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WO2025233420A1 - Utilisation de molécules anticancéreuses - Google Patents

Utilisation de molécules anticancéreuses

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Publication number
WO2025233420A1
WO2025233420A1 PCT/EP2025/062540 EP2025062540W WO2025233420A1 WO 2025233420 A1 WO2025233420 A1 WO 2025233420A1 EP 2025062540 W EP2025062540 W EP 2025062540W WO 2025233420 A1 WO2025233420 A1 WO 2025233420A1
Authority
WO
WIPO (PCT)
Prior art keywords
gen
binding protein
seq
amino acid
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/062540
Other languages
English (en)
Inventor
Lena FREUDENMANN
Jens Hukelmann
Heiko Schuster
Christoph Schräder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Immatics Biotechnologies GmbH
Original Assignee
Immatics Biotechnologies GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Immatics Biotechnologies GmbH filed Critical Immatics Biotechnologies GmbH
Publication of WO2025233420A1 publication Critical patent/WO2025233420A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/555—Interferons [IFN]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

  • the present inven on generally relates to the use of an -cancer molecules.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen- binding protein binds to a pep de according to SEQ ID NO: 25 and wherein said an gen- binding protein is administered in combina on with a pro-inflammatory substance.
  • the inven on also relates to a method of treatment of cancer in a pa ent in need of such treatment, wherein the method comprises administering a combina on of an an gen-binding protein and a pro-inflammatory substance to said pa ent, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25.
  • an an gen- binding protein for use in the treatment of a cancer wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25 and wherein the pa ent to be treated has an inflammatory state. Cancer remains one of the most crucial challenges to modern medicine, with its pervasive impact felt globally.
  • the present invention relates an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein specifically recognizes, is reactive with, or binds to a peptide according to SEQ ID NO: 25, or to the peptide according to SEQ ID NO: 25 bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02 and wherein said antigen-binding protein is administered in combination with a pro-inflammatory substance.
  • MHC major histocompatibility complex
  • the present invention relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein specifically recognizes, is reactive with, or binds to a peptide according to SEQ ID NO: 25, or to the peptide according to SEQ ID NO: 25 bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the patient to be treated has an inflammatory state.
  • MHC major histocompatibility complex
  • the fold increase is profoundly higher than what would be expected by the increase of expression of MHC protein (the structure that presents MAG-003 on the cell surface).
  • MHC protein the structure that presents MAG-003 on the cell surface.
  • the increase of presentation of MAG-003 presentation on the cancer cells cannot be explained by the increase of MHC levels but is a special feature of the MAG- 003 peptide.
  • the presentation of other, unrelated peptides is far less pronounced under inflammatory conditions compared to MAG-003 (Example section 2.2, Figure 2 B and Figure 3).
  • the present inventors demonstrated that a MAG-003 targeting bispecific molecule has a several fold higher cytotoxicity towards tumor cells when said tumor cells were pretreated with IFN- ⁇ to induce an inflammatory state (Example section 2.3, Figure 4).
  • MAGE-A4 and MAGE-A8 are both proteins and members of the MAGE-A gene family.
  • the functions of MAGE-A8 and –A4 are not known, though they may play a role in embryonal development and aspects of tumor transformation/progression. Multiple alternatively spliced variants have been identified for these proteins.
  • the MAGE-A antigen of SEQ ID NO: 25 belongs to cancer/testis (CT) antigens that are expressed in tumors but not in normal tissues except testis and placenta. Expression of MAGE-A proteins and mRNA, for example, has been linked to the development and prognosis of various cancers.
  • MAGE-A derived peptides in particular the MAGE-A4 and/or MAGE-A8 derived peptide ‘KVLEHVVRV’, which are presented by molecules of the major histocompatibility complex (MHC), may be bound by TCRs and are thus a target for T cell- based immunotherapy.
  • MHC major histocompatibility complex
  • WO 2017/158103 discloses TCRs, more par cularly na ve TCRs, such as the na ve TCR R7P1D5 (corresponding to SEQ ID NO: 26 + SEQ ID NO: 32), that bind to a complex of a MAGE-A an genic pep de having the amino acid sequence of KVLEHVVRV (SEQ ID NO: 25; MAG-003) and an HLA class I molecule, and their use in the diagnosis, treatment and preven on of cancerous diseases.
