteins may be used in different formats as also described below, such as membrane bound antigen binding proteins, fusion proteins, monovalent, bivalent and multivalent antigen binding proteins, monospecific, bispecific and multispecific antigen binding proteins.

[0051] The antigen binding protein also includes fusion proteins wherein fragment(s) of the herein provided TCRs further comprise other binding domains. The term antigen binding protein 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 CDRs as herein provided, in particular a variable domain VA comprising TCR- derived CDRal , CDRa3, and optionally CDRa2, and a variable domain VB comprising TCR- derived CDRbl , CDRb3, and optionally CDRb2. Antigen binding proteins of the invention comprise a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, e.g. on a first polypeptide, and a variable domain VB comprising CDRbl , CDRb2, and CDRb3, e.g. on a second polypeptide. In a particular embodiment, the entire A domain and / or the entire VB domain are TCR-derived and are thus TCR alpha, beta, gamma or delta variable domains (Va, Vp, VYor Vs). In preferred embodiments, the antigen binding protein is a TCR or functional fragment(s) thereof, e.g., the variable domains VA and VBof the TCR.

[0052] “VA” or Vain 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 a-chain (Va), p- chain (Vp), y-chain (VY) or b-chain (Vs), preferably from a Va. 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 a-chain, p-chain, y-chain or b-chain, or from a variable domain of an antibody, preferably from a variable domain of a TCR a-chain. In the examples, various framework and CDR mutations / substitutions are shown.

[0053] The CDR and framework sequences of the VA domain 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 VA encoded by TRAV5 and TRAJ17, and the acceptor TCR may comprise a VA encoded by TRAV14 and TRAJ33.

[0054] “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 a-chain (Va), p-chain (Vp), y-chain (VY) or b-chain (Vs), preferably from a Vp. 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 a-chain, p-chain, y-chain or b-chain, or from a variable domain of an antibody, preferably from a variable domain of a TCR p-chain. In the examples, various framework and CDR mutations / substitutions are shown.

[0055] The CDR and framework sequences of the VB domain in context of the present invention may not necessarily be derived from the same TCR. For example, the CDRs derived from one TCR variable domain (of the donor TCR) are grafted onto another TCR variable domain (of the acceptor TCR). For example, the donor TCR may comprise a VB encoded by TRBV2 and TRBJ2-1 , and the acceptor TCR may comprise a VB encoded by TRBV27 and TRBJ 1 -5. CDRs may not only be exchanged / grafted between different alpha variable domains or different beta variable domains, but also may be grafted from a TCR alpha to a TCR beta, gamma or delta variable domain, or from a TCR beta to a TCR alpha, gamma or delta variable domain.

[0056] “Vg” in the context of the present invention refers to a variable domain of a TCR a-chain.

[0057] ”Vg” in the context of the present invention refers to a variable domain of a TCR p-chain.

[0058] ’’Vy” in the context of the present invention refers to a variable domain of a TCR y-chain.

[0059] ”Ve” in the context of the present invention refers to a variable domain of a TCR b-chain.

[0060] ”VL” in the context of the present invention refers to a variable domain of an antibody light chain.

[0061] “VH” in the context of the present invention refers to a variable domain of an antibody heavy chain.

[0062] 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 A 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 the structural 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. 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 development of 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, a-chain, constituent of HLA-A. Variation of HLA-A a- 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).

[0063] “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”.

[0064] The term “HLA-A*02” signifies a specific HLA allele, wherein the letter A signifies the allele and “*02” indicates the A2 serotype. “At least one” herein refers to one or more of the specified objects such as 1 , 2, 3, 4, 5 or 6 or more of the specified objects. For example, at least one binding site herein refers to 1 , 2, 3, 4, 5 or 6 or more binding sites.

[0065] The term “TCR” as used herein includes both native and engineered TCRs.

[0066] 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 op and y<5 forms, which are structurally similar but have distinct locations and probably functions. Native, full-length op heterodimeric TCRs consist of an a-chain and a p-chain. The a-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 p-chain comprises a variable region (V region) encoded by a TRBV gene, a joining region (J region) encoded by a TRBJ 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 a-chain and p-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 / ).

[0067] 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 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. Thus, the invention also relates to proteins that may comprise the antigen binding domains (e.g. the CDRs as provided herein) and further comprise domains / amino acid sequences that are not found in the naturally occurring TCR.

[0068] On the protein level, TCR a-, p-, y- and b-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 (Vaand Vp in op TCRs and VYand Vs in yb TCRs) contain highly polymorphic loops comprising the complementarity determining regions (CDRs).

[0069] 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, CDRal , CDRa2 and CDRa3 denote a-chain CDRs, and CDRbl , CDRb2 and CDRb3 denote p-chain CDRs. The sequences encoding CDRal and CDRa2 are comprised in TRAV, the sequences encoding CDRa3 are comprised in TRAV and TRAJ, the sequences encoding CDRbl 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.

[0070] “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 a-, p-, y- and b-chain variable domains each have four FRs, herein designated FR1-a, FR2-a, FR3-a, FR4-a (for an a- or y-chain), and FR1-b, FR2-b, FR3-b, FR4-b (for a p- or b-chain), respectively. Accordingly, an a-chain or y-chain variable domain may be described as (FR1-a)-(CDRa1)-(FR2-a)-(CDRa2)-(FR3-a)-(CDRa3)-(FR4-a) and a p- or b-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 a- , p, y- or b-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 Va is given in analogy to the IMGT numbering of TRAV24*01 and / or the IMGT position of the CDR / FR amino acid positions of the variable domain Vp is given in analogy to the IMGT numbering of TRBV12-3*01.

[0071] An “engineered TCR” may be a protein resembling a native TCR, but comprising further modifications e.g. in the variable and / or constant domains compared to the naturally occurring sequence, e.g. a humanized TCR or a TCR with altered characteristics (e.g. altered binding, heterodimerization or expression level).

[0072] “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 parental TCR from which it is derived for a target antigen. “Parental TCR” in this context refers to a full length TCR from which a functional fragment may be derived.

[0073] 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 have to be interspersed with framework regions (FRs), however the specific amino acid sequences of the framework regions are not directly involved in target antigen specificity. Examples of functional TCR fragments include single variable domains, such as TCR alpha, beta, gamma or delta variable domains, or fragments of the a, p, 5 or y chain, such as an a, p, 5 or y chain without transmembrane domain and short cytoplasmic tail. The term “fragment” as used herein refers to naturally occurring fragments (e.g. splice variants or peptide fragments) as well as artificially constructed fragments, in particular to those obtained by gene-technological means.

[0074] A functional fragment of a TCR is considered to 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.

[0075] A functional fragment of a TCR may 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.

[0076] “Does not significantly bind” in the context of antigenic peptide variants and in the context of antigen binding proteins of the invention, denotes, typically, a functional avidity was determined for the antigen binding protein binding to an antigenic peptide variant 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 functional avidity obtained for binding to the MAGEB2 peptide consisting of the amino acid sequence of SEQ ID NO: 1 , preferably in the same experimental conditions. For instance, the functional avidity obtained for the antigen binding protein binding to the similar peptide, e.g. SEQ ID NO: 130 (SP-02-1622) is not higher than 30% of the signal obtained in the same experimental conditions for the antigen binding protein binding to the MAGEB2 peptide consisting of the amino acid sequence of SEQ ID NO: 1 . The skilled person knows how to determine whether an antigen binding protein does not significantly bind to an antigenic peptide. An exemplary method is herein disclosed below and exemplified in the appended examples.

[0077] The terms “a / P TCR” or a ”y / 6 TCR” refer to a TCR comprising an a-chain and a p-chain as described above, or a y-chain and a b-chain, respectively. Such a TCR may also be described as “full length TCR” or “conventional TCR”. An a / TCR or a y / 6 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.

[0078] “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.

[0079] 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.

[0080] 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 (A) and kappa (K). 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 (also referred 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 (CHI, CH2 and 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).

[0081] 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 CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, 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)-(CDR1-L)-(FR2- L)-(CDR2-L)-(FR3-L)-(CDR3-L)-(FR4-L) and the heavy chain variable domain may be described as (FR1-H)-(CDR1-H)-(FR2-H)-(CDR2-H)-(FR3-H)-(CDR3-H)-(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 in a TCR is determined based on IMGT definition (Lefranc et al., Dev. Comp. Immunol., 2003, 27(1):55- 77; www.imgt.org). Accordingly, amino acid sequences of the CDR1 , CDR2 and CDR3 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 IMGT definition in the herein provided disclosure.

[0082] Knowing the amino acid sequence of the CDRs an antigen binding protein of the invention, e.g., a TCR, one skilled in the art can easily determine the framework regions, such as the TCR 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 and then determine the amino acid sequences of the framework regions. 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, or multispecific), and the order and orientation of variable domains (e.g. cross-over, parallel).

[0083] 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 CH and CL domains. 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 nonsurface 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 the epitope 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 A1 (the content of which is incorporated by reference in its entirety) (W02009032661A1) and is exemplified in the following applying the 4D humanization to humanize the rat antibody variable light (VL) and heavy (VH) domains. For chimeric antibodies, humanization typically involves modification of the framework regions of the variable region sequences.

[0084] The term “percentage of identity” indicates a quantitative measure of the degree of homology between two sequences, which in the context of the present invention are amino acid sequences. If the two sequences to be compared are not of equal length, they must be aligned to give the best possible fit, allowing the insertion of gaps or alternatively, truncation at the ends of the nucleic acid sequences or amino acid sequences. The skilled person will acknowledge that various means for comparing sequence identity are available (see below).

[0085] For example, in the context of the present application, a sequence that is “at least 85% identical to a reference sequence” is a sequence having, over its entire length, 85%, or more, in particular 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the entire length of a reference sequence (e.g., a variable domain disclosed herein). Proteins consisting of an amino acid sequence “at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% Identical” to a reference sequence may comprise mutations such as deletions, insertions and / or substitutions compared to the reference sequence. In case of substitutions, the protein consisting of an amino acid sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a reference sequence may correspond to a homologous sequence derived from another species than the reference sequence.

[0086] In the context of the present application, the “percentage of identity” can be calculated using a global pairwise alignment (i.e. the two sequences are compared over their entire length). Methods for comparing the identity of two or more sequences are well known in the art. For example, the “needle” program, which uses the Needleman-Wunsch global alignment algorithm (Needleman and Wunsch, 1970 J. Mol. Biol. 48:443-453) to find the optimum alignment (including gaps) of two sequences when considering their entire length, may be used. The needle program is for example available on the ebi.ac.uk World Wide Web site and is further described in the following publication (EMBOSS: The European Molecular Biology Open Software Suite (2000) Rice, P. Longden, I. and Bleasby, A. Trends in Genetics 16, (6) pp. 276-277). The percentage of identity between two polypeptides, in accordance with the invention, is calculated using the EMBOSS: needle (global) program with a “Gap Open” parameter equal to 10.0, a “Gap Extend” parameter equal to 0.5, and a Blosum62 matrix.

[0087] “Amino acid mutations” may be deletions, insertions or substitutions.

[0088] “Amino acid substitutions” may be conservative or non-conservative. In an embodiment, substitutions are conservative substitutions, in which one amino acid is substituted for another amino acid with similar structural and / or chemical properties. An amino acid substitution may also be a post-translational modification of the antigen binding protein and is herein also encompassed. In one embodiment, a conservative amino acid substitution may include the substitution of an amino acid by another amino acid of the same class, for example, (non-polar amino acids substituted by other non-polar amino acids.

[0089] In another embodiment, conservative substitutions may be made in accordance with T able 1. Methods for predicting tolerance to protein modification may be found in, for example,

[0090] Guo et al., Proc. Natl. Acad. Sci., USA, 101 (25):9205-9210 (2004), the contents of which are incorporated by reference in their entirety.

[0091] Table 1. Conservative Amino Acid substitutions

[0092] The antigen binding proteins of the present invention can comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such synthetic amino acids are known in the art, and may include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4- chlorophenylalanine, 4-carboxyphenylalanine, p-phenylserine p-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N'-benzyl-N'-methyl-lysine, N',N'-dibenzyl-lysine, 6-hydroxylysine, ornithine, a- aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a- aminocycloheptane carboxylic acid, a-(2-amino-2-norbornane)-carboxylic acid, a,y- diaminobutyric acid, a,p-diaminopropionic acid, homophenylalanine, and a-tert-butylglycine.

[0093] The antigen binding protein or the nucleic acid(s) encoding the antigen binding protein of the present invention can be recombinant, isolated, engineered and / or purified.

[0094] 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.

[0095] By "purified" is meant, when referring to a polypeptide, e.g. to the antigen binding protein of the invention) or a nucleotide sequence, e.g. encoding antigen binding proteins or functional fragment thereof described herein, that the indicated molecule is present in the substantial absence of other biological macromolecules of the same type. The term "purified" as used herein in particular means that at least 75%, 85%, 95%, or 98% by weight, of biological macromolecules of the same type are present. The term "purified" as used herein may further indicate that the antigen binding protein is free from DNA, RNA, proteins, polypeptides or cells that would interfere with its therapeutic, diagnostic, prophylactic, research or other use.

[0096] A purified nucleic acid molecule that encodes a particular polypeptide refers to a nucleic acid molecule that is substantially free of other nucleic acid molecules that do not encode the subject polypeptide; however, the molecule may include some additional bases or moieties, which do not deleteriously affect the basic characteristics of the composition.

[0097] 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. A "recombinant" molecule is one that has been prepared, expressed, created, or isolated by recombinant means. Recombinant molecules do not exist in nature. Accordingly, “recombinant” refers to a polypeptide or protein molecule which is made using recombinant techniques, i.e., which is not naturally occurring. Methods and techniques for the production of recombinant nucleic acids and polypeptides are well known in the art.

[0098] The term "gene" means a DNA sequence that codes for, or corresponds to, a particular sequence of amino acids which comprises all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed. Some genes, which are not structural genes, may be transcribed from DNA to RNA, but are not translated into an amino acid sequence. Other genes may function as regulators of structural genes or as regulators of DNA transcription. In particular, the term gene may be intended for the genomic sequence encoding a protein, i.e. a sequence comprising regulator, promoter, intron and exon sequences.

[0099] “Affinity” is defined, in the context of the present invention by the equilibrium binding between the antigen binding protein and its antigen, namely the MAGEB2 peptide in a complex with a MHC protein. Affinity is usually expressed as equilibrium dissociation constant (KD).

[0100] “Kp” is the equilibrium dissociation constant, a ratio of k off / kon, between the antigen binding protein and its antigen. KD and affinity are inversely related. The KD value relates to the concentration of the antigen binding protein and the lower the KD value, the higher the affinity of the antigen binding protein. The KD value can be experimentally assessed by a variety of known methods, such as measuring association and dissociation rates with surface plasmon resonance (SPR) or bio-layer interferometry (BLI). For example, the antigen binding protein can be produced as soluble molecule, for instance, by removing the transmembrane domain and introducing an artificial disulfide bridge (Boulter et al. 2003; Stable, soluble T-cell receptor molecules for crystallization and therapeutics; Protein Engineering vol. 16 no. 9 pp. 707-711) or dimerization via a leucin zipper domain. (Willcox et al. 1999; TCR Binding to Peptide-MHC Stabilizes a Flexible Recognition Interface; Immunity, Vol. 10, 357-365). Binding interactions can be measured at a broad range of settings, including, but not limited to, a temperature range of 25°C to 37°C and a shake speed range of 500 rpm to 1500 rpm using a suitable buffer that minimizes nonspecific binding and maintains protein stability. Examples of such buffers are phosphate buffered saline (PBS), Tris buffered saline (TBS), HEPES buffered saline (HBS), or other physiological buffers, with or without additives such as Tween, BSA, DMSO, or EDTA. The analyte can be immobilized on various sensors at a concentration range, including, but not limited to, 1 pg / ml to 100 pg / ml for a duration range of 30 s to 300 s. KD determination can be measured at various molarities of the analyte sample for detecting potential off-target reactivities with high sensitivity. Exemplary determination of the KD is herein provided in the Examples. For example the KD may be determined by the following bio-layer interferometry (BLI) method: using a 384-well tilted bottom microplate, black and loading with 50 pg / ml pMHC (100 pl / well). The antigen binding protein can then be added, e.g. as soluble TCR in 7 concentrations as well as a reference well (only HEPES / Tween): 50 pM; 25 pM; 12,5 pM; 6,25 pM; 3,1 pM; 1 ,6 pM; 0,8 pM with 60 pl / well. The association of off-target TCRs can be against NYESO1-001 at 25pM TCR concentration. Then, the dissociation of soluble TCR can be 100 pl / well HEPES / Tween. The measurements can be conducted by 16 streptavidin sensors: duplicates measured with different sensors (sensor offset: 3).

[0101] “Functional avidity” is defined, in the context of the present invention, as a parameter that describes the capability of an antigen binding protein to activate an effector cell, preferably a T cell, upon binding to its target antigenic peptide in a complex with MHC. The activation of the effector cell, preferably T cell, can be measured in a functional assay, e.g., a cytokine production assay or a cytotoxicity assay as described below. In some embodiments, the functional avidity of an antigen binding protein is considered high if the ECso determined in a functional assay is low, such as less than about 50 nM, less than about 20 nM, or less than about 5 nM in a cytotoxicity assay as described below, and / or the activity determined in a functional assay is high, such as 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 a maximal activity defined in the respective functional assay. Depending on the functional assay, the maximal activity may be the activity of a reference protein with known high functional avidity or the activity of a “maximum lysis control” as described below.

