Bispecific TCER against a magea4- and a prame-derived peptide in combination with an immune checkpoint inhibitor for use in treating cancer

Abstract

The invention relates to the combination of an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a FRAME derived peptide, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins. In particular the invention relates to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a FRAME derived peptide and an immune checkpoint inhibitor for use as medicine.

Description

[0001] New PCT Patent Application

[0002] Applicant: Immatics Biotechnologies GmbH

[0003] Immatics Ref.: P315PC00

[0004] Bispecific proteins, combinations and applications thereof

[0005] The invention relates to the combination of an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a PRAME derived peptide, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins. In particular the invention relates to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a PRAME derived peptide and an immune checkpoint inhibitor for use as medicine.

[0006] Proteins serve as the building blocks of life, orchestrating a multitude of physiological processes within the human body. Leveraging their inherent biological activity, researchers exploit protein-based therapeutics to intervene in disease pathways at the molecular level, offering promising solutions for conditions ranging from cancer and autoimmune disorders to metabolic diseases and infections.

[0007] Bispecific proteins represent an emerging innovative class of protein-based therapeutics designed to simultaneously target two different epitopes or proteins, thereby offering enhanced therapeutic efficacy and versatility compared to traditional monospecific drugs. Bispecific proteins hold immense promise for treating a wide array of diseases, including cancer, autoimmune disorders, and infectious diseases.

[0008] An example for bispecific molecules that hold tremendous potential to treat e.g. cancer is the so called T cell Engaging Receptor (TCER®) format developed by the applicant of the present invention; see e.g. WO 2019 / 012138 Al herein incorporated. TCERs® are off-the-shelf biologies that leverage the body's immune system by redirecting and activating T cells towards cancer cells presenting specific tumor antigens. These novel biologies are engineered to allow T cells in the body to become activated and attack the tumor, regardless of the T cells' intrinsic specificity. A TCER® contains two polypeptide chains harboring a T cell-recruiting antibody domain and a pHLA-binding TCR domain. Furthermore, each of the polypeptide chains contains a Fc domain.

[0009] The development and utilization of such protein-based therapeutics is crucial for the field of immunotherapy.However, the full spectrum of effectiveness of these promising drugs has not yet been recognized. For example, highly effective combination therapies involving immunotherapy are still not standard.

[0010] Accordingly, there is a need for means and methods for additional effective cancer treatments.

[0011] Thus, the technical problem underlying the present invention is the provision of means and methods to treat cancer. The technical problem is solved and the above mentioned needs are addressed by the provision of the embodiments characterized in the claims and as provided herein below.

[0012] The patent applications EP24174662.7, EP24199013.4, EP25151617.5, PCT / EP2025 / 062557, EP24213284.3, EP25166821.6 and PCT / EP2025 / 082828 show the preliminary results of a Phase 1 first-in-human clinical trials that tests the efficiency and safety of the bispecific antigen-binding molecules PRAME-004 TCER® and MAG-003 TCER® as monotherapy and are incorporated herein by reference in their entirety. Said molecules show excellent anti-tumor activity with acceptable side effects against different cancer types.

[0013] In the appended Examples of the present application the inventors found surprisingly and unexpectedly that a synergistic anti-cancer effect is observed when a MAG-003 targeting TCER® and a PRAME-004 targeting TCER® are combined (see Example 1). Furthermore, the inventors found that that individuals who responded to the treatment with either PRAME-004 TCER® and MAG-003 TCER® as monotherapy exhibited a lower expression of PD-L1 as compared to those who did not respond (Example 3-A) and that cancers with high MAG-003 and PRAME-004 prevalence show high PD-L1 expression (Example 3-B). Similar results are provided for LAG-3 expression and TIM-3 expression (Examples 5 and 6). Furthermore, the inventors surprisingly and unexpectedly found that an immune checkpoint inhibitor can trigger substantial cytotoxicity of a MAG-003 targeting TCER® and a PRAME-004 targeting TCER® under conditions where the TCERs® alone do not show pronounced cytotoxicity (Example 4). Accordingly, the effect of a combination of a MAG-003 targeting antigen-binding protein and a PRAME-004 targeting antigen-binding can be further improved by combination with a checkpoint inhibitor. Accordingly, a combination of a MAG-003 targeting antigen-binding protein, a PRAME-004 targeting antigen-binding protein and an immune checkpoint inhibitoris beneficial for the patient outcome. Also a combination of a MAG-003 targeting antigenbinding protein, a PRAME-004 targeting antigen-binding protein, an immune checkpoint inhibitor targeting the PD-L1 axis and an immune checkpoint inhibitor targeting the LAG-3 axis is beneficial for the patient outcome.

[0014] Accordingly, the present invention provides a combination of MAG-003 targeting antigenbinding proteins, PRAME-004 targeting antigen-binding proteins and immune checkpoint inhibitors to allow treatment of a wide range of cancer types while counteracting potential tumor escape mechanism.

[0015] In particular the invention relates to an antigen-binding protein binding to a peptide according to SEQ ID NO: 57 or to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein and an antigen-binding protein binding to a peptide according SEQ ID NO: 58 or to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins for use as medicine, in particular for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders.

[0016] The above mentioned and herein described antigen-binding proteins may be produced separately and administered in combination with a checkpoint inhibitor to a patient in need thereof as produced proteins. The skilled person understands that "combination" does not necessarily mean that the antigen-binding proteins and the checkpoint inhibitor are combined into one pharmaceutical composition and administered as one pharmaceutical composition but that "combination" is used herein in the broadest sense and refers to at least three therapeutically active drugs or compositions which may be administered or co-administered, simultaneously, in either separate or combined formulations, or sequentially at different times separated by minutes, hours or days, but in some way act together to provide the desired therapeutic response.

[0017] It can be desirable to administer the to be combined antigen-binding proteins not as separately produced proteins but encoded by nucleic acids together with the checkpoint inhibitor. In other words, it may be beneficial to administer to the patient nucleic acid(s) encoding the antigen-binding proteins so that antigen-binding proteins are produced by the cells of the patient.In the following, the invention is described in more detail.

[0018] In particular, the invention relates to the following claims.

[0019] 1. An antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein and (an) immune checkpoint inhibitor(s) for use as medicine.

[0020] 2. A nucleic acid or nucleic acids encoding an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, and (an) immune checkpoint inhibitor(s) for use as medicine.

[0021] 3. The antigen-binding proteins of item 1 or the nucleic acid or nucleic acids of item 2 for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders.

[0022] 4. A combination comprising an antigen-binding protein binding to MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid or nucleic acids encoding said antigen-binding proteins and (an) immune checkpoint inhibitor(s).

[0023] 5. A pharmaceutical composition comprising an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid or nucleic acids encoding said antigen-binding proteins and (an) immune checkpoint inhibitor(s).6. A pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding at least two antigenbinding proteins and (an) immune checkpoint inhibitor(s), wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition and wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein.

[0024] 7. An antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with (an) immune checkpoint inhibitor(s) and an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein.

[0025] 8. An antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with and (an) immune checkpoint inhibitor(s) and an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein.

[0026] 9. A method of protein production in a cell population, wherein the method comprises contacting a cell population with a nucleic acid or nucleic acids encoding at least two antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that an effective amount of the protein isproduced in the cell population, wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, wherein (an) immune checkpoint inhibitor(s) is co-administered to the cell population.

[0027] 10. A method for inducing in vivo translation of at least two antigen-binding proteins in a subject in need thereof, comprising administering to the subject an effective amount of a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that the nucleic acid(s) is / are localized into a cell of the subject and the antigen-binding proteins are capable of being translated in the cell from the nucleic acid(s), wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, wherein (an) immune checkpoint inhibitor(s) is co-administered to the subject.

[0028] 11. A method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein and an immune checkpoint inhibitor.

[0029] 12. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 11, comprising one or more further antigen-binding proteins.

[0030] 13. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 12, wherein the antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a majorhistocompatibility complex (MHC) protein, the antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC), the immune checkpoint inhibitor(s) and optionally one or more further antigen-binding proteins act together to provide a desired therapeutic effect.

[0031] 14. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 13, wherein the MAGEA4 / 8 derived peptide is a peptide according to SEQ ID NO: 57.

[0032] 15. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 14, wherein the PRAME derived peptide is a peptide according to SEQ ID NO: 58.

[0033] 16. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 15, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (V|3).

[0034] 17. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 16, wherein the antibody variable light chain domain (VL) and the antibody variable heavy chain domain (VH) associate to form a functional antibody antigen binding site (VD).

[0035] 18. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 16, wherein the TCR alpha variable domain (Va) and the TCR beta variable domain (VP) associate to form a functional TCR antigen binding site (VR).

[0036] 19. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 16, wherein at least one of the antigen-binding proteins is bispecific.The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 16 to 19, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:

[0037] V1-V2-V3-V4,

[0038] wherein VI, V2, V3, and V4 are independently selected from VH, VL, Va and VP in any order and wherein each of VH, VL, Va and VP appears once.

[0039] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 16 to 19, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:

[0040] V1-V2-V3-V4,

[0041] wherein

[0042] VI is VH, V2 is VL, V3 is VP, V4 is Va;

[0043] VI is VL, V2 is VH, V3 is VP, V4 is Va;

[0044] VI is VH, V2 is VL, V3 is Va, V4 is Vp;

[0045] VI is VL, V2 is VH, V3 is Va, V4 is Vp;

[0046] VI is VP, V2 is Va, V3 is VH, V4 is VL;

[0047] VI is VP, V2 is Va, V3 is VL, V4 is VH;

[0048] VI is Va, V2 is VP, V3 is VH, V4 is VL; or

[0049] VI is Va, V2 is VP, V3 is VL, V4 is VH.The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 16 to 19, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:

[0050] V1-V2-V3-V4,

[0051] wherein VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0052] VI is VH, V2 is VP, V3 is Va, V4 is VL;

[0053] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0054] VI is VL, V2 is VP, V3 is Va, V4 is VH;

[0055] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0056] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0057] VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0058] VI is Va, V2 is VH, V3 is VL, V4 is vp.

[0059] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 20 to 22, wherein two or more of the variable domains are connected by linkers.

[0060] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 20 to 23, wherein the antigen-binding protein comprises a structure represented by the formula:

[0061] V1-L1-V2-L2-V3-L3-V4;

[0062] wherein LI, L2 and L3 are linkers and may be the same or different.25. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 24, wherein the linkers LI and / or L3 have a length of at least about 3.5 A, preferably at least about 7 A.

[0063] 26. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 24, wherein the linkers LI and / or L3 consist of at least one amino acid, preferably of at least two amino acids.

[0064] 27. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 24 to 26, wherein the linker L2 has a length of at least about 17.5 A.

[0065] 28. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 24 to 27, wherein the linker L2 consists of at least five amino acids.

[0066] 29. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 24, wherein the linkers LI, L2 and / or L3 comprise or consist of SEQ ID NO: 209 (GGGGS).

[0067] 30. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 24, wherein the linkers LI, L2 and / or L3 comprise or consist of SEQ ID NO: 210 (GGGGS GGGGS GGGGS).

[0068] 31. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 24, wherein the linkers LI and L3 comprise or consist of SEQ ID NO: 209 (GGGS) and L2 comprises or consists of SEQ ID NO: 210 (GGGGS GGGGS GGGGS).

[0069] 32. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 19, wherein at least one of the antigen-binding proteins comprises or consists ofa first polypeptide chain comprising a structure represented by the formula:

[0070] VL-L1-V0-FC1;

[0071] and a second polypeptide chain comprising a structure represented by the formula:

[0072] Va-L2-VH-FC2;

[0073] wherein LI and L2 are linkers and may be the same or different and FC1 and FC2 are Fc-domains and may be the same or different.

[0074] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 32, wherein LI and / or L2 comprise or consist of an amino acid sequence according to SEQ ID NO: 16.

[0075] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 32 or 33, wherein

[0076] FC1 comprises or consists of an amino acid sequence according to SEQ ID NOs: 1, 17, 19, 21 or 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1, 17, 19, 21 or 39

[0077] and / or

[0078] FC2 comprises or consists of an amino acid sequence according to SEQ ID NOs: 2, 18, 20, 22 or 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2, 18, 20, 22 or 40.

[0079] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 14 to 34, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),

[0080] wherein the Va domain comprises

[0081] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 62,

[0082] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 63, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 64; and wherein the VP domain comprises

[0083] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 59,(ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 60, and (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 61, wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0084] 36. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 14 to 35, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprises

[0085] a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 54 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 54 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 62, 63, and 64, respectively; and

[0086] a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 53 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 53 and comprising the CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 59, 60, and 61, respectively.

[0087] 37. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 15 to 36, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),

[0088] wherein the Va domain comprises

[0089] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 68,

[0090] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 69, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 70; and wherein the VP domain comprises

[0091] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 65,

[0092] (ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 66, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 67,wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0093] 38. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 15 to 37, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises

[0094] a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 56 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 56 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 68, 69, and 70, respectively; and

[0095] a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 55 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 55 and comprising the CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 65, 66, and 67, respectively.

[0096] 39. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of item 15 to 36, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),

[0097] wherein the Va domain comprises

[0098] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 95,

[0099] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 96, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 97; and wherein the VP domain comprises

[0100] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 99,

[0101] (ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 100, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 101,wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0102] 40. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 39, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises

[0103] a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 94 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 94 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 95, 96, and 97, respectively; and

[0104] a VP comprising or consisting of the amino acid sequence according to 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 CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 99, 100, and 101, respectively.

[0105] 41. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 15 to 36, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),

[0106] wherein the Va domain comprises

[0107] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 103,

[0108] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 104, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 105; and wherein the VP domain comprises

[0109] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 107,

[0110] (ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 108, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 109,wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0111] 42. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 41, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises

[0112] a Va comprising or consisting of the amino acid sequence according to 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 according to SEQ ID NOs: 103, 104, and 105, respectively; and

[0113] a VP comprising or consisting of the amino acid sequence according to 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 CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 107, 108, and 109, respectively.

[0114] 43. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 17 to 42, wherein one antigen binding site specifically binds to a cell surface molecule of a human immune cell and / or the other antigen binding site specifically binds to an MHC-associated peptide.

[0115] 44. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 43, wherein the cell surface molecule is known to induce the activation of the immune cell, or is at least one selected from the group consisting of immune response-related molecules, CD3, such as the CD3y, CD36, and CD3E chains, CD4, CD7, CD8, CD10, CDllb, CDllc, CD14, CD16, CD18, CD22, CD25, CD28, CD32a, CD32b, CD33, CD41 , CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD55, CD56, CD61, CD64, CD68, CD94, CD90, CD117, CD123, CD125, CD134, CD137, CD152, CD163, CD193, CD203c, CD235a, CD278, CD279, CD287, Nkp46, NKG2D, GITR, FCERI, TCRa / p, TCRy / 6, and HLA-DR.45. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 44, wherein the cell surface molecule is a TCR / CD3 complex, preferably an alpha / beta TCR / CD3 complex.

[0116] 46. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of item 45, wherein at least one of the antigen-binding proteins comprises

[0117] an antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH),

[0118] wherein the VL comprises

[0119] (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,

[0120] (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises

[0121] (i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,

[0122] (ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 11, and (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12; wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0123] 47. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 45 or 46, wherein at least one of the antigen-binding proteins comprises

[0124] a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0125] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 9 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ IDNO: 9 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.

[0126] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 45 or 46, wherein at least one of the antigen-binding proteins comprises

[0127] a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0128] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 93 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 93 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.

[0129] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 45, wherein at least one the antigen-binding proteins comprises

[0130] an antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH),

[0131] wherein the VL comprises

[0132] (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,

[0133] (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises

[0134] (i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,

[0135] (ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 14, and (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12; wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 45 or 50, wherein at least one of the antigen-binding proteins comprises

[0136] a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0137] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 13 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 13 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 14, and 12, respectively.

[0138] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 14 to 50 , wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 134, 135, 136, 137, 138, 139, 140, 141, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 178, 179, 180, 181, 197, 198, 204, 205 or 206;

[0139] or

[0140] wherein the antigen-binding protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 75, 77 79, 80 or 82 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, 81 or 83.

[0141] The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 15 to 51, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,133, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 182, 183, 184, 185, 186, 189, 190, 191, 192, 193, 194, 195, 196, 199, 200, 201, 202, 203, 207 or 208;

[0142] or

[0143] wherein the antigen-binding protein binding comprises a polypeptide comprising or consisting of an amino acid sequence according SEQ ID NOs: 71, 73, 74, 84, 86 or 187 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72, 85, 87 or 188.

[0144] 53. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of item 14 or 15, wherein the antigenbinding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 75 or 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 76 and the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according SEQ ID NO: 71 or 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 72.

[0145] 54. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methodsof any one of the preceding items, wherein the immune checkpoint inhibitor(s) is / are administered before, concomitantly, simultaneously or after administration of the antigen-binding proteins, the nucleic acid, or the separate nucleic acids..

[0146] 55. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methodsof any one of the preceding items, wherein one / the immune checkpoint inhibitor is a PD1 inhibitor, preferably Pembrolizumab or cemiplimab.56. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methodsof any one of the preceding items, wherein one / the immune checkpoint inhibitor is a LAG-3 inhibitor, preferably Fianlimab.

[0147] 57. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 54, wherein the immune checkpoint inhibitors are Nivolumab and Relatlimab.

[0148] 58. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of items 1 to 54, wherein the immune checkpoint inhibitors are Fianlimab and Cemiplimab.

[0149] 59. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methodsof any one of the preceding items, wherein the cancer to be treated is head and neck squamous cell carcinoma (HNSCC), lung squamous cell carcinoma, such as sqNSCLC, lung adenocarcinoma, esophageal carcinoma, triple-negative breast cancer, melanoma, such as skin cutaneous melanoma, bladder carcinoma, endometrial carcinoma or ovarian carcinoma, preferably sqNSCLC.

[0150] In the following, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments, which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.As mentioned above the present inventors identified that a combination of MAG-003 targeting antigen-binding proteins, PRAME-004 targeting antigen-binding proteins and immune checkpoint inhibitors has excellent anti-cancer activity.

[0151] Accordingly, it is envisaged in context of the invention that usually at least three components are used to treat a patient. It is envisaged that an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a PRAME derived peptide and an immune checkpoint inhibitor are used to treat a patient. In other words, it is envisaged that a combination of an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a PRAME derived peptide and an immune checkpoint inhibitor are used to treat a patient. "Combination", "antigen-binding protein" and "immune checkpoint inhibitor" are used herein in the broadest sense and defined further herein below. Importantly, when it is referred herein to an or the immune checkpoint inhibitor always also multiple immune checkpoint inhibitors are encompassed. It is in particular envisaged that two immune checkpoint inhibitors are used, preferably an inhibitor of the PD-1 axis (such as Pembrolizumab, Nivolumab or Cemiplimab) and an inhibitor of the LAG-3 axis (such as Relatlimab or Fianlimab). Accordingly, all the described embodiments are also disclosed with at least four components, an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a PRAME derived peptide and two immune checkpoint inhibitors, preferably an inhibitor of the PD-1 axis (such as Pembrolizumab, Nivolumab or Cemiplimab) and an inhibitor of the LAG-3 axis (such as Relatlimab or Fianlimab).

[0152] Accordingly the invention relates to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide preferably bound to a major histocompatibility complex (MHC) protein, an antigenbinding protein binding to a PRAME derived peptide preferably bound to a major histocompatibility complex (MHC) protein and an immune checkpoint inhibitor for use as medicine. In this aspect it is envisaged that the antigen-binding protein binding to a MAGEA4 / 8 derived peptide, the antigen-binding protein binding to a PRAME derived peptide and the immune checkpoint inhibitor are produced recombinantly, purified and administered to the patient as proteins.

[0153] It is further envisaged that nucleic acids encoding said components are used for the treatment of a patient. In particular it is envisaged that the antigen-binding protein binding to a MAGEA4 / 8 derived peptide and / or the antigen-binding protein binding to a PRAME derivedpeptide are encoded by a nucleic acid and said nucleic acids(s) is / are used to treat a patient and the immune checkpoint inhibitor is used in form of a protein. The skilled person understands that this means that the nucleic acids encoding an antigen-binding protein binding to a MAGEA4 / 8 derived peptide and an antigen-binding protein binding to a PRAME derived peptide are administered to the patient and the immune checkpoint inhibitor is administered in form of a protein. The invention, thus, relates to a nucleic acid or nucleic acids encoding an antigen-binding protein binding to a MAGEA4 / 8 derived peptide preferably bound to a major histocompatibility complex (MHC) protein and an antigen-binding protein binding to a PRAME derived peptide preferably bound to a major histocompatibility complex (MHC) protein, and an immune checkpoint inhibitor for use as medicine.

[0154] It is, however, also envisaged that a nucleic acid encoding the immune checkpoint-inhibitor(s) is used in context of the described embodiments.

[0155] Although evident to the skilled person, it is noted for the sake of clarity that the immune checkpoint inhibitors used in the context of the present invention are typically themselves antigen-binding proteins. Accordingly, when reference is made herein to two antigen-binding proteins (for example, one antigen-binding protein binding to a MAGE-A4 / 8-derived peptide and one antigen-binding protein binding to a PRAME-derived peptide) and an immune checkpoint inhibitor, the skilled person will understand that this may in fact refer to a combination comprising three antigen-binding proteins.

[0156] The invention further relates to a combination comprising an antigen-binding protein binding to MAGEA4 / 8 derived peptide (bound to a major histocompatibility complex (MHC) protein), an antigen-binding protein binding to a PRAME derived peptide (bound to a major histocompatibility complex (MHC) protein) or a nucleic acid or nucleic acids encoding said antigen-binding proteins and an immune checkpoint inhibitor.

[0157] The invention further relates to a pharmaceutical composition comprising an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid or nucleic acids encoding said antigen-binding proteins and an immune checkpoint inhibitor.The invention further relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding at least two antigen-binding proteins and an immune checkpoint inhibitor, wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition and wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigenbinding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein.

[0158] The invention also relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding at least two antigen-binding proteins, wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition and wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein and wherein said pharmaceutical composition is administered in combination with an immune checkpoint inhibitor.

[0159] The invention also relates to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigen-binding protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with an immune checkpoint inhibitor and an antigenbinding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigen-binding protein.

[0160] The invention also relates to an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigen-binding protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-bindingprotein is administered in combination with and an immune checkpoint inhibitor and an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigen-binding protein.

[0161] The invention also relates to a method of protein production in a cell population, wherein the method comprises contacting a cell population with a nucleic acid or nucleic acids encoding at least two antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that an effective amount of the protein is produced in the cell population, wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably wherein an immune checkpoint inhibitor is co-administered to the cell population.

[0162] The invention also relates to a method for inducing in vivo translation of at least two antigenbinding proteins in a subject in need thereof, comprising administering to the subject an effective amount of a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that the nucleic acid(s) is / are localized into a cell of the subject and the antigen-binding proteins are capable of being translated in the cell from the nucleic acid(s), wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably wherein an immune checkpoint inhibitor is co-administered to the subject.

[0163] The invention also relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and an antigen-binding proteinbinding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein and an immune checkpoint inhibitor.

[0164] The skilled person is readily capable to determine which conditions may be treated by the herein described means and methods. For example cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders may be treated.

[0165] Accordingly, the invention relates to the herein described antigen-binding proteins, the nucleic acids, combinations, compositions and methods for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders. Preferably, a cancer, a tumor or tumorous disease is treated.