  • T cells that develop in the thymus are nega vely selected (tolerance induc on) on self-pep de-MHC ligands, such that T cells with too high affinity to such self-pep de-MHCs are deleted.
  • This low affinity may be one possible explana on for tumor immune escape (Aleksic et al.2012, Eur J Immunol.2012 Dec; 42(12):3174-9). Therefore, it is desirable to design TCR variants that bind with higher affinity to cancer an gens for use as an gen-recognizing constructs in an adop ve cell therapy (ACT), or as recogni on module of a soluble approach, i.e.
  • ACT adop ve cell therapy
  • T cell engaging receptor in the following also referred to as “TCER® molecules” or “TCER®”
  • TCER® T cell engaging receptor
  • TCER® molecules T cell engaging receptor molecules
  • TCER® T cell engaging receptor
  • SEQ ID NO: 136 of WO2021/023658 corresponds to SEQ ID NO: 1 in the present applica on and SEQ ID NO: 137 of WO2021/023658 corresponds to SEQ ID NO: 2 in the present applica on.
  • Said TCER® is referred to herein also as MAG-003 TCER®.
  • the T-cell recrui ng part of said TCER® is in par cular described in WO2021/023657 (as BMA031 (V36)).
  • SEQ ID NO: 42 (VL) of WO2021/023657 corresponds to SEQ ID NO: 3 in the present applica on and SEQ ID NO: 43 (VH) of WO2021/023657 corresponds to SEQ ID NO: 7 in the present applica on.
  • said TCER® effec vely binds and kills target cancer cells while maintaining a high safety profile due to low cross-reac vity to similar pep des.
  • a significant in vivo tumor growth inhibi on of said TCER® is demonstrated in WO2021/023658 in a therapeu c mouse model.
  • the present inventors determined a profound an -cancer ac vity when an an gen-binding protein binding to a pep de according to SEQ ID NO: 25 is administered in combina on with a pro-inflammatory substance.
  • the present inventors provide combina on therapies that allow excellent treatment of a wide range of cancer types.
  • the inven on is described in more detail. In par cular, the inven on relates to the following items. 1.
  • An an gen-binding protein for use in the treatment of a cancer wherein the an gen- binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, or to the pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02 and wherein said an gen-binding protein is administered in combina on with a pro-inflammatory substance.
  • MHC major histocompa bility complex
  • a method of treatment of cancer in a pa ent in need of such treatment comprises administering an an gen-binding protein to said pa ent, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, or to the pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02 and wherein said an gen-binding protein is administered in combina on with a pro-inflammatory substance.
  • MHC major histocompa bility complex
  • the cancer is a MAGE-A posi ve cancer, preferably MAGE-A4 or MAGE-A8 posi ve cancer.
  • the an gen-binding protein for use or the method according to any one of items 1 to 3 wherein the an gen-binding protein comprises or consists of an an body or a func onal fragment or deriva ve thereof.
  • an gen-binding protein for use or the method according to any one of items 1 to 4, wherein the an gen-binding protein comprises or consists of a T cell receptor (TCR) or a func onal fragment or deriva ve thereof, op onally wherein the T cell receptor (TCR), the func onal fragment or the deriva ve thereof is part of a host cell, preferably a T-cell.
  • TCR T cell receptor
  • an gen-binding protein for use or the method according to item 5 or 6, wherein the an gen-binding protein comprises a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 15 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 16, 17, and 18, respec vely; a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 11 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 11 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 12, 13, and 14, respec vely.
  • an gen-binding protein for use or the method according to any one of items 4 to 7, wherein the an gen-binding protein comprises: an an body variable light chain domain (V L ) and an an body variable heavy chain domain (V H ), wherein the V L comprises (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 4, (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 5, and (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 6; and wherein the VH comprises (i) a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 8, (ii) a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 9, and (iii) a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 10; wherein one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may comprise one, two or three amino acid
  • an gen-binding protein for use or the method according to any one of items 4 to 8, wherein the an gen-binding protein comprises: a V L comprising or consis ng 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% iden ty to SEQ ID NO: 40 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respec vely; and a V H comprising or consis ng of the amino acid sequence according to SEQ ID NO: 7 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 7 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 8, 9, and 10, respec vely.