[0102] “Efficacy” is defined, in the context of the present invention, as a parameter that describes the capability of an antigen binding protein to activate an effector cell, preferably a T cell, to kill a cancer cell presenting on its surface the target antigenic peptide in a complex with MHC. The efficacy can be determined in a functional assay, for example a live-cell monitoring cytotoxicity assay as described below.

[0103] In a “functional assay”, an antigen binding protein is, for example, expressed in an “effector cell (E)”, and the effector cell is co-cultured with “target cells (T)”, i.e. with antigen presenting cells presenting a peptide:MHC complex. Functional assays can thus also be described as “co-culture assays”. For all cell culture assays described herein, the cell culture temperature preferably is at about 37°C. Preferably, the effector cell is a T cell. The target cells may be cells that are artificially loaded with the antigenic peptide (e.g. T2 cells) or may be cells that endogenously present the target antigenic peptide on their surface (e.g. cancer cells expressing MAGEB2). Binding of the antigen binding protein to the peptide: MHC complex leads to activation of the effector cell. Depending of the type of functional assay, there are different readouts for measuring the degree of activation. In a cytokine production assay or cytokine release assay, such as an ELISA, the production of cytokines (e.g. TNF-a, IFN-y, CD107a+, IL-2 and / or Granzyme B) by the effector cells is determined. In a cytotoxicity assay, the killing of target cells by the effector cells is determined, e.g. by measuring a decline in proliferation of target cells, in particular cancer cells or by measuring the release of intracellular proteins from the target cells. Suitable intracellular proteins to be measured in a cytotoxicity assay can be endogenous proteins, e.g. LDH release assay.

[0104] In the context of the present invention, the term “T2 cell” refers to a cell that expresses an MHCI molecule (HLA-A2) that lacks TAP function. T2 cells can be easily artificially loaded with different concentrations of exogenous antigenic peptides. T2 cell are described e.g. in (Hosken and Bevan, Science 1990 Apr 20;248(4953):367-70). T2 cells are commercially available, e.g. from ATCC (American Type Culture Collection). Loading of T2 cells can be achieved under standard cell culture conditions known to the skilled in the art by incubating the T2 cells for about 2 hours with a desired concentration of antigenic peptide. In the context of the present invention, T2 cells that are incubated with a certain concentration of antigenic peptide, such as 1 pM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 1 pM, are referred to as T2 cells loaded with said concentration of antigenic peptide, e.g. T2 cells incubated with 10 pM of antigenic peptide are referred to as T2 cells loaded with 10 pM of antigenic peptide.

[0105] The term “E:T ratio” refers to the ratio of effector cells (i.e. immune cells, in particular T cells, expressing the antigen binding protein, in particular the TCR) 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, in particular T cells, to target cells. In some embodiments, the E:T ratio is lower than the seeding ratio. This applies to cases where not all immune cells express the antigen binding protein, i.e. not all immune cells are effector cells, for example due to a low electroporation efficiency. In some embodiments, the seeding ratio is used as approximation of the E:T ratio. In some embodiments, the E:T ratio is determined by adjusting the seeding ratio taking into account the electroporation efficiency.

[0106] 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%.

[0107] In an example of a cytokine production assay and cytokine release assay, the effector cells are immune cells. These effector cells are co-cultured with cells (either target cells, e.g. tumor / cancer cells, or peptide loaded cells, e.g. T2 cells) with different expression of the antigenic peptide in complex with MHC, such as an HLA protein, for instance HLA-A*02. An exemplary cytokine release assay is herein disclosed in the Examples. Preferably, the effector cells and the target cells are seeded, e.g. at a ratio between 10:1 and 1 :1. For the cytokine release assay, after a defined time of co-culture, e.g. 24-48 hours, preferably about 48 hours, the supernatants of the co-culture (effector cells + target cells) are collected and subjected to a cytokine release ELISA assay, for example IFN-gamma, TNF alpha, IL-2 and Granzyme B, to determine the amount of cytokine released by the effector cells. In order to determine the efficacy, a cytokine production assay can be applied using target cells, e.g. tumor or cancer cells. Alternatively, the killing of a target cell / cancer cell / tumor cell can be determined in e.g. an LDH assay or a live cell imaging assay. The efficacy of an antigen binding protein may be considered high if the antigen is capable of activating effector cells in a cytokine production assay, in particular if the amount of produced cytokines upon co-culture with target cells is at least about 100 pg / ml, at least about 300 pg / ml, preferably at least about 500 pg / ml, more preferably at least about 1000 pg / ml.

[0108] “Half maximal effective concentration” also called “ECso”, typically refers to the concentration of a molecule, which induces a response halfway between the baseline and maximum after a specified exposure time. The lower the ECso value, the higher the functional avidity of the molecule. EC50 values can be experimentally assessed by a variety of known methods, for example using the functional assays described above or other ELISA- or killing assays.

[0109] To determine the EC50 in a functional assay as described above, different concentrations of antigenic peptide loaded on antigen presenting cells, such as T2 cells have to be used in a “peptide titration experiment”. In particular embodiments, the “EC50” refers to the concentration of the antigenic peptide loaded on target cells, in particular T2 cells loaded with the MAGEB2 antigenic peptide, which induces a response halfway between the baseline and maximum, when said target cells are co-cultured with effector cells in a cytokine release assay. The functional avidity of an antigen binding protein is considered high (as shown in the appended examples) if the EC50 determined in a cytokine release assay, preferably a IFN- gamma ELISA as shown in the Examples, is less than about 60 nM, less than about 50 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 2.5 nM, less than about 1.5 nM or less than about 1 nM, even more preferably if the ECso determined is less than about 100 nM to about 50 pM.

[0110] A “dextramer staining” involves contacting cells expressing an antigen binding protein with fluorescently labelled multimers comprising ten MAGEB2:MHC complexes.

[0111] 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 CDRal , CDRa3, CDRbl and CDRb3. The amino acid sequences of CDRa2 and CDRb2 contact the MHC molecule and are not required for antigen specificity.

[0112] In the context of the present invention “similar peptides” herein refers to potential off- target peptides, i.e. peptides that may potentially be bound by the antigen binding proteins of the invention based on their biochemical / biophysical characteristics, including but not limited to a homologous sequence or a similar motif. Similar peptides comprise typically 8 to 12 amino acids in length. The similar peptides in the context of the present invention are typically MHC, in particular MHC I, presented. Furthermore, similar peptides in the context of the present invention include peptides that comprise or consist of an amino acid sequence that is similar to the amino acid sequence of the MAGEB2 antigenic peptide, more particular, peptides that, in comparison to the epitope of the MAGEB2 antigenic peptide, comprise an epitope wherein some or all amino acids have identical and / or similar biochemical / biophysical characteristics as the amino acids that constitute the epitope of the MAGEB2 antigenic peptide. In some examples, similar peptides investigated in the context of the present invention were selected from a database of tumor and normal tissue-presented HLA-A*02 bound peptides (XPRESIDENT® database) using a similarity scoring within the bindingrelevant positions of MAGEB2 and the requirement of at least one detection on normal tissues. Binding of an antigen binding protein to a similar peptide presented by an MHC protein may lead to adverse reactions. Such adverse reactions may be “off-tumor” side effects, such as cross-reactivity of a specific TCR with a similar peptide in healthy tissues as reported in Lowdell et al., Cytotherapy, published on December 4, 2018).

[0113] In particular, the following peptides are similar peptides in the context of the present invention: SEQ ID NOs: 129-137.

[0114] The skilled person is aware that among the similar peptides, there are some that are not bound by the antigen binding proteins of the invention to a detectable degree, e.g. peptides for which no binding signal during affinity determination or no response in a functional assay beyond the background level is detectable. “Background level” in this context refers to a response in a functional assay observed for the co-culture of target cells and effector cells at the respective E:T ratio without the addition of bispecific TCR-antibody fusion protein.

[0115] For other similar peptides, a low, but non-significant binding may be detectable. These latter similar peptides may also be described as "potentially relevant" similar peptides. An antigen binding protein is considered to not significantly bind to a similar peptide and to be specific for its target antigenic peptide if at least one of the following applies when binding to the similar peptide and the target antigenic peptide is compared under similar, preferably identical experimental conditions:

[0116] The functional avidity in response to the similar peptide, determined in a functional assay as described above, is 25% or less, 20% or less, 15% or less, 10% or less of the functional avidity in response to the target antigenic peptide MAGEB2.

[0117] The cytotoxic activity in response to the similar peptide, determined in a cytotoxicity assay as described above, is 25% or less, 20% or less, 15% or less, 10% or less of the cytotoxic activity in response to the target antigenic peptide MAGEB2.

[0118] The ECso of the similar peptide, determined in a functional assay, preferably a cytotoxicity assay, as described above, is increased by a factor of at least 50, at least 100, at least 200 or at least 500, compared to the EC50 of the target antigenic peptide MAGEB2.

[0119] The KD for the similar peptide is increased by a factor at least 25, at least 30, at least 40, at least 50, at least 75, or at least 100, compared to the KD for the target antigenic peptide MAGEB2. The relative response signal for the similar peptide is not higher than 30%, not higher than 25%, not higher than 20%, or not higher than 15%, compared to the response signal to the target antigenic peptide.

[0120] “Copy number” herein refers to the number of MAGEB2 / MHC complexes as defined in the context of the present invention that are present on the cell surface of a cell, such as a MAGEB2 / MHC presenting cell, for example a cancer cell, or a healthy cell. Copy numbers of a protein can be determined by a variety of art known methods including FACS analysis of diseased cells with fluorescently labelled antigen binding proteins.

[0121] “Safety profile” herein refers to the capacity to distinguish tumor cells from healthy tissue cells and this is often determined by determining the safety window.

[0122] The “safety window” or “therapeutic window” herein refers to a factor that compares the half maximal concentration of a compound that is required for inducing 100% cytotoxicity in a tumor cell line in comparison to the half maximal concentration of a compound that is required for inducing 100% cytotoxicity healthy tissue cells. If for an antigen binding protein of interest the ECso determined for a tumor cell line is 1 pM and the ECso value determined for, for instance, primary cells is 1000 pM then the safety window is 1000 since the EC50 for the tumor cell line is 1000 times smaller than the ECso for the primary cells.

[0123] The term “nucleic acid” refers in the context of this invention to single or double-stranded oligo- or polymers of deoxyribonucleotide or ribonucleotide bases or both. Nucleotide monomers are composed of a nucleobase, a five-carbon sugar (such as but not limited to ribose or 2'-deoxyribose), and one to three phosphate groups. Typically, a nucleic acid is formed through phosphodiester bonds between the individual nucleotide monomers, In the context of the present invention, the term nucleic acid includes but is not limited to ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) molecules but also includes synthetic forms of nucleic acids comprising other linkages (e.g., peptide nucleic acids as described in Nielsen et al. (Science 254:1497-1500, 1991). Typically, nucleic acids are single- or double-stranded molecules and are composed of naturally occurring nucleotides. The depiction of a single strand of a nucleic acid also defines (at least partially) the sequence of the complementary strand. The nucleic acid may be single or double stranded or may contain portions of both double and single stranded sequences. Exemplified, double-stranded nucleic acid molecules can have 3‘ or 5‘ overhangs and as such are not required or assumed to be completely double-stranded over their entire length. The term nucleic acid comprises chromosomes or chromosomal segments, vectors (e.g., expression vectors), expression cassettes, naked DNA or RNA polymer, primers, probes, cDNA, genomic DNA, recombinant DNA, cRNA, mRNA, tRNA, microRNA (miRNA) or small interfering RNA (siRNA). A nucleic acid can be, e.g., single-stranded, double-stranded, or triple-stranded and is not limited to any particular length. Unless otherwise indicated, a particular nucleic acid sequence comprises or encodes complementary sequences, in addition to any sequence explicitly indicated.

[0124] In preferred embodiments, the nucleic acid is an isolated nucleic acid. In preferred embodiments, the nucleic acid is a recombinant nucleic acid.

[0125] The nucleic acids may be present in whole cells, in a cell lysate, or may be nucleic acids in a partially purified or substantially pure form. A nucleic acid is "isolated" or "rendered substantially pure" when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques.

[0126] The terms "vector", "cloning vector" and "expression vector" refers to a vehicle by which a DNA or RNA sequence (e.g. a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g. transcription and translation) of the introduced sequence. A “vector” may also be referred to as a “genetic construct” herein.

[0127] The term “viral vector” refers to a nucleic acid vector construct that includes at least one element of viral origin and has the capacity to be packaged into a viral vector particle and encodes at least an exogenous nucleic acid. The vector and / or particle can be utilized for the purpose of transferring a nucleic acid of interest into cells either in vitro or in vivo. Numerous forms of viral vectors are known in the art. Useful viral vectors include vectors based on retroviruses, lentiviruses, adenoviruses, adeno-associated viruses, herpes viruses, vectors based on SV40, papilloma virus, Epstein Barr virus, vaccinia virus vectors, and Semliki Forest virus (SFV). Recombinant viruses may be produced by techniques known in the art, such as by transfecting packaging cells or by transient transfection with helper plasmids or viruses. Typical examples of virus packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells, etc. Detailed protocols for producing such replication-defective recombinant viruses may be found for instance in WO 95 / 14785, WO 96 / 22378, US 5,882,877, US 6,013,516, US 4,861 ,719, US 5,278,056 and WO 94 / 19478.

[0128] The term "transformation" means the introduction of a "foreign" (i.e. extrinsic) gene, DNA or RNA sequence to a host cell, so that the host cell will express the introduced gene or sequence to produce a desired substance, typically the antigen-binding protein or functional fragment thereof described herein. A host cell that receives and expresses introduced DNA or RNA bas been "transformed".

[0129] The term "expression system" means a host cell and compatible vector under suitable conditions, e.g. for the expression of a protein coded for by foreign DNA carried by the vector and introduced to the host cell.

[0130] A “host cell” is a cell that can be used to express a nucleic acid, e.g., a nucleic acid disclosed herein. The host cell may be transfected, infected or transduced or transformed, in particular with nucleic acid(s) and / or a vector(s) according to the invention. The terms "pharmaceutical composition" or "therapeutic composition" as used herein refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a subject.

[0131] The terms “subject” or “individual” are used interchangeably and include all mammals, preferably humans. In some embodiments, the subject to be treated may also be referred to as “patient”.

[0132] A “therapeutic agent” herein refers to an agent that has a therapeutic effect. In one embodiment, such a therapeutic agent may be a growth inhibitory agent, such as a cytotoxic agent or a radioactive isotope.

[0133] A "growth inhibitory agent", or “anti-proliferative agent”, which can be used indifferently, refers to a compound or composition which inhibits growth of a cell, especially a tumor cell, either in vitro or in vivo.

[0134] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells. The term "cytotoxic agent" is intended to include chemotherapeutic agents, enzymes, antibiotics, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof, and the various antitumor or anticancer agents disclosed below. In some embodiments, the cytotoxic agent is a taxoid, vincas, taxanes, a maytansinoid or maytansinoid analog such as DM1 or DM4, a small drug, a tomaymycin or pyrrolobenzodiazepine derivative, a cryptophycin derivative, a leptomycin derivative, an auristatin or dolastatin analog, a prodrug, topoisomerase II inhibitors, a DNA alkylating agent, an anti-tubulin agent, a CC-1065 or CC-1065 analog.

[0135] The term “radioactive isotope” is intended to include radioactive isotopes suitable for treating cancer, such as At211, Bi212, Er169, I131, I125, Y90, In111, P32, Re186, Re188, Sm153, Sr89, and radioactive isotopes of Lu. Such radioisotopes generally emit mainly beta-radiation. In an embodiment the radioactive isotope is alpha-emitter isotope, more precisely Thorium 227 which emits alpha-radiation.

[0136] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier refers to a non-toxic solid, semi-solid or liguid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0137] A “pharmaceutically acceptable carrier” and may include solvents, bulking agents, stabilizing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are physiologically compatible. In one embodiment the carrier is an agueous carrier. In some embodiments, the agueous carrier is capable of imparting improved properties when combined with an antigen binding protein described herein, for example, improved solubility, efficacy, and / or improved immunotherapy.

[0138] In the context of the invention, the terms "treating" or "treatment", include both therapeutic treatment (i.e. on a subject having a given disease) and / or preventive or prophylactic treatment (i.e. on a subject susceptible of developing a given disease). Therapeutic treatment and means reversing, alleviating and / or inhibiting the progress of one or more symptoms of a disorder or condition. Prophylactic treatment means preventing the occurrence of one or more symptoms of a disorder or condition. Therefore, treatment does not only refer to a treatment that leads to a complete cure of the disease, but also to treatments that slow down the progression of the disease, prevent or delay the occurrence of the disease and / or prolong the survival of the subject.

[0139] By a "therapeutically effective amount" of the antigen binding protein or pharmaceutical composition thereof is meant a sufficient amount of the antigen binding protein to treat said proliferative disease, at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the antigen binding proteins, the nucleic acid or vector, the host cell or the pharmaceutical composition of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific antigen binding protein employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific polypeptide employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[0140] In one embodiment, a "disease" or "disorder" is any condition that would benefit from treatment with the antigen binding protein of the invention. In one embodiment, this includes chronic and acute disorders or diseases including those pathological conditions which predisposes the subject to the disorder in question. The term “in need of treatment” refers to a subject already having the disorder as well as a subject in which the disorder is to be prevented.