[0166] "Cancer", "tumor" or "tumorous disease" may be used interchangeably herein. "Cancer" in particular refers to disease characterized by the uncontrolled, abnormal proliferation of cells that may have acquired the ability to invade surrounding tissues and, in many cases, to spread (metastasize) to distant organs via the blood or lymphatic systems. "Tumor" in particular refers to an abnormal mass of tissue resulting from excessive or unregulated cell division.

[0167] It is evident that in most embodiments two antigen-binding proteins are combined with an immune checkpoint inhibitor. The immune checkpoint inhibitor may also be an antigenbinding protein. Nevertheless, the skilled person understands that when it is referred herein to "two antigen-binding proteins" or "at least two antigen-binding proteins" usually the antigen-binding protein binding to a MAGEA4 / 8 derived peptide and an antigen-binding protein binding to a PRAME derived peptide are meant. When combinations of an antigenbinding protein binding to a MAGEA4 / 8 derived peptide and an antigen-binding protein binding to a PRAME derived peptide are disclosed without explicitly mentioning the immune checkpoint inhibitor it is nevertheless evident to the skilled person that such combinations are also disclosed as embodiments further comprising an immune checkpoint inhibitor.

[0168] Similar when it is referred to "one or more further antigen-binding proteins" it is evident for the skilled person that this refers to embodiments including an antigen-binding protein binding to a MAGEA4 / 8 derived peptide, an antigen-binding protein binding to a PRAME derived peptide, an immune checkpoint inhibitor and at least one additional antigen-binding protein, preferably wherein the at least one additional antigen-binding protein binds to a differentantigen than the antigen-binding protein binding to a MAGEA4 / 8 derived peptide and the antigen-binding protein binding to a PRAME derived peptide.

[0169] Furthermore, it is pointed out that all embodiments referring to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide and an antigen-binding protein binding to a PRAME derived peptide are also disclosed as embodiments with at least one antigen-binding protein binding to a MAGEA4 / 8 derived peptide and at least one antigen-binding protein binding to a PRAME derived peptide. In other words, all embodiments disclosed herein may have two or several antigen-binding proteins binding to a MAGEA4 / 8 derived peptide and two or several antigen-binding proteins binding to a PRAME derived peptide.

[0170] Furthermore, it is explicitly stated for the sake of clarity that, where reference is made herein (in particular in the claims and the item list) to features in connection with "at least one" antigen-binding protein (e.g. "wherein at least one of the antigen-binding proteins is bispecific"), preferred embodiments are encompassed in which said feature is present in both the antigen-binding protein binding to a MAG E-A4 / 8-de rived peptide and the antigen-binding protein binding to a PRAME-derived peptide (e.g. wherein the antigen-binding protein binding to a MAG E-A4 / 8-de rived peptide is bispecific and the antigen-binding protein binding to a PRAME-derived peptide is bispecific).

[0171] The term "amino acid variant" as used herein may refer to a change in the sequence of amino acids in a protein, resulting from a substitution, insertion or deletion. For example, S354C means that the serine at position 354 in the CH3-domain of an antibody is exchanged / replaced by a cysteine.

[0172] Preferably, the inventive molecule is an antigen-binding protein. "Antigen-binding protein" as used herein refers to a protein that specifically recognizes an antigen through its antigenbinding site(s). 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 at least one antigen binding site of e.g. an antigen-binding protein. The terms "antigen" and "epitope" may be used interchangeably herein. However, "epitope" may also refer to a specific molecular structure on the antigen. The antigen or epitope is bound by the antigen-binding site or antigen-binding domain. Accordingly, the term "antigen-binding site" or "antigen-binding domain" as used herein refers to the structure in the antigen-binding protein that interacts with the antigen or epitope e.g. via hydrogen bonds, electrostatic interactions and hydrophobic interactions.The phrases "the antigen-binding protein specifically recognizes", "the antigen-binding protein is reactive with", "the antigen-binding protein binds" or "the antigen-binding protein specifically binds" may be used synonymously herein and refers to the ability of a protein to bind to another molecule, typically another protein / peptide, a specific region on a protein / peptide, a protein / protein complex or a protein / peptide complex, with high affinity and specificity. This recognition may occur through complementary molecular surfaces or structures, where specific interactions take place, such as hydrogen bonds, electrostatic interactions and hydrophobic interactions.

[0173] Affinity refers to the strength of the interaction between two molecules. In the context of proteins, it typically describes how tightly a protein binds to another molecule, such as an antigen. Higher affinity implies a stronger binding interaction, while lower affinity suggests a weaker binding. Affinity is often quantified by the dissociation constant (Kd). Lower Kd values indicate higher affinity.

[0174] Specificity refers to the selectivity of a molecular interaction, particularly the ability of a molecule (such as a protein) to discriminate between different ligands or binding partners. Thus, in the context of proteins, specificity may relate to the ability of a protein to bind selectively to its cognate ligand or binding partner, despite the high concentration of other molecules present in the corresponding environment. It is evident for the skilled person that in context of the present invention specificity may mean the ability of an antigen-binding protein to discriminate between different antigens and to bind selectively to its target antigen.

[0175] It is envisaged that the antigen-binding proteins in context of the invention have more than one antigen-binding site. In other words, the antigen-binding protein in context of the invention may be a bispecific, trispecific or multispecific antigen-binding protein, preferably a bispecific antigen-binding protein. Accordingly, the invention relates to the herein described embodiments, wherein the antigen-binding proteins are a bispecific, trispecific or multispecific antigen-binding protein, preferably a bispecific antigen-binding protein.

[0176] The term "bispecific" in connection with the herein described antigen-binding proteins refers to antigen-binding proteins with at least two valences and binding specificities for two different antigens and, thus, comprise at least two antigen-binding sites. The term "valence" refers to the number of binding sites of an antigen-binding protein, e.g. a bivalent antigenbinding protein relates to an antigen-binding protein that has two binding sites. It should benoted, that, the term valence refers to the number of binding sites, wherein those binding sites may bind to the same or different targets, i.e. a bivalent antigen binding protein may be monospecific, i.e. binding one target, or bispecific, i.e. binding two different targets. Targets may be antigens, such as (target) peptides.

[0177] In the context of "bispecific" it is preferred herein that at least one specificity of the antigen binding sites is derived from a TCR, more particularly, that at least one antigen-binding site comprises the TCR derived CDRs as described herein. It may also refer to that at least one binding site is derived from antibodies. In particular, the term "bispecific" in the context of the present invention may refer to an antigen-binding protein which combines at least one antigen-binding site comprising TCR derived CDRs, and at least one further antigen-binding site, wherein said at least one further antigen-binding site, may be derived from an antibody and thus comprises antibody CDRs, or from a further TCR and thus comprises the CDRs of a further TCR, preferably said further antigen binding site, is derived from an antibody and thus comprises antibody CDRs. A preferred format is the TCER® format as described in WO 2019 / 012138, which is herein incorporated by reference in its entirety or the single-chain diabody format as described in EP25213127, which is herein incorporated by reference in its entirety. When it is referred to a bispecific molecule it is, however, possible that e.g. the Fc part of said molecule has an additional binding partner e.g. FcRn.

[0178] Thus, the the antigen-binding proteins in context of the invention may have a first binding domain / site and a second binding domain / site. Accordingly, the invention relates to the herein described proteins, wherein the antigen-binding protein comprises a first binding domain / site and a second binding domain / site. "Binding domain / site" and "antigen-binding domain / site" may be used interchangeably herein.

[0179] It is envisaged that one antigen binding domain binds to a cell surface molecule of a human immune cell. It is envisaged that said surface molecule is known to induce the activation of the immune cell, or is at least one selected from the group consisting of immune response-related molecules, CD3, such as the CD3y, CD36, and CD3E chains, CD4, CD7, CD8, CD10, CDllb, CDllc, CD14, CD16, CD18, CD22, CD25, CD28, CD32a, CD32b, CD33, CD41 , CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD55, CD56, CD61, CD64, CD68, CD94, CD90, CD117, CD123, CD125, CD134, CD137, CD152, CD163, CD193, CD203c, CD235a, CD278, CD279, CD287, Nkp46, NKG2D, GITR, FCERI, TCRa / P, TCRy / 6, and HLA-DR. In particular, the cell surface molecule may be a TCR / CD3 complex, preferably an alpha / beta TCR / CD3 complex. Said antigen binding sitemay be antibody derived. Accordingly, a VH and VL may form an antigen-binding domain that specifically binds to a T cell receptor complex. Binding of the antigen-binding domain that specifically binds to a T cell receptor complex may activate the T cell. Corresponding variable domains and CDRs are described throughout this application. The domain may bind to any part or epitope of the alpha / beta TCR / CD3 complex.

[0180] It is also envisaged that one binding domain specifically binds to an MHC-associated peptide or MHC-associated peptide epitope. MHC proteins are a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates, which inter alia determines histocompatibility. The main function of MHC molecules is to bind to antigens derived from pathogens and tumor antigens and display them on the cell surface for recognition by the appropriate T cells. It is preferred that the MHC protein belongs to MHC class I. It is further preferred that the MHC protein is of the serotype group HLA-A, preferably HLA-A*24 or HLA-A*02. It is most preferred that the MHC protein is of the serotype HLA-A*02. The skilled person is well aware that HLA-A*02 can be further subdivided. A preferred serotype is HLA-A*02:01. The skilled person understands that when it is referred herein to HLA-A*02 the serotype HLA-A*02:01 is preferred. As described further herein it is in particular envisaged that the antigen-binding domain binding to an MHC-associated peptide comprises or consists of a T cell receptor (TCR) or a functional fragment or derivative thereof.

[0181] Accordingly, it is envisaged that the herein described antigen-binding proteins comprises a first binding domain specifically binding to a cell surface molecule of a human immune cell and / or a second binding domain specifically binding to an MHC-associated peptide epitope.

[0182] Furthermore, it is envisaged that in the antigen-binding proteins in context of the invention the first and / or second binding domain comprises or consists of an antibody or a functional fragment or derivative thereof.

[0183] In an "antibody" also called "immunoglobulin" two 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 (I) 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 sequence domains. The light chain includes two domains or regions, a variable domain (VL) and a constant domain (CL). The heavy chain includes four domains, a variable domain (VH) and three constant domains (CHI, CH2 and CH3, collectivelyreferred to as CH or Fc or Fc domain). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site (synonym to antibody binding site) and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). CDRs refer to amino acid sequences that together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, that may be referred to as CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, respectively or CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively. A conventional antibody antigen binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region.

[0184] In the context of the application, an antibody may be an IgM, IgD, IgG, IgA or IgE.

[0185] "Antibody Framework Regions" (FRs) referto amino acid sequences interposed between CDRs, i.e. to those portions of immunoglobulin light and heavy chain variable regions that are relatively conserved among different immunoglobulins in a single species. The light and heavy chains of an immunoglobulin 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 thus be designated as (FR1-L)-(CDR1-L)-(FR2-L)-(CDR2-L)-(FR3-L)-(CDR3-L)-(FR4-L) and the heavy chain variable domain may thus be designated as (FR1-H)-(CDR1-H)-(FR2-H)-(CDR2-H)-(FR3-H)-(CDR3-H)-(FR4-H).

[0186] CDR / FR definition in an immunoglobulin light or heavy chain, may be determined based on IMGT definition (Lefranc et al. Dev. Comp. Immunol., 2003, 27(l):55-77; www.imgt.org). In context of the present application it is preferred that CDR / FR definition in an immunoglobulin light or heavy chain are determined according to Kabat numbering (Kabat et al., 1992, Sequences of Proteins of Immunological Interest). Accordingly, amino acid sequences of the CDR1, CDR2 and CDR3 of a given variable chain of an antibody or antibody fragment are indicated according to said Kabat definition.Knowing the amino acid sequence of the CDRs of an antibody, a TCR or an antigen binding protein of the invention, one skilled in the art can easily determine the framework regions, such as the TCR framework regions or antibody framework regions. However, in cases where the CDRs are not indicated, the person skilled in the art can first determine the CDR amino acid sequences based on the IMGT definition for TCRs or the IMGT definition or Kabat definition for antibodies and then determine the amino acid sequences of the framework regions.

[0187] 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 antigen-binding protein, such as a naturally occurring human antibody or human TCR.

[0188] A functional fragment or derivative of an antibody refers to a modified form of the antibody molecule that retains some or all of its functional properties but may have altered characteristics such as size or structure. These modifications can be made to enhance the antibody's therapeutic potential, improve its stability, reduce immunogenicity or enable specific interactions with target molecules.

[0189] Fragments of antibodies may comprise a portion of an intact antibody, in particular the antigen-binding region or variable region of the intact antibody. Examples of antibody fragments include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv and sc(Fv)2. A fragment of an antibody may also be a single domain antibody, such as a heavy chain antibody (including nanobodies) orVHH.

[0190] Furthermore, it is envisaged that in the herein described antigen-binding proteins the first and / or second binding domain comprises or consists of a T cell receptor (TCR) or a functional fragment or derivative thereof.

[0191] A TCR is a heterodimeric cell surface protein of the immunoglobulin super-family, which is associated with invariant proteins of the CD3 complex involved in mediating signal transduction. TCRs exist in a|3 and y6 forms, which are structurally similar but have quite distinct anatomical locations and probably functions. The extracellular portion of native heterodimeric a|3 TCR and y6 TCR each contain two polypeptides, each of which has a membrane-proximal constant domain and a membrane-distal variable domain. Each of the constant and variable domains include an intra-chain disulfide bond. The variable domainscontain the highly polymorphic loops analogous to the complementarity determining regions (CDRs) of antibodies.

[0192] The term TCR herein denotes TCRs and fragments thereof, as well as single chain TCRs and fragments thereof, in particular variable alpha and beta domains of single domain TCRs, and chimeric, humanized, bispecific or multispecific TCRs.

[0193] Fragments of a TCR comprise a portion of an intact or native TCR, in particular the antigenbinding region or variable region of the intact or native TCR. Examples of TCR fragments include fragments of the a, |3, 6, y chain, such as Va- Caor Vp- Cp or portions thereof, such fragments might also further comprise the corresponding hinge region or single variable domains, such as Va, Vp, Vs, VY, or single chain VaVP fragments. Fragments of a TCR may exert identical functions compared to the naturally occuring full-length TCR, i.e. fragments selectively and specifically bind to their target peptide.

[0194] The TCR may also be a single chain TCR (scTCR). scTCR herein denotes a protein wherein the variable domains of the TCR, such as the Vaand Vp or Vs and VYare located on one polypeptide. Typically, the variable domains are separated by a linker, wherein said linker typically comprises 5 to 20, such as 5 to 15 amino acids.

[0195] "Native" as used for example in the wording "native TCR" refers to a wildtype TCR.

[0196] Native alpha-beta heterodimericTCRs have an alpha chain and a beta chain. The skilled person is well aware how the TCR chains are assembled by recombination of the corresponding genomic regions (Lefranc, (2001), Curr Protoc Immunol Appendix 1: Appendix 10; 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). For more information on immunoglobulin antibody and TCR genes see the international ImMunoGeneTics information system®, Lefranc M-P et al (Nucleic Acids Res.

[0197] 2015 Jan; 43 (Database issue):D413-22; and http: / / www.imgt.org / ). Each variable region, herein referred to as alpha variable domain and beta variable domain, comprises three Complementarity Determining Regions (CDRs) embedded in a framework sequence, one being the hypervariable region named CDR3. The alpha variable domain CDRs may be referred to as CDRal, CDRa2 and CDRa3 or CDRal, CDRa2, and CDRa3 and the beta variable domain CDRs may herein referred to as CDRbl, CDRb2 and CDRb3 or CDR|31, CDR|32, and CDR|33. A conventional TCR antigen binding site, therefore, includes, usually, six CDRs, comprising the CDR set from each of an alpha and a beta chain variable region, wherein CDR1 and CDR3sequences are relevant for the recognition and binding of the peptide antigen that is bound to the HLA protein and the CDR2 sequences are relevant for the recognition and binding of the HLA protein.

[0198] Analogous to antibodies, TCR framework regions (FRs) refer to amino acid sequences interposed between CDRs, i.e. to those portions of TCR alpha and beta chain variable regions that are to some extent conserved among different TCRs in a single species. The alpha and beta chains of a TCR each have four FRs, herein designated FRl-a, FR2-a, FR3-a, FR4-a, and FRl-b, FR2-b, FR3-b, FR4-b, respectively. Accordingly, the alpha chain variable domain may thus be designated as (FRl-a)-(CDRal)-(FR2-a)-(CDRa2)-(FR3-a)-(CDRa3)-(FR4-a) and the beta chain variable domain may thus be designated as (FRl-b)-(CDRbl)-(FR2-b)-(CDRb2)-(FR3-b)-(CDRb3)-(FR4-b).

[0199] In the context of the invention, CDR / FR definition in an a or p chain is to be determined based on IMGT definition (Lefranc et al. Dev. Comp. Immunol., 2003, 27(l):55-77; www.imgt.org). Similarly, native gamma-delta heterodimeric TCRs have a gamma chain and a delta chain. The skilled person is well aware how the TCR chains are assembled by recombination of the corresponding genomic regions (Lefranc, (2001), Curr Protoc Immunol Appendix 1: Appendix 10; 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). For more information on immunoglobulin antibody and TCR genes see 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 / ). Also, CDR / FR definition in an y or 6 chain is to be determined based on IMGT definition (Lefranc et al. Dev. Comp. Immunol., 2003, 27(l):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. The invention also encompasses the described embodiments with antigen-binding proteins with the CDRs of all the described variable domains (i.e. of all Va, VP, VL and VH) as determined by the skilled person by the above described means.

[0200] An antigen-binding protein in context of the invention may comprise a first binding domain comprising or consisting of an antibody or a functional fragment or derivative thereof and a second binding domain comprising or consisting of a T cell receptor (TCR) or a functional fragment or derivative thereof.In the herein described antigen-binding proteins, the first binding domain may comprise or consist of an antibody antigen binding site (or a TCR antigen binding site) (VD).

[0201] Although evident for the skilled person it is pointed out that it is envisaged that the antibody variable light chain domain (VL) and the antibody variable heavy chain domain (VH) associate to form a functional antibody antigen-binding site (VD).

[0202] It is further envisaged that in the herein described antigen-binding proteins the second binding domain may comprise or consist of a TCR antigen binding site (VR). In further certain embodiments, the first and the second binding domain may be derived from antibodies, and may comprise fragments of antibodies, e.g. variable domains of antibodies.

[0203] The TCR antigen binding site may comprise a TCR alpha variable domain (Va) and a TCR beta variable domain (VP). Although evident for the skilled person it is pointed out that it is envisaged that TCR alpha variable domain (Va) and the TCR beta variable domain (VP) associate to form a functional TCR antigen binding site (VR).

[0204] The antigen-binding protein may be a single-chain polypeptide. In particular single-chain antigen-binding proteins (single chain diabodies) as described in EP25213127.1, which is incorporated herein by reference in its entirety.

[0205] As used herein, the term "single-chain polypeptide" refers to a (recombinant) polypeptide expressed as a single, continuous amino acid sequence that may comprises two or more domains. The domains are covalently joined, either directly or via one or more linker sequences, thereby forming a single translation product from a single open reading frame. A single-chain polypeptide is distinguished from multimeric proteins composed of separate polypeptide chains that are associated non-covalently.

[0206] As used herein, the term "at least two different" refers to two or more entities / molecules that are not identical in at least one respect, including but not limited to differences in amino acid sequence, domain arrangement, binding specificity, target antigen or biological function, i.e. the differences may be structural and / or functional. The molecules may differ in one or more functional properties, such as affinity, specificity, stability, or expression level. However, the molecules may differ only in sequence or structural arrangement while retaining a common binding specificity.The term "format" herein refers to an antigen-binding protein comprising a specific number and type of domains that are present in said antigen-binding protein and the spatial organization thereof.

[0207] It is envisaged that the antigen-binding proteins in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:

[0208] V1-V2-V3-V4,

[0209] wherein

[0210] VI is VH, V2 is VL, V3 is VP, V4 is Va;

[0211] VI is VL, V2 is VH, V3 is VP, V4 is Va;

[0212] VI is VH, V2 is VL, V3 is Va, V4 is V£;

[0213] VI is VL, V2 is VH, V3 is Va, V4 is V£;

[0214] VI is VP, V2 is Va, V3 is VH, V4 is VL;

[0215] VI is VP, V2 is Va, V3 is VL, V4 is VH;

[0216] VI is Va, V2 is VP, V3 is VH, V4 is VL; or

[0217] VI is Va, V2 is VP, V3 is VL, V4 is VH.

[0218] Furthermore, it is envisaged that the antigen-binding proteins comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:

[0219] V1-V2-V3-V4,

[0220] wherein VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0221] VI is VH, V2 is VP, V3 is Va, V4 is VL;

[0222] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0223] VI is VL, V2 is VP, V3 is Va, V4 is VH;

[0224] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0225] VI is Va, V2 is VL, V3 is VH, V4 is VP;VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0226] VI is Va, V2 is VH, V3 is VL, V4 is vp.

[0227] It is pointed out that all of the described antigen-binding proteins may be used in all aspects of the invention. The skilled person understands that particular preferred embodiments relate to a combination of two single-chain antigen-binding proteins and an immune checkpoint inhibitor, wherein one single-chain antigen-binding protein binds to a MAGEA4 / 8 derived peptide and the other single-chain antigen-binding protein binds to a PRAME derived peptide. Certain parts of the described antigen binding proteins, especially the variable domains may be connected by linkers. Accordingly, the invention relates to the herein described antigenbinding proteins, wherein two or more of the variable domains are connected by linkers, in particular wherein all variable domains are connected by linkers.

[0228] Thus the invention relates to the described antigen-binding proteins, wherein the antigenbinding protein comprises a structure represented by the formula:

[0229] V1-L1-V2-L2-V3-L3-V4;

[0230] wherein LI, L2 and L3 are linkers and may be the same or different.

[0231] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure VH-Va-VP-VL, in particular VH-Ll-Va-L2-V|3-L3-VL.

[0232] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure VH-VP-Va-VL, in particular VH-Ll-VP-L2-Va-L3-VL.

[0233] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure VL-Va-VP-VH, in particular VL-Ll-Va-L2-VP-L3-VH.

[0234] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain(Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure VL-VP-Va-VH, in particular VL-Ll-VP-L2-Va-L3-VH.

[0235] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure Vp-VL-VH-Va, in particular Vp-Ll-VL-L2-VH-L3-Va.

[0236] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure Va-VL-VH-VP, in particular Va-Ll-VL-L2-VH-L3-Vp.

[0237] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure Vp-VH-VL-Va, in particular Vp-Ll-VH-L2-VL-L3-Va.

[0238] An antigen-binding protein in context of the invention may comprise an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the antigen-binding protein comprises the structure Va-VH-VL-VP, in particular Va-Ll-VH-L2-VL-L3-Vp.

[0239] In the described antigen-binding proteins the linkers LI and / or L3 may be absent or have a length of about 3.5 A to about 87.5 A, about 3.5 A to about 70 A, about 3.5 A to about 52.5 A, about 3.5 A to about 52.5 A, about 3.5 A to about 35 A, about 7 A to about 87.5 A, about 7 A to about 70 A, about 7 A to about 52.5 A, about 7 A to about 52.5 A or about 7 A to about 35 A, preferably about 7 A to about 87.5 A, about 7 A to about 70 A, about 7 A to about 52.5 A, about 7 A to about 52.5 A or about 7 A to about 35 A, in particular about 7 A to about 35 A. The antigen-binding proteins may comprise linkers LI and / or L3 having a length of at least about 3.5 A, at least about 7 A, at least about 10.5 A, at least about 14 A, at least about 17.5 A, preferably at least about 7 A or at least about 17.5 A, more preferably at least about 17.5 A.