  • V ⁇ and V ⁇ form afirst an gen-binding site that specifically binds to a MAGE-A4 or MAGE- A8 an genic pep de according to SEQ ID NO: 25 in a complex with a human MHC protein
  • V H and V L form a second an gen-binding site that specifically binds to a T cell receptor complex.
  • an gen-binding protein for use or the method according to any one of items 4 to 10, wherein the an gen-binding protein comprises or consists of afirst polypep de chain comprising a structure represented by the formula: V L -L1-V ⁇ [I]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-V H [II]; wherein L1 and L2 are linkers.
  • an gen-binding protein for use or the method according to any one of items 4 to 11, wherein the an gen-binding protein comprises or consists of afirst polypep de chain comprising a structure represented by the formula: V L -L1-V ⁇ -FC1 [III]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-V H -FC2 [IV]; wherein L1 and L2, are linkers and FC1 and FC2 are Fc-domains and may be the same or different.
  • an gen-binding protein for use or the method according to any one of items 4 to 12, wherein the an gen-binding protein comprises or consists of afirst polypep de chain comprising a structure represented by the formula: V L -L1-V ⁇ -L3-FC1 [V]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-V H -L4-FC2 [VI]; wherein L1, L2, L3 and L4 are linkers and FC1 and FC2 are Fc-domains and may be the same or different.
  • FC1 comprises or consists of the amino acid sequence according to SEQ ID NO: 19 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 19
  • FC2 comprises or consists of the amino acid sequence according to SEQ ID NO: 20 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 20.
  • an gen-binding protein for use or the method according to any one of items 1 to 14 wherein the an gen-binding protein comprises or consists of afirst polypep de chain that 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% iden ty to SEQ ID NO: 39 and comprising the CDRL1, CDRL2, CDRL3, CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respec vely; and a second polypep de chain that 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% iden ty to SEQ ID NO: 2 and comprising the CDR ⁇ 1, CDR ⁇ 2, CDR ⁇ 3, CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 16, 17, 18, 8, 9, and 10, respec ve
  • an gen-binding protein for use or the method according to item 26, wherein the an gen-binding protein comprises a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 42 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 42 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 28, 29, and 30, respec vely; a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 44 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 44 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 34, 35, and 36, respec vely.
  • an gen-binding protein for use or the method according to item 26 or 27, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a constant region having at least 70% sequence iden ty to an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region having at least 70% sequence iden ty to an amino acid sequence according to SEQ ID NO: 37.
  • an gen-binding protein for use or the method according to any one of items 26 to 28, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a amino acid sequence according to SEQ ID NO: 41 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 41 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 28, 29, and 30, respec vely; and wherein the TCR beta chain sequence comprises an amino acid sequence according to SEQ ID NO: 43 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 43 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 34, 35, and 36, respec vely.
  • the TCR alpha chain sequence comprises a amino
  • a host cell comprising the an gen-binding protein, the nucleic acid or separate nucleic acids, or the vector or the separate vectors according to any one of the preceding items for use in the treatment of cancer, wherein said host cell is administered in combina on with a pro-inflammatory substance, preferably wherein the host cell is a lymphocyte, more preferably a T lymphocyte or T lymphocyte progenitor, most preferably a CD4 or CD8 posi ve T-cell.
  • an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to any one of the preceding items, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell are formulated in a first pharmaceutical composition and the pro-inflammatory substance is formulated in a second pharmaceutical composition.
  • the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to any one of the preceding items, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell are formulated in a first pharmaceutical composition contained in a first vessel and the pro-inflammatory substance is formulated in a second pharmaceutical composition contained in a second vessel.
  • the antigen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to item 34, wherein the first vessel and/or second vessel is a vial or a syringe.
  • the antigen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to any one of the preceding items, wherein the antigen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell and the pro-inflammatory substance are each present in an amount effective to achieve a synergistic therapeutic effect when administered in combination.
  • the antigen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to any one of the preceding items wherein the pro-inflammatory substance is administered before, concomitantly to, concurrently to, simultaneously to or after administration of the antigen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell.
  • the PD-1 inhibitor is selected from the group consis ng of Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Re fanlimab-dlwr and Tislelizumab, preferably Pembrolizumab
  • interleukin interleukin-2 (IL-2), interleukin-12 (IL-12) or interleukin-18 (IL-18).