[0141] “Proliferative diseases”, such as cancer, involve the unregulated and / or inappropriate proliferation of cells. A cancer is considered to be a “MAGEB2-expressinq cancer” (also referred to as MAGEB2 “positive” cancer), if the related peptide, such as, for example the MAGEB2 antigenic peptide of SEQ ID NO: 1 , is over-presented in patient cancer cells as defined herein. In all other indications named here a biopsy can be performed as it is standard in the treatment of these cancers and the peptide can be identified according to the XPresident® and related methods (according to WO 03 / 100432; WO 2005 / 076009; WO 2011 / 128448; WO 2016 / 107740, US 7,811 ,828, US 9,791 ,444, and US 2016 / 0187351 , the contents of each are hereby incorporated by reference in their entirety). In one embodiment, the cancer is readily assayed (i.e. diagnosed) for instance by using an antigen binding protein of the invention. Methods to identify an antigen expressing cancer using an antigen binding protein are known to the skilled in the art. It is to be understood that the terms “cancer” and “carcinoma” are not used interchangeably herein since a carcinoma is a specific type of cancer emerging in the skin or in tissues that line or cover body organs.

[0142] As used herein, the term “adoptive cell therapy” (“ACT”) is a type of immunotherapy in which T cells are administered to a patient to treat a disease, in this case cancer. In autologous ACT, T cells that have been extracted from a patient are cultured in vitro and are typically genetically modified to improve TCR function and are then returned to the same patient for therapy. Comparatively, allogeneic ACT involves T cells isolated and expanded from a donor or donors different from the patient receiving the T cells for therapy.

[0143] The terms “first container” and “second container” refer to the chambers of a multichambered pre-filled syringe (e.g., lyosyringes).

[0144] The term “diagnostic agent” as used herein refers to a detectable molecule or substance, such as a fluorescent molecule, a radioactive molecule or any other labels known in the art that provide (either directly or indirectly) a signal.

[0145] “Fluorescent molecules” are known in the art include fluorescein isothiocyanate (FITC), phycoerythrin (PE), fluorophores for use in the blue laser (e.g. PerCP, PE-Cy7, PE-Cy5, FL3 and APC or Cy5, FL4), fluorophores for use in the red, violet or uv laser (e.g. Pacific blue, pacific orange).

[0146] “Radioactive molecules” include but are not limited radioactive atom for scintigraphic studies such as 1123, 1124, In111 , Re186, Re188, Tc99. Antigen-binding proteins of the invention may also comprise a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, indium-111 , fluorine- 19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

[0147] Such diagnostic agents are may be either directly coupled (i.e., physically linked) to the antigen-binding protein or may be indirectly linked. In the context of the present specification, the term “about” or "approximately" when referring to a specific value is meant to indicate that the value may deviate by ±20%, ±15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2% or ± 1 %. It also includes the concrete value, e.g., "about 50" includes the value "50".

[0148] Throughout the instant application, the term “and / or” is a grammatical conjunction that is to be interpreted as encompassing that one or more of the cases it connects may occur.

[0149] Furthermore, throughout the instant application, the term “comprising” is to be interpreted as encompassing all specifically mentioned features as well optional, additional, unspecified ones. As used herein, the use of the term “comprising” also discloses the embodiment wherein no features other than the specifically mentioned features are present ( / .e. “consisting of”'). Accordingly, both meanings are specifically intended, and hence individually disclosed, embodiments according to the present invention.

[0150] Furthermore, the indefinite article "a or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Accordingly, the articles “a” and “an” preceding an element or component are intended to be non-restrictive regarding the number of instances (i.e., occurrences) of the element or component. Therefore, “a” or “an” is to be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0151] The terms “of the invention” or “according to the invention” as used herein are intended to refer to all aspects and embodiments of the invention disclosed and / or claimed herein. Any aspects, items or embodiments referred to herein as being “disclosed herein” or “described herein” are to be understood as being aspects, items or embodiments “of the invention” or “according to the invention”.

[0152] The invention will now be described in more details with reference to the following figures and examples. All literature and patent documents cited herein are hereby incorporated by reference. While the invention has been illustrated and described in detail in the foregoing description, the examples are to be considered illustrative or exemplary and not restrictive.

[0153] Antigen Binding Proteins

[0154] 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 seguence GVYDGEEHSV (SEQ ID NO: 1), wherein the antigen binding protein comprises a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3 as provided herein, and comprises a variable domain B comprising CDRbl , CDRb2, and CDRb3 as provided herein. For example, the antigen binding protein comprises:

[0155] CDRal comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs: 2, 3, 4, 5, and 6, CDRa3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs: 7, 8, 9, 10, 11 , 12, 13, and 14, CDRbl comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs: 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, and 25, and CDRb3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs: 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , and 52; wherein the CDRal , CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations. In another embodiment, the CDRal , CDRa3, CDRbl and / or CDRb3 sequence(s) may each comprise at most one, at most two or at most three amino acid mutations.

[0156] In some embodiments of the antigen binding protein, CDRa2 comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, and 81 , and CDRb2 comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, and 96; 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.

[0157] In another aspect, the present 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 VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, and a second polypeptide comprising a variable domain VB comprising CDRbl , CDRb2, and CDRb3; wherein

[0158] (1) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0159] (2) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0160] (3) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, and CDRb3 comprises SEQ ID NO: 26; (4) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, and CDRb3 comprises SEQ ID NO: 26;

[0161] (5) CDRal comprises SEQ ID NO: 3, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, and CDRb3 comprises SEQ ID NO: 27;

[0162] (6) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, and CDRb3 comprises SEQ ID NO: 28;

[0163] (7) CDRal comprises SEQ ID NO: 4, CDRa3 comprises SEQ ID NO: 11, CDRbl comprises SEQ ID NO: 20, and CDRb3 comprises SEQ ID NO: 29;

[0164] (8) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21 , and CDRb3 comprises SEQ ID NO: 30;

[0165] (9) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31 ;

[0166] (10) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, and CDRb3 comprises SEQ ID NO: 31 ;

[0167] (11) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, and CDRb3 comprises SEQ ID NO: 31 ;

[0168] (12) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 32;

[0169] (13) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 33;

[0170] (14) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 34;

[0171] (15) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 35;

[0172] (16) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 36;

[0173] (17) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 37;

[0174] (18) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 38;

[0175] (19) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 39;

[0176] (20) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 40;

[0177] (21) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 41 ; (22) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 42;

[0178] (23) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 43;

[0179] (24) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 44;

[0180] (25) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 45;

[0181] (26) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 46;

[0182] (27) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 47;

[0183] (28) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 48;

[0184] (29) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 49;

[0185] (30) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 50;

[0186] (31) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 51 ; or

[0187] (32) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal , CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0188] In another aspect, the present invention provides an antigen binding protein comprising a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, and a variable domain VB comprising CDRbl , CDRb2, and CDRb3; wherein

[0189] (1) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0190] (2) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0191] (3) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, and CDRb3 comprises SEQ ID NO: 26;

[0192] (4) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, and CDRb3 comprises SEQ ID NO: 26; (5) CDRal comprises SEQ ID NO: 3, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, and CDRb3 comprises SEQ ID NO: 27;

[0193] (6) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, and CDRb3 comprises SEQ ID NO: 28;

[0194] (7) CDRal comprises SEQ ID NO: 4, CDRa3 comprises SEQ ID NO: 11, CDRbl comprises SEQ ID NO: 20, and CDRb3 comprises SEQ ID NO: 29;

[0195] (8) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21 , and CDRb3 comprises SEQ ID NO: 30;

[0196] (9) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31 ;

[0197] (10) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, and CDRb3 comprises SEQ ID NO: 31 ;

[0198] (11) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, and CDRb3 comprises SEQ ID NO: 31 ;

[0199] (12) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 32;

[0200] (13) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 33;

[0201] (14) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 34;

[0202] (15) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 35;

[0203] (16) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 36;

[0204] (17) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 37;

[0205] (18) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 38;

[0206] (19) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 39;

[0207] (20) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 40;

[0208] (21) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 41 ;

[0209] (22) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 42; (23) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 43;

[0210] (24) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 44;

[0211] (25) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 45;

[0212] (26) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 46;

[0213] (27) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 47;

[0214] (28) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 48;

[0215] (29) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 49;

[0216] (30) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 50;

[0217] (31) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 51; or

[0218] (32) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal, CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0219] In preferred embodiments of the antigen binding protein,

[0220] CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0221] CDRal comprises SEQ ID NO: 3, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, and CDRb3 comprises SEQ ID NO: 27;

[0222] CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, and CDRb3 comprises SEQ ID NO: 28;

[0223] CDRal comprises SEQ ID NO: 4, CDRa3 comprises SEQ ID NO: 11 , CDRbl comprises SEQ ID NO: 20, and CDRb3 comprises SEQ ID NO: 29;

[0224] CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21 , and CDRb3 comprises SEQ ID NO: 30;

[0225] CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31; or CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal, CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0226] More preferably,

[0227] CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26; or

[0228] CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31; wherein the CDRal, CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0229] In some embodiments of the antigen binding protein, the CDRal , CDRa3, CDRbl and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRal, CDRa3, CDRbl and CDRb3.

[0230] In some embodiments of the antigen binding protein,

[0231] (1) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0232] (2) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 54, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0233] (3) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 55, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0234] (4) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 56, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0235] (5) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0236] (6) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0237] (7) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26; (8) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 83, and CDRb3 comprises SEQ ID NO: 26;

[0238] (9) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 84, and CDRb3 comprises SEQ ID NO: 26;

[0239] (10) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 85, and CDRb3 comprises SEQ ID NO: 26;

[0240] (11) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 86, and CDRb3 comprises SEQ ID NO: 26;

[0241] (12) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 87, and CDRb3 comprises SEQ ID NO: 26;

[0242] (13) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 57, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0243] (14) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 88, and CDRb3 comprises SEQ ID NO: 26;

[0244] (15) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 89, and CDRb3 comprises SEQ ID NO: 26;

[0245] (16) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 58, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0246] (17) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 59, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0247] (18) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 60, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0248] (19) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 61, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26; (20) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 62, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0249] (21) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 63, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0250] (22) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 64, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0251] (23) CDRal comprises SEQ ID NO: 3, CDRa2 comprises SEQ ID NO: 65, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, CDRb2 comprises SEQ ID NO: 90, and CDRb3 comprises SEQ ID NO: 27;

[0252] (24) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, CDRb2 comprises SEQ ID NO: 91 , and CDRb3 comprises SEQ ID NO: 28;

[0253] (25) CDRal comprises SEQ ID NO: 4, CDRa2 comprises SEQ ID NO: 66, CDRa3 comprises SEQ ID NO: 11, CDRbl comprises SEQ ID NO: 20, CDRb2 comprises SEQ ID NO: 92, and CDRb3 comprises SEQ ID NO: 29;

[0254] (26) CDRal comprises SEQ ID NO: 5, CDRa2 comprises SEQ ID NO: 67, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21, CDRb2 comprises SEQ ID NO: 93, and CDRb3 comprises SEQ ID NO: 30;

[0255] (27) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0256] (28) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 95, and CDRb3 comprises SEQ ID NO: 31 ;

[0257] (29) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 69, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0258] (30) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 70, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0259] (31) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 71, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ; (32) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 72, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0260] (33) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 73, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0261] (34) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0262] (35) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0263] (36) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 32;

[0264] (37) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 33;

[0265] (38) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 34;

[0266] (39) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 74, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0267] (40) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 35;

[0268] (41) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 36;

[0269] (42) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 37;

[0270] (43) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 38; (44) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 39;

[0271] (45) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 40;

[0272] (46) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 41 ;

[0273] (47) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 42;

[0274] (48) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 43;

[0275] (49) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 44;

[0276] (50) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 75, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0277] (51) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 45;

[0278] (52) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 46;

[0279] (53) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 47;

[0280] (54) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 48;

[0281] (55) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 49; (56) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 50;

[0282] (57) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 51 ;

[0283] (58) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 76, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0284] (59) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 77, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0285] (60) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 78, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0286] (61) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 79, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0287] (62) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 80, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0288] (63) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 81, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31; or

[0289] (64) CDRal comprises SEQ ID NO: 5, CDRa2 comprises SEQ ID NO: 67, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, CDRb2 comprises SEQ ID NO: 96, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal, CDRa2, CDRa3, CDRbl, CDRb2 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations. In another embodiment, the CDRal, CDRa2, CDRa3, CDRbl, CDRb2 and / or CDRb3 sequence(s) may each comprise at most one, at most two or at most three amino acid mutations.

[0290] In a preferred embodiment,

[0291] CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26; wherein the CDRal, CDRa2, CDRa3, CDRbl, CDRb2 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0292] In a preferred embodiment,

[0293] CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ; wherein the CDRal, CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0294] In some embodiments of the antigen binding protein, the CDRal, CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRal, CDRa2, CDRa3, CDRbl, CDRb2 and CDRb3.

[0295] In some embodiments of the antigen binding protein, the VA comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 98, 97, 99, 100, 101 , 102, and 103, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 97, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 7, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 98, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 3, 65, and

[0296] 9, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 99, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and

[0297] 10, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 100, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 4, 66, and 11 , respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 101, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 12, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 102, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 6, 68, and 13, respectively, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 103, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 14, respectively, and the VB comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 105, 104, 106, 107, 108, 109, and 110, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 104, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 15, 82, and 26, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 105, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 18, 90, and 27, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 106, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 19, 91 , and 28, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 107, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 20, 92, and 29, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 108, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 21, 93, and 30, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 109, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 22, 94, and 31 , respectively, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 110, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 25, 96, and 52, respectively, wherein optionally the CDRal, CDRa2, CDRa3, CDRbl, CDRb2, and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

[0298] In some embodiments of the antigen binding protein, the CDRal, CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRal, CDRa2, CDRa3, CDRbl, CDRb2 and CDRb3.

[0299] In some embodiments, of the antigen binding protein, the VA comprises an amino acid sequence of SEQ ID NO: 97 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 97, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 7, respectively, and the VB comprises an amino acid sequence of SEQ ID NO: 104 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 104, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 15, 82, and 26, respectively; the VA comprises an amino acid sequence of SEQ ID NO: 98 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 98, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 3, 65, and 9, respectively, and the VB comprises an amino acid sequence of SEQ ID NO: 105 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 105, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 18, 90, and 27, respectively; the VA comprises an amino acid sequence of SEQ ID NO: 99 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 99, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 10, respectively, and the B comprises an amino acid sequence of SEQ ID NO: 106 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 106, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 19, 91 , and 28, respectively; the VA comprises an amino acid sequence of SEQ ID NO: 100 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 100, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 4, 66, and 11 , respectively, and the VB comprises an amino acid sequence of SEQ ID NO: 107 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 107, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 20, 92, and 29, respectively; the VA comprises an amino acid sequence of SEQ ID NO: 101 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 101 , and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 12, respectively, and the VB comprises an amino acid sequence of SEQ ID NO: 108 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 108, and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NOs: 21, 93, and 30, respectively; the VA comprises an amino acid sequence of SEQ ID NO: 102 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 102, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 6, 68, and 13, respectively, and the VB comprises an amino acid sequence of SEQ ID NO: 109 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 109, and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NOs: 22, 94, and 31, respectively; or the VA comprises an amino acid sequence of SEQ ID NO: 103 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 103, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 14, respectively, and the VB comprises an amino acid sequence of SEQ ID NO: 110 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 110, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 25, 96, and 52, respectively; wherein optionally said CDRal , CDRa2, CDRa3, CDRbl , CDRb2, and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

[0300] In some embodiments of the antigen binding protein, the CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3.

[0301] In some embodiments of the antigen binding protein, the CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3.

[0302] In all embodiments of the antigen binding protein of the invention, amino acid mutations within the CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3 sequences - if present - are preferably amino acid substitutions, more preferably conservative amino acid substitutions (see Table 1). It is preferred that the CDR sequences comprise not more than two, preferably not more than one, amino acid mutations. It is further preferred that the amino acid mutations - 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.

[0303] 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.

[0304] 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 dextramer staining.

[0305] 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 5.

[0306] In some embodiments, not more than 1 or 2 amino acid mutations, preferably not more than 1 amino acid mutation, more preferably not more than 1 amino acid substitution, most preferably not more than 1 conservative amino acid substitution is comprised within the central 8 amino acids of the CDRa3 and / or CDRb3, i.e. within the CDR3 core. In cases where the CDR3 comprises more than 12 amino acids, it is even more preferred that not more than 1 or 2 amino acid mutations, preferably not more than 1 amino acid mutation, more preferably not more than 1 amino acid substitution, most preferably not more than 1 conservative amino acid substitution is comprised within the central 9-13 amino acids of the CDRa3 and / or CDRb3, i.e. within the CDR3 core max.

[0307] 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 wherein the CDRal , CDRa3, CDRbl 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 B domain comprise a conservative substitution, and preferably wherein the CDRa3 and / or CDRb3 may comprise one, two or three amino acid mutations.

[0308] In some embodiments, the antigen binding protein of the invention maybe engineered, for example, by the introduction of heterologous sequences, e.g. mouse sequences, which may increase expression and stability. Also, further stabilizing mutations as known from the state of the art (e.g. WO2018 / 104407, PCT / EP2018 / 069151 , WO2011 / 044186, WO20 14 / 018863) may be introduced, such as replacement of amino acids in the variable domains and / or the introduction of a disulfide bonds, e.g. between the constant domains of a TCR and the removal of unpaired cysteine.

[0309] The TCR constant domain sequences may be modified by truncation or substitution to delete the native disulphide bond, e.g. between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC1 or TRBC2. The alpha and / or beta chain constant domain sequence(s) may also be modified by substitution of cysteine residues for example for Thr 48 of TRAC and Ser 57 of TRBC1 or TRBC2, the said cysteines forming a disulphide bond between the alpha and beta constant domains of the TCR. TRBC1 or TRBC2 may additionally include a cysteine to alanine mutation at position 75 of the constant domain and an asparagine to aspartic acid mutation at position 89 of the constant domain. The constant domain may additionally or alternatively contain further mutations, substitutions or deletions relative to the native TRAC and / or TRBC1 / 2 sequences. The term TRAC and TRBC1 / 2 encompasses natural polymophic variants, for example N to K at position 4 of TRAC (Bragado et al I nt Immunol. 1994 Feb;6(2):223-30).