[0240] In the described antigen-binding proteins the linkers LI and / or L3 may be absent or consist of at least 1 amino acid, at least 2 amino acids, at least 3 amino acids, at least 4 amino acids or at least 5 amino acids, preferably at least 2 amino acids or at least 5 amino acids, more preferably at least 5 amino acids.In the described antigen-binding proteins the linkers LI and / or L3 may be absent or consist of 1 to 25 amino acids, 1 to 20 amino acids, 1 to 15 amino acids, 1 to 10 amino acids, 2 to 25 amino acids, 2 to 20 amino acids, 2 to 15 amino acids, 2 to 10 amino acids, 3 to 10 amino acids, 3 to 8 amino acids or 3 to 7 amino acids, preferably 2 to 10 amino acids.

[0241] In the described antigen-binding proteins the linkers LI and / or L3 may be absent or consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 amino acids, in particular 5 or 8 amino acids.

[0242] In the described antigen-binding proteins the linker L2 may have a length of at least about 17.5 A, at least about 35 A or at least about 52.5 A, preferably at least about 17.5 A.

[0243] The linker L2 may have a length of about 17.5 A to about 140 A, about 17.5 A to about 105 A, about 17.5 A to about 87.5 A or about 17.5 A to about 70 A.

[0244] In the described antigen-binding proteins the linker L2 may have a length of at least 5 amino acids, at least 6 amino acids, at least 7 amino acids, at least 8 amino acids, at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids or at least 15 amino acids, preferably at least 5 amino acids, at least 10 amino acids or at least 15 amino acids.

[0245] In the described antigen-binding proteins the linker L2 may have a length of 5 to 40 amino acids, 5 to 35 amino acids, 5 to 30 amino acids, 5 to 25 amino acids, 5 to 20 amino acids, 10 to 40 amino acids, 10 to 35 amino acids, 10 to 30 amino acids, 10 to 25 amino acids or 10 to 20 amino acids, in particular 5 to 25 amino acids or 10 to 25 amino acids.

[0246] In the described antigen-binding proteins the linker L2 may consist of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 amino acids, in particular 15 amino acids.

[0247] The linkers may comprise glycine and serine residues or may consist of glycine and serine residues. In particular, the linkers may comprise or consist of multiples of SEQ ID NO: 209 (GGGS) such as SEQ ID NO: 210 (GGGGS GGGGS GGGGS).

[0248] Accordingly, in preferred embodiments the invention relates to antigen-binding proteins comprising or consisting of the structure

[0249] VH-Ll-Va-L2-VP- L3-VL;VH-Ll-VP-L2-Va-L3-VL;

[0250] VL-Ll-Va-L2-VP-L3-VH;

[0251] VL-Ll-VP-L2-Va-L3-VH;

[0252] VP-Ll-VL-L2-VH-L3-Va;

[0253] Va-Ll-VL-L2-VH-L3-VP;

[0254] Vp-Ll-VH-L2-VL-L3-Va; or

[0255] Va-Ll-VH-L2-VL-L3-VP;

[0256] wherein the linkers LI and L3 consist of 2 to 10 amino acids and L2 consists of 5 to 25 amino acids or 10 to 25 amino acids.

[0257] It is envisaged that in the described antigen binding proteins the linkers LI, L2 and / or L3 comprise or consist of SEQ ID NO: 209 (GGGS). It is further envisaged that in the described antigen binding proteins the linkers LI, L2 and / or L3 comprise or consist of SEQ ID NO: 210 (GGGGS GGGGS GGGGS).

[0258] It is preferred that in the described antigen binding proteins the linkers LI and L3 comprise or consist of SEQ ID NO: 209 (GGGS) and L2 comprises or consists of SEQ ID NO: 210 (GGGGS GGGGS GGGGS). It is in particularly preferred that in the described antigen binding proteins the linkers LI and L3 consist of SEQ ID NO: 209 (GGGS) and L2 consists of SEQ ID NO: 210 (GGGGS GGGGS GGGGS).

[0259] Accordingly, in preferred embodiments the invention relates to antigen-binding proteins comprising or consisting of the structure

[0260] VH-Ll-Va-L2-VP- L3-VL;

[0261] VH-Ll-VP-L2-Va-L3-VL;

[0262] VL-Ll-Va-L2-VP-L3-VH;

[0263] VL-Ll-VP-L2-Va-L3-VH;

[0264] VP-Ll-VL-L2-VH-L3-Va;

[0265] Va-Ll-VL-L2-VH-L3-VP;Vp-Ll-VH-L2-VL-L3-Va; or

[0266] Va-Ll-VH-L2-VL-L3-VP;

[0267] wherein the linkers LI and L3 consist of SEQ ID NO: 1 (GGGS) and L2 consists of SEQ ID NO: 2 (GGGGS GGGGS GGGGS).

[0268] In further preferred embodiments the antigen-binding proteins used for the embodiments of the invention comprise two polypeptides.

[0269] It is envisaged that one part of the antibody antigen binding site (VD) is on one CH3-containing polypeptide and the other part of the antibody antigen binding site (VD) is on the other CH3-containing polypeptide. Accordingly, in specific embodiments, the antigen-binding protein comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the antibody variable light chain domain (VL) of an antigen binding site (VD) and the other polypeptide comprises the antibody variable heavy chain domain (VH) of an antigen binding site (VD).

[0270] In certain embodiments, the antigen-binding protein comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the antibody variable light chain domain (VL) of an antigen-binding site (VD) and the other polypeptide comprises the antibody variable heavy chain domain (VH) of an antigen-binding site (VD), wherein the antibody variable light chain domain (VL) and the antibody variable heavy chain domain (VH) associate to form a functional antibody antigen-binding site (VD). One part of the TCR antigen binding site (VR) may be on one CH3-containing polypeptide and the other part of the TCR antigen binding site (VR) may be on the other CH3-containing polypeptide. Accordingly, in such embodiments, the antigen-binding protein comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the TCR alpha variable domain (Va) of a TCR antigen-binding site (VR) and the other polypeptide comprises the TCR beta variable domain (VP) of a TCR antigenbinding site (VR).

[0271] Accordingly, in particular embodiments, the antigen-binding protein comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the TCR alpha variable domain (Va) of a TCR antigen-binding site (VR) and the other polypeptide comprises the TCR beta variable domain (VP) of a TCR antigen-binding site (VR), wherein the TCR alpha variabledomain (Va) and the TCR beta variable domain (VP) associate to form a functional TCR antigen binding site (VR).

[0272] Specifically, the antigen-binding protein may comprise two of the herein described IgG CH3-containing polypeptides, wherein one polypeptide comprises an antibody variable light chain domain (VL) and a TCR beta variable domain (VP) and the other polypeptide comprises an antibody variable heavy chain domain (VH) and a TCR alpha variable domain (Va).

[0273] Furthermore, the antigen-binding protein may comprise two of the described IgG CH3-containing polypeptides, wherein one polypeptide comprises an antibody variable light chain domain (VL) and a TCR alpha variable domain (Va) and the other polypeptide comprises an antibody variable heavy chain domain (VH) and a TCR beta variable domain (VP).

[0274] The herein described antigen-binding proteins may comprise further antibody-derived domains. In particular, it is envisaged that the herein described antigen-binding proteins further comprise a CH2 domain. The CH2-domain is the second constant domain of the heavy chain of an antibody and is located in the Fc region. The antigen-binding proteins may comprise two (of the described) IgG CH3-containing polypeptides, wherein the first polypeptide further comprises a CH2 domain and / or the second polypeptide further comprises a CH2 domain. It is envisaged that in the herein described antigen-binding proteins a CH2 domain and a CH3 domain form a Fc domain. Accordingly, in one polypeptide the CH2 domain and the CH3 domain may form a Fc domain FC1 and / or in the other polypeptide the CH2 domain and the CH3 domain may form a Fc domain FC2.

[0275] The term "Fc domain" as used in the context of the present invention encompasses native Fc domains and Fc domain variants and sequences as further defined herein below. As with Fc variants and native Fc molecules, the term "Fc domain" includes molecules in monomeric or multimeric form, whether digested from whole antibody or produced by other means.

[0276] The term "native Fc" as used herein refers to a molecule comprising the sequence of a non-antigen-binding fragment resulting from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and may contain the hinge region. The original immunoglobulin source of the native Fc is, in particular, of human origin and can be any of the immunoglobulins, preferably IgGl or lgG2, most preferably IgGl. Native Fc molecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent association. The numberof intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgGl, lgG2, lgG3, IgAl, and lgA2). One example of a native Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG. The term "native Fc" as used herein is generic to the monomeric, dimeric, and multimeric forms.

[0277] The "hinge" or "hinge region" or "hinge domain" refers typically to the flexible portion of a heavy chain located between the CHI domain and the CH2 domain. It is approximately 25 amino acids long, and is divided into an "upper hinge," a "middle hinge" or "core hinge," and a "lower hinge." A "hinge subdomain" refers to the upper hinge, middle (or core) hinge or the lower hinge. The skilled person understands at least when looking at the sequences described herein that FC1 and / or FC2 may comprise a hinge region, in particular the hinge region according to SEQ ID NO: 15 (EPKSS).

[0278] Accordingly, FC1 and / or FC2 may be formed by a Fc domain and a hinge region, preferably wherein the hinge region comprises or consists of SEQ ID NO: 15 (EPKSS).

[0279] When it is referred herein to amino acid positions in the Fc domain, these amino acid positions or residues are indicated according to the EU numbering system as described, for example in Edelman et al., Proc. Natl. Acad. USA, 1969, 63, 78-85.

[0280] The term "Fc variant" or "Fc domain variant" as used herein refers to a molecule or sequence that is modified from a native Fc but still comprises e.g. a binding site for the salvage receptor, FcRn (neonatal Fc receptor). Exemplary Fc variants, and their interaction with the salvage receptor, are known in the art. Thus, the term "Fc variant" can comprise a molecule or sequence that is humanized from a non-human native Fc. Furthermore, a native Fc comprises regions that can be removed because they provide structural features or biological activity that are not required for e.g. the bispecific antigen-binding proteins described herein. Thus, the term "Fc variant" comprises a molecule or sequence that lacks one or more native Fc sites or residues, or in which one or more Fc sites or residues have been modified, that affect or are involved in: (1) disulfide bond formation, (2) incompatibility with a selected host cell, (3) N-terminal heterogeneity upon expression in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fc receptor other than a salvage receptor, or (7) antibody-dependent cellular cytotoxicity (ADCC).

[0281] In particular, when the bispecific antigen-binding protein comprises two Fc domains, i.e. in the TCER® format described herein (such as FC1 and FC2), the two Fc domains may be of the sameimmunoglobulin isotype or isotype subclass or of different immunoglobulin isotypes or isotype subclasses, preferably of the same. Accordingly, FC1 and FC2, may be of the IgGl subclass, or of the lgG2 subclass, or of the IgG 3 subclass, or of the lgG4 subclass, preferably of the IgGl subclass, or of the lgG2 subclass, more preferably of the IgGl subclass.

[0282] The Fc domain may be a Fc domain variant and thus comprises one or more of the amino acid substitutions described herein below.

[0283] The Fc domain may comprises or further comprise the "RF" mutation. The "RF mutation" typically refers to the amino acid substitutions of the amino acids HY into RF in the CH3 domain of Fc domains, such as the amino acid substitution H435R and Y436F in CH3 domain as described by Jendeberg et al. (Jendeberg et al., J. Immunological Meth., 1997, 201: 25-34) and is described as advantageous for purification purposes as it abolishes binding to protein A. In case the bispecific antigen binding protein comprises two Fc domains, the RF mutation may be in one or both, preferably in one Fc domain.

[0284] The Fc domain on one or both, preferably both polypeptide chains of the antigen-binding protein may comprise one or more alterations that inhibit Fc gamma receptor (FcyR) binding. Such alterations may include L234A or L235A.

[0285] With the inclusion of Fc-parts consisting of Hinges, CH2 and CH3 domains, or parts thereof, into antigen-binding proteins, more particularly into bispecific antigen-binding proteins the problem of unspecific immobilization of these molecules, induced by Fc:Fc-gamma receptor (FcgR) interactions may arise. FcgRs are composed of different cell surface molecules (FcgRI, FcgRIla, FcgRI lb, FcgRI 11) binding with differing affinities to epitopes displayed by Fc-parts of IgG-molecules. As such an unspecific (i.e. not induced by either of the two binding domains of a bispecific molecule) immobilization is unfavorable due to i) influence on pharmacokinetics of a molecule and ii) off-target activation of immune effector cells various Fc-variants and mutations to ablate FcgR-binding have been identified. In this context, Morgan et al. disclose the exchange of the residues 233-236 of human IgGl with the corresponding sequence derived from human lgG2, i.e. the residues 233P, 234V and 235A and wherein no amino acid is present at position 236, resulting in abolished FcgRI binding, abolished Clq binding and diminished FcgRIII binding (Morgan et al., Immunology., 1995, 86(2): 319-324). EP1075496 discloses antibodies and other Fc-containing molecules with variations in the Fc region (such as one or more of 233P, 234V, 235A and no residue or G in position 236 and 327G, 330S and331S) wherein the recombinant antibody is capable of binding the target molecule without triggering significant complement-dependent lysis or cell mediated destruction of the target. Accordingly, the Fc region may comprise or further comprise one or more of the amino acids or deletions selected from the group consisting of 233P, 234V, 235A, 236 (No residue) or G, 327G, 330S, 331S, preferably, the Fc region comprises or further comprises the amino acids 233P, 234V, 235A, 236 (No residue) or G and one or more amino acids selected from the group consisting of 327G, 330S, 331S, most preferably, the Fc region comprises or further comprises the amino acids 233P, 234V, 235A, 236 (No residue) and 331S.

[0286] It is also envisaged that FC1 and / or FC2 comprises at least one effector function silencing mutation / substitution at a residue selected from positions 233, 234, 235, 236, 297 and 331, preferably wherein said effector function silencing mutation / substitution is generated by replacing / substituting at least one residue in position 233, 234, 235, 236, and 331 with the corresponding residue derived from lgG2 or lgG4.

[0287] The Fc domain may comprise or further comprise the amino acid substitution N297Q, N297G or N297A, preferably N297Q.

[0288] The amino acid substitution "N297Q", "N297G" or "N297A" refer to amino acid substitutions at position 297 that abrogate the native N-Glycosylation site within the Fc-domain. This amino acid substitution prevents Fc-gamma-receptor interaction and decreases the variability of the final protein products, i.e. the bispecific antigen-binding proteins described herein, due to sugar residues as described for example in Tao and Morrison (Tao and Morrison, J Immunol., 1989, 143(8):2595-601).

[0289] The described antigen binding proteins may further comprise L242C and K334C located in the same Fc-domain, either in the FC1 or FC2 of one or both polypeptides to form a intradomain C-C bridge.

[0290] The skilled person is readily capable to determine whether the above described mutations / substitutions are present in the disclosed sequences. Accordingly, the skilled person knows that when it is referred herein to antigen-binding proteins via sequence identity to disclosed sequences said mutations / substitutions may need to be present in said antigenbinding proteins. In particular, it is evident for the skilled person that when it is referred herein to the described FC1 and / or FC2 via sequence identity the substitutions improving heteromerization need to be present.In the herein described antigen-binding proteins comprising at least two polypeptide chains the polypeptide chains may be connected by a linker.

[0291] As mentioned above, in context of the described embodiments the described antigen-binding domains may comprise an antigen-binding site derived from an antibody, wherein the antibody variable light chain domain (VL) and the antibody variable heavy chain domain (VH) are on different polypeptide chains and an antigen-binding site derived from a TCR, wherein TCR alpha variable domain (Va) and the TCR beta variable domain (VP) are on different polypeptide chains.

[0292] Accordingly, in context of the invention the antigen-binding proteins may comprise a first polypeptide comprising a structure represented by the formula:

[0293] V1-V2 [I];

[0294] and a second polypeptide comprising a structure represented by the formula:

[0295] V3-V4 [II];

[0296] wherein VI is Va, V2 is VH, V3 is VL, V4 is Vp;

[0297] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0298] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0299] VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0300] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0301] VI is VL, V2 is VP, V3 is Va, V4 is VH;

[0302] VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0303] VI is VH, V2 is VP, V3 is Va, V4 is VL.

[0304] It is envisaged that in the herein described antigen-binding proteins the variable domains are connected by linkers.

[0305] Accordingly, in context of the invention the antigen-binding proteins may comprise afirst polypeptide comprising a structure represented by the formula:

[0306] V1-L1-V2 [Hi];and a second polypeptide comprising a structure represented by the formula:

[0307] V3-L2-V4 [IV];

[0308] wherein LI and L2 are linkers and may be the same or different,

[0309] wherein VI is Va, V2 is VH, V3 is VL, V4 is V£;

[0310] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0311] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0312] VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0313] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0314] VI is VL, V2 is VP, V3 is Va, V4 is VH;

[0315] VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0316] VI is VH, V2 is VP, V3 is Va, V4 is VL.

[0317] As mentioned above, it is envisaged that the described antigen-binding proteins comprise FC1 and / or FC2. Accordingly, in context of the invention the antigen-binding proteins may comprise a first polypeptide comprising a structure represented by the formula:

[0318] V1-L1-V2-FC1 [V];

[0319] and a second polypeptide comprising a structure represented by the formula:

[0320] V3-L2-V4-FC2 [VI];

[0321] wherein LI and L2 are linkers and may be the same or different,

[0322] wherein VI is Va, V2 is VH, V3 is VL, V4 is VP;

[0323] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0324] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0325] VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0326] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0327] VI is VL, V2 is VP, V3 is Va, V4 is VH;VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0328] VI is VH, V2 is VP, V3 is Va, V4 is VL.

[0329] Such an antigen binding protein is herein referred to as a TCER®. It is further envisaged that any other antigen binding protein is used, e.g. single chain or Tandem diabodies, VHHs, ImmTACs, Anticalins, Nanobodies, BiTE®, a Fab, ankyrin repeat proteins or DARPINs, Avimers, a DART, other TCR-like antibodies, Adnectins, Affilins, Trans-bodies, Affibodies, a TrimerX, Micro Proteins, Fynomers, Centyrins ora KALBITOR®.

[0330] It is envisaged that also the variable domains and FC1 and / or FC2 are connected by linkers. Accordingly, in context of the invention the antigen-binding proteins may comprise a first polypeptide comprising a structure represented by the formula:

[0331] V1-L1-V2-L3-FC1 [VII];

[0332] and a second polypeptide comprising a structure represented by the formula:

[0333] V3-L2-V4-L4-FC2 [VIII];

[0334] wherein LI, L2, L3 and L4 are linkers and may be the same or different, and

[0335] wherein VI is Va, V2 is VH, V3 is VL, V4 is VP;

[0336] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0337] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0338] VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0339] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0340] VI is VL, V2 is VP, V3 is Va, V4 is VH;

[0341] VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0342] VI is VH, V2 is VP, V3 is Va, V4 is VL.

[0343] In a preferred embodiment an antigen-binding protein in context of the invention comprises or consists of

[0344] a first polypeptide chain comprising a structure represented by the formula:VL-L1-V0-FC1;

[0345] and a second polypeptide chain comprising a structure represented by the formula:

[0346] Va-L2-VH-FC2;

[0347] wherein LI and L2 are linkers and may be the same or different and FC1 and FC2 are Fc-domains and may be the same or different.

[0348] The skilled person is readily capable to choose suitable linkers. In particular the skilled person is readily capable to choose suitable linkers for LI, L2, L3 and / or L4 used herein.

[0349] The term "linker" as used herein refers to one or more amino acid residues inserted between domains to provide sufficient mobility for the domains or elements, for example the variable domains of bispecific antigen-binding proteins to fold correctly to form the antigen-binding sites. In some embodiments, a linker consists of 0 amino acids meaning that the linker is absent. A linker, as long as it is not specified otherwise in the respective context, can be from at least 1 to 30 amino acids in length. A linker can be 2-25, 2-20, or 3-18 amino acids long. A linker can be a peptide of a length of no more than 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 amino acids. A linker can be 5-25, 5-15, 4-11, 10-20, or 20-30 amino acids long. A linker can also be about, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids long, preferably 8 amino acids long. A linker can be less than 24, less than 20, less than 16, is less than 12, less than 10, for example from 5 to 24, 10 to 24 or 5-10 amino acid residues in length. A linker may be equal to 1 or more amino acid residues in length, such as more than 1, more than 2, more than 5, more than 10, more than 20 amino acid residues in length, or more than 22 amino acid residues in length. Preferably, the linker is a glycine / serine linker, i.e. a linker consisting of or essentially consisting of glycine and serine residues. Preferably, the linker comprises or consists of SEQ ID NO: 16 (GGGSGGGG). Accordingly, the invention relates to the herein described antigen-binding proteins, wherein the linkers LI, L2, L3 and / or L4 comprise or consist of SEQ ID NO: 16 (GGGSGGGG).

[0350] In particular FC1 may comprise or consist of the amino acid sequence according to SEQ ID NO: 1. FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1.FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1 and comprise the substitution of amino acids at position 351 and at position 368 by a negatively charged amino acid and the amino acid variant Y349C.

[0351] FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1 and comprise the substitution of amino acids at position 351 and at position 368 by aspartic acid or glutamic acid and the amino acid variant Y349C.

[0352] FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1 and comprise the substitution of the amino acid at position 351 by aspartic acid and the substitution of the amino acid at position 368 by glutamic acid and the amino acid variant Y349C. It is pointed out that when it is referred herein to "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1" in particular the wording "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1 and comprising the substitution of the amino acid at position 351 by aspartic acid and the substitution of the amino acid at position 368 by glutamic acid and the amino acid variant Y349C" is encompassed.

[0353] FC1 may also comprise or consist of the amino acid sequence according to SEQ ID NO: 39. FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39.

[0354] FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39 and comprise the substitution of amino acids at position 351 and at position 368 by a negatively charged amino acid and the amino acid variant S354C. FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39 and comprise the substitution of amino acids at position 351 and at position 368 by aspartic acid or glutamic acid and the amino acid variant S354C.

[0355] FC1 may comprise or consist of the amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39 and comprise the substitution of the amino acid at position 351 by aspartic acid and the substitution of the amino acid at position 368 by glutamic acid and the amino acid variant S354C. It is pointed out that when it is referred herein to "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39" in particular the wording "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39 and comprising the substitution of the amino acid at position 351 byaspartic acid and the substitution of the amino acid at position 368 by glutamic acid and the amino acid variant S354C" is encompassed.

[0356] FC2 may comprise or consist of the amino acid sequence according to SEQ ID NO: 2. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2 and comprise the substitution of amino acids at position 351 and at position 366 by a positively charged amino acid and the amino acid variant S354C. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2 and comprise the substitution of amino acids at position 351 and at position 366 by lysine, arginine or histidine and the amino acid variant S354C. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2 and comprise the substitution of the amino acid at position 351 by lysine and the substitution of the amino acid at position 366 by lysine and the amino acid variant S354C. It is pointed out that when it is referred herein to "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2" in particular the wording "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2 and comprising the substitution of the amino acid at position 351 by lysine and the substitution of the amino acid at position 366 by lysine and the amino acid variant S354C" is encompassed.