  • IL-2 interleukin-2
  • IL-12 interleukin-12
  • IL-18 interleukin-18
  • the antigen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to any one of the preceding items, wherein the subject to be treated is a mammal, preferably a human.
  • an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to any one of the preceding items, wherein the subject benefits from an increase of the presenta on level of the pep de according to SEQ ID NO: 25.
  • a kit comprising an an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell as defined in any one of the preceding items and one or more pro-inflammatory substances as defined in any one of the preceding items.
  • a method of trea ng a pa ent having an inflammatory state comprising administering to the pa ent an effec ve amount of the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell as defined in any one of the preceding items
  • the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to any one of items 47, 51 and 52, wherein the inflammatory state is iden fied systemically, in liquid biopsies and/or within the tumor.
  • CRP C-reac ve protein
  • ESR erythrocyte sedimenta on rate
  • the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to item 54 wherein the elevated level of C-reac ve protein (CRP) is 5 mg/l to 10 mg/l blood or higher.
  • CRP C-reac ve protein
  • the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use or the method according to item 54 wherein TNF- ⁇ is 8.1 pg/ml blood or higher, IL-1 ⁇ is 5.0 pg/ml blood or higher, IL-6 is 7.0 pg/ml blood or higher and/or IL-8 is 62 pg/ml or higher.
  • SAA serum amyloid A
  • MDA malondialdehyde
  • an an gen-binding protein that binds to a pep de with the amino acid sequence “KVLEHVVRV” (SEQ ID NO: 25) is used for cancer treatment.
  • the herein described an gen- binding proteins preferably bind the pep de according to SEQ ID NO: 25 when said pep de is bound to a major histocompa bility complex (MHC) protein.
  • MHC proteins are a set of cell surface proteins essen al for the adap ve immune system to recognize foreign molecules in vertebrates, which inter alia determines histocompa bility.
  • the main func on of MHC molecules is to bind to an gens derived from pathogens and tumor an gens and display them on the cell surface for recogni on by the appropriate T cells.
  • the MHC protein in context of the inven on belongs to MHC class I.
  • the MHC protein is of the serotype group HLA-A.
  • the MHC protein is of the serotype HLA-A*02. Accordingly, it is envisaged herein that an an gen-binding protein that binds the pep de according to SEQ ID NO: 25 when said pep de is bound to HLA-A*02 is used for cancer treatment.
  • HLA-A*02 can be further subdivided.
  • a preferred serotype is HLA-A*02:01. Accordingly, it is envisaged herein that an an gen-binding protein that binds the pep de according to SEQ ID NO: 25 when said pep de is bound to HLA-A*02:01 is used for cancer treatment. The skilled person understands that when it is referred herein to HLA-A*02 the serotype HLA-A*02:01 is preferred. Accordingly, the present inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25.
  • the inven on relates an an gen- binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02.
  • MHC major histocompa bility complex
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, or to the pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02 and wherein said an gen- binding protein is administered in combina on with a pro-inflammatory substance.
  • MHC major histocompa bility complex
  • the phrases “the an gen-binding protein specifically recognizes”, “the an gen-binding protein is reac ve with”, “the an gen-binding protein binds” or “the an gen-binding protein specifically binds” may be used synonymously herein and refer to the ability of a protein to bind to another molecule, typically another protein/pep de, a specific region on a protein/pep de, a protein/protein complex or a protein/pep de complex, with high affinity and specificity. This recogni on may occur through complementary molecular surfaces or structures, where specific interac ons take place, such as hydrogen bonds, electrosta c interac ons and hydrophobic interac ons.
  • Affinity refers to the strength of the interac on between two molecules. In the context of proteins, it typically describes how ghtly a protein binds to another molecule, such as an an gen. Higher affinity implies a stronger binding interac on, while lower affinity suggests a weaker binding. Affinity is o en quan fied by the dissocia on constant (Kd). Lower Kd values indicate higher affinity. Specificity refers to the selec vity of a molecular interac on, par cularly the ability of a molecule (such as a protein) to discriminate between different ligands or binding partners.