[0310] In some embodiments of the antigen binding protein, the VA comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 97, 98, 99, 100, 101 , 102, and 103; and the VB comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 104, 105, 106, 107, 108, 109, and 110. In preferred embodiments of the antigen binding protein, the VA comprises an amino acid sequence of SEQ ID NO: 98 and the VB comprises an amino acid sequence of SEQ ID NO: 105; the VA comprises an amino acid sequence of SEQ ID NO: 97 and the B comprises an amino acid sequence of SEQ ID NO: 104; the VA comprises an amino acid sequence of SEQ ID NO: 99 and the VB comprises an amino acid sequence of SEQ ID NO: 106; the VA comprises an amino acid sequence of SEQ ID NO: 100 and the VB comprises an amino acid sequence of SEQ ID NO: 107; the VA comprises an amino acid sequence of SEQ ID NO: 101 and the VB comprises an amino acid sequence of SEQ ID NO: 108; the VA comprises an amino acid sequence of SEQ ID NO: 102 and the VB comprises an amino acid sequence of SEQ ID NO: 109; or the VA comprises an amino acid sequence of SEQ ID NO: 103 and the VB comprises an amino acid sequence of SEQ ID NO: 110; optionally wherein the framework region(s) comprise(s) at least one amino acid substitution.

[0311] 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: 111 , 112, 113, and 114, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 111 , 112, 113, and 114.

[0312] In some embodiments of the antigen binding protein, the first polypeptide comprises an amino acid sequence of SEQ ID NO: 115, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 115 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 7, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 116, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 116 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 3, 65, and

[0313] 9, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 117, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 117 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and

[0314] 10, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 118, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 118 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 4, 66, and

[0315] 11 , respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 119, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 119 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and

[0316] 12, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 120, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 120 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 6, 68, and

[0317] 13, respectively; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 121 , or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 121 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and

[0318] 14, respectively; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 122, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 122 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 15, 82, and

[0319] 26, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 123, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 123 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 18, 90, and

[0320] 27, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 124, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 124 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 19, 91 , and

[0321] 28, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 125, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 125 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 20, 92, and

[0322] 29, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 126, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 126 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 21 , 93, and

[0323] 30, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 127, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 127 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 22, 94, and 31 , respectively; or the second polypeptide comprises an amino acid sequence of SEQ ID NO: 128, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 128 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 25, 96, and 52, respectively; wherein optionally said CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

[0324] In some embodiments of the antigen binding protein, the CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3.

[0325] In some embodiments of the antigen binding protein, the first polypeptide comprises an amino acid sequence of SEQ ID NO: 115, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 115 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 7, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 122, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 122 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 15, 82, and

[0326] 26, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 116, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 116 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 3, 65, and

[0327] 9, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 123, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 123 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 18, 90, and

[0328] 27, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 117, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 117 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and

[0329] 10, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 124, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 124 and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NO: 19, 91 , and

[0330] 28, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 118, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 118 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 4, 66, and

[0331] 11 , respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 125, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 125 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 20, 92, and

[0332] 29, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 119, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 119 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and

[0333] 12, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 126, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 126 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 21 , 93, and

[0334] 30, respectively; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 120, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 120 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 6, 68, and

[0335] 13, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 127, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 127 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 22, 94, and

[0336] 31 , respectively; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 121 , or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 121 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and

[0337] 14, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 128, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 128 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 25, 96, and 52, respectively; wherein optionally said CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

[0338] In some embodiments of the antigen binding protein, the CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3 sequence(s) comprise up to three amino acid mutations in each of CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and CDRb3.

[0339] In some embodiments of the antigen binding protein, the first polypeptide comprises an amino acid sequence of SEQ ID NO: 115 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 122; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 116 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 123; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 117 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 124; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 118 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 125; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 119 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 126; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 120 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 127; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 121 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 128.

[0340] In some embodiments, the antigen binding protein is derived from a TCR, or is a TCR or fragment(s) thereof.

[0341] In a preferred embodiment, the TCR is selected from the group consisting of an a / TCR, a y / b TCR, functional fragments of a TCR, and a fusion protein or chimeric protein comprising (a) functional fragment(s) of a TCR.

[0342] In some embodiments, VA and VB are TCR variable domains, in particular TCR alpha, beta, gamma or delta variable domains. In some embodiments, VA is a TCR alpha, gamma or delta variable domain and B is a TCR beta, gamma or delta variable domain. Preferably, VA is a TCR alpha variable domain and VB is a TCR beta variable domain, or VA is a TCR gamma variable domain and VB is a TCR delta variable domain, or VA is a TCR alpha variable domain and VB is a TCR gamma variable domain, or VA is a TCR delta variable domain and VB is a TCR beta variable domain. In preferred embodiments, VA and VB are TCRa and TCR domains, respectively. In some embodiments, VA is a TCR gamma variable domain comprising CDR1 and CDR3 and optionally CDR2 derived from a TCR alpha variable domain, and / or B is a TCR delta variable domain comprising CDR1 and CDR3 and optionally CDR2 derived from a TCR beta variable domain.

[0343] In some embodiments, the MHC protein is an HLA protein, preferably HLA-A, more preferably HLA-A*02.

[0344] 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. The inventors demonstrate in Example 6 that the antigen binding proteins of the present invention bind the target antigen, i.e. the MAGEB2 antigenic peptide in a complex with a MHC protein, with high specificity.

[0345] The inventors identified potential off-target peptides that are, for example, similar to the sequence and / or motif of MAGEB2, and thus have an increased risk of being bound by an antigen binding protein binding to MAGEB2. However, the antigen binding proteins of the invention do not specifically bind to these peptides.

[0346] Accordingly, in some embodiments, the antigen binding protein does not significantly bind to at least 1 , at least 2, at least 3, at least 4, at least 5, or all similar peptides selected from the group consisting of SEQ ID NO: 129 (SP-02-1621), SEQ ID NO: 130 (SP-02-1622), SEQ ID NO: 131 (SP-02-1623), SEQ ID NO: 132 (SP-02-1624), SEQ ID NO: 133 (SP-02- 1625), SEQ ID NO: 134 (SP-02-1626), SEQ ID NO: 135 (SP-02-1627), SEQ ID NO: 136 (SP-02-1628) and SEQ ID NO: 137 (SP-02-1629).

[0347] In some embodiments, the antigen binding protein further comprises a transmembrane domain, optionally including a cytoplasmic signaling region.

[0348] In preferred embodiments, the antigen binding protein is membrane-bound, for example, a membrane-bound TCR or a membrane-bound functional fragment of a TCR.

[0349] In some embodiments, the variable domains herein provided or the CDRs as herein provided are comprised / included in antigen binding proteins in various formats.

[0350] In some aspects, the antigen binding protein is in the format of an scFv or scTV. In some aspects, the herein provided antigen binding protein comprise the variable domains comprising the herein provided CDRs and further comprise e.g. linkers, such as a serineglycine linker. For example, the antigen binding protein comprises a single chain TCR (scTCR). Further antigen binding sites may also be comprised in the antigen binding protein in some embodiments.

[0351] In some embodiments, the amino acid sequences of the variable regions VA and VB are chimeric, humanized or human.

[0352] In preferred embodiments, the antigen binding protein induces an immune response, for example, in the cell expressing the antigen binding protein (if the antigen binding protein is membrane-bound), preferably a lymphocyte, more preferably a T cell or an NK cell, more preferably a T cell. In some embodiments, the immune response may also be induced in a cell recruited by an antigen binding protein of the invention (if the antigen binding protein is a soluble, bispecific antigen binding protein capable of binding to and thereby recruiting e.g. a T cell or an NK cell). Preferably, the immune response is characterized by an increased production of interferon (IFN) y and / or tumor necrosis factor (TNF) a. The immune response is preferably directed against a tumor cell presenting on its surface a complex of the MAGEB2 antigenic peptide and an MHC protein. In particular embodiments, the antigen binding protein of the invention has an EC50 determined in a cytokine release assay of less than about 60 nM, less than about 50 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 2.5 nM, less than about 1.5 nM or less than about 1 nM. In further particular embodiments, the antigen binding protein of the invention has an EC50 determined in a cytokine release assay between less than about 100 nM to about 50 pM. In these particular aspects, the cytokine release assay is an IFN-y ELISA. An exemplary IFN-y ELISA is described in Example 2 herein below.

[0353] In some embodiments, the antigen binding protein 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.

[0354] 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 < 200 pM, preferably <100 pM, more preferably < 50 pM, or most preferably < 30 pM. In the context of cell therapy, e.g. adoptive autologous or heterologous cell therapy, higher KD values may be sufficient for targeting cancer cells. In an 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 an HLA molecule, preferably HLA-A*02, with a KD which is between less than about 100 pM and higher than about 1 pM. In case the antigen binding proteins are used as soluble proteins, lower KD values may be suitable for targeting cancer cells. Thus, in an 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 an HLA molecule, preferably HLA-A*02, with a KD which is < 25 pM, < 1 pM, < 500 nM, < 100 nM, < 50 nM, < 10 nM, < 5 nM. “KD” and “affinity” are as defined herein above. The KD is preferably determined by BLI as disclosed above.

[0355] In one example, the antigen binding proteins of the invention are expressed, for instance, in T cells and are analyzed for their functional avidity towards the HLA- A*02 / MAGEB2 antigenic peptide complex. 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 that is determined by AbsQuant® (e.g. as disclosed in PCT / EP2015 / 079873).

[0356] Thus, the antigen binding proteins of the present invention have a high safety profile, i.e. , a broad “safety window”.

[0357] Nucleic Acids, Vectors and Recombinant Host Cells

[0358] The polypeptides of the antigen binding proteins of the invention can be encoded by nucleic acids and expressed in vivo, ex vivo or in vitro. Thus, in a second aspect, the invention provides a nucleic acid or nucleic acids encoding the antigen binding protein of the first aspect of the invention. For example, one, two, three, or four or more nucleic acids may encode any antigen binding protein as defined herein.

[0359] Nucleic acid molecules of the disclosure can be obtained using standard molecular biology techniques, including but not limited to methods of amplification, and reverse transcription of RNA. Once DNA fragments encoding, for example, variable chains are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length chain genes. In these manipulations, a variant-encoding DNA fragment is operatively linked to another DNA molecule, or to a fragment encoding another protein, such as a constant region or a flexible linker. The term "operatively linked", as used in this context, is intended to mean that the two DNA fragments are joined in a functional manner, for example, such that the amino acid sequences encoded by the two DNA fragments remain in-frame, or such that the protein is expressed under control of a desired promoter. The isolated DNA encoding the variable region, e.g. the variable alpha region and / or variable beta region, can be converted to a full- length chain gene by operatively linking the variable-encoding DNA to another DNA molecule encoding constant regions. The sequences of human constant region genes, e.g. for TCRs or antibodies, are known in the art and DNA fragments encompassing these regions can be obtained by standard PCR amplification.

[0360] Typically, said nucleic acid comprises one or more DNA or RNA molecules, which may be included in one or more suitable vectors.

[0361] The nucleic acid may also be a DNA or RNA molecule, which may be included in a suitable vector.

[0362] Accordingly, also provided herein are expression vectors and host cells. In a further aspect, the invention relates to a vector or a collection of vectors comprising the nucleic acid(s) of the second aspect of the invention. Preferably, the sequence encoding the antigen binding protein is operably linked to a promoter sequence. “Collection of vectors” herein refers to two or more vectors. If two or more antigen binding protein polypeptide chains are encoded on one vector, the two or more antigen binding protein polypeptide chains can be under the control of the same promoter or under the control of separate promoters.

[0363] In a third aspect, the invention relates to a vector comprising the nucleic acid of the second aspect of the invention.

[0364] Various expression vectors can be employed to express the polynucleotides encoding the antigen binding proteins or functional fragments thereof. Both viral-based and non-viral expression vectors can be used to produce the antigen binding proteins or functional fragments thereof described herein in a mammalian host cell. Non-viral vectors and systems include plasmids, plasmid, cosmid, episome, artificial chromosome, phage or a viral vector.

[0365] Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct expression of said polypeptide upon administration to a subject. Examples of promoters and enhancers used in the expression vector for animal cell include early promoter and enhancer of SV40 (Mizukami T. et al. 1987), LTR promoter and enhancer of Moloney mouse leukemia virus (Kuwana Y et al. 1987), promoter (Mason JO et al. 1985) and enhancer (Gillies SD et al. 1983) of antibody heavy chain and the like.

[0366] For example, non-viral vectors useful forexpression of polynucleotides and polypeptides described herein in mammalian (e.g. human or non-human) cells include all suitable vectors known in the art for expressing proteins Other examples of plasmids and include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance plIC, pcDNA, pBR, and the like.

[0367] In a fourth aspect, the invention relates to a host cell comprising the antigen binding protein of the first aspect, the nucleic acid(s) of the second aspect or the vector(s) of the third aspect of the invention. The host cell may have been transfected, infected or transformed with a nucleic acid and / or a vector according to the invention.

[0368] The nucleic acids of the invention may be used to produce a recombinant antigen binding protein of the invention in a suitable expression system.

[0369] According to the above, in one embodiment, the invention refers to a host cell comprising the antigen binding protein of the invention which is defined herein above, or the nucleic acid(s) encoding the antigen binding protein of the invention, or the vector(s) encoding the antigen binding protein of the invention, wherein said host cell preferably is a) a lymphocyte, such as a T lymphocyte or T lymphocyte progenitor cell, for example a CD4 or CD8 positive T cell or b) a cell for recombinant expression, such as a Chinese Hamster Ovary (CHO) cell. Preferably, the host cell is a human cell. While the host cell can be of any cell type, can originate from any type of tissue, and can be of any developmental stage, the host cell preferably is a peripheral blood leukocyte (PBL) or a peripheral blood mononuclear cell (PBMC). More preferably, the host cell is a lymphocyte, such as a T cell, a T cell progenitor or a NK cell. NK cells are naturally occurring lymphoid non-T cells that can rapidly kill virally infected cells and tumour cells. NK cells can be engineered to express a tumor-specific TCR for use as a cell therapy product in cancer therapy (Shimasaki et al., Nat Rev Drug Discov. 2020 Mar;19(3):200-218). In preferred embodiments, the host cell is a T cell, for example a CD4 or CD8 positive T cell. The T cell can be any T cell, such as a cultured T cell, preferably a primary T cell, or a T cell from a cultured T cell line, e.g., Jurkat, SupT1 , etc., or a T cell obtained from a mammal, preferably a T cell or T cell precursor obtained from a human patient. In some embodiments, the host cell is a primary T cell isolated from a cancer patient. In some embodiments, the host cell is autologous or allogeneic. If obtained from a mammal, the T cell can be obtained from numerous sources, including but not limited to blood, bone marrow, lymph node, the thymus, or other tissues or fluids. T cells can also be enriched for or purified. Preferably, the T cell is a human T cell. More preferably, the T cell is a T cell isolated from a human. The T cell can be any type of T cell and can be of any developmental stage, including but not limited to, CD4-positive helper T cells, e.g., Th1 and Th2 cells, CD8- positive T cells (e.g., cytotoxic T cells), tumor infiltrating cells (TILs), memory T cells, naive T cells, and the like.

[0370] For the purposes of producing a recombinant antigen binding protein, for example a TCR, polypeptide, or protein, the host cell is preferably a mammalian cell. Accordingly, in embodiments for recombinant expression, the host cell can be a Chinese Hamster Ovary (CHO) cell.

[0371] The present invention also provides a method of treating cancer involving host cells as defined herein (see section “Therapeutic Methods and Uses).

[0372] Methods of Producing Antigen Binding Proteins

[0373] The recombinant host cells of the fourth aspect can be used for the production or expression of at least one antigen binding protein of first aspect of the invention. Thus, in a fifth aspect, the present invention provides a method of making any of the antigen binding proteins of the first aspect of the invention, comprising culturing the host cell of the fourth aspect of the invention under suitable conditions and, optionally, isolating the antigen binding protein produced by the host cells.

[0374] Accordingly, an antigen binding protein of the invention can be produced or expressed by method of the fifth aspect. In one embodiment, the method comprises the steps of (a) providing a host cell of the fourth aspect of the invention, (b) providing a genetic construct comprising a nucleic acid or nucleic acids of the second aspect encoding the antigen binding protein of the first aspect, such as a vector or vectors of the third aspect, (c) introducing the vector into the host cell of the fourth aspect, and (d) expressing the vector by the host cell.

[0375] In one embodiment, the method further comprises the isolation and purification of the antigen binding protein from the host cell.

[0376] In some embodiments, the method comprises cell surface presentation of said antigen binding protein.

[0377] In some embodiments, the genetic construct is an expression construct comprising a promoter sequence operably linked to the nucleic acid encoding the antigen binding protein.

[0378] In some embodiments, the genetic construct is introduced into the host cell by retroviral transfection.

[0379] An antigen binding protein of the invention may be produced by any technique known in the art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination.

[0380] Antigen binding proteins of the invention are suitably isolated and purified from the culture medium by antibody purification procedures such as, for example, protein A- sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0381] In one embodiment, recovering the expressed antigen binding proteins or polypeptides herein refers to performing a protein A chromatography, a Kappa select chromatography, and / or a size exclusion chromatography, preferably a protein A chromatography and / or a size exclusion chromatography, more preferably a protein A chromatography and a size exclusion chromatography.