[0357] FC2 may also comprise or consist of the amino acid sequence according to SEQ ID NO: 40. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 40 and comprise the substitution of amino acids at position 351 and at position 366 by a positively charged amino acid and amino acid variant Y349C. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 40 and comprise the substitution of amino acids at position 351 and at position 366 by lysine, arginine or histidine and amino acid variant Y349C. FC2 may comprise or consist of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 40 and comprise the substitution of the amino acid at position 351 by lysine and the substitution of the amino acid at position 366 by lysine and amino acid variant Y349C. It is pointed out that when it is referred herein to "an aminoacid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 40" in particular the wording "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 40 and comprising the substitution of the amino acid at position 351 by lysine and the substitution of the amino acid at position 366 by lysine and amino acid variant Y349C" is encompassed.

[0358] Accordingly, the antigen-binding proteins may comprise FC1 comprising or consisting of the amino acid sequence according to SEQ ID NO: 1 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1; and / or

[0359] FC2 comprising or consisting of the amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2.

[0360] Furthermore, the antigen-binding proteins may comprise FC1 comprising or consisting of the amino acid sequence according to SEQ ID NO: 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39; and / or

[0361] FC2 comprising or consisting of the amino acid sequence according to SEQ ID NO: 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 40.

[0362] In particular, the antigen-binding proteins may comprise a first polypeptide comprising a structure represented by the formula:

[0363] V1-L1-V2-FC1

[0364] and a second polypeptide comprising a structure represented by the formula:

[0365] V3-L2-V4-FC2

[0366] wherein LI and L2 are linkers and may be the same or different,

[0367] wherein VI is Va, V2 is VH, V3 is VL, V4 is V£;

[0368] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0369] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0370] VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0371] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0372] VI is VL, V2 is VP, V3 is Va, V4 is VH;VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0373] VI is VH, V2 is VP, V3 is Va, V4 is VL; and

[0374] wherein FC1 comprises or consists of the amino acid sequence according to SEQ ID NO: 1 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1; and / or

[0375] FC2 comprises or consists of the amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2.

[0376] Furthermore, the antigen-binding proteins may comprise a first polypeptide comprising a structure represented by the formula:

[0377] V1-L1-V2-FC1

[0378] and a second polypeptide comprising a structure represented by the formula:

[0379] V3-L2-V4-FC2

[0380] wherein LI and L2 are linkers and may be the same or different,

[0381] wherein VI is Va, V2 is VH, V3 is VL, V4 is VP;

[0382] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0383] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0384] VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0385] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0386] VI is VL, V2 is VP, V3 is Va, V4 is VH;

[0387] VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0388] VI is VH, V2 is VP, V3 is Va, V4 is VL; and

[0389] wherein FC1 comprises or consists of the amino acid sequence according to SEQ ID NO: 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 39; and / or

[0390] FC2 comprises or consists of the amino acid sequence according to SEQ ID NO: 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 40.In certain embodiments in the antigen-binding proteins in context of the invention FC1 comprises or consists of an amino acid sequence according to SEQ ID NOs: 1, 17, 19, 21 or 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1, 17, 19, 21 or 39

[0391] and / or

[0392] FC2 comprises or consists of an amino acid sequence according to SEQ ID NOs: 2, 18, 20, 22 or 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2, 18, 20, 22 or 40.

[0393] As mentioned above, it is envisaged that an antigen-binding site / domain of the herein described antigen-binding domains binds to a cell surface molecule of an immune cell. In particular, it is envisaged that an antibody antigen-binding domain binds to a TCR / CD3 complex, preferably an alpha / beta TCR / CD3 complex. Said antigen-binding domain may also be referred to as T-cell recruiting part. It is in particular envisaged that said antigen-binding domain binding to a TCR / CD3 complex is the antigen-binding domain of the antibody BMA031 (V36) as described in WQ2021 / 023657. SEQ ID NO: 42 (VL) of WQ2021 / 023657 corresponds to SEQ ID NO: 3 in the present application and SEQ ID NO: 43 (VH) of WQ2021 / 023657 corresponds to SEQ ID NO: 9 in the present application.

[0394] Accordingly, it is envisaged that the herein described antigen-binding proteins comprise an antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH), wherein the VL comprises

[0395] (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,

[0396] (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and

[0397] (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises

[0398] (i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,

[0399] (ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 11, and

[0400] (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12;

[0401] wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.In particular it is envisaged that the T cell recruiting domain comprises a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 3 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 3 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively;

[0402] It is evident for the skilled person that under certain conditions a glutamine amino acid residue may be converted into pyro-glutamate. In particular, N-terminal glutamine may be converted into pyro-glutamate. Accordingly, it is evident for the skilled person that the present application also encompasses the described antigen-binding proteins with pyro-glutamate at the N-terminus instead of glutamine. In other words, when an antigen-binding protein as described herein has a glutamine residue at the N-terminus also the corresponding amino acid sequence with pyro-glutamate instead of glutamine at the N-terminus is encompassed. For example, when in the described antigen-binding protein the VL having the amino acid sequence according to SEQ ID NO: 3 is at the N-terminus said VL may comprise or consist of the amino acid sequence according to SEQ ID NO: 4 (with pyro-glutamate at the N-terminus). Accordingly, the antigen-binding proteins according to the invention may comprise a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 4. The antigenbinding proteins according to the invention may also comprise a VL comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 4. The antigen-binding proteins according to the invention may comprise a VL comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 4 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively. For simplicity it is mostly referred to SEQ ID NO: 5 (encompassing glutamine and pyro-glutamate at the N-terminus) herein in context of the preferred VL. It is evident for the skilled person that SEQ ID NO: 5 and "SEQ ID NO: 3 or SEQ ID NO: 4" may be used interchangeably herein. In other words, when it is referred to SEQ ID NO: 5 it may also be referred to as "SEQ ID NO: 3 and SEQ ID NO: 4" or "SEQ ID NO: 3 or SEQ ID NO: 4". It is evident for the skilled person that the herein described antigen-binding proteins may be a mixture of molecules with pyro-glutamate at the N-terminus and molecules with glutamine at the N-terminus. Accordingly, when it is referred herein to an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 it is evident for the skilled person that it may be referred to a composition comprising an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQID NO: 3 and optionally comprising an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 4. Similarly, when it is referred herein to an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 it is evident for the skilled person that it may be referred to a composition comprising an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 4 and optionally comprising an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 3.

[0403] When it is referred herein to an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 it is evident for the skilled person that it may be referred to a composition comprising an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 3 and optionally comprising at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of an antigen-binding protein comprising a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 4.

[0404] It is pointed out that the disclosure above with respect to pyro-glutamate is encompassed for all amino acid sequences disclosed herein with an N-terminal gutamine.

[0405] The antigen-binding proteins in context of the invention may comprise a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5. The described antigenbinding proteins may comprise a VL comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5. The described antigen-binding proteins may comprise a VL comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively.

[0406] The described antigen-binding proteins may comprise a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 9. The described antigen-binding proteins may comprise a VH comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 9. The described antigen-binding proteins may comprise a VH comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 9 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.Thus, the antigen-binding proteins may comprise:

[0407] a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0408] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 9 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 9 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.

[0409] It is also envisaged that the antigen-binding domain binding to a TCR / CD3 complex is the antigen-binding domain of the antibody BMA031 (V10) as described in WO 2019 / 012138, which is incorporated herein by reference in its entirety.

[0410] Thus, the antigen-binding proteins may comprise:

[0411] a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0412] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 93 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 93 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.

[0413] Furthermore, it is envisaged that the antigen-binding domain binding to a TCR / CD3 complex is the antigen-binding domain of a version of the antibody BMA031 as described in WO2022 / 233957. SEQ ID NO: 2 (VL) of WO2022 / 233957 corresponds to SEQ ID NO: 3 in the present application and SEQ ID NO: 32 (VH) of WO2022 / 233957 corresponds to SEQ ID NO: 13 in the present application.

[0414] Accordingly, it is envisaged that the herein described antigen-binding proteins comprise an antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH), wherein the VL comprises

[0415] (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,

[0416] (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and(iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises

[0417] (i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,

[0418] (ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 14, and

[0419] (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12;

[0420] wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0421] The T cell recruiting domain may also comprise a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 13. Accordingly, the described antigen-binding proteins may comprise a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 13. The described antigen-binding proteins may comprise a VH comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 13. The described antigen-binding proteins may comprise a VH comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 13 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NQs: 10, 14, and 12, respectively.

[0422] Accordingly, the described antigen-binding proteins may comprise a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0423] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 13 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 13 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 14, and 12, respectively.

[0424] It is envisaged that the TCR antigen binding site (VR) of the described antigen-binding proteins may specifically bind to a bacterial peptide, a viral peptide or a tumor associated antigen peptide, preferably bound to a major histocompatibility complex (MHC) protein.Preferably, the TCR antigen binding site (VR) of the described antigen-binding proteins may specifically bind to a tumor associated antigen peptide, preferably bound to a major histocompatibility complex (MHC) protein.

[0425] A preferred tumor associated antigen that is bound by the antigen-binding proteins described herein is the MAGE-A antigenic peptide comprising or consisting of the amino acid sequence "KVLEHVVRV" (SEQ ID NO: 57), more particularly, the MAGE-A antigenic peptide comprising or consisting of the amino acid sequence "KVLEHVVRV" (SEQ ID NO: 57) in a complex with a MHC protein.

[0426] "MAGE-A" or "melanoma associated antigen A" subfamily proteins were the first tumor associated antigens identified at the molecular level (van der Bruggen et al., Science. 1991; 254:1643-47). MAGE-A is a sub-family of 12 genes (MAGE-A1 to -A12) located in the q28 region of the X chromosome. Members of the MAGE-A subfamily proteins are normally expressed only in testis or placenta and their restricted expression suggests that they may function in germ cell development. MAGE-A proteins were also detected in the early development of the central nervous system, the spinal cord and brainstem, revealing that MAGE-A proteins may also be involved in neuronal development. The members of this family encode proteins with 50 to 80% sequence identity to each other and all MAGE proteins share the common MAGE homology domain, a highly conserved domain consisting of approximately 170 amino acids. The biological functions and underlying regulatory mechanism of MAGE-A proteins expression in cancer is still not fully understood.

[0427] The "MAGE-A4" or "Melanoma-associated antigen 4" protein is a member of the MAGE-A gene family and has the Uniprot accession number P43358 (as available on September 2, 2024). MAGE-A4 localization has been described as cytoplasmic. However, MAGE-A4 staining has also been detected in nuclei, with differential distribution between nucleus and cytoplasm in well-differentiated versus less differentiated cancers (Sarcevic et. al., Oncology, 2003, 64, 443-449). MAGE-A4 is used as a male germ cell marker. It is not expressed in gonocytes, but expressed in pre-spermatogonia and mature germ cells (Mitchell et al., Mod. Pathol., 2014, 27, 1255-1266). Expression of the MAGE-A4 protein and mRNA has been linked to the development and prognosis of various cancers.The "MAGE-A8" or "Melanoma-associated antigen 8" protein is a member of the MAGE-A superfamily and has the Uniprot accession number P43361 (as available on September 2, 2024).

[0428] The "MAGE-A4" and "MAGE-A8" proteins have a sequence identity of 72% as determined by a protein sequence alignment using the BLASTP 2.9.0 algorithm (Stephen et al., Nucleic Acids Res., 1997, 25:3389-3402). Furthermore, "MAGE-A4" and "MAGE-A8" both comprise the MAG-003 peptide, i.e. "KVLEHVVRV" (SEQ ID NO: 57).

[0429] It is evident for the skilled person that it is in particular envisaged herein that cancer is treated that presents the peptide according to SEQ ID NO: 57 in complex with a MHC protein.

[0430] Accordingly, it is envisaged that the herein described antigen-binding proteins may comprise a TCR antigen binding site (VR) that binds to the MAG-003 peptide.

[0431] In line with the above, it is envisaged that the antigen-binding protein may comprise a T cell receptor (TCR) alpha variable domain (Va) as part of a TCR antigen binding site (VR) that binds to the MAG-003 peptide. "Va" and "Va domain" may be used synonymously herein. The Va domain may comprise a CDRal comprising or consisting of the amino acid sequence according to SEQ ID NO: 62. The Va domain may comprise a CDRa2 comprising or consisting of the amino acid sequence according to SEQ ID NO: 63. The Va domain may comprise a CDRa3 comprising or consisting of the amino acid sequence according to SEQ ID NO: 64. Said CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution. Accordingly, the antigen-binding protein according to the invention may comprise a Va domain comprising a CDRal comprising the amino acid sequence according to SEQ ID NO: 62, a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 63 and / or a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 64. The antigen-binding protein according to the invention may comprise a Va domain comprising a CDRal consisting of the amino acid sequence according to SEQ ID NO: 62, a CDRa2 consisting of the amino acid sequence according to SEQ ID NO: 63 and / or a CDRa3 consisting of the amino acid sequence according to SEQ ID NO: 64.

[0432] It is further envisaged that the antigen-binding protein in context of the invention comprises a TCR beta variable domain (VP) as part of a TCR antigen binding site (VR) that binds to the MAG-003 peptide. "V|3" and "V|3 domain" may be used synonymously herein. The V|3 domain may comprise a CDR 1 comprising or consisting of the amino acid sequence according to SEQID NO: 59. The V|3 domain may comprise a CDR 2 comprising or consisting of the amino acid sequence according to SEQ ID NO: 60. The V|3 domain may comprise a CDR 3 comprising or consisting of the amino acid sequence according to SEQ ID NO: 61. Said CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution. Accordingly, the antigen-binding protein binding to the MAG-003 peptide may comprise a V|3 domain comprising a CDR 1 comprising the amino acid sequence according to SEQ ID NO: 59, a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 60 and / or a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 61. The antigen-binding protein binding to the MAG-003 peptide may comprise a V|3 domain comprising a CDR 1 consisting of the amino acid sequence according to SEQ ID NO: 59, a CDR 2 consisting of the amino acid sequence according to SEQ ID NO: 60 and / or a CDR 3 consisting of the amino acid sequence according to SEQ ID NO: 61. Accordingly, it is envisaged that that the antigen-binding protein in context of the invention binding to the MAG-003 peptide may comprise a Va and a V|3 wherein the Va comprises (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 62,

[0433] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 63, and / or (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 64; and wherein the V|3 comprises

[0434] (i) a CDR 1 comprising the amino acid sequence according to SEQ ID NO: 59,

[0435] (ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 60, and / or

[0436] (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 61,

[0437] wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0438] Furthermore, it is envisaged that the antigen-binding protein in context of the invention binding to the MAG-003 peptide comprises a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 54. It is envisaged that the antigen-binding protein comprises a Va comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 54. It is envisaged that the antigen-binding proteincomprises a Va comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 54 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 62, 63, and 64, respectively.

[0439] It is envisaged that the antigen-binding protein binding to to the MAG-003 peptide for use according to the invention comprises a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 53. It is also envisaged that the antigen-binding protein comprises a VP comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 53. It is also envisaged that the antigen-binding protein comprises a VP comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 53 and comprising the CDRpi, CDRP2, and CDRP3 according to SEQ ID NOs: 59, 60, and 61, respectively.

[0440] Furthermore, it is envisaged that the antigen-binding protein in context of the invention binding to the MAG-003 peptide comprises a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 54 and a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 53.

[0441] Furthermore, it is envisaged that the antigen-binding protein binding to the MAG-003 peptide for use according to the invention comprises a Va comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 54 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 62, 63, and 64, respectively and a VP comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 53 and comprising the CDRpi, CDRP2, and CDRP3 according to SEQ ID NOs: 59, 60, and 61, respectively.

[0442] Another preferred tumor associated antigen that is bound by the antigen-binding proteins described herein is the the PRAME antigenic peptide comprising or consisting of the amino acid sequence "SLLQHLIGL" (SEQ ID NO: 58), more particularly, the PRAME antigenic peptide comprising or consisting of the amino acid sequence "SLLQHLIGL" (SEQ ID NO: 58) in a complex with a MHC protein.

[0443] "PRAME" or "Preferentially Expressed Antigen In Melanoma" was first identified as an antigen that is overexpressed in melanoma (Ikeda et al Immunity. 1997 Feb;6(2): 199-208); it is also known as CT130, MAPE, OIP-4 and has the Uniprot accession number P78395 (as available on January 11, 2019). The protein functions as a repressor of retinoic acid receptor signaling(Epping et al., Cell. 2005 Sep 23; 122(6):835-47). PRAME belongs to the family of germline-encoded antigens known as cancer testis antigens. Cancer testis antigens are attractive targets for immunotherapeutic intervention since they typically have limited or no expression in normal adult tissues. PRAME is expressed in a number of solid tumors as well as in leukemia and lymphomas (Doolan et al., Breast Cancer Res Treat. 2008 May; 109(2):359-65; Epping et al., Cancer Res. 2006 Nov 15;66(22): 10639-42; Ercolak et al., Breast Cancer Res Treat. 2008 May; 109(2):359-65; Matsushita et al., Leuk Lymphoma. 2003 Mar;44(3):439-44; Mitsuhashi et al., Int. J Hematol. 2014; 100(l):88-95; Proto-Sequeire et al., Leuk Res. 2006 Nov;30(ll): 1333-9; Szczepanski et al., Oral Oncol. 2013 Feb;49(2): 144-51; Van Baren et al., Br J Haematol.

[0444] 1998 Sep; 102(5): 1376-9).

[0445] It is evident for the skilled person that it is in particular envisaged herein that cancer is treated that presents the peptide according to SEQ ID NO: 58 in complex with a MHC protein.

[0446] Accordingly, it is envisaged that the herein described antigen-binding proteins comprise a TCR antigen binding site (VR) that binds to the PRAME-004 peptide.

[0447] Described herein are three TCR variable domains that bind PRAME-004, termed A (SEQ ID NO: 56 + SEQ ID NO: 55), B (SEQ ID NO: 94 + SEQ ID NO: 98) and C (SEQ ID NO: 102 + SEQ ID NO: 106).

[0448] In line with the above, it is envisaged that the antigen-binding protein in context of the invention comprises a T cell receptor (TCR) alpha variable domain (Va) as part of a TCR antigen binding site (VR) that binds to the PRAME-004 peptide. The Va domain may comprise a CDRal comprising or consisting of the amino acid sequence according to SEQ ID NO: 68. The Va domain may comprise a CDRa2 comprising or consisting of the amino acid sequence according to SEQ ID NO: 69. The Va domain may comprise a CDRa3 comprising or consisting of the amino acid sequence according to SEQ ID NO: 70. Said CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution. Accordingly, the antigen-binding protein in context of the invention binding to the PRAME-004 peptide may comprise a Va domain comprising a CDRal comprising the amino acid sequence according to SEQ ID NO: 68, a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 69 and / or a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 70. The antigen-binding protein according to the invention may comprise a Va domain comprising a CDRal consisting of the amino acid sequence according to SEQ ID NO: 68, a CDRa2 consisting of the amino acid sequenceaccording to SEQ ID NO: 69 and / or a CDRa3 consisting of the amino acid sequence according to SEQ ID NO: 70.

[0449] It is further envisaged that the antigen-binding protein binding to the PRAME-004 peptide comprises a TCR beta variable domain (V|3) as part of a TCR antigen binding site (VR) that binds to the PRAME-004 peptide. The V|3 domain may comprise a CDR 1 comprising or consisting of the amino acid sequence according to SEQ ID NO: 65. The V|3 domain may comprise a CDR 2 comprising or consisting of the amino acid sequence according to SEQ ID NO: 66. The V|3 domain may comprise a CDR 3 comprising or consisting of the amino acid sequence according to SEQ ID NO: 67. Said CDRs may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution. Accordingly, the antigen-binding protein binding to the PRAME-004 peptide may comprise a V|3 domain comprising a CDR 1 comprising the amino acid sequence according to SEQ ID NO: 65, a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 66 and / or a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 67. The antigenbinding protein binding to the PRAME-004 peptide may comprise a V|3 domain comprising a CDR 1 consisting of the amino acid sequence according to SEQ ID NO: 65, a CDR 2 consisting of the amino acid sequence according to SEQ ID NO: 66 and / or a CDR 3 consisting of the amino acid sequence according to SEQ ID NO: 67.

[0450] Accordingly, it is envisaged that that the antigen-binding protein in context of the invention binding to the PRAME-004 peptide comprises a Va and a V|3 wherein the Va comprises (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 68,

[0451] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 69, and / or (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 70; and wherein the V|3 comprises

[0452] (i) a CDR 1 comprising the amino acid sequence according to SEQ ID NO: 65,

[0453] (ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 66, and / or (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 67,wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0454] Furthermore, it is envisaged that an antigen-binding protein in context of the invention comprises a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 56. It is envisaged that the antigen-binding protein comprises a Va comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 56. It is envisaged that the antigen-binding protein comprises a Va comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 56 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 68, 69, and 70, respectively.

[0455] It is envisaged that an antigen-binding protein in context of the invention comprises a V|3 comprising or consisting of the amino acid sequence according to SEQ ID NO: 55. It is also envisaged that the antigen-binding protein comprises a V|3 comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 55. It is also envisaged that the antigen-binding protein comprises a V|3 comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 55 and comprising the CDR 1, CDR 2, and CDR 3 according to SEQ ID NOs: 65, 66, and 67, respectively.

[0456] Furthermore, an antigen-binding protein binding to the PRAME-004 peptide for use according to the invention may comprise a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 56 and a V|3 comprising or consisting of the amino acid sequence according to SEQ ID NO: 55.

[0457] Furthermore, the antigen-binding protein binding to the PRAME-004 peptide for use according to the invention may comprise a Va comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 56 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 68, 69, and 70, respectively and a V|3 comprising or consisting of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 55 and comprising the CDR 1, CDR 2, and CDR 3 according to SEQ ID NOs: 65, 66, and 67, respectively.An antigen-binding protein binding to the PRAME-004 peptide may also comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the Va domain comprises

[0458] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 95,

[0459] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 96, and

[0460] (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 97; and wherein the VP domain comprises

[0461] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 99,

[0462] (ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 100, and

[0463] (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 101,

[0464] wherein one or more of CDRal, CDRa2, CDRa3, CDR|31, CDR|32 and CDR|33 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0465] An antigen-binding protein binding to the PRAME-004 peptide may also comprise a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 94 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 94 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 95, 96, and 97, respectively; and

[0466] a VP comprising or consisting of the amino acid sequence according to 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 CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 99, 100, and 101, respectively.

[0467] An antigen-binding protein binding to the PRAME-004 peptide may also comprise a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the Va domain comprises

[0468] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 103,

[0469] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 104, and

[0470] (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 105; and wherein the VP domain comprises

[0471] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 107,

[0472] (ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 108, and(iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 109, wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0473] An antigen-binding protein binding to the PRAME-004 peptide may also comprise a Va comprising or consisting of the amino acid sequence according to 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 according to SEQ ID NOs: 103, 104, and 105, respectively; and

[0474] a VP comprising or consisting of the amino acid sequence according to 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 CDR 1, CDR 2, and CDR 3 according to SEQ ID NOs: 107, 108, and 109, respectively.

[0475] In particular embodiments, an antigen binding protein used in context of the invention comprises a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 23 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 24.

[0476] An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 25 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 26. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 27 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 28. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 29 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 30. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 31 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 32.An antigen binding protein in context of the invention comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 33 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 34.

[0477] An antigen binding protein may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 35 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 36.