  • specificity may relate to the ability of a protein to bind selec vely to its cognate ligand or binding partner, despite the high concentra on of other molecules present in the corresponding environment. It is evident for the skilled person that in context of the present inven on specificity may mean the ability of an an gen-binding protein to discriminate between different an genes and to bind selec vely to its target an gen.
  • 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 preferred 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: 25), more particularly, the MAGE-A antigenic peptide comprising or consisting of the amino acid sequence “KVLEHVVRV” (SEQ ID NO: 25) in a complex with a MHC protein.
  • MAGE-A” or “melanoma associated an gen A” subfamily proteins were thefirst tumor associated an gens iden fied at the molecular level (van der Bruggen P, 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.
  • MAGE-A subfamily proteins are normally expressed only in tes s or placenta and their restricted expression suggests that they may func on 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 iden ty to each other and all MAGE proteins share the common MAGE homology domain, a highly conserved domain consis ng of approximately 170 amino acids.
  • MAGE-A4 or “Melanoma-associated an gen 4” protein is a member of the MAGE-A gene family and has the UniProt accession number P43358 (as available on April 30, 2024). MAGE-A4 localiza on has been described as cytoplasmic. However, MAGE-A4 staining has also been detected in nuclei, with differen al distribu on between nucleus and cytoplasm in well- differen ated versus less differen ated cancers (Sarcevic B et. al., 2003, Oncology 64, 443- 449).
  • MAGE-A4 is used as a male germ cell marker. lt is not expressed in gonocytes, but expressed in pre-spermatogonia and mature germ cells (Mitchell et al., 2014, Mod. Pathol.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 an gen 8” protein is a member of the MAGE-A superfamily and has the Uniprot accession number P43361 (as available on July 8, 2019).
  • MAGE-A4 and MAGE-A8 proteins have a sequence iden ty of 72% as determined by a protein sequence alignment using the BLASTP 2.9.0 algorithm (Stephen et al., 1997, Nucleic Acids Res.25:3389-3402). Furthermore, “MAGE-A4” and “MAGE-A8” both comprise the MAG- 003 pep de, i.e. “KVLEHVVRV” (SEQ ID NO: 25). It is evident for the skilled person that it is in par cular envisaged herein that a cancer is treated that presents the pep de according to SEQ ID NO:25 in complex with a MHC protein.
  • Pro-inflammatory substance is used herein in the broadest sense and refers to any drug, chemical compound or agent that induces or exacerbates the inflammatory response in the body. These substances may s mulate the produc on of inflammatory mediators, such as cytokines, prostaglandins, or histamines, leading to increased inflamma on. The skilled person is aware how to determine whether a substance is a pro-inflammatory substance. For example, a substance may be referred to as a pro-inflammatory substance when it affects any of the parameter linked with an inflammatory state as described herein.
  • a pro- inflammatory substance may elevate levels of C-reac ve protein (CRP), elevate erythrocyte sedimenta on rate (ESR), elevate levels of pro-inflammatory cytokines including TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, type I interferons, type II interferons and type III interferons, elevate white blood cell count, elevate plasmafibrinogen, elevate serum amyloid A (SAA), elevate levels of adhesion molecules such as ICAM-1 and VCAM-1, elevate levels of nitric oxide, elevate oxida ve stress markers such as malondialdehyde (MDA) and 8-isoprostane and/or triggerflu-like symptoms.
  • CRP C-reac ve protein
  • ESR erythrocyte sedimenta on rate
  • pro-inflammatory cytokines including TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, type I interferons, type II interferons and type III interferons
  • SAA serum amyloid
  • Inflamma on may be used herein in the broadest sense and may refer to the complex biological response of the body's immune system to harmful s muli, such as pathogens (bacteria, viruses, fungi), damaged cells, cancer cells, toxic compounds, or physical injury.
  • harmful s muli such as pathogens (bacteria, viruses, fungi), damaged cells, cancer cells, toxic compounds, or physical injury.
  • pathogens bacteria, viruses, fungi
  • One purpose of inflamma on is to eliminate the ini al cause of cell injury, clear out necro c cells and ssues damaged from the original injury, and ini ate ssue repair.
  • Inflamma on may include several phase that may start with recogni on of harmful s muli by immune cells that triggers the release of inflammatory mediators such as cytokines.