[0382] Knowing the amino acid sequence of the desired sequence, one skilled in the art can produce the antigen binding proteins of the present invention, by standard techniques for production of polypeptides. For instance, antigen binding proteins of the invention can be produced by recombinant DNA and gene transfection techniques well known in the art (see Morrison SL. et al. (1984) and patent documents US5,202,238; and US5,204,244; the contents of which are incorporated by reference in their entireties). For example, fragments can be obtained as DNA expression products after incorporation of DNA sequences encoding the desired (poly)peptide into expression vectors and introduction of such vectors into suitable eukaryotic or prokaryotic hosts that will express the desired polypeptide, from which they can be later isolated using well-known techniques. In one example, vectors for the expression of the recombinant antigen binding proteins of the invention can be designed as monocistronic, for instance, controlled by HCMV-derived promoter elements, pUC19-derivatives. Plasmid DNA can be amplified, for example, in E.coli according to standard culture methods and subsequently purified using commercial-available kits (Macherey & Nagel). Purified plasmid DNA can be used for transient transfection of, for example, CHO-S cells according to instructions of the manufacturer (ExpiCHO™ system; Thermo Fisher Scientific). Transfected CHO-cells may be cultured, for instance, for 6-14 days at, for example, 32°C to 37°C and received one to two feeds of ExpiCHO™ Feed solution.

[0383] Conditioned cell supernatant may be cleared by, for example, filtration (0.22 pm) utilizing, for instance, Sartoclear Dynamics® Lab Filter Aid (Sartorius). Antigen binding proteins can also be purified using, for example, an Akta Pure 25 L FPLC system (GE Lifesciences) equipped to perform affinity and size-exclusion chromatography in line. Affinity chromatography can be performed on, for example protein A or L columns (GE Lifesciences), following standard affinity chromatographic protocols. For instance, size exclusion chromatography can be performed directly after elution (pH 2.8) from the affinity column to obtain highly pure monomeric protein using, for example, Superdex 200 pg 16 / 600 columns (GE Lifesciences) following standard protocols. Protein concentrations can be determined on, for example, a NanoDrop system (Thermo Scientific) using calculated extinction coefficients according to predicted protein sequences. Quality of purified antigen binding proteins can be determined by, for example, HPLC-SEC on MabPac SEC-1 columns (5 pm, 7.8x300 mm) running in, for example, 50 mM sodium-phosphate pH 6.8 containing 300 mM NaCI within a Vanquish UHPLC-System.

[0384] Pharmaceutical Compositions

[0385] In a sixth aspect, the invention provides a pharmaceutical composition comprising the antigen binding protein of the first aspect of the invention, the nucleic acid or nucleic acids of the second aspect of the invention, the vector or vectors of the third aspect of the invention or the host cell or host cells of the fourth aspect of the invention, and optionally a pharmaceutically acceptable carrier.

[0386] Antigen binding proteins of the present invention have been shown to have high avidity against cells presenting the MAGEB2 antigenic peptide. Since this peptide is specifically presented by tumor cells, the antigen binding proteins of the present invention may be useful for destroying tumor cells in a patient. An immune response in a patient can be induced by direct administration of the described antigen binding proteins to the patient, ideally in combination with an agent enhancing the immunogenicity (i.e. an adjuvant). The immune response originating from such a therapeutic vaccination can be expected to be highly specific against tumor cells because the peptide GVYDGEEHSV (SEQ ID NO: 1) is not presented or over-presented on normal tissues in comparable copy numbers, preventing the risk of undesired autoimmune reactions against normal tissue cells in the patient.

[0387] The invention also relates to a pharmaceutical composition of the invention for use as a medicament (see section “Therapeutic Methods and Uses).

[0388] Such pharmaceutical compositions may comprise a therapeutically effective amount of an antigen binding protein of the invention or an antigen binding protein of the invention further comprising a therapeutic agent, in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration.

[0389] In some embodiments, the antigen binding protein of the present invention will be supplied as part of a sterile pharmaceutical composition, which will normally include at least one pharmaceutically acceptable carrier.

[0390] Examples of pharmaceutically acceptable carriers or diluents useful in the present invention include stabilizers such as SPGA, carbohydrates (e.g. sorbitol, mannitol, starch, sucrose, glucose, dextran), proteins such as albumin or casein, protein containing agents such as bovine serum or skimmed milk and buffers (e.g. phosphate buffer).

[0391] The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and gender of the patient, etc. This pharmaceutical composition may be in any suitable form (depending upon the desired method of administering it to a patient). It may be provided in unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.

[0392] The pharmaceutical composition can be administered by injection, e.g., intravenously. When the pharmaceutical composition comprises a host cell expressing the antigen binding protein of the invention, preferably a TOR, the pharmaceutically acceptable carrier for the cells for injection may include any isotonic carrier such as, for example, normal saline (about 0.90% w / v of NaCI in water, about 300 mOsm / L NaCI in water, or about 9.0 g NaCI per liter of water), NORMOSOL R electrolyte solution (Abbott, Chicago, IL), PLASMALYTE A (Baxter, Deerfield, IL), about 5% dextrose in water, or Ringer's lactate. In an embodiment, the pharmaceutically acceptable carrier is supplemented with human serum albumen.

[0393] Empirical considerations, such as the biological half-life, generally will contribute to the determination of the dosage. Frequency of administration may be determined and adjusted over the course of therapy and is based on reducing the number of cancer cells, maintaining the reduction of cancer cells, reducing the proliferation of cancer cells, or killing the cancer cells. Alternatively, sustained continuous release formulations of the antigen binding protein may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

[0394] In one embodiment, dosages for the antigen binding proteins may be determined empirically in individuals who have been given one or more administration(s). Individuals are given incremental dosages of the antigen binding protein. To assess efficacy of the antigen binding protein, a marker of the cancer cell state can be followed. These include direct measurements of cancer cell proliferation and cell death by FACS, other imaging techniques; an improvement in health as assessed by such measurements, or an increase in quality of life as measured by accepted tests or prolongation of survival. It will be apparent to one of skill in the art that the dosage will vary depending on the individual, the stage of the disease, and the past and concurrent treatments being used.

[0395] The doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.

[0396] Pharmaceutical compositions (including antigen binding proteins, vectors and / or nucleic acids) of the invention may be provided in substantially pure form, for example at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% pure.

[0397] In some embodiments, the antigen binding protein is dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. In some embodiments, certain amino acid residues may undergo post-translational modification when the antigen binding protein is dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. In some embodiments, the post-translational modification may be an N-terminal modification. In some embodiments, the post-translational N-terminal modification may be the cyclization of one or more glutamine (Q) residues of the antigen binding protein. In some embodiments, the post-translational N-terminal modification may be the cyclization of one or more glutamate (E) residues of the antigen binding protein. In some embodiments, the post- translational N-terminal modification may result in a pyroglutamate residue. The residues marked in bold in Table 5 are exemplary residues which may undergo N-terminal post- translational modification, as specified elsewhere herein. Said post-translational N-terminal modification may for example result in a pyroglutamate residue, as specified elsewhere herein.

[0398] Therapeutic Methods and Uses

[0399] In a seventh aspect, the invention provides the antigen binding protein of the first aspect of the invention, the nucleic acid or nucleic acids of the second aspect of the invention, the vector or vectors of the third aspect of the invention, the host cell or host cells of the fourth aspect of the invention or the pharmaceutical composition of the fifth aspect of the invention for use in the treatment of a proliferative disease, wherein preferably the proliferative disease is cancer.

[0400] The antigen binding proteins of the invention are in particular for use in immune therapy for the treatment of a proliferative disease.

[0401] In preferred embodiments, the antigen binding proteins of the first aspect of the invention, the nucleic acid or nucleic acids of the second aspect of the invention, the vector or vectors of the third aspect of the invention, or the pharmaceutical composition of the sixth aspect of the invention are for use in the treatment of a MAGEB2-expressing cancer.

[0402] In a similar aspect, the present invention also relates to a method of treatment of a proliferative disease, wherein preferably the proliferative disease is cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the antigen binding protein of the first aspect of the invention, the nucleic acid or nucleic acids of the second aspect of the invention, the vector or vectors of the third aspect of the invention, the host cell or host cells of the fourth aspect of the invention or the pharmaceutical composition of the fifth aspect of the invention. In one embodiment, the cells of the cancer present GVYDGEEHSV (SEQ ID NO: 1) in a complex with an MHC molecule on the cell surface.

[0403] In preferred embodiments of method of treatment, the cancer is a MAGEB2-expressing cancer.

[0404] In some embodiments of the medical use and the method of treatment, the MAGEB2- expressing cancer is a solid cancer.

[0405] Beneficial treatment of particular cancer / tumor is shown in the prior art e.g. WO 2016 / 102272.

[0406] Thus and in further embodiments, the medical use and the method of treatment may be selected from the group consisting of liver cancer, lung cancer, chronic lymphocytic leukemia (CLL), colorectal cancer (ORC), gallbladder cancer (GBC), glioblastoma (GBM), gastric cancer (GO), hepatocellular carcinoma (HOC), head and neck cancer, head and neck squamous cell carcinoma (HNSCC), melanoma (MEL), Non-Hodgkin lymphoma (NHL), nonsmall 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 (ROC), small cell lung cancer (SCLC), urinary bladder carcinoma (UBC), and uterine and endometrial cancer (UEC).

[0407] In particular embodiments, the medical use and the method of treatment may be selected from the group consisting of hepatocellular carcinoma cancer (HOC), melanoma, non-small cell lung cancer (NSCLC), non-Hodgkin lymphoma (NHL) and UEC (uterine endometrial cancer).

[0408] In one embodiment, the method of treatment comprises immune therapy, in particular adoptive autologous or heterologous cell therapy, preferably T-cell therapy.

[0409] In a preferred embodiment, the antigen binding protein is or comprises a TCR or (a) functional fragment(s) thereof.

[0410] It is preferred that the antigen binding protein is expressed on the surface of a host cell.

[0411] In one embodiment, the method of treatment comprises administration of a host cell expressing the antigen binding protein, wherein the host cell is a T cell, T cell progenitor or NK cell, preferably a T cell.

[0412] In one embodiment, the host cell, preferably a T cell, T cell progenitor or NK cell, more preferably a T cell, is autologous.

[0413] In one embodiment, the host cell, preferably a T cell, T cell progenitor or NK cell, more preferably a T cell, is allogeneic.

[0414] In some embodiments, the antigen binding protein is conjugated to a therapeutically active agent.

[0415] Preferably, the therapeutically active agent is selected from the group consisting of a radionuclide, a chemotherapeutic agent and a toxin.

[0416] In one embodiment, the treatment further comprises administering at least one chemotherapeutic agent to the subject in need of treatment.

[0417] In one embodiment, the treatment further comprises administering radiation therapy to the subject in need of treatment.

[0418] In a related aspect, the invention relates to a method of eliciting an immune response in a patient who has a proliferative disease, in particular a cancer that presents MAGEB2 in a complex with an MHC protein, comprising administering to the patient an antigen binding protein of the present disclosure, wherein said cancer is selected from the group of cancers consisting of lung squamous cell carcinoma, head and neck squamous cell carcinoma, esophageal carcinoma, bladder cancer, and ovarian. In one embodiment, the immune response referred to in said method is a cytotoxic T cell response.

[0419] In yet another aspect, the invention relates to the use of an antigen binding protein, the nucleic acid(s), vector(s), or the pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment of a proliferative disease in a subject.

[0420] In yet another aspect, the invention relates to the use of the antigen binding protein, the nucleic acid(s) or vector(s), or the pharmaceutical composition according to the invention for treating a disease in a subject. Among the texts providing guidance for cancer therapy is Cancer, Principles and Practice of Oncology, 4th Edition, DeVita et al, Eds. J. B. Lippincott Co., Philadelphia, Pa. (1993). An appropriate therapeutic approach is chosen according to the particular type of cancer, and other factors such as the general condition of the patient, as is recognized in the pertinent field. An antigen binding protein of the present invention can be used by itself or can be added to a therapy regimen using other anti-neoplastic agents in treating a cancer patient.

[0421] Accordingly, in some embodiments, the antigen binding protein can be administered concurrently with, before, or after a variety of drugs and treatments widely employed in cancer treatment such as, for example, chemotherapeutic agents, non-chemotherapeutic, anti- neoplastic agents, and / or radiation.

[0422] In one embodiment, efficacy of the treatment with an antigen binding protein of the invention is assayed in vivo, for instance in a mouse model of cancer and by measuring, for example, changes in tumor volume between treated and control groups.

[0423] The antigen binding protein of the invention, the nucleic acid of the invention, the vector of the invention or the pharmaceutical composition of the invention can be administered by any feasible method.

[0424] As herein disclosed, in some embodiments host cells as defined herein above are used in the herein described medical uses or treatment methods. In such embodiments, the host cell is preferably a lymphocyte, such as an NK cell, a T cell or T cell progenitor, preferably a CD4 and / or CD8 positive T cell or a yb T cell, most preferably a CD4 and / or CD8 positive T cell, most preferably a CD4 and / or CD8 positive T cell.

[0425] Accordingly, the host cell of the present invention, preferably the T cells, may be used as active ingredients of a therapeutic composition. Thus, the invention also provides a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising the peptide GVYDGEEHSV (SEQ ID NO: 1), the method comprising administering to the patient an effective number of host cells, preferably T cells. In the context of this method the host cells, once administered to the subject, preferably elicit an immune response.

[0426] By "aberrantly expressed" it is meant that the peptide is over-expressed compared to levels of expression in normal (healthy) tissues or that the gene is silent in the tissue from which the tumor is derived but, in the tumor, it is expressed. By "overexpressed" the inventors mean that the peptide is present at a level at least 1 .2-fold of that present in normal tissue; preferably at least 2-fold, and more preferably at least 5-fold or 10-fold the level present in normal tissue.

[0427] In an aspect, the TCR-elicited immune response or T cell response may refer to the proliferation and activation of effector functions induced by a peptide, such as GVYDGEEHSV (SEQ ID NO: 1), in vitro, ex vivo or in vivo. For MHC class I restricted cytotoxic T cells, for example, effector functions may be lysis of peptide-pulsed, peptide-precursor pulsed or naturally peptide-presenting target cells, secretion of cytokines, preferably Interferon-gamma, TNF-alpha, or IL-2 induced by peptide, secretion of effector molecules, for example, granzymes or perforins induced by peptide, or degranulation.

[0428] In the context of the present invention, when a T cell is used as a medicament, usually, T cells are collected from a subject by apheresis. Then the T cells are genetically engineered to express the antigen binding protein of the present invention on their cell surface, the genetically engineered T cells are then expanded and then re-infused into the subject. In this example, the antigen binding protein is preferably a membrane bound antigen binding protein, more preferably a TCR.

[0429] Accordingly, the host cell has been transfected, infected or transformed with (a) nucleic acid(s) and / or (a) vector(s) according to the invention.

[0430] When the host cell is transfected to express the antigen binding protein of the invention, preferably the cell comprises an expression vector capable of expressing the antigen binding protein. The host cell may then be referred to as activated host cell.

[0431] Protocols for this so-called adoptive transfer of T cells are well known in the art. Reviews can be found in: Gattioni et al. and Morgan et al. (Gattinoni, L. et al., Nat.Rev. Immunol. 6 (2006): 383-393; Morgan, R. A. et al., Science 314 (2006): 126-129).

[0432] For the purposes of the invention, the amount or dose of the antigen binding protein of the first aspect of the invention, the nucleic acid(s) of the second aspect of the invention, the vector(s) of the third aspect of the invention, or the pharmaceutical composition of the fifth aspect of the invention administered may be sufficient to effect, e.g., a therapeutic or prophylactic response, in the subject or animal over a reasonable time frame. For example, the dose of the antigen binding protein, the nucleic acid(s), the vector(s), or the pharmaceutical composition according to the invention should be sufficient to bind to a cancer antigen, or detect, treat or prevent cancer in a period of from about 2 hours or longer, e.g., 12 to 24 or more hours, from the time of administration. In certain embodiments, the time period could be even longer. The dose will be determined by the efficacy of the antigen binding protein, nucleic acid(s), vector(s), or pharmaceutical composition according to the invention and the condition of the animal (e.g., human), as well as the body weight of the animal (e.g., human) to be treated.

[0433] A number of other methods may be used for generating T cells in vitro. For example, autologous tumor-infiltrating lymphocytes can be used in the generation of CTL. Piebanski et al. (Piebanski, M. et al., Eur.J Immunol 25 (1995): 1783-1787) made use of autologous peripheral blood lymphocytes (PLBs) in the preparation of T cells. Also, B cells can be used in the production of autologous T cells. Further, methods for generating T cells are disclosed in Guha, Katz, Methods Cell Biol. 2022;167:203-226.

[0434] In some embodiments, T cells may be manufactured according to the methods described in US20190175650, US Application No. 16 / 271 ,393, and US Application No. 16 / 361 ,043, the contents of which are hereby incorporated by reference in their entireties.

[0435] Allogeneic cells may also be used in the preparation of T cells and a method is described in detail in US6805861 , incorporated herein by reference.

[0436] Host cells expressing the antigen binding protein of the invention directed against the peptides GVYDGEEHSV (SEQ ID NO: 1) are useful in therapy. Thus, a further aspect of the invention provides activated host cells obtainable by the methods disclosed herein.

[0437] Activated host cells may specifically recognize a cell that aberrantly expresses a polypeptide that comprises the peptide GVYDGEEHSV (SEQ ID NO: 1).