[0478] An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 37 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 38. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 41 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 42. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 43 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 44. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 45 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 46. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 47 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 48. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 49 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 50. An antigen binding protein in context of the invention may comprise a first polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 51 and a second polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 52. The above molecules are also disclosed in WO 2025 / 233431, which is incorporated herein by reference in its entirety.

[0479] It is pointed out that the above molecules may be combined (in particular MAG-003 binding and PRAME-004 binding molecules) and used for treatment in combination with immune checkpoint inhibitors.All described embodiments are also envisaged with nucleic acids and / or vectors encoding the herein described antigen-binding proteins and are encompassed by the invention. Thus, nucleic acids and / or vectors encoding the herein described antigen-binding proteins may be also used for the herein described uses and methods.

[0480] Thus, the polypeptides of the antigen-binding proteins may be encoded by nucleic acids and expressed in vivo, ex vivo or in vitro.

[0481] The nucleic acid may be comprised in one nucleic acid molecule or may be separated into two or more nucleic acid molecules, wherein each nucleic acid molecule comprises at least one of the two or more sequences encoding the described antigen-binding proteins. One nucleic acid molecule may encode one part or monomer of an antigen-binding protein (for example one of two chains of a TCER®), and another nucleic acid molecule may encode another part or monomer of an antigen-binding protein (for example the other one of two chains of the TCER®).

[0482] The nucleic acid may encode two or more antigen-binding protein polypeptide chains, for example, at least two polypeptides of a TCER®. Nucleic acids encoding multiple antigenbinding protein polypeptide chains may include a nucleic acid cleavage site between at least two chain encoding sequences, may encode a transcription or translation start site, such as an internal ribosomal entry site (IRES) between two or more chain sequences, and / or may encode a proteolytic target site between two or more antigen-binding protein chains. If two or more antigen-binding protein polypeptide chains are encoded on one nucleic acid molecule, the two or more antigen-binding protein polypeptide chains may be under the control of the same promoter or under the control of separate promoters.

[0483] 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. As used herein, 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 nucleicacid 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 is used herein in the broadest sense and comprises chromosomes or chromosomal segments. Unless otherwise indicated, a particular nucleic acid sequence comprises or encodes complementary sequences, in addition to any sequence explicitly indicated. Preferably, the nucleic acid is an isolated nucleic acid. The nucleic acid may be a recombinant nucleic acid. 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. Nucleic acid molecules of the disclosure may 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 may 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. forTCRs or antibodies, are known in the art and DNA fragments encompassing these regions can be obtained by standard PCR amplification.

[0484] The described nucleic acids may be included in one or more suitable vectors. If two or more antigen-binding protein polypeptide chains are encoded on one vector, the two or more antigen-binding protein polypeptide chains may be under the control of the same promoter or under the control of separate promoters.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.

[0485] Various expression vectors may be employed to express the polynucleotides encoding the antigen-binding proteins. Both viral-based and non-viral expression vectors may be used to produce the antigen-binding proteins described herein in a mammalian host cell. Non-viral vectors and systems include plasmids, cosmids, episomes, and artificial chromosomes.

[0486] 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 et al. J Biochem., 1987, 101(5):1307-10), LTR promoter and enhancer of Moloney mouse leukemia virus (Kuwana et al. FEBS Lett., 1987, 219(2):360-4), promoter (Mason et al. Cell., 1985, 41(2) :479-87) and enhancer (Gillies et al. Cell., 1983, 33(3) :717-28) of antibody heavy chain and the like.

[0487] Examples of plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance pllC, pcDNA, pBR and the like.

[0488] 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, HEK293 cells, etc. Detailed protocols for producing such replication-defective recombinant viruses may be found for instance in WO95 / 14785, WO96 / 22378, US 5,882,877, US 6,013,516, US 4,861,719, US 5,278,056 and WO94 / 19478.

[0489] Also encompassed herein is a host cell comprising the described antigen-binding proteins, the described nucleic acid(s) or the described vector(s). The host cell may be transfected, infected,transduced or transformed, in particular with a nucleic acid and / or a vector as described herein.

[0490] The host cell is preferably a eukaryotic cell. The host cell may be a cultured cell or a primary cell, i.e., isolated directly from an organism, e.g., a human. The host cell can be an adherent cell or a suspended cell, i.e., a cell that grows in suspension. For purposes of producing a recombinant antigen-binding protein, for example a TCER®, the host cell is preferably a mammalian cell. The host cell for recombinant expression may be a Chinese Hamster Ovary (CHO) cell or a yeast cell.

[0491] The host cell may also be a peripheral blood leukocyte (PBL) or a peripheral blood mononuclear cell (PBMC). The host cell may also be a lymphocyte, such as a T cell, a T cell progenitor or a NK cell.

[0492] The invention also relates to pharmaceutical compositions. In particular the invention relates to pharmaceutical compositions comprising the herein described antigen-binding proteins and immune checkpoint inhibitors.

[0493] 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. The subject may also be referred to as patient. Preferably, the subject is a mammal, more preferably a human.

[0494] Such therapeutic or pharmaceutical compositions may comprise a therapeutically effective amount of the antigen-binding proteins or nucleic acids encoding said antigen-binding proteins and (an) immune checkpoint inhibitor(s), in admixture with a pharmaceutically or physiologically acceptable formulation agent, carrier or aqueous medium selected for suitability with the mode of administration.

[0495] The antigen-binding protein will usually be supplied as part of a sterile, pharmaceutical composition which may include a pharmaceutically acceptable carrier.

[0496] "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 or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.A "pharmaceutically-acceptable carrier" may also be referred to as "pharmaceutically acceptable diluent" or "pharmaceutically acceptable vehicle" 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. The carrier may be an aqueous carrier or an aqueous medium.

[0497] The pharmaceutical compositions may 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.

[0498] In particular, the pharmaceutical compositions may contain vehicles, which are pharmaceutically acceptable for a formulation suitable for injection. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.

[0499] To prepare pharmaceutical compositions, an effective amount of the antigen-binding proteins and (an) immune checkpoint inhibitor(s) may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Accordingly, the invention relates to a pharmaceutical composition, wherein the herein described antigen-binding proteins and (an) immune checkpoint inhibitor(s) is dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

[0500] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that administration via a syringe is possible. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0501] Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.An antigen binding protein described herein may be formulated into a composition in a neutral or salt form using pharmaceutically acceptable salts.

[0502] Sterile injectable solutions are prepared by incorporating the active compounds (antigenbinding proteins) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders forthe preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously steri le-filtered solution thereof.

[0503] The preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.

[0504] It is pointed out that pharmaceutical compositions comprising the herein described nucleic acids, vectors and host cells are also encompassed.

[0505] The invention also relates to the use of the described antigen-binding proteins, nucleic acids, vectors, host cells and / or pharmaceutical compositions in the manufacture of a medicament. The invention also relates to the use of the described antigen-binding protein, nucleic acids, vectors, host cells and / or pharmaceutical compositions in the manufacture of a medicament for the treatment of cancer.

[0506] The invention also relates to the described antigen-binding protein, nucleic acids, vectors, host cells and / or pharmaceutical compositions for use in medicine. The invention further relates to the described antigen-binding protein, nucleic acids, vectors, host cells and / or pharmaceutical compositions for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders.

[0507] In particular the invention relates to an RNA encoding the described antigen-binding proteins as well as a pharmaceutical composition comprising an RNA encoding the described antigenbinding proteins and an immune checkpoint inhibitor for use in medicine. Accordingly, the invention in particular relates to an RNA encoding the described antigen-binding proteins as well as a pharmaceutical composition comprising an RNA encoding the described antigen-binding proteins and an immune checkpoint inhibitor for use use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders. Although evident for the skilled person it is pointed out that the disclosures in context of the methods described herein are disclosed as corresponding use mutatis mutandis. The disclosures in context of the use described herein are disclosed as corresponding methods mutatis mutandis.

[0508] Accordingly, the invention relates to a method of treatment of a disease or disorder comprising administering a therapeutically effective amount of the described antigen-binding protein, pharmaceutical composition, nucleic acid or separate nucleic acids, vector or the separate vectors, the host cell and / or the antigen-binding protein as obtained or obtainable by the described methods and an immune checkpoint inhibitor to a patient in need thereof.

[0509] The invention also relates to a pharmaceutical composition / formulation for use in a method of treating a condition or disease by producing an antigen-binding proteins in vivo, wherein the pharmaceutical composition / formulation comprises a nucleic acid encoding the two antigen-binding proteins and wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition / formulation, wherein (an) immune checkpoint inhibitor(s) is co-administered to the a cell, tissue or organism. Preferably, the nucleic acid is a mRNA.

[0510] The invention also relates to a method comprising administering to a subject in need thereof a pharmaceutical composition comprising the herein described antigen-binding protein or a nucleic acid encoding the herein described antigen-binding protein and an immune checkpoint inhibitor.

[0511] The invention also relates to a method of efficient protein production in a cell population, the method comprising contacting a cell population with a nucleic acid encoding the herein described antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid under conditions such that an effective amount of the antigen-binding protein is produced in the cell population, wherein (an) immune checkpoint inhibitor(s) is co-administered.

[0512] The invention also relates to a method for inducing in vivo translation of the described antigenbinding proteins in a mammalian subject in need thereof, comprisingadministering to the subject an effective amount of a nucleic acid encoding the herein described antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid under conditions such that the nucleic acid is localized into a cell of the subject and the antigen-binding proteins are capable of being translated in the cell from the nucleic acid, wherein (an) immune checkpoint inhibitor(s) is co-administered.

[0513] It is evident for the skilled person that the amino acid positions provided herein are not necessarily the positions in the described protein but refer to the corresponding position in a (wildtype / native) IgG antibody.

[0514] It is pointed out that when it is referred to "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 17" also the wording "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 17 and the amino acid variants S354C and T366W" is encompassed. Similarly, when it is referred to "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 18" also the wording "an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 18 and the amino acid variants Y349C, T366S, L368A and Y407V" is encompassed.

[0515] Thus, when it is referred to (at least) two different (heteromeric) antigen-binding proteins herein a first antigen-binding protein of the (at least) two different (heteromeric) antigenbinding proteins may comprise two IgG CH3-containing polypeptides, wherein

[0516] (i) the first polypeptide comprises the substitution of the amino acid at position 351 by aspartic acid and the substitution of the amino acid at position 368 by glutamic acid and the amino acid variant Y349C, and

[0517] the second polypeptide comprises the substitution of the amino acid at position 351 by lysine and the substitution of the amino acid at position 366 by lysine and amino acid variant S354C; or

[0518] (ii) the first polypeptide comprises the substitution of the amino acid at position 351 by aspartic acid and the substitution of the amino acid at position 368 by glutamic acid and the amino acid variant S354C, and

[0519] the second polypeptide comprises the substitution of the amino acid at position 351 by lysine and the substitution of the amino acid at position 366 by lysine and amino acid variant Y349C; anda second antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 17 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 17 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 18 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 18.

[0520] In particular, a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 1 or 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1 or 39; and

[0521] the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 2 or 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2 or 40; and

[0522] wherein a second antigen-binding protein of the (at least) two different (heteromeric) antigenbinding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 17 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 17 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 18 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 18.

[0523] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises a structure represented by the formula:

[0524] V1-L1-V2-FC1

[0525] and the second polypeptide comprises a structure represented by the formula:

[0526] V3-L2-V4-FC2

[0527] wherein LI and L2 are linkers and may be the same or different,wherein VI is Va, V2 is VH, V3 is VL, V4 is V£;

[0528] VI is VL, V2 is Va, V3 is VP, V4 is VH;

[0529] VI is VP, V2 is VL, V3 is VH, V4 is Va;

[0530] VI is VH, V2 is Va, V3 is VP, V4 is VL;

[0531] VI is Va, V2 is VL, V3 is VH, V4 is VP;

[0532] VI is VL, V2 is VP, V3 is Va, V4 is VH;

[0533] VI is VP, V2 is VH, V3 is VL, V4 is Va; or

[0534] VI is VH, V2 is VP, V3 is Va, V4 is VL; and

[0535] wherein FC1 comprises or consists of the amino acid sequence according to SEQ ID NO: 1 or 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1 or 39; and / or

[0536] FC2 comprises or consists of the amino acid sequence according to SEQ ID NO: 2 or 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2 or 40; and

[0537] wherein a second antigen-binding protein of the (at least) two different (heteromeric) antigenbinding proteins comprises two IgG CH3-containing polypeptides,

[0538] wherein the first polypeptide comprises a structure represented by the formula:

[0539] V5-L5-V6-FC3

[0540] and the second polypeptide comprises a structure represented by the formula:

[0541] V7-L6-V8-FC4

[0542] wherein L5 and L6 are linkers and may be the same or different,

[0543] wherein V5 is Va, V6 is VH, V7 is VL, V4 is VP;

[0544] V5 is VL, V6 is Va, V7 is VP, V8 is VH;

[0545] V5 is VP, V6 is VL, V7 is VH, V8 is Va;

[0546] V5 is VH, V6 is Va, V7 is VP, V8 is VL;

[0547] V5 is Va, V6 is VL, V7 is VH, V8 is VP;

[0548] V5 is VL, V6 is VP, V7 is Va, V8 is VH;

[0549] V5 is VP, V6 is VH, V7 is VL, V8 is Va; orV5 is VH, V6 is V , V7 is Va, V8 is VL; and

[0550] wherein FC3 comprises or consists of the amino acid sequence according to SEQ ID NO: 17 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 17; and / or

[0551] FC4 comprises or consists of the amino acid sequence according to SEQ ID NO: 18 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 18.

[0552] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises a structure represented by the formula:

[0553] VL-L1-V -FC2 ;

[0554] and a second polypeptide chain comprising a structure represented by the formula:

[0555] Va-L2-VH-FCl ;

[0556] wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 53, FC1 comprises or consists of SEQ ID NO: 1 or 39; Va comprises or consists of the amino acid according to SEQ ID NO: 54, VH comprises or consists of the amino acid according to SEQ ID NO: 9 and FC2 comprises or consists of SEQ ID NO: 2 or 40;

[0557] and

[0558] a second antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides,

[0559] wherein the first polypeptide comprises a structure represented by the formula:

[0560] VL-L1-VP-FC1 ;

[0561] and the second polypeptide chain comprising a structure represented by the formula:

[0562] Va-L2-VH-FC2 ;

[0563] wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 55, FC1 comprises or consists of SEQ ID NO: 17; Va comprises or consists of the amino acid according to SEQ ID NO: 56, VH comprises or consists of the amino acid according to SEQ ID NO: 13 and FC2 comprises or consists of SEQ ID NO: 18.In particular, a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises a structure represented by the formula:

[0564] VL-L1-VP-FC1 ;

[0565] and the second polypeptide chain comprising a structure represented by the formula:

[0566] Va-L2-VH-FC2 ;

[0567] wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 53, FC1 comprises or consists of SEQ ID NO: 17; Va comprises or consists of the amino acid according to SEQ ID NO: 54, VH comprises or consists of the amino acid according to SEQ ID NO: 9 and FC2 comprises or consists of SEQ ID NO: 18;

[0568] and

[0569] a second antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides,

[0570] wherein the first polypeptide comprises a structure represented by the formula:

[0571] VL-L1-V -FC2 ;

[0572] and the second polypeptide chain comprising a structure represented by the formula:

[0573] Va-L2-VH-FCl ;

[0574] wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 55, FC1 comprises or consists of SEQ ID NO: 1 or 39; Va comprises or consists of the amino acid according to SEQ ID NO: 56, VH comprises or consists of the amino acid according to SEQ ID NO: 13 and FC2 comprises or consists of SEQ ID NO: 2 or 40.

[0575] In particular, a first antigen-binding protein of the (at least) two different heteromeric antigenbinding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises a structure represented by the formula:

[0576] VL-L1-V -FC2 ;

[0577] and the second polypeptide chain comprising a structure represented by the formula:

[0578] Va-L2-VH-FCl ;wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 53, FC1 comprises or consists of SEQ ID NO: 1 or 39; Va comprises or consists of the amino acid according to SEQ ID NO: 54, VH comprises or consists of the amino acid according to SEQ ID NO: 9 and FC2 comprises or consists of SEQ ID NO: 2 or 40;

[0579] and

[0580] a second antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides,

[0581] wherein the first polypeptide comprises a structure represented by the formula:

[0582] VL-L1-V -FC2 ;

[0583] and the second polypeptide chain comprising a structure represented by the formula:

[0584] Va-L2-VH-FCl ;

[0585] wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 55, FC1 comprises or consists of SEQ ID NO: 17; Va comprises or consists of the amino acid according to SEQ ID NO: 56, VH comprises or consists of the amino acid according to SEQ ID NO: 13 and FC2 comprises or consists of SEQ ID NO: 18.

[0586] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises a structure represented by the formula:

[0587] VL-L1-V -FC2 ;

[0588] and the second polypeptide chain comprising a structure represented by the formula:

[0589] Va-L2-VH-FCl ;

[0590] wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 53, FC1 comprises or consists of SEQ ID NO: 17; Va comprises or consists of the amino acid according to SEQ ID NO: 54, VH comprises or consists of the amino acid according to SEQ ID NO: 9 and FC2 comprises or consists of SEQ ID NO: 18;and

[0591] a second antigen-binding protein of the (at least) two different heteromeric antigen-binding proteins may comprise two IgG CH3-containing polypeptides,

[0592] wherein the first polypeptide comprises a structure represented by the formula:

[0593] VL-L1-VP-FC2 ;

[0594] and the second polypeptide chain comprising a structure represented by the formula:

[0595] Va-L2-VH-FCl ;

[0596] wherein LI and L2 are linkers and comprise or consist of the amino acid according to SEQ ID NO: 16, VL comprises or consists of the amino acid according to SEQ ID NO: 5, V|3 comprises or consists of the amino acid according to SEQ ID NO: 55, FC1 comprises or consists of SEQ ID NO: 1 or 39; Va comprises or consists of the amino acid according to SEQ ID NO: 56, VH comprises or consists of the amino acid according to SEQ ID NO: 13 and FC2 comprises or consists of SEQ ID NO: 2 or 40.

[0597] The skilled person understands that in the described antigen-binding proteins comprising the knob-into-hole substitutions the cysteines forming a disulphide bridge may be exchanged / flipped between the CH3-domain containing polypeptides, i.e. the first polypeptide comprises the amino acid variant S349C and T366W and the second polypeptide comprises the amino acid variants Y354C, T366S, L368A and Y407V.

[0598] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 41 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 42; and

[0599] a second antigen-binding protein of the (at least) two different heteromeric antigen-binding proteins may comprise two IgG CH3-containing polypeptides,

[0600] wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 49 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 50.

[0601] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 41 andthe second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 42; and

[0602] a second antigen-binding protein of the (at least) two different heteromeric antigen-binding proteins may comprise two IgG CH3-containing polypeptides,

[0603] wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 51 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 52.

[0604] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 43 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 44; and

[0605] a second antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides,

[0606] wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 47 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 48.

[0607] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 45 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 46; and

[0608] a second antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins comprises two IgG CH3-containing polypeptides,

[0609] wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 47 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 48.

[0610] In particular a first antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins may comprise two IgG CH3-containing polypeptides, wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 25 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 26; anda second antigen-binding protein of the (at least) two different (heteromeric) antigen-binding proteins comprises two IgG CH3-containing polypeptides,

[0611] wherein the first polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 27 and the second polypeptide comprises or consists of an amino acid sequence according to SEQ ID NO: 28.

[0612] It is also envisaged that the Fc parts of the disclosed antigen-binding proteins are exchanged between the CH3-domain containing polypeptides. The skilled person is readily capable to determine the FC1 and / or FC2 in the disclosed antigen-binding proteins and knows that these regions may be exchanged between the CH3-domain containing polypeptides. In other words when a herein described antigen-binding protein comprises a first IgG CH3-containing polypeptide comprising FC1 and a second IgG CH3-containing polypeptide comprising FC2 also the antigen-binding protein with FC2 in first IgG CH3-containing polypeptide and FC1 in the second IgG CH3-containing polypeptide is disclosed.

[0613] The above molecules are also disclosed in WO 2025 / 233431, which is incorporated herein by reference in its entirety.

[0614] It is pointed out that the above molecules may be combined (in particular MAG-003 binding and PRAME-004 binding molecules) and used for treatment in combination with immune checkpoint inhibitors.

[0615] It is envisaged that the described antigen-binding proteins are combined with further antigenbinding proteins having further target antigens. In particular, it is envisaged that the described antigen-binding proteins targeting MAG-003 and / or PRAME-004 and (an) immune checkpoint inhibitor(s) are combined with further antigen-binding proteins having further target antigens.

[0616] As mentioned above it is in particular envisaged that the described antigen-binding proteins are co-expressed in a patient, preferably a human, in combination with administration of (an) immune checkpoint inhibitor(s).

[0617] Accordingly, in further embodiments of the invention, all the embodiments directed to (a method for producing) at least two different heteromeric antigen-binding proteins (in a single host cell) also refer to a method of treatment, wherein nucleic acids encoding said antigenbinding proteins are administered to a patient and the cells of the patient produce said antigen-binding proteins.The herein described antigen-binding proteins described herein a particularly useful for such application because they have excellent heterodimerisation properties and do not form incorrectly assembled dimers or a single-chain molecules when co-expressed.

[0618] Accordingly the invention relates to a pharmaceutical composition / formulation for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition / formulation comprises a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins and wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition / formulation.

[0619] Preferably, the nucleic acid is a mRNA.

[0620] The invention relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins, wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition, wherein a first antigen-binding protein of the at least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 1 or 39 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 2 or 40; and wherein a second antigen-binding protein of the least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 17 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 18, and wherein one of the antigen-binding proteins binds to the peptide according to SEQ ID NO: 57 and the other antigen-binding proteins binds to the peptide according to SEQ ID NO: 58; and wherein (an) immune checkpoint inhibitor(s) is coadministered to the cell, tissue or organism.

[0621] In particular it is envisaged that the TCER® molecules of Table 1 targeting MAG-003 or PRAME-004, respectively, are combined in the herein described methods of treating. It is evident that in particular the combination of TPP-9501 with TPP-9505 or TPP-9506 and the combination of TPP-9504 with TPP-9502 or TPP-9503 is envisaged.Accordingly, the invention also relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins, wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition, wherein a first antigen-binding protein of the at least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein

[0622] one polypeptide comprises the amino acid sequence according to SEQ ID NO: 41 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 42; and wherein a second antigen-binding protein of the least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 49 or 51 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 50 or 52; and wherein (an) immune checkpoint inhibitor(s) is co-administered to the cell, tissue or organism.

[0623] The invention further relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins, wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition, wherein a first antigen-binding protein of the at least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 47 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 48; and wherein a second antigen-binding protein of the least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 43 or 45 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 44 or 46; and wherein (an) immune checkpoint inhibitor(s) is co-administered to the cell, tissue or organism.

[0624] It is evident that a cell or tissue may refer to the cell or tissue of a patient and an organism may be a patient. ""

[0625]

[0626] Table 1: MAG-003 and PRAME-004 targeting TCER®s partly with the herein described heterodimerisation improving substitutions in the CH3-domain. The disulphide substitutions may be exchanged between the polypeptide chains. Accordingly, also the amino acid sequences of the polypeptides with the exchanged disulphide substitutions are considered to be encompassed / disclosed herein. For example, SEQ ID NOs: 41 is disclosed with S354C but the same sequence with Y349C is also encompassed (i.e. the sequence with a serine at the position corresponding to position 354 and cysteine at the position corresponding to position 349).