  • blood vessels may dilate to increase bloodflow to the affected area, leading to redness and heat.
  • Increased vascular permeability may allow plasma proteins and immune cells to enter the ssue, causing swelling (edema).
  • white blood cells leukocytes
  • inflamma on subsides once the harmful s muli are removed.
  • An -inflammatory signals and mechanisms such as the release of an -inflammatory cytokines and the ac va on of regulatory immune cells, help restore ssue homeostasis. Examples for pro-inflammatory substances and characteris cs of inflamma on are provided throughout this applica on.
  • the present inven on relates to a method of treatment of cancer in a pa ent in need of such treatment, wherein the method comprises administering an an gen- binding protein to said pa ent, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, or to the pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA- A*02 and wherein said an gen-binding protein is administered in combina on with a pro- inflammatory substance.
  • MHC major histocompa bility complex
  • the herein described uses and methods preferably relate to the treatment of cancer in humans.
  • the pa ents referred to herein are preferably humans.
  • the cancer or tumor to be treated presents certain pep des on its surface.
  • the cancer to be treated presents certain pep des of MAGE-A on its surface.
  • MAGE-A posi ve cancer When a cancer presents pep des of MAGE-A on its surface said cancer is referred to as MAGE-A posi ve cancer.
  • MAGE-A posi ve cancer.
  • the cancer to be treated presents certain pep des of MAGE-A4 and/or MAGE-A8 on its surface.
  • MAGE-A4 and/or MAGE-A8 When a cancer presents pep des of MAGE-A4 and/or MAGE-A8 on its surface said cancer is referred to as MAGE-A4 and/or MAGE-A8 posi ve cancer. It is preferred that the cancer to be treated presents the pep de according to SEQ ID NO: 25 on its surface (also referred to as MAG-003 or MAG-003 pep de). When a cancer presents the MAG-003 pep de on its surface it is referred to as MAG-003 posi ve cancer.
  • the present inven on relates to the herein described an gen-binding proteins for use in the treatment of cancer, wherein the cancer is a MAGE-A posi ve cancer, preferably MAGE-A4 or MAGE-A8 posi ve cancer.
  • the inven on relates to the herein described an gen- binding proteins for use in the treatment of cancer, wherein the cancer is a MAG-003 posi ve cancer.
  • the inven on relates to an an gen-binding protein for use in the treatment of a MAGE-A posi ve cancer, preferably MAGE-A4 and/or MAGE-A8 posi ve cancer, more preferably a MAG-003 posi ve cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, or to the pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02 and wherein said an gen- binding protein is administered in combina on with a pro-inflammatory substance.
  • MHC major histocompa bility complex
  • a cancer may be considered to be “MAG-003 posi ve” if the MAG-003 pep de is presented in >50%, >60%, >70%, >80%, >90%, >95% or >98% of all cancers according to the guidelines by the NCI.
  • biopsy may be performed (as it may be standard in the treatment of these cancers) and the pep de can be iden fied according to e.g.
  • the MAGEA4/MAGEA8 expression can be determined by qPCR from a fresh frozen (FF) or formalin- fixed paraffin-embedded (FFPE) biopsy sample.
  • MAGEA4/8 expression may be measured using immunohistochemistry staining of FFPE or fresh biopsy samples with appropriate an bodies binding to the MAGEA4/8 protein.
  • afluorophore-tagged an body or an enzyme-linked an body catalyzing a color-producing reac on may be used and signal strength may be detected and quan fied as a measure of MAGEA4/8 protein presence and indirectly MAG-003 presenta on.
  • 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.
  • MAG-003 presenta on is massively increased upon s mula on with a pro-inflammatory substance it is plausible for the skilled person that tumors may be treated with the herein described combina ons that have low MAG-003 presenta on levels and may, thus, respond less well to treatment with the herein described MAG-003 an gen-binding proteins alone.
  • the described combina ons provide an unexpected therapeu c effec veness for all subjects suffering from a MAG-003-posi ve cancer
  • the present inven on provides a new pa ent sub-group, which has cancer with a low number of presented MAG-003 copies per cell and has a par cular benefit from the herein disclosed therapy.
  • the inven on also relates to a method of treatment of a pa ent/subject suffering from a cancer or tumor that shows low MAG-003 presenta on levels comprising administering to said pa ent/subject the herein described combina ons.