[0438] In an aspect, the host cell, in particular the T cell, recognizes the cell by interacting through its antigen binding protein, in particular its TOR, with the MAGEB2 antigenic peptide in a complex with a MHC protein. The host cells are useful in a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising the peptide GVYDGEEHSV (SEQ ID NO: 1), wherein the patient is administered an effective number of the activated host cells. The T cells that are administered to the patient may be derived from the patient and activated as described above (i.e. they are autologous T cells). Alternatively, the T cells are not from the patient but are from another individual or a group of other individuals (i.e. they are heterologous T cells). In such instances, it is preferred if the individual or the group of individuals is a healthy individual or a group of healthy individuals. By "healthy individual" it is meant that the individual(s) is / are generally in good health, preferably has a competent immune system and, more preferably, is not suffering from any disease that can be readily tested for and detected.

[0439] In vivo, the target cells for the CD8-positive T cells according to the present invention can be cells of the tumor (which sometimes express MHC class II) and / or stromal cells surrounding the tumor (tumor cells) (which sometimes also express MHC class II; (Dengjel, J. et al., Clin Cancer Res 12 (2006): 4163-4170).

[0440] The present invention also provides a method of treating cancer involving host cells as defined herein. The antigen binding proteins of the invention are in particular for use in immune therapy, preferably adoptive cell therapy, more preferably adoptive T cell therapy, for the treatment of a proliferative disease. The administration of the compounds of the invention can, for example, involve the infusion of lymphocytes, preferably NK cells or T cells, more preferably T cells of the invention into said patient. Preferably, such lymphocytes are autologous lymphocytes of the patient and in vitro transduced with a nucleic acid or antigen binding protein of the present invention.

[0441] In one embodiment, the method of treating cancer in a subject in need thereof comprises a) isolating cells from said subject; b) transforming the cells with (a) vector(s) or (a) nucleic acid(s) encoding the antigen binding protein disclosed herein to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

[0442] In another embodiment, the method of treating cancer in a subject in need thereof comprises a) isolating cells from a healthy subject; b) transforming the cells with (a) vector(s) and / or nucleic acid(s) encoding the antigen binding protein disclosed herein to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

[0443] In another embodiment, the method of treating cancer in a subject in need thereof comprises a) isolating cells from a subject or a group of subjects; b) transforming the cells with (a) vector and / or (a) nucleic acid(s) encoding the antigen binding protein disclosed herein to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

[0444] The cells from a group of subjects may include the cells from cell libraries, or from patients and / or healthy subjects. For example, a healthy subject may also be a subject who was not diagnosed with a tumorous and / or cancerous disease and / or disorder but may suffer from other diseases and / or disorders.

[0445] Preferably, the transformed cell(s) is / are (a) lymphocyte(s), preferably (an) NK cell(s) or T cell(s) or T cell progenitor(s), more preferably (a) T cell(s).

[0446] Diagnostic uses

[0447] MAGEB2 is expressed on the surface of cancers defined herein above. The MAGEB2 antigenic peptide constitutes a cancer marker and, therefore, has the potential to be used to indicate the effectiveness of an anti-cancer therapy or detecting recurrence of the disease.

[0448] Thus, in an eighth aspect, the invention provides the antigen-binding protein of the first aspect, the nucleic acid or nucleic acids of the second aspect, the vector or vectors of the third aspect, the host cell or host cells of the fourth aspect, or the pharmaceutical composition of the sixth aspect for use as a diagnostic agent, in particular for use as an in vivo diagnostic agent. In preferred embodiments, the diagnostic agent is for the diagnosis of a proliferative disease. In more preferred embodiments, the diagnostic agent is for the diagnosis of a cancer that presents a peptide comprising or consisting of the amino acid sequence of GVYDGEEHSV (SEQ ID NO: 1) in a complex with an MHC protein, preferably wherein said cancer is selected from the group of cancers consisting of liver cancer, lung cancer, chronic lymphocytic leukemia (CLL), colorectal cancer (CRC), gallbladder cancer (GBC), glioblastoma (GBM), gastric cancer (GO), 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 (ROC), small cell lung cancer (SCLC), urinary bladder carcinoma (UBC), and uterine and endometrial cancer (UEC).

[0449] In an embodiment, the antigen-binding protein of the invention is used as component of an assay in the context of a therapy targeting MAGEB2 expressing tumours, in order to determine susceptibility of the patient to the therapeutic agent, monitor the effectiveness of the anti-cancer therapy or detect recurrence of the disease after treatment.

[0450] Thus, a further object of the invention relates to an antigen-binding protein according to the invention for use for in vivo detecting MAGEB2 expression in a subject, or for use for ex vivo or in vitro detecting MAGEB2 expression in biological sample of a subject. Said detection may be intended in particular for a) diagnosing the presence of a cancer in a subject, or b) determining susceptibility of a patient having cancer to a therapeutic agent targeting MAGEB2, or c) monitoring effectiveness of anti-MAGEB2 cancer therapy or detecting cancer relapse after anti-MAGEB2 cancer therapy, in particular for therapy with an antigenbinding protein according to the invention; by detecting presentation of the MAGEB2 antigenic peptide on tumor cells.

[0451] In an embodiment, the antigen-binding protein is intended for an in vitro or ex vivo use.

[0452] In still another aspect, the invention relates to an in vitro method of detecting cancer in a biological sample comprising the steps of (a) contacting the biological sample with the antigen-binding protein of the first aspect of the invention, and (b) detecting binding of the antigen-binding protein to the biological sample.

[0453] Kits

[0454] In a ninth aspect, the invention also provides kits comprising the antigen binding protein of the first aspect of the invention, a nucleic acid or nucleic acids of the second aspect of the invention, a vector or vectors of the third aspect of the invention and / or host cells of the fourth aspect of the invention.

[0455] In one embodiment, the kit comprises a) at least one antigen binding protein of the invention as defined herein above in the section “Antigen binding proteins”, nucleic acid(s) encoding said antigen binding protein, vector(s) comprising said nucleic acid(s), and / or the host cells comprising the antigen binding proteins, nucleic acid(s) and / or vector(s); b) optionally packaging material; and c) optionally a label or packaging insert contained within said packaging material indicating that said antigen binding protein is effective for a method of treating cancer or for use in the treatment of cancer.

[0456] In some embodiments, the kit comprises (a) nucleic acid(s) encoding the antigen binding protein of the invention, or (a) vector(s) comprising said nucleic acid(s).

[0457] In preferred embodiments, the kit comprises the host cells comprising the antigen binding proteins, nucleic acid(s) and / or vector(s).

[0458] The kits of the present disclosure may further include any other reagents useful for transfection / transduction for introducing the nucleic acid(s) or expression vector(s) into cells.

[0459] Components of the kits may be present in separate containers, or multiple components may be present in a single container. A suitable container includes a single tube, one or more wells of a plate (e.g., a 96-well plate, a 384-well plate, etc.), or the like.

[0460] In a related embodiment, the at least one antigen binding proteins of the invention is contained in a single and / or multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).

[0461] In one embodiment, the invention encompasses kits for producing a single-dose administration unit.

[0462] Accordingly, in one embodiment, the at least one antigen binding protein of the invention as mentioned in a) of the kit of the invention is a dried antigen binding protein of the invention contained in a first container. The kit then further contains a second container having an aqueous formulation.

[0463] Accordingly, in one embodiment, the kit comprises a) a first container comprising at least one dried antigen binding protein of the invention as defined herein above in the section "Antigen Binding Proteins”, b) a second container comprising an aqueous formulation; c) optionally packaging material, and d) optionally a label or packaging insert contained within said packaging material indicating that said antigen binding protein is effective for a method of treating cancer or for use in the treatment of cancer.

[0464] The aqueous formulation is typically an aqueous solution comprising pharmaceutically acceptable carriers as defined herein above. The definitions of the words or drawing elements described herein are meant to include not only the combination of elements which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense, it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements described and its various embodiments or that a single element may be substituted for two or more elements in a claim.

[0465] Changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalents within the scope intended and its various embodiments. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements. This disclosure is thus meant to be understood to include what is specifically illustrated and described herein, what is conceptually equivalent, what can be obviously substituted, and also what incorporates the essential ideas.

[0466] ITEMS

[0467] The present invention can also be characterised in terms of the following items:

[0468] 1 . 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 a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, and a variable domain VB comprising CDRbl , CDRb2, and CDRb3; preferably wherein the VA comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 98, 97, 99, 100, 101 , 102, and 103 or an amino acid sequence having at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 98% or preferably at least 99% identity to SEQ ID NO: 98, 97, 99, 100, 101 , 102, or 103, preferably wherein the B comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 105, 104, 106, 107, 108, 109, and 110 or an amino acid sequence having at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 98% or preferably at least 99% identity to SEQ ID NO: 105, 104, 106, 107, 108, 109, and 110, preferably wherein

[0469] CDRal comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 2, 3, 4, 5, and 6, CDRa3 comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 7, 8, 9, 10, 11 , 12, 13, and 14, CDRbl comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, and 25, and CDRb3 comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , and 52; wherein the CDRal , CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0470] 2. The antigen binding protein of item 1 , wherein

[0471] CDRa2 comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, and 81 , and CDRb2 comprises an amino acid sequence selected from the group consisting of: SEQ ID NOs: 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, and 96; wherein the CDRa2 and / or CDRb2 sequence(s) may comprise one, two or three amino acid mutations.

[0472] 3. 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 a first polypeptide comprising a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, and a second polypeptide comprising a variable domain VB comprising CDRbl, CDRb2, and CDRb3; wherein

[0473] (1) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0474] (2) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0475] (3) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, and CDRb3 comprises SEQ ID NO: 26;

[0476] (4) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, and CDRb3 comprises SEQ ID NO: 26;

[0477] (5) CDRal comprises SEQ ID NO: 3, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, and CDRb3 comprises SEQ ID NO: 27;

[0478] (6) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, and CDRb3 comprises SEQ ID NO: 28;

[0479] (7) CDRal comprises SEQ ID NO: 4, CDRa3 comprises SEQ ID NO: 11, CDRbl comprises SEQ ID NO: 20, and CDRb3 comprises SEQ ID NO: 29;

[0480] (8) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21, and CDRb3 comprises SEQ ID NO: 30;

[0481] (9) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31;

[0482] (10) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, and CDRb3 comprises SEQ ID NO: 31;

[0483] (11) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, and CDRb3 comprises SEQ ID NO: 31;

[0484] (12) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 32; (13) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 33;

[0485] (14) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 34;

[0486] (15) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 35;

[0487] (16) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 36;

[0488] (17) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 37;

[0489] (18) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 38;

[0490] (19) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 39;

[0491] (20) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 40;

[0492] (21) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 41;

[0493] (22) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 42;

[0494] (23) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 43;

[0495] (24) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 44;

[0496] (25) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 45;

[0497] (26) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 46;

[0498] (27) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 47;

[0499] (28) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 48;

[0500] (29) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 49;

[0501] (30) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 50; (31) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 51 ; or

[0502] (32) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal , CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0503] 4. The antigen binding protein of item 3, wherein

[0504] (1) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0505] (2) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 54, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0506] (3) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 55, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0507] (4) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 56, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0508] (5) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0509] (6) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0510] (7) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, CDRb2 comprises SEQ ID NO:

[0511] 82, and CDRb3 comprises SEQ ID NO: 26;

[0512] (8) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:

[0513] 83, and CDRb3 comprises SEQ ID NO: 26;

[0514] (9) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:

[0515] 84, and CDRb3 comprises SEQ ID NO: 26; (10) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:

[0516] 85, and CDRb3 comprises SEQ ID NO: 26;

[0517] (11) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:

[0518] 86, and CDRb3 comprises SEQ ID NO: 26;

[0519] (12) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:

[0520] 87, and CDRb3 comprises SEQ ID NO: 26;

[0521] (13) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 57, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0522] (14) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:

[0523] 88, and CDRb3 comprises SEQ ID NO: 26;

[0524] (15) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:

[0525] 89, and CDRb3 comprises SEQ ID NO: 26;

[0526] (16) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 58, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0527] (17) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 59, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0528] (18) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 60, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0529] (19) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 61 , CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0530] (20) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 62, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0531] (21) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 63, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26; (22) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 64, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;

[0532] (23) CDRal comprises SEQ ID NO: 3, CDRa2 comprises SEQ ID NO: 65, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, CDRb2 comprises SEQ ID NO: 90, and CDRb3 comprises SEQ ID NO: 27;

[0533] (24) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, CDRb2 comprises SEQ ID NO: 91 , and CDRb3 comprises SEQ ID NO: 28;

[0534] (25) CDRal comprises SEQ ID NO: 4, CDRa2 comprises SEQ ID NO: 66, CDRa3 comprises SEQ ID NO: 11 , CDRbl comprises SEQ ID NO: 20, CDRb2 comprises SEQ ID NO: 92, and CDRb3 comprises SEQ ID NO: 29;

[0535] (26) CDRal comprises SEQ ID NO: 5, CDRa2 comprises SEQ ID NO: 67, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21 , CDRb2 comprises SEQ ID NO: 93, and CDRb3 comprises SEQ ID NO: 30;

[0536] (27) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0537] (28) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 95, and CDRb3 comprises SEQ ID NO: 31 ;

[0538] (29) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 69, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0539] (30) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 70, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0540] (31) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 71 , CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0541] (32) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 72, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ;

[0542] (33) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 73, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31 ; (34) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0543] (35) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0544] (36) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 32;

[0545] (37) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 33;

[0546] (38) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 34;

[0547] (39) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 74, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0548] (40) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 35;

[0549] (41) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 36;

[0550] (42) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 37;

[0551] (43) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 38;

[0552] (44) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 39;

[0553] (45) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 40; (46) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 41;

[0554] (47) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 42;

[0555] (48) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 43;

[0556] (49) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 44;

[0557] (50) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 75, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0558] (51) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 45;

[0559] (52) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 46;

[0560] (53) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 47;

[0561] (54) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 48;

[0562] (55) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 49;

[0563] (56) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 50;

[0564] (57) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 51; (58) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 76, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0565] (59) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 77, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0566] (60) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 78, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0567] (61) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 79, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0568] (62) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 80, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;

[0569] (63) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 81 , CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31; or

[0570] (64) CDRal comprises SEQ ID NO: 5, CDRa2 comprises SEQ ID NO: 67, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, CDRb2 comprises SEQ ID NO: 96, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal, CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0571] 5. The antigen binding protein of any one of items 1 to 4, wherein the VA comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 98, 97, 99, 100, 101 , 102, and 103, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 97, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 7, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 98, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 3, 65, and 9, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 99, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 10, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 100, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 4, 66, and 11, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 101, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 12, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 102, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 6, 68, and 13, respectively, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 103, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 14, respectively, and wherein the VB comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 105, 104, 106, 107, 108, 109, and 110, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 104, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 15, 82, and

[0572] 26, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 105, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 18, 90, and

[0573] 27, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 106, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 19, 91, and

[0574] 28, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 107, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 20, 92, and

[0575] 29, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 108, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 21, 93, and

[0576] 30, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 109, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 22, 94, and

[0577] 31, respectively, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 110, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 25, 96, and 52, respectively, wherein optionally the CDRal, CDRa2, CDRa3, CDRbl, CDRb2, and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

[0578] 6. The antigen binding protein of any one of items 1 to 5, wherein the VA comprises an amino acid sequence of SEQ ID NO: 97 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 97, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 7, respectively, and wherein the VB comprises an amino acid sequence of SEQ ID NO: 104 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 104, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 15, 82, and 26, respectively; wherein the VA comprises an amino acid sequence of SEQ ID NO: 98 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 98, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 3, 65, and 9, respectively, and wherein the B comprises an amino acid sequence of SEQ ID NO: 105 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 105, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 18, 90, and 27, respectively; wherein the VA comprises an amino acid sequence of SEQ ID NO: 99 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 99, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 10, respectively, and wherein the VB comprises an amino acid sequence of SEQ ID NO: 106 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 106, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 19, 91 , and 28, respectively; wherein the VA comprises an amino acid sequence of SEQ ID NO: 100 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 100, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 4, 66, and 11 , respectively, and wherein the VB comprises an amino acid sequence of SEQ ID NO: 107 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 107, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 20, 92, and 29, respectively; wherein the VA comprises an amino acid sequence of SEQ ID NO: 101 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 101, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 12, respectively, and wherein the VB comprises an amino acid sequence of SEQ ID NO: 108 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 108, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 21, 93, and 30, respectively; wherein the VA comprises an amino acid sequence of SEQ ID NO: 102 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 102, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 6, 68, and 13, respectively, and wherein the VB comprises an amino acid sequence of SEQ ID NO: 109 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 109, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 22, 94, and 31, respectively; or wherein the VA comprises an amino acid sequence of SEQ ID NO: 103 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 103, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 14, respectively, and wherein the B comprises an amino acid sequence of SEQ ID NO: 110 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 110, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 25, 96, and 52, respectively; wherein optionally said CDRal , CDRa2, CDRa3, CDRbl, CDRb2, and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

[0579] 7. The antigen binding protein of any one of items 1 to 6, wherein the VA comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 98, 97, 99, 100, 101 , 102, and 103; and wherein the VB comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 105, 104, 106, 107, 108, 109, and 110.