[0627] It is evident for the skilled person that the antigen-binding molecules of Table 1 contain a C-terminal Strep-Tag. Accordingly, it is evident for the skilled person that when said antigenbinding molecules are used in medical or therapeutic setings the antigen-binding molecules without Strep-Tag may be preferred. Table 2 shows the sequences of the antigen-binding proteins of Table 1 without Strep-Tag. Accordingly, it is evident for the skilled person that the antigen-binding proteins shown in Table 2 may be preferred for medical or therapeutic setings.

[0628] ""

[0629]

[0630]

[0631] Table 2: MAG-003 and PRAME-004 targeting TCER®s partly with the herein described heterodimerisation improving substitutions in the CH3-domain. The disulphide substitutions may be exchanged between the polypeptide chains. Accordingly, also the amino acid sequences of the polypeptides with the exchanged disulphide substitutions are considered to be encompassed / disclosed herein.

[0632] Accordingly, the invention also relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins, wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition, wherein a first antigen-binding protein of the at least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein

[0633] one polypeptide comprises the amino acid sequence according to SEQ ID NO: 79 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 76; and wherein a second antigen-binding protein of the least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 84 or 86 and the other polypeptide comprises the aminoacid sequence according to SEQ ID NO: 85 or 87; and wherein (an) immune checkpoint inhibitor(s) is co-administered to the cell, tissue or organism.

[0634] The invention further relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins, wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition, wherein a first antigen-binding protein of the at least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 74 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 72; and wherein a second antigen-binding protein of the least two antigen-binding proteins comprises two IgG CH3-containing polypeptides, wherein one polypeptide comprises the amino acid sequence according to SEQ ID NO: 80 or 82 and the other polypeptide comprises the amino acid sequence according to SEQ ID NO: 81 or 83; and wherein (an) immune checkpoint inhibitor(s) is co-administered to the cell, tissue or organism.

[0635] The invention also relates to a method comprising administering to a subject in need thereof a pharmaceutical composition comprising at least two of the herein described antigen-binding proteins or nucleic acids encoding at least two of the herein described antigen-binding proteins and (an) immune checkpoint inhibitor(s).

[0636] The invention also relates to a method of efficient protein production in a cell population, the method comprising contacting a cell population with nucleic acids encoding at least two of the herein described antigen-binding proteins or a pharmaceutical composition comprising said nucleic acids under conditions such that an effective amount of the protein is produced in the cell population, wherein (an) immune checkpoint inhibitor(s) is co-administered to the cell population.

[0637] The invention also relates to a method for inducing in vivo translation of at least two (recombinant) antigen-binding proteins in a mammalian subject in need thereof, comprising administering to the subject an effective amount of (a) nucleic acid(s) encoding at least two of the herein described antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid(s) under conditions such that the nucleic acid(s) is / are localized into a cell ofthe subject and the antigen-binding proteins are capable of being translated in the cell from the nucleic acid(s), wherein (an) immune checkpoint inhibitor(s) is co-administered to the subject.

[0638] The invention also relates to kits comprising the described antigen-binding proteins, nucleic acids, vectors, host cells or pharmaceutical compositions / formulations and (an) immune checkpoint inhibitor(s).

[0639] Suitable pharmaceutical compositions and modifications of the nucleic acids that allow treatment of patients by the above described uses and methods are described e.g. in W02012 / 019168, WO2013 / 151663 or WO2013 / 151665 which are incorporated by reference in their entirety.

[0640] As mentioned above, the invention also relates to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins for use as medicine. The antigen-binding proteins an immune checkpoint inhibitor may be administered or coadministered, simultaneously, in either separate or combined formulations, or sequentially at different times separated by minutes, hours or days, but in some way act together to provide the desired therapeutic response.

[0641] The invention also relates to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC), preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein, an antigenbinding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders.The invention also relates to a combination comprising an antigen-binding protein binding to MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins.

[0642] The invention also relates to a pharmaceutical composition comprising an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins.

[0643] The invention also relates to a pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding at least two antigen-binding proteins (and an immune checkpoint inhibitor), wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition and wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein.

[0644] The invention also relates to an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered incombination with an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins.

[0645] The invention also relates to an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins.

[0646] "Co-administration", "administered in combination", "administration of a combination", "coadministration of a combination", "combined therapy" and / or "combined treatment regimen" is used herein in the broadest sense and refers to (at least three) therapeutically active drugs or compositions which may be administered or co-administered, simultaneously, in either separate or combined formulations, or sequentially at different times separated by minutes, hours or days, but in some way act together to provide the desired therapeutic response. Accordingly, the described antigen-binding proteins and immune checkpoint inhibitor may be administered or co-administered, simultaneously, in either separate or combined formulations, or sequentially at different times separated by minutes, hours or days.

[0647] Simultaneous administration means that the therapeutically active agents (the described antigen-binding proteins and immune checkpoint inhibitors) can be administered at the same time. This can occur either by combining them into a single formulation / composition or by administering them separately but concurrently or concomitantly. The described antigenbinding proteins may be administered in separate formulations which means that the active agents may be provided in different formulations / compositions, meaning each drug or composition retains its own distinct form. Even though they are administered together or in close succession, they are not physically combined into one dosage form (e.g. pharmaceutical composition). It is also envisaged that the antigen-binding proteins are combined in one formulation and the checkpoint inhibitor is in a separate formulation. It is also envisage thatthe checkpoint inhibitor is combined with one antigen-binding protein and the other antigenbinding protein is in a separate formulation.

[0648] Sequential Administration means that the described antigen-binding proteins and immune checkpoint inhibitors are administered at different times. This could mean administering them minutes, hours or even days apart. Despite this staggered timing, the agents are considered part of a combined therapy because they interact or work in concert to achieve the desired therapeutic effect.

[0649] The skilled person knows that the key aspect of these combined approaches is that, regardless of the timing or method of delivery, the active agents may act in synergy or complement each other in a way that contributes to the intended therapeutic outcome or therapeutic effect. Accordingly, the invention relates to the described antigen-binding proteins for use in the treatment of cancer, wherein the antigen-binding proteins and immune checkpoint inhibitors are administered in combination, wherein the antigen-binding proteins and immune checkpoint inhibitors are each present in an amount effective to achieve a synergistic therapeutic effect when administered in combination.

[0650] The invention also relates to a method of protein production in a cell population, wherein the method comprises contacting a cell population with a nucleic acid or nucleic acids encoding at least two antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that an effective amount of the protein is produced in the cell population, wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein. Said method may be combined with an immune checkpoint inhibitor.

[0651] The invention also relates to a method for inducing in vivo translation of at least two antigenbinding proteins in a mammalian subject in need thereof, comprising administering to the subject an effective amount of a nucleic acid or nucleic acids encoding the at least two antigenbinding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that the nucleic acid(s) is / are localized into a cell of the subject and theantigen-binding proteins are capable of being translated in the cell from the nucleic acid(s), wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein. Said method may be combined with an immune checkpoint inhibitor.

[0652] The invention also relates to a method of treatment of cancer, a tumor or tumorous disease or disorder comprising administering to a subject in need thereof an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein and an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, preferably a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein, an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins.

[0653] Although evident for the skilled person it is pointed out that in the above described embodiments the antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and the antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC), an immune checkpoint inhibitor and optionally one or more further antigen-binding proteins act together to provide a desired therapeutic effect.

[0654] In particular the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein may comprise a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),

[0655] wherein the Va domain comprises

[0656] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 62,

[0657] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 63, and

[0658] (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 64; and wherein the VP domain comprises

[0659] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 59,(ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 60, and (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 61,

[0660] wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0661] The antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein may also comprises

[0662] a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 54 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 54 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 62, 63, and 64, respectively; and

[0663] a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 53 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 53 and comprising the CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 59, 60, and 61, respectively.

[0664] Furthermore, the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein may comprise

[0665] an antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH),

[0666] wherein the VL comprises

[0667] (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,

[0668] (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and

[0669] (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises

[0670] (i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,

[0671] (ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 11, and

[0672] (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12;

[0673] wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.The antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein may further comprise

[0674] a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0675] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 9 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 9 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.

[0676] The antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein may comprises or consists of

[0677] a first polypeptide chain comprising a structure represented by the formula:

[0678] VL-L1-V0-FC1;

[0679] and a second polypeptide chain comprising a structure represented by the formula:

[0680] Va-L2-VH-FC2;

[0681] wherein LI and L2 are linkers and may be the same or different and FC1 and FC2 are Fc-domains and may be the same or different.

[0682] LI and / or L2 may comprise or consist of an amino acid sequence according to SEQ ID NO: 16. FC1 may comprise or consist of an amino acid sequence according to SEQ ID NOs: 1, 17, 19, 21 or 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1, 17, 19, 21 or 39 and / or FC2 may comprise or consist of an amino acid sequence according to SEQ ID NOs: 2, 18, 20, 22 or 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2, 18, 20, 22 or 40.

[0683] The antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein may comprise a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 75, 79, 80 or 82 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, 81 or 83.

[0684] The antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein may comprise a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),wherein the Va domain comprises

[0685] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 68,

[0686] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 69, and

[0687] (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 70; and wherein the V|3 domain comprises

[0688] (i) a CDR 1 comprising the amino acid sequence according to SEQ ID NO: 65,

[0689] (ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 66, and

[0690] (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 67,

[0691] wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0692] The antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein may comprise

[0693] a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 56 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 56 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 68, 69, and 70, respectively; and

[0694] a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 55 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 55 and comprising the CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 65, 66, and 67, respectively.

[0695] The antigen-binding protein binding to a peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein may comprise

[0696] an antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH),

[0697] wherein the VL comprises

[0698] (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,

[0699] (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and

[0700] (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises

[0701] (i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,

[0702] (ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 14, and(iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12;

[0703] wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0704] The antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein may comprise

[0705] a VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; and

[0706] a VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 13 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 13 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 14, and 12, respectively.

[0707] The antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein may comprise or consist of

[0708] a first polypeptide chain comprising a structure represented by the formula:

[0709] VL-L1-V0-FC1;

[0710] and a second polypeptide chain comprising a structure represented by the formula:

[0711] Va-L2-VH-FC2;

[0712] wherein LI and L2 are linkers and may be the same or different and FC1 and FC2 are Fc-domains and may be the same or different.

[0713] LI and / or L2 may comprise or consist of an amino acid sequence according to SEQ ID NO: 16. FC1 may comprise or consist of an amino acid sequence according to SEQ ID NOs: 1, 17, 19, 21 or 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1, 17, 19, 21 or 39 and / or FC2 comprise or consist of an amino acid sequence according to SEQ ID NOs: 2, 18, 20, 22 or 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2, 18, 20, 22 or 40.

[0714] The antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein may comprise a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 71, 74, 84 or 86 and apolypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72, 85 or 87.

[0715] In preferred embodiments the antigen-binding proteins to be combined with an immune checkpoint inhibitor are the MAG-003 TCER® and the PRAME-004 TCER®.

[0716] Thus, in a preferred embodiment, the invention relates to an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and (an) immune checkpoint inhibitor (s) for use as medicine.

[0717] In another preferred embodiment, the invention relates to an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and (an) immune checkpoint inhibitor(s) for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders.

[0718] In another preferred embodiment, the invention relates to a combination comprising an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and (an) immune checkpoint inhibitor(s).

[0719] In another preferred embodiment, the invention relates to a combination comprising an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising apolypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and (an) immune checkpoint inhibitor(s) for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders.

[0720] In another preferred embodiment, the invention relates to a pharmaceutical composition comprising an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and (an) immune checkpoint inhibitor(s).

[0721] In another preferred embodiment, invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and (an) immune checkpoint inhibitor(s).

[0722] In another preferred embodiment, the invention relates to an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and (an) immune checkpoint inhibitor(s).

[0723] In another preferred embodiment, the invention relates to an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 and (an) immune checkpoint inhibitor(s).

[0724] The described antigen-binding proteins may be administered in the described embodiments in doses as described in EP24174662.7, EP24199013.4, EP25151617.5, EP24213284.3, EP25166821.6, PCT / EP2025 / 062557, PCT / EP2025 / 082829 and PCT / EP2025 / 082828, which are incorporated herein by reference in its entirety.

[0725] In particular, the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 may be administered at a dose of about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 80 pg, about 100 pg, about 120 pg, about 140 pg, about 150 pg, about 160 pg, about 180 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 360 pg, about 400 pg, about 450 pg, about 500 pg, about 540 pg, about 550 pg, about 600 pg, about 800 pg, about 1200 pg, about 1500 pg, about 1600 pg, about 1800 pg, about 2500 pg, about 3000 pg, about 3500 pg, about 4000 pg, about 4500 pg, about 5000 pg, about 5500 pg, about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg or about 50 mg, preferably about 20 pg, about 60 pg, about 120 pg, about 360 pg, about 800 pg, about 1600 pg, about 3000 pg, about 3500 pg, about 4000 pg, about 4500 pg, about 5000 pg, about 5500 pg, or about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg or about 20 mg,more preferably about 1600 pg, about 3000 pg, about 4000 pg, about 5000 pg, about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg about 20 mg, about 30 mg, about 40 mg or about 45 mg, most preferably about 10 mg, about 12 mg, about 20 mg, about 30 mg or about 45 mg. In particular, the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 may be administered at a dose of about 6.6 pg, about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 80 pg, about 100 pg, about 120 pg, about 140 pg, about 150 pg, about 160 pg, about 180 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg, about 540 pg, about 600 pg, about 1000 pg, about 1200 pg, about 1800 pg or about 2500 pg, about 5000 pg, or about 10 mg, preferably about 6.6 pg, about 20 pg, about 60 pg, about 180 pg, about 300 pg, about 540 pg, about 600 pg, about 1000 pg, about 1200 pg, about 1800 pg, about 2000 pg, about 2500 pg, about 5000 pg, or about 10 mg more preferably about 1000 pg, about 1200 pg, about 1800 pg, about 2000 pg or about 2500 pg, or about 1000 pg to about 2500 pg or about 1200 pg to about 2500 pg.

[0726] The skilled person understands that these doses may be target doses and step dosing may be performed as described herein below and in PCT / EP2025 / 062557, PCT / EP2025 / 082829 and PCT / EP2025 / 082828, which are incorporated herein by reference in its entirety.

[0727] Accordingly, the invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof (a combination of) an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 at a dose of about 6.6 pg, about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 80 pg, about 100 pg, about 120 pg, about 140 pg, about 150 pg, about 160 pg, about 180 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg, about 540 pg, about 600 pg, about 1000 pg, about 1200 pg, about 1800 pg or about 2500 pg, about 5000 pg, or about 10 mg, preferably about 6.6 pg, about 20 pg, about 60 pg, about 180 pg, about 300 pg, about 540 pg, about 600 pg, about 1000 pg, about 1200 pg, about 1800 pg, about 2000 pg, about 2500 pg, about 5000 pg, orabout 10 mg more preferably about 1000 pg, about 1200 pg, about 1800 pg, about 2000 pg or about 2500 pg, or about 1000 pg to about 2500 pg or about 1200 pg to about 2500 pg and an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 at a dose of about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 80 pg, about 100 pg, about 120 pg, about 140 pg, about 150 pg, about 160 pg, about 180 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 360 pg, about 400 pg, about 450 pg, about 500 pg, about 540 pg, about 550 pg, about 600 pg, about 800 pg, about 1200 pg, about 1500 pg, about 1600 pg, about 1800 pg, about 2500 pg, about 3000 pg, about 3500 pg, about 4000 pg, about 4500 pg, about 5000 pg, about 5500 pg, about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg or about 50 mg, preferably about 20 pg, about 60 pg, about 120 pg, about 360 pg, about 800 pg, about 1600 pg, about 3000 pg, about 3500 pg, about 4000 pg, about 4500 pg, about 5000 pg, about 5500 pg, or about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg or about 20 mg, more preferably about 1600 pg, about 3000 pg, about 4000 pg, about 5000 pg, about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg or about 45 mg, most preferably about 10 mg, about 12 mg, about 20 mg, about 30 mg or about 45 mg and (an) immune checkpoint inhibitor(s).

[0728] The invention also relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof (a combination of) an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 at a dose of about 1000 pg, about 1200 pg, about 1800 pg, about 2000 pg or about2500 ng, or about 1000 ng to about 2500 ng or about 1200 ng to about 2500 ng, an antigenbinding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 at a dose of about 1600 pg, about 3000 pg, about 4000 pg, about 5000 pg, about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg or about 15 mg or about 1600 pg to about 5000 pg, about 5000 pg to about 8000 pg, about 8000 pg to about 12 mg, about 12 mg to about 20 mg, about 20 mg to about 30 mg or about 30 mg to about 50 mg, preferably about 5000 pg to about 8000 pg, about 8000 pg to about 12 mg or about 12 mg to about 20 mg and an immune checkpoint inhibitor.

[0729] The invention also relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof (a combination of) an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 at a dose of about 1000 pg, about 1200 pg, about 1800 pg, about 2000 pg or about 2500 pg, or about 1000 pg to about 2500 pg, about 1000 pg to about 4000 pg or about 1200 pg to about 2500 pg, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 at a dose of about 1600 pg, about 3000 pg, about 4000 pg, about 5000 pg, about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg or about 15 mg or about 1600 pg to about 5000 pg, about 3000 pg to about 8000 pg, about 5000 pg to about 8000 pg, about 8000 pg to about 12 mg, about 12 mg to about 20 mg, about 20 mg to about 30 mg or about 30 mg to about 50 mg, preferably about 3000 pg to about 8000 pg, about 5000 pg to about 8000 pg, about 8000 pg to about 12 mg or about 12 mg to about 20 mg and an immune checkpoint inhibitor.

[0730] The invention also relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof (a combination of) an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ IDNOs: 76 at a dose of about 1000 ng, about 1200 ng, about 1800 ng, about 2000 ng or about 2500 ng, or about 1000 ng to about 2500 ng, about 1000 ng to about 4000 ng or about 1200 Hg to about 2500 ng, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 at a dose of about 1600 pg, about 3000 pg, about 4000 pg, about 5000 pg, about 6000 pg, about 7000 pg, about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg or about 15 mg or about 1600 pg to about 5000 pg, about 3000 pg to about 8000 pg, about 5000 pg to about 8000 pg, about 8000 pg to about 12 mg, about 12 mg to about 20 mg, about 20 mg to about 30 mg or about 30 mg to about 50 mg, preferably about 3000 pg to about 8000 pg, about 5000 pg to about 8000 pg, about 8000 pg to about 12 mg or about 12 mg to about 20 mg and an immune checkpoint inhibitor.

[0731] In a preferred embodiment invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof (a combination of) an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 at a dose of about 1000 pg, about 1200 pg, about 1500 pg, about 1800 pg, about 2000 pg or about 2500 pg, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 at a dose of about 10 mg, about 12 mg, 20 mg, about 30 mg or about 45 and (an) immune checkpoint inhibitor(s).

[0732] Also the concentrations used in the in vitro assay of Example 1 can be used to estimate the doses that may be used for the combination of the MAG-003 TCER® and the PRAME-004 TCER®. Doses can be calculated using the molecular weight of the respective TCER® molecule derived from the amino acid sequence and the assumption that ~10% of the Cmax patient plasma or serum TCER® concentration corresponds to the expected TCER® concentration at the tumor site. Cmax values may be derived from EP24174662.7, EP24199013.4, EP25151617.5, EP24213284.3, EP25166821.6, PCT / EP2025 / 062557, PCT / EP2025 / 082829 and PCT / EP2025 / 082828.The invention also relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof (a combination of) an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 at a dose of about 0.34 pg to about 34 mg, such as about 0.34 pg, about 3.4 pg, about 34 pg, about 340 pg, about 3400 pg or about 34 mg and an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 at a dose of about 0.38 pg to about 38 mg, such as about 0.38 pg, about 3.8 pg, about 38 pg, about 380 pg, about 3800 pg or about 38 mg.

[0733] The invention also relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof (a combination of) an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 at a dose of about 34 pg to about 3400 pg, such as about 34 pg, about 340 pg or about 3400 pg and an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 at a dose of about 380 pg to about 38 mg, such as about 380 pg, about 3800 pg, about 30 mg or about 38 mg.

[0734] It is envisaged that the antigen-binding proteins are administered weekly for the first administrations and then administered bi-weekly, every three weeks or every four weeks. The antigen-binding proteins may administered weekly for the first four, the first five, the first six, the first seven or the first eight administrations and then administered bi-weekly, every three weeks or every four weeks. The antigen-binding proteins may administered weekly for the first seven administrations and then administered bi-weekly. The antigen-binding proteins may administered weekly for the first seven administrations and then administered every three weeks. The antigen-binding proteins may administered weekly for the first seven administrations and then administered every four weeks.In preferred embodiments administration of the antigen-binding proteins is switched to administration every four weeks when combined with Opdulalag®. In further preferred embodiments administration of the antigen-binding proteins is switched to administration every three weeks when combined with Fianlimab and Cemiplimab.

[0735] Step dosing and administration schedules of the antigen-binding proteins may be performed as described in EP24174662.7, EP24199013.4, EP25151617.5, EP24213284.3, EP25166821.6, PCT / EP2025 / 062557, PCT / EP2025 / 082829 and PCT / EP2025 / 082828 which are incorporated herein by reference in their entirety.

[0736] The invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein the treatment comprises administration to the patient

[0737] a) at least one first dose of about 200 pg to about 1000 pg, such as 300 pg;

[0738] b) at least one second dose of about 400 pg to about 1000 pg, such as about 600 pg; c) at least one third dose in the range of about 600 pg to about 6000 pg, such as about 1000 pg, about 1100 pg, about 1200 pg, about 1300 pg, about 1400 pg, about 1500 pg about 1600 pg, about 1700 pg, about 1800 pg, about 1900 pg, about 2000 pg, about 2100 pg, about 2200 pg, about 2300 pg, about 2400 pg, about 2500 pg, about 2600 pg, about 2700 pg, about 2800 pg, about 2900 pg, about 3000 pg, about 3100 pg, about 3200 pg, about 3300 pg, about 3400 pg, about 3500 pg, about 3600 pg, about 3700 pg, about 3800 pg, about 3900 pg, about 4000 pg, about 4100 pg, about 4200 pg, about 4300 pg, about 4400 pg, about 4500 pg, about 4600 pg, about 4700 pg, about 4800 pg, about 4900 pg, about 5000 pg, about 5100 pg, about 5200 pg, about 5300 pg, about 5400 pg, about 5500 pg, about 5600 pg, about 5700 pg, about 5800 pg, about 5900 pg or about 6000 pg or about 1000 pg to about 4000 pg, such as about 1000 pg to about 2500 pg or about 1200 pg to about 2500 pg of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76; and

[0739] a) at least one first dose in the range of about 40 pg to about 120 pg such as about 40 pg, about 50 pg, about 60 pg, about 70 pg or about 80 pg;b) at least one second dose in the range of about 120 ng to about 400 ng, such as about 120 ng, about 200 ng, about 300 ng or about 400 ng;

[0740] c) optionally at least one third dose in the range of about 400 pg to about 2000 pg, such as 1600 pg or 2000 pg; and

[0741] d) at least one further dose in the range of about 2000 pg to about 6000 pg or about 6000 pg to about 30 mg, such as about 4000 pg, about 5000 pg or about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg or about 20 mg of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72.

[0742] The invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein the treatment comprises administration to the patient

[0743] a) at least one first dose of about 200 pg to about 1000 pg, such as 300 pg;

[0744] b) at least one second dose of about 400 pg to about 1000 pg, such as about 600 pg; c) at least one third dose in the range of about 600 pg to about 6000 pg, such as about 1000 pg, about 1100 pg, about 1200 pg, about 1300 pg, about 1400 pg, about 1500 pg about 1600 pg, about 1700 pg, about 1800 pg, about 1900 pg, about 2000 pg, about 2100 pg, about 2200 pg, about 2300 pg, about 2400 pg, about 2500 pg, about 2600 pg, about 2700 pg, about 2800 pg, about 2900 pg, about 3000 pg, about 3100 pg, about 3200 pg, about 3300 pg, about 3400 pg, about 3500 pg, about 3600 pg, about 3700 pg, about 3800 pg, about 3900 pg, about 4000 pg, about 4100 pg, about 4200 pg, about 4300 pg, about 4400 pg, about 4500 pg, about 4600 pg, about 4700 pg, about 4800 pg, about 4900 pg, about 5000 pg, about 5100 pg, about 5200 pg, about 5300 pg, about 5400 pg, about 5500 pg, about 5600 pg, about 5700 pg, about 5800 pg, about 5900 pg or about 6000 pg or about 1000 pg to about 4000 pg, such as about 1000 pg to about 2500 pg or about 1200 pg to about 2500 pg of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76; anda) at least one first dose in the range of about 5 ng to about 120 ng such as about 10 ng, about 15 ng, about 40 ng, about 40 ng, about 50 ng, about 60 ng, about 70 ng or about 80 ng; b) at least one second dose in the range of about 120 ng to about 400 ng, such as about 120 ng, about 200 ng, about 300 ng or about 400 ng;

[0745] c) optionally at least one third dose in the range of about 400 pg to about 10 mg, such as about 1600 pg, about 2000 pg, about 4000 pg, about 6000 pg or about 8000 pg; and d) at least one further dose in the range of about 2000 pg to about 6000 pg or about 6000 pg to about 30 mg, such as about 4000 pg, about 5000 pg or about 8000 pg, about 9000 pg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 40 mg or about 45 mg of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 and an immune checkpoint inhibitor.

[0746] In preferred embodiments the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 is administered to the patient at

[0747] a) at least one first dose of about 30 pg;

[0748] b) at least one second dose of about 300 pg;

[0749] c) at least one third dose of about 600 pg; and

[0750] d) at least one further dose of about 1000 pg, about 1200 pg, about 1500 pg, about 1800 pg, about 2000 pg or about 2500 pg;

[0751] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly, every three weeks or every four weeks.

[0752] In preferred embodiments the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 is administered to the patient at

[0753] a) at least one first dose of about 30 pg;b) at least one second dose of about 300 ng;

[0754] c) at least one third dose of about 600 ng; and

[0755] d) at least one further dose of about 1000 ng;

[0756] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly.

[0757] In preferred embodiments the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 is administered to the patient at

[0758] a) at least one first dose of about 30 pg;

[0759] b) at least one second dose of about 300 pg;

[0760] c) at least one third dose of about 6000 pg; and

[0761] d) at least one further dose of about 10 mg, about 12 mg, about 20 mg, about 30 mg or about 45 mg;

[0762] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly, every three weeks or every four weeks.

[0763] In preferred embodiments the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 is administered to the patient at

[0764] a) at least one first dose of about 30 pg;

[0765] b) at least one second dose of about 300 pg;

[0766] c) at least one third dose of about 6000 pg; and

[0767] d) at least one further dose of about 12000 pg;

[0768] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly.In preferred embodiments the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 is administered to the patient at

[0769] a) at least one first dose of about 30 pg;

[0770] b) at least one second dose of about 300 pg;

[0771] c) at least one third dose of about 600 pg; and

[0772] d) at least one further dose of about 1000 pg, about 1200 pg, about 1500 pg, about 1800 pg, about 2000 pg or about 2500 pg;

[0773] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly;

[0774] and

[0775] the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 is administered to the patient at a) at least one first dose of about 30 pg;

[0776] b) at least one second dose of about 300 pg;

[0777] c) at least one third dose of about 6000 pg; and

[0778] d) at least one further dose of about 10 mg, about 12 mg, about 20 mg, about 30 mg or about 45 mg;

[0779] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly.

[0780] In preferred embodiments the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76 is administered to the patient at

[0781] a) at least one first dose of about 30 pg;

[0782] b) at least one second dose of about 300 pg;Ill

[0783] c) at least one third dose of about 600 ng; and

[0784] d) at least one further dose of about 1000 ng;

[0785] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly;

[0786] and

[0787] the antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72 is administered to the patient at a) at least one first dose of about 30 pg;

[0788] b) at least one second dose of about 300 pg;

[0789] c) at least one third dose of about 6000 pg; and

[0790] d) at least one further dose of about 12000 pg;

[0791] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly.

[0792] Thus, the invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, wherein the treatment comprises administration to the patient

[0793] a) at least one first dose of about 30 pg;

[0794] b) at least one second dose of about 300 pg ;

[0795] c) at least one third dose of about 600 pg;

[0796] d) at least one further dose of about 1000 pg

[0797] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76;

[0798] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly;

[0799] and

[0800] a) at least one first dose of about 30 ng;b) at least one second dose of about 300 ng;

[0801] c) at least one third dose of about 6000 ng; and

[0802] d) at least one further dose of about 12000 ng

[0803] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72;

[0804] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly.

[0805] A preferred target dose of the MAG-003 TCER® is about 1000 pg. Another preferred target dose of the MAG-003 TCER® is about 1200 pg. Another preferred target dose of the MAG-003 TCER® is about 1500 pg. Another preferred target dose of the MAG-003 TCER® is about 1800 pg. Another preferred target dose of the MAG-003 TCER® is about 2000 pg. Another preferred target dose of the MAG-003 TCER® is about 2500 pg;

[0806] A preferred target dose of the PRAME-004 targeting TCER® is about 10 mg, Another preferred target dose of the PRAME-004 targeting TCER® is about 12 mg, Another preferred target dose of the PRAME-004 targeting TCER® is about 20 mg, Another preferred target dose of the PRAME-004 targeting TCER® is about 30 mg. Another preferred target dose of the PRAME-004 targeting TCER® is about 45 mg.

[0807] In the described embodiments it is envisaged that one of the at least two antigen-binding proteins comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),

[0808] wherein the Va domain comprises

[0809] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 62,

[0810] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 63, and

[0811] (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 64; and wherein the VP domain comprises

[0812] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 65,

[0813] (ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 66, and

[0814] (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 67,wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution;

[0815] and the other of the at least two antigen-binding proteins comprises

[0816] i) a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the Va domain comprises

[0817] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 68,

[0818] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 69, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 70; and wherein the VP domain comprises

[0819] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 65,

[0820] (ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 66, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 67, wherein one or more of CDRal, CDRa2, CDRa3, CDR|31, CDR|32 and CDR|33 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution;

[0821] ii) a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP), wherein the Va domain comprises

[0822] (i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 95,

[0823] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 96, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 97; and wherein the VP domain comprises

[0824] (i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 99,

[0825] (ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 100, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 101, wherein one or more of CDRal, CDRa2, CDRa3, CDR|31, CDR|32 and CDR|33 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution; or

[0826] iii) comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),

[0827] wherein the Va domain comprises(i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 103,

[0828] (ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 104, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 105; and wherein the VP domain comprises

[0829] (i) a CDR 1 comprising the amino acid sequence according to SEQ ID NO: 107,

[0830] (ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 108, and (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 109, wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

[0831] Accordingly, the invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins comprises

[0832] a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 54 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 54 and preferably comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 62, 63, and 64, respectively, and

[0833] a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 53 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 53 and preferably comprising the CDRpi, CDR|32, and CDR|33 according to SEQ ID NOs: 59, 60, and 61, respectively;

[0834] and the other of the at least two antigen-binding proteins comprises

[0835] i) a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 56 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 56 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 68, 69, and 70, respectively; and

[0836] a VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 55 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 55 and preferably comprising the CDRpi, CDRP2, and CDRP3 according to SEQ ID NOs: 65, 66, and 67, respectively;ii) a Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 94 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 94 and preferably comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 95, 96, and 97, respectively; and

[0837] a VP comprising or consisting of the amino acid sequence according to 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 preferably comprising the CDRpi, CDR|32, and CDR|33 according to SEQ ID NOs: 99, 100, and 101, respectively; or

[0838] iii) a Va comprising or consisting of the amino acid sequence according to 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 preferably comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 103, 104, and 105, respectively; and

[0839] a VP comprising or consisting of the amino acid sequence according to 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 preferably comprising the CDRpi, CDRP2, and CDRP3 according to SEQ ID NOs: 107, 108, and 109, respectively.

[0840] In particular, the invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: (75 + 76), 134, 135, 136, 137, 138, 139, 140, 141, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 177, 178, 179, 180, 181, 197, 198, 204, 205 or 206;

[0841] and the other of the at least two antigen-binding proteins comprises or consists of i) the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207 or 208;

[0842] ii) the amino acid sequence according to SEQ ID NO: 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201 or 202; or

[0843] iii) the amino acid sequence according to SEQ ID NO: 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0844] comprises or consists of the amino acid sequence according to SEQ ID NO: 134;

[0845] and the other of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.

[0846] The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0847] comprises or consists of the amino acid sequence according to SEQ ID NO: 135;

[0848] and the other of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.

[0849] The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0850] comprises or consists of the amino acid sequence according to SEQ ID NO: 136;

[0851] and the other of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.

[0852] The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0853] comprises or consists of the amino acid sequence according to SEQ ID NO: 137;

[0854] and the other of the at least two antigen-binding proteins comprises or consists ofthe amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.

[0855] The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0856] comprises or consists of the amino acid sequence according to SEQ ID NO: 138;

[0857] and the other of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.

[0858] The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0859] comprises or consists of the amino acid sequence according to SEQ ID NO: 139;

[0860] and the other of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.

[0861] The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0862] comprises or consists of the amino acid sequence according to SEQ ID NO: 140;

[0863] and the other of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.The invention relates to the described uses, pharmaceutical compositions, combinations and methods, wherein one of the at least two antigen-binding proteins

[0864] comprises or consists of the amino acid sequence according to SEQ ID NO: 141;

[0865] and the other of the at least two antigen-binding proteins comprises or consists of the amino acid sequence according to SEQ ID NO: 126, 127, 128, 129, 130, 131, 132, 133, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 182, 183, 184, 185, 186, 199, 200, 203, 207, 208, 118, 119, 120, 121, 122, 123, 124, 125, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 172, 173, 174, 175, 176, 193, 194, 195, 196, 201, 202, 110, 111, 112, 113, 114, 115, 116, 117, 189, 190, 191 or 192.

[0866] Independent of the above it is pointed out that all the herein disclosed antigen-binding proteins may be combined with each other and (an) immune checkpoint inhibitor(s). In particular one or several MAG-003 binding antigen-binding proteins and one or several PRAME-004 binding antigen-binding proteins may be combined with each other and (an) immune checkpoint inhibitor.

[0867] The described antigen-binding proteins may be administered intravenously.

[0868] The subject or patient to be treated is preferably human.

[0869] As mentioned above, it is envisaged that in particular cancer is treated by the herein described antigen-binding proteins, nucleic acids, vectors, host cells, uses and methods.

[0870] The skilled person is readily capable to choose cancers that can be treated by the herein described means and methods.

[0871] The cancer may also be selected from the group consisting of adrenocortical carcinoma, bladder cancer, preferably (urinary) bladder carcinoma or bladder urothelial carcinoma, brain tumor, in particular glioblastoma, primary brain cancer, or atypical meningioma, breast cancer, in particular triple-negative breast cancer or breast carcinoma, cervical carcinoma, in particular cervical squamous cell carcinoma or endocervical adenocarcinoma, cholangiocellular carcinoma, colorectal cancer, in particular colon cancer, endometrial cancer, in particular uterine carcinoma or uterine carcinosarcoma, epithelial cancer of the larynx, esophageal cancer, preferably large cell neuroendocrine tumor of the esophagus, esophageal carcinoma or esophageal squamous cell carcinoma, gastroesophageal junction cancer (GEJC), fallopian tube cancer, gallbladder cancer, preferably gallbladder adenocarcinoma, gastro-intestinalcancer, gastric cancer (GC), preferably gastric adenocarcinoma; colorectal cancer (CRC); pancreatic cancer (PACA), germ cell tumor, head and neck cancer, in particular head and neck adenocarcinoma, head and neck squamous cell carcinoma or cervical squamous cell carcinoma, liver cancer, in particular hepatocellular cancer or hepatocellular carcinoma, leukemia, in particular acute myeloid leukemia or chronic lymphocytic leukemia, lung cancer, in particular small cell lung cancer, non-small cell lung cancer, non-small cell lung adenocarcinoma, non-small cell lung squamous cell carcinoma (sqNSCLC), large cell neuroendocrine tumor of the lung or large cell carcinoma of the lung, lymphoma, in particular extranodal T / NK-cell lymphoma, non-Hodgkin lymphoma, or H. pylori-induced MALT nonHodgkin lymphoma, malignant peripheral nerve sheath tumors, skin cancer, in particular melanoma, in particular amelanotic melanoma, uveal melanoma, mucosal melanoma or cutaneous melanoma, mesothelioma, oral cavity carcinomas, oral squamous carcinoma, ovarian cancer, in particular epithelial ovarian cancer, serous ovarian cancer, ovarian carcinoma or ovarian carcinosarcoma, ovarian serous carcinoma, epithelial ovarian, fallopian tube, and primary peritoneal cancers (EOFPC), papillary thyroid carcinoma, primary peritoneal cancer, in particular restricted to serous, clear cell, and endometrioid subtypes, prostate cancer, renal cancer, in particular renal carcinoma, in particular renal clear cell carcinoma, renal papillary cell carcinoma, salivary duct carcinoma, sarcoma, in particular Ewing's sarcoma, fibrosarcoma, liposarcoma, osteosarcoma, sarcoma of the tonsil or synovial sarcoma (spindle cell, biphasic, and poorly differentiated subtypes), testicular cancer, in particular testicular germ cell tumor, thymoma, urothelial carcinoma, uterine cancer (UEC), preferably uterine carcinosarcoma or uterine carcinoma, Merkel cell carcinoma, Neuroendocrine neoplasms (NEN), preferably Neuroendocrine Tumor CUP, gallbladder cancer (GBC), preferably gallbladder adenocarcinoma and bile duct cancer (CCC).

[0872] The cancer may also be selected from the group consisting of adrenocortical carcinoma, bladder cancer, brain tumor, in particular glioblastoma, primary brain cancer, or atypical meningioma, breast cancer, in particular triple-negative breast cancer, cervical carcinoma, in particular cervical squamous cell carcinoma or endocervical adenocarcinoma, cholangiocellular carcinoma, colorectal cancer, in particular colon cancer, endometrial cancer, in particular uterine carcinosarcoma, epithelial cancer of the larynx, esophageal carcinoma, fallopian tube cancer, gallbladder cancer, gastro-intestinal cancer, germ cell tumor, head and neck cancer, in particular head and neck adenocarcinoma, or head and neck squamous cellcarcinoma, hepatocellular carcinoma, leukemia, in particular acute myeloid leukemia or chronic lymphocytic leukemia, lung cancer, in particular small cell lung cancer, non-small cell lung cancer, non-small cell lung adenocarcinoma, non-small cell lung squamous cell carcinoma (sqNSCLC), lymphoma, in particular extranodal T / NK-cell lymphoma, non-Hodgkin lymphoma, or H. pylori-induced MALT non-Hodgkin lymphoma, malignant peripheral nerve sheath tumors, melanoma, in particular amelanotic melanoma, uveal melanoma, or cutaneous melanoma, mesothelioma, oral cavity carcinomas, oral squamous carcinoma, ovarian cancer, in particular epithelial ovarian cancer, serous ovarian cancer or ovarian carcinosarcoma, papillary thyroid carcinoma, primary peritoneal cancer, in particular restricted to serous, clear cell, and endometrioid subtypes, prostate cancer, renal carcinoma, in particular renal clear cell carcinoma, renal papillary cell carcinoma, salivary duct carcinoma, sarcoma, in particular Ewing's sarcoma, fibrosarcoma, liposarcoma, osteosarcoma, or synovial sarcoma, testicular cancer, in particular testicular germ cell tumor, thymoma, urothelial carcinoma and uterine carcinoma.

[0873] The cancer may also be selected from the group consisting of lung cancer such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) or large cell lung cancer (LCLC), preferably non-small cell lung cancer adenocarcinoma (NSCLCadeno), squamous cell non-small cell lung cancer (NSCLCsquam) or large cell neuroendocrine tumor of the lung; liver cancer, preferably hepatocellular cancer (HCC); head and neck cancer, preferably head and neck squamous cell carcinoma (HNSCC) or cervical squamous cell carcinoma; skin cancer, preferably melanoma (MEL), preferably cutaneous melanoma or mucosal melanoma; renal cell cancer (RCC); brain cancer, preferably glioblastoma (GBM); gastric cancer (GC), preferably gastric adenocarcinoma; colorectal cancer (CRC); pancreatic cancer (PACA); prostate cancer (PRAD); leukemia, preferably acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL); lymphoma, preferably non-Hodgkin lymphoma (NHL); breast cancer (BRCA), preferably triple-negative breast cancer (TNBC); Merkel cell carcinoma; ovarian cancer (OC), preferably ovarian carcinoma or ovarian serous carcinoma; (urinary) bladder cancer (UBC), preferably (urinary) bladder carcinoma or bladder urothelial carcinoma; uterine cancer (UEC), preferably uterine carcinosarcoma; gallbladder cancer (GBC), preferably gallbladder adenocarcinoma; bile duct cancer (CCC); sarcoma (SARC), preferably synovial sarcoma, sarcoma of the tonsil or osteosarcoma; esophageal cancer, preferably large cell neuroendocrine tumor of the esophagus or esophageal squamous cell carcinoma; gastroesophageal junction cancer (GEJC);Neuroendocrine neoplasms (NEN), preferably Neuroendocrine Tumor CUP; and testicular cancer, preferably testicular germ cell tumor.

[0874] In particular the cancer types identified in the appended examples are envisaged to be treated by the described embodiments, such as head & neck squamous cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, esophageal carcinoma, triple-negative breast cancer, skin cutaneous melanoma, bladder carcinoma, or ovarian carcinoma. In particular head & neck squamous cell carcinoma and lung squamous cell carcinoma may be treated by the herein described embodiments.

[0875] The skilled person is readily capable to determine when a cancer can be treated with the herein described means and methods. For example, the skilled person understands that when the described antigen-binding proteins bind to the tumor antigen MAG-003 the cancer to be treated should present said peptide MAG-003. Similarily, the skilled person understands that when the described antigen-binding proteins bind to the tumor antigen PRAME-004 the cancer to be treated should present said peptide PRAME-004. When a cancer is to be treated by a combination of an antigen-binding protein binding to MAG-003 and an antigen-binding protein binding to PRAME-004 the cancer should preferably present both peptides MAG-003 and PRAME-004. Accordingly, the cancer to be treated may be a MAG-003 positive and / or PRAME-004 positive.

[0876] In the context of the present invention, a cancer may be considered to be "MAG-003 positive" if the MAG-003 peptide is presented in >50%, >60%, >70%, >80%, >90%, >95% or >98% of all cancers according to the guidelines by the NCI. In other indications biopsy may be performed (as it may be standard in the treatment of these cancers) and the peptide can be identified according to e.g. the XPRESIDENT® platform and related methods (according to WO 2003 / 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 conclusion, it is evident that the skilled person (who may also be a physician) can readily determine when a cancer may be treated by the herein described antigen-binding proteins.

[0877] A threshold to determine MAGEA4 or MAGEA8 positivity has been described in Tsimberidou et al. (Tsimberidou et al., Cancer Immunol Res., 2023, ll(7):925-945) and may be set to7.26 / 8.06 (FF / FFPE) or 7.58 / 8.51 (FF / FFPE) Delta Ct (DCt), respectively to select for patients with sufficient MAGEA4 / 8 expression for the herein described treatments. The MAGEA4 / MAGEA8 expression can be determined by qPCR from a fresh frozen (ff) or formalin-fixed paraffin-embedded (FFPE) biopsy sample. It may also be in the range of 1 and 10, preferably set to 7.26 / 8.06, 6.26 / 7.06 or 5.26 / 6.06 or 4.26 / 5.06 or 3.26 / 4.06 (FF / FFPE) DCt for MAGEA4 and 7.58 / 8.51, 6.58. / 7.51, 5.58 / 6.54, 4.58 / 5.54 or 4.58 / 5.54 (FF / FFPE) DCt for MAGEA8 to select for patients with high MAGEA4 / 8 expression. Alternatively, MAGEA4 / 8 expression may be measured using immunohistochemistry staining of FFPE-embedded or fresh biopsy samples with appropriate antibodies binding to the MAGEA4 / 8 protein. For detection of the binding of the antibody to MAGEA4 / 8 protein, a fluorophore-tagged antibody or an enzyme-linked antibody catalyzing a color-producing reaction (e.g. horse radish peroxidase) may be used and signal strength may be detected and quantified as a measure of MAGEA4 / 8 protein presence and indirectly MAG-003 presentation.

[0878] The cancer or tumor to be treated may have >1, >25, >50, >75, > 100, > 120 or > 1000 presented MAG-003 copies per cell, preferably >75, > 100, > 120, or > 1000 copies per cell. In the context of the present invention, a cancer may be considered to be "PRAME-004 positive" if the PRAME-004 peptide is presented in >50%, >60%, >70%, >80%, >90%, >95% or >98% of all cancers according to the guidelines by the NCI. In other indications biopsy may be performed (as it may be standard in the treatment of these cancers) and the peptide can be identified according to e.g. the XPRESIDENT® platform and related methods (according to WO 2003 / 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 conclusion, it is evident that the skilled person (who may also be a physician) can readily determine when a cancer may be treated by the herein described antigen-binding proteins in the herein described doses.

[0879] PRAME expression can be determined by qPCR from a fresh frozen (FF) or formalin-fixed paraffin-embedded (FFPE) biopsy sample. As an example, the delta Ct value may be in the range of 1 and 10 to select for patients with high PRAME expression. An exemplary method for determining the expression of a tumor antigen by qPCR is described in Tsimberidou et al. (Tsimberidou et al., Cancer Immunol Res., 2023, ll(7):925-945). As an example, to select for patients with high PRAME expression, the PRAME delta Ct value may be in the range between1 and 10. Alternatively, PRAME expression may be measured using immunohistochemistry staining of FFPE-embedded or fresh biopsy samples with appropriate antibodies binding to the PRAME protein. For detection of the binding of the antibody to PRAME protein, a fluorophore-tagged antibody or an enzyme-linked antibody catalyzing a color-producing reaction (e.g. horse radish peroxidase) may be used and signal strength may be detected and quantified as a measure of PRAME protein presence and indirectly PRAME-004 presentation.

[0880] The cancer or tumor to be treated may have >1, >25, >50, >75, > 100 or > 1000 presented PRAME-004 copies per cell, preferably >75, > 100 or > 1000 copies per cell.