[0580] 8. The antigen binding protein of any one of items 1 to 7, wherein the VA comprises an amino acid sequence of SEQ ID NO: 98 and the VB comprises an amino acid sequence of SEQ ID NO: 105; wherein the VA comprises an amino acid sequence of SEQ ID NO: 97 and the VB comprises an amino acid sequence of SEQ ID NO: 104; wherein the VA comprises an amino acid sequence of SEQ ID NO: 99 and the VB comprises an amino acid sequence of SEQ ID NO: 106; wherein the VA comprises an amino acid sequence of SEQ ID NO: 100 and the VB comprises an amino acid sequence of SEQ ID NO: 107; wherein the VA comprises an amino acid sequence of SEQ ID NO: 101 and the VB comprises an amino acid sequence of SEQ ID NO: 108; wherein the VA comprises an amino acid sequence of SEQ ID NO: 102 and the VB comprises an amino acid sequence of SEQ ID NO: 109; or wherein the VA comprises an amino acid sequence of SEQ ID NO: 103 and the VB comprises an amino acid sequence of SEQ ID NO: 110; and optionally wherein the framework region(s) comprise(s) at least one amino acid substitution.

[0581] 9. The antigen binding protein of any one of items 1 to 8, further comprising a constant domain, wherein the constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 111 , 112, 113, and 114, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 111 , 112, 113, and 114.

[0582] 10. The antigen binding protein of any one of items 1 to 9, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 115, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0583] 115 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 7, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 116, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0584] 116 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 3, 65, and 9, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 117, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0585] 117 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 10, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 118, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0586] 118 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 4, 66, and 11 , respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 119, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0587] 119 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and 12, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 120, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0588] 120 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 6, 68, and 13, respectively; or wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 121 , or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0589] 121 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and 14, respectively; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 122, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0590] 122 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 15, 82, and 26, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 123, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0591] 123 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 18, 90, and 27, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 124, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0592] 124 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 19, 91 , and 28, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 125, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0593] 125 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 20, 92, and 29, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 126, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0594] 126 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 21 , 93, and 30, respectively; the second polypeptide comprises an amino acid sequence of SEQ ID NO: 127, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0595] 127 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 22, 94, and 31 , respectively; or the second polypeptide comprises an amino acid sequence of SEQ ID NO: 128, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0596] 128 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 25, 96, and 52, respectively; wherein optionally said CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions. 11 . The antigen binding protein of any one of items 1 to 10, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 115, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0597] 115 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 7, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 122, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0598] 122 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 15, 82, and 26, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 116, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0599] 116 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 3, 65, and 9, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 123, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0600] 123 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 18, 90, and 27, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 117, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0601] 117 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 10, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 124, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0602] 124 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 19, 91 , and 28, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 118, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0603] 118 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 4, 66, and 11 , respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 125, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0604] 125 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 20, 92, and 29, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 119, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 119 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and 12, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 126, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0605] 126 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 21 , 93, and 30, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 120, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0606] 120 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 6, 68, and 13, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 127, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0607] 127 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 22, 94, and 31 , respectively; or wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 121 , or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0608] 121 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and 14, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 128, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:

[0609] 128 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 25, 96, and 52, respectively; wherein optionally said CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

[0610] 12. The antigen binding protein of any one of items 1 to 11 , wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 115 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 122; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 116 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 123; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 117 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 124; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 118 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 125; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 119 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 126; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 120 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 127; or wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 121 and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 128.

[0611] 13. The antigen binding protein of any one of items 1 to 12, wherein the antigen binding protein is derived from a TCR, or is a TCR or fragments thereof.

[0612] 14. The antigen binding protein of item 13, wherein the TCR is selected from the group consisting of an a / TCR, a y / b TCR, functional fragments of a TCR, and a fusion protein or chimeric protein comprising (a) functional fragment(s) of a TCR.

[0613] 15. The antigen binding protein of item 14, wherein VA and VB are TCRa and TCR domains, respectively.

[0614] 16. The antigen binding protein of any one of items 1 to 15, wherein the MHC protein is an HLA protein, preferably HLA-A, more preferably HLA-A*02.

[0615] 17. The antigen binding protein of any one of items 1 to 16, wherein the antigen binding protein does not significantly bind to at least 1 , at least 2, at least 3, at least 4, at least 5, or all similar peptides selected from the group consisting of SEQ ID NOs: 129 to 137.

[0616] 18. The antigen binding protein of any one of items 1 to 17, wherein the antigen binding protein is membrane-bound.

[0617] 19. The antigen binding protein of any one of items 1 to 18, wherein the antigen binding protein is a membrane-bound TCR or a membrane-bound functional fragment of a TCR.

[0618] 20. The antigen binding protein of any one of items 1 to 19, wherein the antigen binding protein is an scFv.

[0619] 21. The antigen binding protein according to any one of items 1 to 20, wherein said antigen binding protein comprises a single chain TCR (scTCR). 22. The antigen binding protein of any one of items 1 to 21 , wherein the amino acid sequences of the variable regions VA and VB are chimeric, humanized or human.

[0620] 23. The antigen binding protein of any one of items 1 to 22, wherein the antigen binding protein is capable of activating a CD4+ T cell, preferably a CD4+ CD8- T cell.

[0621] 24. The antigen binding protein of any one of items 1 to 23, wherein the antigen binding protein is capable of activating a CD8+ T cell, preferably a CD8+ CD4-T cell.

[0622] 25. The antigen binding protein of any one of items 1 to 24, wherein the antigen binding protein has an EC50 determined in a cytokine release assay between less than about 100 nM to about 50 pM.

[0623] 26. The antigen binding protein of any one of items 1 to 25, wherein the antigen binding protein further comprises a transmembrane domain, optionally including a cytoplasmic signaling region.

[0624] 27. A nucleic acid or nucleic acids encoding the antigen binding protein as defined in any one of items 1 to 26.

[0625] 28. A vector or vectors comprising the nucleic acid or nucleic acids of item 27.

[0626] 29. A host cell comprising the nucleic acid or nucleic acids of item 27 and / or the vector(s) of item 28.

[0627] 30. The host cell of item 29, wherein the host cell is a cell for recombinant expression, such as a Chinese Hamster Ovary (CHO) cell or a yeast cell.

[0628] 31. A host cell comprising the antigen binding protein as defined any one of items 1 to 26, the nucleic acid(s) of item 27, or the vector(s) of item 28.

[0629] 32. The host cell of item 31 , wherein the host cell is a lymphocyte, preferably a T cell, a T cell progenitor or an NK cell, more preferably a CD4 or CD8 positive T cell.

[0630] 33. The host cell of item 31 , wherein the host cell is a primary T cell. 34. The host cell of item 31 , wherein the host cell is a primary T cell isolated from a cancer patient.

[0631] 35. The host cell of any one of items 31 to 34, wherein the host cell is autologous.

[0632] 36. The host cell of any one of items 31 to 34, wherein the host cell is allogeneic.

[0633] 37. A pharmaceutical composition comprising an antigen binding protein of any one of items 1 to 26, (a) nucleic acid(s) of item 27, (a) vector(s) of item 28, or a host cell of any one of items 31 to 36, and optionally a pharmaceutically acceptable carrier.

[0634] 38. The antigen binding protein of any one of items 1 to 26, the nucleic acid(s) of item 27, the vector(s) of item 28, the host cell of any one of items 31 to 36, or the pharmaceutical composition of item 37, for use in the treatment of cancer.

[0635] 39. The antigen binding protein of any one of items 1 to 26, the nucleic acid(s) of item 27, the vector(s) of item 28, the host cell of any one of items 31 to 36, or the pharmaceutical composition of item 37, for use in the treatment of a MAGEB2-expressing cancer.

[0636] 40. A method of treatment of a MAGEB2-expressing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the antigen binding protein of any one of items 1 to 26, the nucleic acid(s) of item 27, the vector(s) of item 28, the host cell of any one of items 31 to 36, or the pharmaceutical composition of item 37.

[0637] 41 . The antigen binding protein for the use of item 38 or item 39, or the method of treatment of item 40, wherein the MAGEB2-expressing cancer is selected from the group consisting of hepatocellular carcinoma cancer (HCC), melanoma, non-small cell lung cancer (NSCLC), and non-Hodgkin lymphoma (NHL) and UEC (uterine endometrial cancer).

[0638] 42. The antigen binding protein, nucleic acid(s), vector(s), host cell or pharmaceutical composition for the use of items 38, 39 or 41 , or the method of treatment of item 40 or item 41 , wherein the treatment comprises adoptive autologous or heterologous T-cell therapy.

[0639] 43. The antigen binding protein, nucleic acid(s), vector(s), host cell or pharmaceutical composition for the use of any one of items 38, 39, 41 or 42, or the method of treatment of any one of items 40 to 42, wherein the antigen binding protein is conjugated to a therapeutically active agent.

[0640] 44. The antigen binding protein, nucleic acid(s), vector(s), host cell or pharmaceutical composition for the use of item 43, or the method of treatment of item 43, wherein the therapeutically active agent is selected from the group consisting of a radionuclide, a chemotherapeutic agent and a toxin.

[0641] 45. The antigen binding protein, nucleic acid(s), vector(s), host cell or pharmaceutical composition for the use of any one of items 38, 39, or 41 to 44, or the method of treatment of any one of items 40 to 44, wherein the treatment further comprises administering at least one chemotherapeutic agent to the subject in need of treatment.

[0642] 46. The antigen binding protein, nucleic acid(s), vector(s), host cell or pharmaceutical composition for the use of any one of items 38, 39, or 41 to 45, or the method of treatment of any one of items 40 to 45, wherein the treatment further comprises administering radiation therapy to the subject in need of treatment.

[0643] 47. A kit comprising an antigen binding protein of any one of items 1 to 26, (a) nucleic acid(s) of item 27, (a) vector(s) of item 28, and / or a host cell of any one of items 31 to 36.

[0644] 48. A method of treating cancer in a subject in need thereof, comprising: a) isolating cells from said subject; b) transforming the cells with (a) vector(s) and / or nucleic acid(s) encoding the antigen binding protein of any one of items 1 to 26 to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

[0645] 49. A method of treating cancer in a subject in need thereof, comprising: a) isolating cells from a healthy subject; b) transforming the cells with (a) vector(s) and / or nucleic acid(s) encoding the antigen binding protein of any one of items 1 to 26 to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

[0646] 50. A method of treating cancer in a subject in need thereof, comprising: a) isolating cells from a subject or a group of subjects; b) transforming the cells with (a) vector(s) and / or (a) nucleic acid(s) encoding the antigen binding protein of any one of items 1 to 26 to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

[0647] 51 . The method of any one of items 48 to 50, wherein the transformed cell is a lymphocyte, preferably an NK cell or T cell or T cell progenitor, more preferably a T cell.

[0648] 52. A method of producing the antigen binding protein according to any one of items 1 to 26, comprising: a) providing a host cell, b) providing a genetic construct comprising a nucleic acid or nucleic acids encoding the antigen binding protein of any of items 1 to 26, c) introducing the genetic construct into the host cell, and d) expressing the genetic construct by the host cell.

[0649] 53. The method of item 52, further comprising the isolation and purification of the antigen binding protein from the host cell and, optionally, reconstitution of the antigen binding protein in a T cell.

[0650] 54. The method of item 52 or item 53, further comprising cell surface presentation of said antigen binding protein.

[0651] 55. The method of any one of items 52 to 54, wherein the genetic construct is an expression construct comprising a promoter sequence operably linked to the nucleic acid encoding the antigen binding protein.

[0652] 56. The method according to any one of items 52 to 55, wherein the genetic construct is introduced into the host cell by retroviral transfection.

[0653] 57. A pharmaceutical composition comprising an antigen binding protein as produced according to any one of items 52 to 56, and optionally a pharmaceutically acceptable carrier.

[0654] 58. An in-vitro method of detecting cancer, in particular cancer expressing MAGEB2, in a biological sample comprising: a. contacting the biological sample with the antigen binding protein of any one of items 1 to 26, and b. detecting binding of the antigen binding protein to the biological sample.

[0655] 59. The method of any one of items 48 to 51, wherein cells of the cancer present GVYDGEEHSV (SEQ ID NO: 1) in a complex with an MHC molecule on the cell surface.

[0656] 60. An antigen binding protein comprising a first polypeptide comprising a variable domain VA comprising complementarity determining regions (CDRs) CDRal, CDRa2, and CDRa3, and a second polypeptide comprising a variable domain VB comprising CDRbl , CDRb2, and CDRb3; wherein

[0657] (1) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0658] (2) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;

[0659] (3) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, and CDRb3 comprises SEQ ID NO: 26;

[0660] (4) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, and CDRb3 comprises SEQ ID NO: 26;

[0661] (5) CDRal comprises SEQ ID NO: 3, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, and CDRb3 comprises SEQ ID NO: 27;

[0662] (6) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, and CDRb3 comprises SEQ ID NO: 28;

[0663] (7) CDRal comprises SEQ ID NO: 4, CDRa3 comprises SEQ ID NO: 11, CDRbl comprises SEQ ID NO: 20, and CDRb3 comprises SEQ ID NO: 29;

[0664] (8) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21, and CDRb3 comprises SEQ ID NO: 30;

[0665] (9) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31;

[0666] (10) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, and CDRb3 comprises SEQ ID NO: 31 ;

[0667] (11) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, and CDRb3 comprises SEQ ID NO: 31;

[0668] (12) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 32;

[0669] (13) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 33; (14) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 34;

[0670] (15) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 35;

[0671] (16) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 36;

[0672] (17) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 37;

[0673] (18) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 38;

[0674] (19) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 39;

[0675] (20) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 40;

[0676] (21) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 41;

[0677] (22) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 42;

[0678] (23) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 43;

[0679] (24) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 44;

[0680] (25) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 45;

[0681] (26) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 46;

[0682] (27) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 47;

[0683] (28) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 48;

[0684] (29) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 49;

[0685] (30) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 50;

[0686] (31) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 51; or (32) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal, CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

[0687] 61. The antigen binding protein of item 60, wherein the one, two, or three amino acid mutations are conservative substitutions.

[0688] EXAMPLES

[0689] Example 1 : Identification of MAGEB2-001 specific TCRs that are target-specific and have a high avidity

[0690] Target-specific, high avidity TCRs are required for potential use in ACT. From healthy donors we identified seven TCRs targeting MAGEB2-001 (SEQ ID NO: 1) which fulfil these criteria.

[0691] All identified TCRs target the MAGEB2-001 (SEQ ID NO: 1) peptide, presented by HLA- A*02 molecules. All TCRs have been isolated after in vitro stimulation. In brief, the T cells were repeatedly stimulated with artificial antigen-presenting cells coated with peptide-MHC and CD28 as described in Walter et al., 2003 J Immunol., Nov 15;171 (10):4974-8 and subsequently, single-cell sorted using MAGEB2-001-HLA-A*02 tetramers. The paired T cell receptor alpha and beta chain sequences were obtained via 5’ RACE in combination with Sanger sequencing as described e.g. in Molecular Cloning, Laboratory Manual, Fourth Edition by Green and Sambrook. The TCR chain usage is listed in Table 2.

[0692] Table 2: Overview of identified parental TCRs and TOR chain usage

[0693] Example 2: The selected TCRs show a high functional avidity in a cytokine release assay

[0694] All seven identified MAGEB2-001 -specific TCRs show high functional avidity as measured by peptide titration experiments which is expressed as half maximal IFN-y release ECso shown in Table 2 and Figure 1. The functional characteristics of the TCRs were assessed in co-culture experiments with T2 cells. For that purpose, CD8 T cells were prestimulated with OKT3 and CD28 and after 3 days, electroporated with TCR mRNA. On the day of co-culture, T2 cells were loaded with different concentrations of peptide MAGEB2-001 (SEQ ID NO: 1). T cells and peptide-loaded T2 cells were seeded at a ratio of 1 :1 and incubated for 24h until supernatant harvest. Supernatants were subjected to an IFN- y ELISA. The EC50 values of the TCRs range from 0.08 nM (TCR-1) to 27.5 nM (TCR-4). High avidity TCRs, such as the described TCRs, are suitable candidates for adoptive cell therapy approaches.

[0695] Example 3: The TCRs are specific for MAGEB2-001

[0696] The herein described TCRs were tested for their specificity profiles by testing their ability to recognize 10 MAGEB2-001 sequence-similar peptides (SEQ ID NOs: 129-137). As a threshold for specific detection of a similar peptide we defined a significant difference between the response against T2-cells loaded with an irrelevant peptide (SEQ ID NO: 150) and the respective similar peptide determined by ANOVA. None of the examined seven high-avidity TCRs recognized a peptide other than MAGEB2-001 as shown in Figure 2 and summarized in Table 2 (cross-recognition). High target-specificity is of utmost importance in the context of ACT therapy to ensure a safe product without any unwanted off-target reactions against healthy tissues.

[0697] Example 4: TCR-motif determination

[0698] The TCR characterization also involved the determination of the TCR binding motif to the peptide MAGEB2-001 . For this purpose, MAGEB2-001 amino acid exchange peptide variants (SEQ ID NO 138-145) were tested in co-culture experiments with all seven TCRs. A relevant position is indicated by a number (referring to the position of the amino acid in the peptide). A position is considered relevant when the exchange leads to a response reduction of >70% (considering the response against wild type MAGEB2-001 peptide as 100% and the response against the irrelevant peptide NYESQ1-001 as 0%). A non-relevant position is represented by a hyphen, and not tested positions such as 2 and 10 are labeled with “x”. The TCR-motifs range from as broad as 6 relevant amino acids (e.g. TCR-2) to as narrow as 2 relevant positions (e.g. TCR-1). A TCR with a broad binding motif is more likely to cover a smaller similar peptide space than a TCR with a narrow binding motif. The results are shown in Figure 3 and summarized in Table 2 (binding-motif).