[0881] The skilled person knows how to choose suitable immune checkpoint inhibitors. An immune checkpoint inhibitor is an agent that inhibits the interaction or signaling of an immune checkpoint molecule thereby enhancing immune cell activation. Immune checkpoint inhibitors used in context of the present invention may target and inhibit proteins such as PD-1 (programmed death-1), PD-L1 (programmed death-ligand 1), Lymphocyte-activation gene 3 (LAG-3) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). Accordingly, an immune checkpoint inhibitor used in context of the present invention may be a PD-1 inhibitor, a PD-L1 inhibitor, LAG-3 inhibitor or a CTLA-4 inhibitor.

[0882] A PD-1 inhibitor may be selected from the group consisting of Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Retifanlimab-dlwr and Tislelizumab, preferably Pembrolizumab. A PD-L1 inhibitor may be selected from the group consisting of Atezolizumab, Durvalumab and Avelumab. A LAG-3 inhibitor may be Relatlimab or Fianlimab. A CTLA-4 inhibitor may be Ipilimumab orTremelimumab.

[0883] It is evident for the skilled person that also combinations of checkpoint inhibitors may be used in context of the invention. For example a combination of Nivolumab and Relatlimab (Opdualag®) or a combination of Fianlimab and Cemiplimab may be used. Also, bispecific monoclonal antibodies, like Cadonilimab targeting PD-1 and CTLA-4 may be used.

[0884] Thus in a preferred embodiment, the invention relates to a combination comprising an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ IDNOs: 72 and Pembrolizumab for use in the treatment of cancer, a tumor or tumorous disease or disorder.

[0885] In another preferred embodiment, the invention relates to a combination comprising an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72, Nivolumab and Relatlimab for use in the treatment of cancer, a tumor or tumorous disease or disorder.

[0886] In another preferred embodiment, the invention relates to a combination comprising an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72, Fianlimab and Cemiplimab for use in the treatment of cancer, a tumor or tumorous disease or disorder.

[0887] Again, it is pointed out that a "combination comprising" does not necessarily mean that all four components are combined in one formulation. It is envisaged that all four components are (e.g. the antigen-binding protein binding to the MAG-003 peptide, the antigen-binding protein binding to the PRAME-004 peptide, Nivolumab and Relatlimab) are administered to the patient as separate formulations. However, it is also envisaged that the antigen-binding protein binding to the MAG-003 peptide and the antigen-binding protein binding to the PRAME-004 peptide are administered as one formulation and the two checkpoint inhibitors (e.g. Nivolumab and Relatlimab) are administered as one formulation. It is also envisaged that the antigen-binding protein binding to the MAG-003 peptide and the antigen-binding protein binding to the PRAME-004 peptide are administered as separate formulations and the two checkpoint inhibitors ( e.g. Nivolumab and Relatlimab) are administered as one formulation. All time intervals between administrations are possible as long as the components act together to provide a desired therapeutic effect.Although evident for the skilled person it is pointed out that the immune checkpoint inhibitors are preferably used in the described embodiments according to their summary of product characteristics, which are herein incorporated by reference in their entirety.

[0888] It is envisaged that the immune checkpoint inhibitor is administered every two weeks. It is envisaged that the immune checkpoint inhibitor is administered every three weeks. It is envisaged that the immune checkpoint inhibitor is administered every four weeks. It is envisaged that the immune checkpoint inhibitor is administered every five weeks. It is also envisaged that the immune checkpoint inhibitor is administered every six weeks.

[0889] It is envisaged that Nivolumab is administered every two weeks. It also is envisaged that Nivolumab is administered every four weeks.

[0890] It is envisaged that Pembrolizumab is administered every three weeks. It also is envisaged that Pembrolizumab is administered every six weeks. It is also envisaged that the first administration of Pembrolizumab is performed seven days before the first administration of the herein described antigen-binding proteins. Accordingly, when Pembrolizumab is administered every six weeks Pembrolizumab is administered in week -1, the antigen-binding proteins are administered in week 1, 2, 3, 4, 5 and the antigen-binding protein and Pembrolizumab are administered in week 6, the antigen-binding proteins are administered in week 7, 8, 9, 10, 11 and the antigen-binding proteins and Pembrolizumab are administered in week 12 and so forth.

[0891] However, the first Pembrolizumab administration may also be performed together with the first administration of the described antigen-binding proteins. Accordingly, when Pembrolizumab is administered every six weeks Pembrolizumab and the antigen-binding proteins are administered in week 1 and the antigen binding protein is administered in week 2, 3, 4, 5, 6 and the antigen-binding protein and Pembrolizumab are administered in week 7 and so forth.

[0892] It is envisaged that a dose of 200 mg Pembrolizumab is administered to the patient. It is in particular envisaged that a dose of 200 mg Pembrolizumab is administered to the patient every three weeks. It is also envisaged that a dose of 400 mg Pembrolizumab is administered to the patient. It is in particular envisaged that a dose of 400 mg Pembrolizumab is administered to the patient every six weeks.It is envisaged that Nivolumab and Relatlimab (Opdualag®) is administered every 4 weeks. Nivolumab may be administered at a dose of about 480 mg and Relatlimab at a dose of about 160 mg.

[0893] It is envisaged that a combination of Fianlimab and Cemiplimab is administered every 3 weeks. Fianlimab may be administered at a dose of about 1600 mg and Cemiplimab at a dose of about 350 mg.

[0894] In a preferred embodiment, the invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, wherein the treatment comprises administration to the patient

[0895] a) at least one first dose of about 30 pg;

[0896] b) at least one second dose of about 300 pg ;

[0897] c) at least one third dose of about 600 pg;

[0898] d) at least one further dose of about 1000 pg, about 1200 pg, about 1500 pg, about 1800 pg, about 2000 pg or about 2500 pg

[0899] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76;

[0900] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly;

[0901] a) at least one first dose of about 30 pg;

[0902] b) at least one second dose of about 300 pg;

[0903] c) at least one third dose of about 6000 pg; and

[0904] d) at least one further dose of about 10 mg, 12 mg, 20 mg, 30 mg or 45 mg

[0905] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72;preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly; and

[0906] and an immune checkpoint inhibitor.

[0907] In a preferred embodiment, the invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, wherein the treatment comprises administration to the patient

[0908] a) at least one first dose of about 30 pg;

[0909] b) at least one second dose of about 300 pg ;

[0910] c) at least one third dose of about 600 pg;

[0911] d) at least one further dose of about 1000 pg, about 1200 pg, about 1500 pg, about 1800 pg, about 2000 pg or about 2500 pg

[0912] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76;

[0913] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly;

[0914] a) at least one first dose of about 30 pg;

[0915] b) at least one second dose of about 300 pg;

[0916] c) at least one third dose of about 6000 pg; and

[0917] d) at least one further dose of about 10 mg, 12 mg, 20 mg, 30 mg or 45 mg

[0918] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72;

[0919] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly; and

[0920] Nivolumab and Relatlimab (Opdualag®), preferably wherein Nivolumab is administered at a dose of about 480 mg and Relatlimab is administered at a dose of about 160 mg, preferably wherein Nivolumab and Relatlimab are administered every 4 weeks.In a preferred embodiment, the invention relates to a method of treatment of cancer, a tumor or tumorous disease or disorder, wherein the treatment comprises administration to the patient

[0921] a) at least one first dose of about 30 pg;

[0922] b) at least one second dose of about 300 pg ;

[0923] c) at least one third dose of about 600 pg;

[0924] d) at least one further dose of about 1000 pg, about 1200 pg, about 1500 pg, about 1800 pg, about 2000 pg or about 2500 pg

[0925] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76;

[0926] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly;

[0927] a) at least one first dose of about 30 pg;

[0928] b) at least one second dose of about 300 pg;

[0929] c) at least one third dose of about 6000 pg; and

[0930] d) at least one further dose of about 10 mg, 12 mg, 20 mg, 30 mg or 45 mg

[0931] of an antigen-binding protein comprising a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72;

[0932] preferably wherein the antigen-binding proteins is administered weekly for the first seven weeks and then administered bi-weekly; and

[0933] Fianlimab and Cemiplimab, preferably wherein Fianlimab is administered at a dose of about 1600 mg and Cemiplimab is administered at a dose of about 350 mg, preferably wherein Fianlimab and Cemiplimab are administered every 3 weeks.

[0934] It is preferred that the first administration of the antigen-binding proteins and the immune checkpoint inhibitors is performed in the same week.In the context of the present application, the "percentage of identity" and "percentage of sequence identity" may be used interchangeably. It may 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. 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 for example be used. The needle program is for example available on the World Wide Web site and is further described in the 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, may be 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.

[0935] Further antigen-binding proteins that may be used in context of the present invention are disclosed in WO2025 / 233431 and EP25213127 which are incorporated herein by reference in their entirety.

[0936] As used herein, the terms "comprising", "including", "having" or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. The terms "comprising" / "including" / "having" encompass the terms "consisting of" and "consisting essentially of". Thus, whenever the terms "comprising" / "including" / "having" are used herein, they can be replaced by "consisting essentially of" or, preferably, by "consisting of".

[0937] The terms "comprising" / "including" / "having" mean that any further component (or likewise features, integers, steps and the like) can be present.

[0938] The term "consisting of" means that no further component (or likewise features, integers, steps and the like) can be present.The term "consisting essentially of" or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof but only if the additional features, integers, steps, components or groups thereof do not materially alterthe basicand novel characteristics ofthe claimed product, composition, device or method and the like.

[0939] Thus, the term "consisting essentially of" means that specific further components (or likewise features, integers, steps and the like) can be present, namely those ...

Claims

Claims1. An antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein and (an) immune checkpoint inhibitor(s) for use as medicine.

2. A nucleic acid or nucleic acids encoding an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, and (an) immune checkpoint inhibitor(s) for use as medicine.

3. The antigen-binding proteins of claim 1 or the nucleic acid or nucleic acids of claim 2 for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders.

4. A combination comprising an antigen-binding protein binding to MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid or nucleic acids encoding said antigen-binding proteins and (an) immune checkpoint inhibitor(s).

5. A pharmaceutical composition comprising an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid or nucleic acids encoding said antigen-binding proteins and (an) immune checkpoint inhibitor(s).

6. A pharmaceutical composition for use in a method of treating a condition or disease by producing at least two antigen-binding proteins in vivo, wherein the pharmaceutical composition comprises a nucleic acid or nucleic acids encoding at least two antigen-binding proteins and (an) immune checkpoint inhibitor(s), wherein the method comprises contacting a cell, tissue or organism with the pharmaceutical composition and wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein.

7. An antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with (an) immune checkpoint inhibitor(s) and an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein.

8. An antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein for use in the treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders, wherein said antigen-binding protein is administered in combination with and (an) immune checkpoint inhibitor(s) and an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein or a nucleic acid encoding said antigenbinding protein.

9. A method of protein production in a cell population, wherein the method comprises contacting a cell population with a nucleic acid or nucleic acids encoding at least two antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that an effective amount of the protein is produced in the cell population, wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to ainPRAME derived peptide bound to a major histocompatibility complex (MHC) protein wherein (an) immune checkpoint inhibitor(s) is co-administered to the cell population.

10. A method for inducing in vivo translation of at least two antigen-binding proteins in a subject in need thereof, comprising administering to the subject an effective amount of a nucleic acid or nucleic acids encoding the at least two antigen-binding proteins or a pharmaceutical composition comprising said nucleic acid or nucleic acids under conditions such that the nucleic acid(s) is / are localized into a cell of the subject and the antigen-binding proteins are capable of being translated in the cell from the nucleic acid(s), wherein one of the at least two antigen-binding proteins binds to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and another of the at least two antigen-binding proteins binds to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein, wherein (an) immune checkpoint inhibitor(s) is co-administered to the subject.

11. A method of treatment of cancer, a tumor or tumorous disease or disorder, infectious diseases, or immunological disorders comprising administering to a subject in need thereof an antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein and an antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC) protein and an immune checkpoint inhibitor.

12. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 11, comprising one or more further antigen-binding proteins.

13. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 12, wherein the antigen-binding protein binding to a MAGEA4 / 8 derived peptide bound to a major histocompatibility complex (MHC) protein, the antigen-binding protein binding to a PRAME derived peptide bound to a major histocompatibility complex (MHC), the178immune checkpoint inhibitor(s) and optionally one or more further antigen-binding proteins act together to provide a desired therapeutic effect.

14. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 13, wherein the MAGEA4 / 8 derived peptide is a peptide according to SEQ ID NO: 57.

15. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 14, wherein the PRAME derived peptide is a peptide according to SEQ ID NO: 58.

16. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 15, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (V|3).

17. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 16, wherein the antibody variable light chain domain (VL) and the antibody variable heavy chain domain (VH) associate to form a functional antibody antigen binding site (VD).

18. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 16, wherein the TCR alpha variable domain (Va) and the TCR beta variable domain (VP) associate to form a functional TCR antigen binding site (VR).

19. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 16, wherein at least one of the antigen-binding proteins is bispecific.17920. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 16 to 19, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:V1-V2-V3-V4,wherein VI, V2, V3, and V4 are independently selected from VH, VL, Va and VP in any order and wherein each of VH, VL, Va and VP appears once.

21. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 16 to 19, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:V1-V2-V3-V4,whereinVI is VH, V2 is VL, V3 is VP, V4 is Va;VI is VL, V2 is VH, V3 is VP, V4 is Va;VI is VH, V2 is VL, V3 is Va, V4 is Vp;VI is VL, V2 is VH, V3 is Va, V4 is Vp;VI is VP, V2 is Va, V3 is VH, V4 is VL;VI is VP, V2 is Va, V3 is VL, V4 is VH;VI is Va, V2 is VP, V3 is VH, V4 is VL; orVI is Va, V2 is VP, V3 is VL, V4 is VH.18022. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 16 to 19, wherein at least one of the antigen-binding proteins comprises an antibody variable light chain domain (VL), an antibody variable heavy chain domain (VH), a TCR alpha variable domain (Va) and a TCR beta variable domain (VP), wherein said antigen-binding protein comprises a structure represented by the formula:V1-V2-V3-V4,wherein VI is VH, V2 is Va, V3 is VP, V4 is VL;VI is VH, V2 is VP, V3 is Va, V4 is VL;VI is VL, V2 is Va, V3 is VP, V4 is VH;VI is VL, V2 is VP, V3 is Va, V4 is VH;VI is VP, V2 is VL, V3 is VH, V4 is Va;VI is Va, V2 is VL, V3 is VH, V4 is VP;VI is VP, V2 is VH, V3 is VL, V4 is Va; orVI is Va, V2 is VH, V3 is VL, V4 is vp.

23. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 20 to 22, wherein two or more of the variable domains are connected by linkers.

24. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 20 to 23, wherein the antigen-binding protein comprises a structure represented by the formula:V1-L1-V2-L2-V3-L3-V4;wherein LI, L2 and L3 are linkers and may be the same or different.18125. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 24, wherein the linkers LI and / or L3 have a length of at least about 3.5 A, preferably at least about 7 A.

26. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 24, wherein the linkers LI and / or L3 consist of at least one amino acid, preferably of at least two amino acids.

27. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 24 to 26, wherein the linker L2 has a length of at least about 17.5 A.

28. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 24 to 27, wherein the linker L2 consists of at least five amino acids.

29. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 24, wherein the linkers LI, L2 and / or L3 comprise or consist of SEQ ID NO: 209 (GGGGS).

30. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 24, wherein the linkers LI, L2 and / or L3 comprise or consist of SEQ ID NO: 210 (GGGGS GGGGS GGGGS).

31. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 24, wherein the linkers LI and L3 comprise or consist of SEQ ID NO: 209 (GGGS) and L2 comprises or consists of SEQ ID NO: 210 (GGGGS GGGGS GGGGS).

32. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 19, wherein at least one of the antigen-binding proteins comprises or consists ofa first polypeptide chain comprising a structure represented by the formula:VL-L1-V0-FC1;and a second polypeptide chain comprising a structure represented by the formula:Va-L2-VH-FC2;wherein LI and L2 are linkers and may be the same or different and FC1 and FC2 are Fc- domains and may be the same or different.

33. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 32, wherein LI and / or L2 comprise or consist of an amino acid sequence according to SEQ ID NO: 16.

34. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 32 or 33, whereinFC1 comprises or consists of an amino acid sequence according to SEQ ID NOs: 1, 17, 19, 21 or 39 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1, 17, 19, 21 or 39and / orFC2 comprises or consists of an amino acid sequence according to SEQ ID NOs: 2, 18, 20, 22 or 40 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2, 18, 20, 22 or 40.

35. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 14 to 34, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),wherein the Va domain comprises(i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 62,(ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 63, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 64; and wherein the VP domain comprises(i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 59,(ii) a CDR 2 comprising the amino acid sequence according to SEQ ID NO: 60, and (iii) a CDR 3 comprising the amino acid sequence according to SEQ ID NO: 61, wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

36. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 14 to 35, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprisesa Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 54 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 54 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 62, 63, and 64, respectively; anda VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 53 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 53 and comprising the CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 59, 60, and 61, respectively.

37. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 15 to 36, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),wherein the Va domain comprises(i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 68,(ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 69, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 70; and wherein the VP domain comprises(i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 65,(ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 66, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 67,184wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

38. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 15 to 37, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprisesa Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 56 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 56 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 68, 69, and 70, respectively; anda VP comprising or consisting of the amino acid sequence according to SEQ ID NO: 55 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 55 and comprising the CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 65, 66, and 67, respectively.

39. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claim 15 to 36, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),wherein the Va domain comprises(i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 95,(ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 96, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 97; and wherein the VP domain comprises(i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 99,(ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 100, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 101,185wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

40. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 39, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprisesa Va comprising or consisting of the amino acid sequence according to SEQ ID NO: 94 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 94 and comprising the CDRal, CDRa2, and CDRa3 according to SEQ ID NOs: 95, 96, and 97, respectively; anda VP comprising or consisting of the amino acid sequence according to 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 CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 99, 100, and 101, respectively.

41. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 15 to 36, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a T cell receptor (TCR) alpha variable domain (Va) and a TCR beta variable domain (VP),wherein the Va domain comprises(i) a CDRal comprising the amino acid sequence according to SEQ ID NO: 103,(ii) a CDRa2 comprising the amino acid sequence according to SEQ ID NO: 104, and (iii) a CDRa3 comprising the amino acid sequence according to SEQ ID NO: 105; and wherein the VP domain comprises(i) a CDRpi comprising the amino acid sequence according to SEQ ID NO: 107,(ii) a CDR|32 comprising the amino acid sequence according to SEQ ID NO: 108, and (iii) a CDR|33 comprising the amino acid sequence according to SEQ ID NO: 109,186wherein one or more of CDRal, CDRa2, CDRa3, CDR 1, CDR 2 and CDR 3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

42. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 41, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprisesa Va comprising or consisting of the amino acid sequence according to 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 according to SEQ ID NOs: 103, 104, and 105, respectively; anda VP comprising or consisting of the amino acid sequence according to 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 CDR|31, CDR|32, and CDR|33 according to SEQ ID NOs: 107, 108, and 109, respectively.

43. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 17 to 42, wherein one antigen binding site specifically binds to a cell surface molecule of a human immune cell and / or the other antigen binding site specifically binds to an MHC-associated peptide.

44. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 43, wherein the cell surface molecule is known to induce the activation of the immune cell, or is at least one selected from the group consisting of immune response-related molecules, CD3, such as the CD3y, CD36, and CD3E chains, CD4, CD7, CD8, CD10, CDllb, CDllc, CD14, CD16, CD18, CD22, CD25, CD28, CD32a, CD32b, CD33, CD41 , CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD55, CD56, CD61, CD64, CD68, CD94, CD90, CD117, CD123, CD125, CD134, CD137, CD152, CD163, CD193, CD203c, CD235a, CD278, CD279, CD287, Nkp46, NKG2D, GITR, FCERI, TCRa / p, TCRy / 6, and HLA-DR.18745. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 44, wherein the cell surface molecule is a TCR / CD3 complex, preferably an alpha / beta TCR / CD3 complex.

46. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claim 45, wherein at least one of the antigen-binding proteins comprisesan antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH),wherein the VL comprises(i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,(ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises(i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,(ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 11, and (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12; wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.

47. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 45 or 46, wherein at least one of the antigen-binding proteins comprisesa VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; anda VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 9 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID188NO: 9 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.

48. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 45 or 46, wherein at least one of the antigen-binding proteins comprisesa VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; anda VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 93 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 93 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 11, and 12, respectively.

49. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 45, wherein at least one the antigen-binding proteins comprisesan antibody variable light chain domain (VL), and an antibody variable heavy chain domain (VH),wherein the VL comprises(i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 6,(ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 7, and (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 8; and wherein the VH comprises(i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 10,(ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 14, and (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 12; wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid mutations, wherein the mutation may be a deletion, an insertion, or a substitution, preferably a conservative substitution.18950. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 45 or 50, wherein at least one of the antigen-binding proteins comprisesa VL comprising or consisting of the amino acid sequence according to SEQ ID NO: 5 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 5 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 6, 7, and 8, respectively; anda VH comprising or consisting of the amino acid sequence according to SEQ ID NO: 13 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 13 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 10, 14, and 12, respectively.

51. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 14 to 50, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 134, 135, 136, 137, 138, 139, 140, 141, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 178, 179, 180, 181, 197, 198, 204, 205 or 206;orwherein the antigen-binding protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 75, 77, 79, 80 or 82 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 76, 81 or 83.

52. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 15 to 51, wherein the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,190133, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 182, 183, 184, 185, 186, 189, 190, 191, 192, 193, 194, 195, 196, 199, 200, 201, 202, 203, 207 or 208;orwherein the antigen-binding protein binding comprises a polypeptide comprising or consisting of an amino acid sequence according SEQ ID NOs: 71, 73, 74, 84, 86 or 187 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NOs: 72, 85, 87 or 188.

53. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of claim 14 or 15, wherein the antigenbinding protein binding to the peptide according to SEQ ID NO: 57 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 79 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 76 and the antigen-binding protein binding to the peptide according to SEQ ID NO: 58 bound to a major histocompatibility complex (MHC) protein comprises a polypeptide comprising or consisting of an amino acid sequence according SEQ ID NO: 74 and a polypeptide comprising or consisting of an amino acid sequence according to SEQ ID NO: 72.

54. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of the preceding claims, wherein the immune checkpoint inhibitor(s) is / are administered before, concomitantly, simultaneously or after administration of the antigen-binding proteins, the nucleic acid, or the separate nucleic acids..

55. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of the preceding claims, wherein one / the immune checkpoint inhibitor is a PD1 inhibitor, preferably Pembrolizumab or cemiplimab.19156. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of the preceding claims, wherein one / the immune checkpoint inhibitor is a LAG-3 inhibitor, preferably Fianlimab.

57. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 54, wherein the immune checkpoint inhibitors are Nivolumab and Relatlimab.

58. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methods of any one of claims 1 to 54, wherein the immune checkpoint inhibitors are Fianlimab and Cemiplimab.

59. The antigen binding proteins for use, the nucleic acid(s) for use, the combination, the pharmaceutical compositions or the methodsof any one of the preceding items, wherein the cancer to be treated is head and neck squamous cell carcinoma (HNSCC), lung squamous cell carcinoma, such as sqNSCLC, lung adenocarcinoma, esophageal carcinoma, triple-negative breast cancer, melanoma, such as skin cutaneous melanoma, bladder carcinoma, endometrial carcinoma or ovarian carcinoma, preferably sqNSCLC.

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