[0699] Example 5: Generation of stable scTCRs

[0700] For the present invention, the TCRs TCR-1 and TCR-6 (SEQ ID NO: 115 together with 122, and SEQ ID NO: 120 together with 127, respectively) were converted into single chain TCR constructs (TCR-1_scTCR and TCR-6_scTCR, SEQ IDs NOs: 151 and 154, respectively) using their variable alpha (SEQ IDs NOs: 97 and 102, respectively) and beta (SEQ IDs NOs: 104 and 109, respectively) domains and a glycine-serine linker sequence (SEQ ID NO: 147). For TOR maturation via yeast surface display, the DNA of the corresponding sequence was synthesized and transformed into Saccharomyces cerevisiae EBY100 (MATa AGA1::GAL1--AGA1::URA3 ura3-52 trp1 leu2--delta200 his3--delta200 pep4::HIS3 prbd1.6R can1 GAL) (ATCC® MYA-14941 ™) together with a yeast display vector based on pCT302 (Boder and Wittrup, Methods Enzymol. 2000;328:430-44). The resulting fusion protein after homologous recombination in the yeast (SEQ ID NOs: 152 and 155) contains a leader peptide at the N-terminus of the Aga2p protein (SEQ ID NO: 146) (Boder and Wittrup, Nat Biotechnol. 1997 Jun; 15(6): 553-7), the protein of interest, namely TCR- 1_scTCR and TCR-6_scTCR (SEQ ID NO: 151 and 154) or its variants and additional peptide tags (FLAG and Myc (SEQ ID NOs: 148 and 149)) to determine the expression level of the fusion protein. Libraries of scTCR variants were generated via PCR using degenerate primers and the transformation of yeast cells was performed as described in WO 2018 / 091396 and resulted in up to 109yeast clones per library.

[0701] The selection process for the yeast clones bearing mutant scTCR variants with improved binding to MAGEB2-001 in the context of HLA-A*02 was essentially performed as described in Smith et al. (Methods Mol Biol. 2015;1319:95-141). Functional binding via HLAA*02 / MAGEB2001 tetramer staining was applied to select for most promising candidates. The starting point for the scTCR conversion was always the parental scTCRs sequence (SEQ ID NOs: 151 and 154). For TCR-6, a further stabilized version of the TCR-6_scTCR_S (SEQ ID NO: 156) was selected, containing 4 framework mutations and one mutation in the CDRb2 (SEQ ID NO: 95). The further stabilized version scTCR TCR-1_scTCR_S (SEQ ID NO: 153) contained three amino acid substitutions in the framework compared to the parental TCR- 1_scTCR. These amino acid substitutions improved the presentation of scTCR molecules on the yeast surface (Figure 4) and could be used for further maturation steps.

[0702] Example 6: Affinity maturation of stabilized scTCR and specificity assessment

[0703] To generate scTCR molecules with higher binding affinity towards HLA-A*02 / MAGEB2- 001 , all CDRs were maturated individually, based on the library on the previously identified stabilized TCR-1_scTCR_s or TCR-6_scTCR_S, respectively (SEQ ID NOs: 153 and 156). The CDR residues were randomized by using degenerate DNA oligo primers essentially as described previously (Smith et al., Methods Mol Biol. 2015;1319:95-141). The resulting DNA libraries were transformed as described in Example 5.

[0704] For the selection of affinity enhanced and specific scTCR variants, decreasing concentrations of HLA-A*02 / MAGEB2-001 tetramer or monomer were used for each selection round. After four selection rounds, single scTCR clones were isolated and sequenced, resulting in a multitude of affinity maturated CDR sequences. A strong improvement in binding of HLA-A*02 / MAGEB2-001 tetramers or monomers could be demonstrated for TCR-6_scTCR_S with maturated CDRa2, CDRbl and CDRb3 (SEQ ID NOs: 23, 24, 32-51 , 69-81). The specificity of HLA-A*02 / MAGEB2-001 binding was retained during maturation as confirmed by the low binding of the scTCR to a mix of HLA-A*02 tetramers containing peptides (similar peptides or SimPeps, SEQ ID NOs: 129-137) with high degree of sequence similarity to MAGEB2-001 peptide (SEQ ID NO: 1). While all selected scTCR maturation variants showed substantial staining with HLA-A*02 / MAGEB2-001 monomers, the non-maturated stabilized TCR-6_scTCR_S as reference did not show staining (Figure 5A and Table 3). Furthermore, binding of maturated scTCR to a mix of similar peptides, applied in a high avidity format of HLA-A*02 tetramers at a concentration of 25 nM, could not be detected, which confirms the capability of the scTCR maturation variants to bind the MAGEB2-001 target peptide in a highly specific manner.

[0705] For TCR-1 , a similar selection process was performed, resulting in improved binding variants for CDR libraries CDRa2, CDRa3, CDRbl and CDRb2 (SEQ ID NOs: 8, 16, 17, 54- 64, 83-89). Likewise, binding analysis to HLA-A*02 / MAGEB2-001 was investigated, using a dimeric or monomeric form of the target. The specificity of the binders was addressed identically to the binders described above. Taking the TCR-1_scTCR_S (SEQ ID NO: 153) as reference, all selected binders showed strongly improved target binding to HLA- A*02 / MAGEB2-001 dimers or monomers, but could retain their specificity as addressed by the similar peptides (Figure 5B and Table 4).

[0706] Table 3. Binding data of yeast bearing TCR-6_scTCR_S variants with mutant CDRs.1

[0707] 1Stabilized scTCR comprising non-modified and maturated CDRa2 and CDRbl were stained with 100 nM HLA-A*02 / MAGEB2-001 monomer and counterstained with a mix of HLA-A*02 tetramers, each applied at a concentration of 25 nM, containing peptides (similar peptides or SimPeps, SEQ ID NOs: 129-137) with high sequence similarity to MAGEB2-001 (SEQ ID NO: 1). Positive staining for selected CDRb3 clones was performed at a concentration of 10 nM HLA-A*02 / MAGEB2- 001 monomer. *: corresponding CDR from TCR-6_scTCR_S (SEQ ID NO: 156). Table 4. Binding data of yeast bearing TCR-1_scTCR_S variants with mutant CDRs.2

[0708] 2Stabilized scTCR comprising non-modified and maturated CDRa2 and CDRbl were stained with 2 nM HLA-A*02 / MAGEB2-001 dimer and counterstained with a mix of HLA-A*02 tetramers, each applied at a concentration of 25 nM, containing peptides (similar peptides or SimPeps, SEQ ID NO: 129-137) with high sequence similarity to MAGEB2-001 (SEQ ID NO: 1). Positive staining for selected CDRa3 clones was performed at a concentration of 10 nM HLA-A*02 / MAGEB2- 001 dimer, CDRb2 variants were positive stained with 100 nM HLA-A*02 / MAGEB2-001 monomer. *: corresponding CDR from TCR-1_scTCR_S (SEQ ID NO: 153). SEQUENCES

[0709] Table 5: Exemplary amino acid sequences referred to herein

[0710]

[0711]

Claims

CLAIMS1. 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 a first polypeptide comprising a variable domain VA comprising complementarity determining regions (CDRs) CDRal , CDRa2, and CDRa3, and a second polypeptide comprising a variable domain VB comprising CDRbl, CDRb2, and CDRb3; wherein the VA comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 98, 97, 99, 100, 101, 102, and 103 or an amino acid sequence having at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 98% or preferably at least 99% identity to SEQ ID NO: 98, 97, 99, 100, 101, 102, or 103, wherein the B comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 105, 104, 106, 107, 108, 109, and 110 or an amino acid sequence having at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 98% or preferably at least 99% identity to SEQ ID NO: 105, 104, 106, 107, 108, 109, and 110, preferably wherein(1) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;(2) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, and CDRb3 comprises SEQ ID NO: 26;(3) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, and CDRb3 comprises SEQ ID NO: 26;(4) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, and CDRb3 comprises SEQ ID NO: 26;(5) CDRal comprises SEQ ID NO: 3, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, and CDRb3 comprises SEQ ID NO: 27;(6) CDRal comprises SEQ ID NO: 2, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, and CDRb3 comprises SEQ ID NO: 28;(7) CDRal comprises SEQ ID NO: 4, CDRa3 comprises SEQ ID NO: 11, CDRbl comprises SEQ ID NO: 20, and CDRb3 comprises SEQ ID NO: 29;(8) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21, and CDRb3 comprises SEQ ID NO: 30;(9) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 31;(10) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, and CDRb3 comprises SEQ ID NO: 31;(11) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, and CDRb3 comprises SEQ ID NO: 31 ;(12) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 32;(13) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 33;(14) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 34;(15) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 35;(16) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 36;(17) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 37;(18) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 38;(19) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 39;(20) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 40;(21) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 41;(22) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 42;(23) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 43;(24) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 44;(25) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 45;(26) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 46;(27) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 47;(28) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 48;(29) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 49;(30) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 50;(31) CDRal comprises SEQ ID NO: 6, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, and CDRb3 comprises SEQ ID NO: 51; or(32) CDRal comprises SEQ ID NO: 5, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal, CDRa3, CDRbl and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

2. The antigen binding protein of claim 1 , wherein(1) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(2) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 54, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(3) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 55, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(4) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 56, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(5) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 8, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(6) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 16, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(7) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 17, CDRb2 comprises SEQ ID NO:82, and CDRb3 comprises SEQ ID NO: 26;(8) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:83, and CDRb3 comprises SEQ ID NO: 26;(9) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:84, and CDRb3 comprises SEQ ID NO: 26;(10) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:85, and CDRb3 comprises SEQ ID NO: 26;(11) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:86, and CDRb3 comprises SEQ ID NO: 26;(12) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:87, and CDRb3 comprises SEQ ID NO: 26;(13) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 57, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(14) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:88, and CDRb3 comprises SEQ ID NO: 26;(15) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO:89, and CDRb3 comprises SEQ ID NO: 26;(16) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 58, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(17) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 59, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(18) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 60, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(19) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 61 , CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(20) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 62, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(21) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 63, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(22) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 64, CDRa3 comprises SEQ ID NO: 7, CDRbl comprises SEQ ID NO: 15, CDRb2 comprises SEQ ID NO: 82, and CDRb3 comprises SEQ ID NO: 26;(23) CDRal comprises SEQ ID NO: 3, CDRa2 comprises SEQ ID NO: 65, CDRa3 comprises SEQ ID NO: 9, CDRbl comprises SEQ ID NO: 18, CDRb2 comprises SEQ ID NO: 90, and CDRb3 comprises SEQ ID NO: 27;(24) CDRal comprises SEQ ID NO: 2, CDRa2 comprises SEQ ID NO: 53, CDRa3 comprises SEQ ID NO: 10, CDRbl comprises SEQ ID NO: 19, CDRb2 comprises SEQ ID NO: 91, and CDRb3 comprises SEQ ID NO: 28;(25) CDRal comprises SEQ ID NO: 4, CDRa2 comprises SEQ ID NO: 66, CDRa3 comprises SEQ ID NO: 11, CDRbl comprises SEQ ID NO: 20, CDRb2 comprises SEQ ID NO: 92, and CDRb3 comprises SEQ ID NO: 29;(26) CDRal comprises SEQ ID NO: 5, CDRa2 comprises SEQ ID NO: 67, CDRa3 comprises SEQ ID NO: 12, CDRbl comprises SEQ ID NO: 21, CDRb2 comprises SEQ ID NO: 93, and CDRb3 comprises SEQ ID NO: 30;(27) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(28) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 95, and CDRb3 comprises SEQ ID NO: 31;(29) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 69, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(30) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 70, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(31) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 71 , CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(32) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 72, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(33) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 73, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(34) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 23, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(35) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 24, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(36) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 32;(37) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 33;(38) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 34;(39) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 74, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(40) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 35;(41) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 36;(42) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 37;(43) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 38;(44) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 39;(45) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 40;(46) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 41;(47) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 42;(48) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 43;(49) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 44;(50) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 75, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(51) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 45;(52) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 46;(53) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 47;(54) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 48;(55) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 49;(56) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 50;(57) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 68, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 51;(58) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 76, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(59) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 77, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(60) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 78, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(61) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 79, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(62) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 80, CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31;(63) CDRal comprises SEQ ID NO: 6, CDRa2 comprises SEQ ID NO: 81 , CDRa3 comprises SEQ ID NO: 13, CDRbl comprises SEQ ID NO: 22, CDRb2 comprises SEQ ID NO: 94, and CDRb3 comprises SEQ ID NO: 31; or(64) CDRal comprises SEQ ID NO: 5, CDRa2 comprises SEQ ID NO: 67, CDRa3 comprises SEQ ID NO: 14, CDRbl comprises SEQ ID NO: 25, CDRb2 comprises SEQ ID NO: 96, and CDRb3 comprises SEQ ID NO: 52; wherein the CDRal, CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequence(s) may comprise one, two or three amino acid mutations.

3. The antigen binding protein of any claim 1 or claim 2, wherein the VA comprisesan amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 97, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 7, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 98, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 3, 65, and 9, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 99, and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NOs: 2, 53, and 10, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 100, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 4, 66, and 11, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 101, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 12, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 102, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 6, 68, and 13, respectively, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 103, and comprising the CDRal, CDRa2, and CDRa3 of SEQ ID NOs: 5, 67, and 14, respectively, and wherein the VB comprises, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 104, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 15, 82, and26, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 105, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 18, 90, and27, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 106, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 19, 91, and28, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 107, and comprising the CDRbl, CDRb2, and CDRb3 of SEQ ID NOs: 20, 92, and29, respectively,an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 108, and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NOs: 21 , 93, and30, respectively, an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 109, and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NOs: 22, 94, and31 , respectively, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 110, and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NOs: 25, 96, and 52, respectively, wherein optionally the CDRal , CDRa2, CDRa3, CDRbl , CDRb2, and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

4. The antigen binding protein of any one of claims 1 to 3, wherein the VA comprises an amino acid sequence of SEQ ID NO: 98 and the VB comprises an amino acid sequence of SEQ ID NO: 105; wherein the VA comprises an amino acid sequence of SEQ ID NO: 97 and the B comprises an amino acid sequence of SEQ ID NO: 104; wherein the VA comprises an amino acid sequence of SEQ ID NO: 99 and the VB comprises an amino acid sequence of SEQ ID NO: 106; wherein the VA comprises an amino acid sequence of SEQ ID NO: 100 and the VB comprises an amino acid sequence of SEQ ID NO: 107; wherein the VA comprises an amino acid sequence of SEQ ID NO: 101 and the VB comprises an amino acid sequence of SEQ ID NO: 108; wherein the VA comprises an amino acid sequence of SEQ ID NO: 102 and the VB comprises an amino acid sequence of SEQ ID NO: 109; or wherein the VA comprises an amino acid sequence of SEQ ID NO: 103 and the VB comprises an amino acid sequence of SEQ ID NO: 110; and optionally wherein the framework region(s) comprise(s) at least one amino acid substitution.

5. The antigen binding protein of any one of claims 1 to 4, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 115, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 115 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 7, respectively, andthe second polypeptide comprises an amino acid sequence of SEQ ID NO: 122, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:122 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 15, 82, and 26, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 116, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:116 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 3, 65, and 9, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 123, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:123 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 18, 90, and 27, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 117, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:117 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 2, 53, and 10, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 124, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:124 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 19, 91 , and 28, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 118, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:118 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 4, 66, and 11 , respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 125, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:125 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 20, 92, and 29, respectively; wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 119, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:119 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and 12, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 126, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:126 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 21 , 93, and 30, respectively;wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 120, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:120 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 6, 68, and 13, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 127, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:127 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 22, 94, and 31 , respectively; or wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 121 , or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:121 and comprising the CDRal , CDRa2, and CDRa3 of SEQ ID NO: 5, 67, and 14, respectively, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 128, or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:128 and comprising the CDRbl , CDRb2, and CDRb3 of SEQ ID NO: 25, 96, and 52, respectively; wherein optionally said CDRal , CDRa2, CDRa3, CDRbl , CDRb2 and / or CDRb3 sequences may comprise one, two or three amino acid mutations, preferably amino acid substitutions.

6. The antigen binding protein of any one of claims 1 to 5, wherein the antigen binding protein is derived from a TCR, or is a TCR or fragments thereof.

7. The antigen binding protein of any one of claims 1 to 6, wherein the antigen binding protein has an EC50 determined in a cytokine release assay between less than about 100 nM to about 50 pM.

8. A nucleic acid or nucleic acids encoding the antigen binding protein as defined in any one of claims 1 to 7.

9. A vector or vectors comprising the nucleic acid or nucleic acids of claim 8.

10. A host cell comprising the antigen binding protein as defined any one of claims 1 to 7, the nucleic acid(s) of claim 8, or the vector(s) of claim 9.

11. The host cell of claim 10, wherein the host cell is a lymphocyte, preferably a T cell, a T cell progenitor or an NK cell, more preferably a CD4 or CD8 positive T cell.

12. A pharmaceutical composition comprising an antigen binding protein of any one of claims 1 to 7, (a) nucleic acid(s) of claim 8, (a) vector(s) of claim 9, or a host cell of claim 10 or claim 11 , and optionally a pharmaceutically acceptable carrier.

13. The antigen binding protein of any one of claims 1 to 7, the nucleic acid(s) of claim 8, the vector(s) of claim 9, the host cell of claim 10 or claim 11 , or the pharmaceutical composition of claim 12, for use in the treatment of cancer.

14. A method of treating cancer in a subject in need thereof, comprising: a) isolating cells from said subject; b) transforming the cells with (a) vector(s) and / or with (a) nucleic acid(s) encoding the antigen binding protein of any one of claims 1 to 7 to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

15. A method of treating cancer in a subject in need thereof, comprising: a) isolating cells from a healthy subject; b) transforming the cells with (a) vector(s) and / or with (a) nucleic acid(s) encoding the antigen binding protein of any one of claims 1 to 7 to produce transformed cells; c) expanding the transformed cells; and d) administering the transformed cells to said subject.

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