  • the inven on also relates to a method of treatment of a pa ent/subject suffering from a cancer or tumor, wherein the cancer or tumor has ⁇ 1, ⁇ 25, ⁇ 50, ⁇ 75, ⁇ 100, ⁇ 120 or ⁇ 1000 MAG-003 copies per cell, preferably ⁇ 75, ⁇ 100 or ⁇ 1000 MAG-003 copies per cell comprising administering to said pa ent/subject the herein described combina ons.
  • the inven on also relates to the herein described combina ons for use in the treatment of a tumor that shows low MAG-003 presenta on levels.
  • the inven on also relates to the herein described combina ons for use in the treatment of a tumor, wherein the tumor has ⁇ 1, ⁇ 25, ⁇ 50, ⁇ 75, ⁇ 100, ⁇ 120 or ⁇ 1000 MAG-003 copies per cell, preferably ⁇ 75, ⁇ 100, ⁇ 120 or ⁇ 1000 MAG-003 copies per cell.
  • the invention relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the cancer has ⁇ 1, ⁇ 25, ⁇ 50, ⁇ 75, ⁇ 100, ⁇ 120 or ⁇ 1000 MAG-003 copies per cell, preferably ⁇ 75, ⁇ 100, ⁇ 120 or ⁇ 1000 MAG-003 copies per cell, preferably wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • the number of MAG-003 copies per cell may be determined e.g. by AbsQuant® as described in sec on 1.4 of the Examples or in US10545154B2.
  • AbsQuant® as described in sec on 1.4 of the Examples or in US10545154B2.
  • the present inven on relates to an an gen-binding protein for use in the treatment of a metasta c cancer and/or metastases, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25 (bound to a major histocompa bility complex (MHC) protein, preferably HLA- A*02).
  • MHC major histocompa bility complex
  • metasta c cancer and/or advanced cancer and/or unresectable cancer and/or recurrent cancer and/or refractory cancer is treated by the herein described an gen-binding proteins.
  • an gen-binding proteins Defini ons and explana ons regarding metasta c cancer, advanced cancer, unresectable cancer and recurrent cancer can be found e.g. in EP24174662.
  • the present inven on relates to an an gen-binding protein for use in the treatment of a metasta c cancer and/or advanced cancer and/or unresectable cancer and/or recurrent cancer and/or refractory cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25 (bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02) and wherein said an gen-binding protein is administered in combina on with a pro-inflammatory substance.
  • MHC major histocompa bility complex
  • the an gen-binding protein for use or the methods according to the inven on comprises or consists of an an body or a func onal fragment or deriva ve thereof.
  • an “an body” 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.
  • Each chain contains dis nct sequence domains.
  • the light chain includes two domains or regions, a variable domain (V L ) and a constant domain (C L ).
  • the heavy chain includes four domains, a variable domain (V H ) and three constant domains (CH1, CH2 and CH3, collec vely referred to as CH or Fc or Fc domain).
  • the variable regions of both light (V L ) and heavy (V H ) chains determine binding recogni on and specificity to the an gen.
  • the constant region domains of the light (C L ) and heavy (C H ) chains confer important biological proper es such as an body chain associa on, secre on, 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 por ons of one light chain and one heavy chain.
  • the specificity of the an body resides in the structural complementarity between the an body combining site (synonym to an body binding site) and the an genic determinant.
  • An body 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 na ve 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, respec vely or CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respec vely.
  • a conven onal an body an gen-binding site therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region.
  • an an body may be an IgM, IgD, IgG, IgA or IgE.
  • FRs Body Framework Regions
  • 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, respec vely.
  • 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).
  • CDR/FR defini on in an immunoglobulin light or heavy chain may be determined based on IMGT defini on (Lefranc et al. Dev. Comp. Immunol., 2003, 27(1):55-77; www.imgt.org).
  • CDR/FR defini on 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 an body or an body fragment are indicated according to said Kabat defini on. Knowing the amino acid sequence of the CDRs of an an body, a TCR or an an gen-binding protein of the inven on, one skilled in the art can easily determine the framework regions, such as the TCR framework regions or an body framework regions.
  • a "human framework region” is a framework region that is substan ally iden cal (about 85%, or more, in par cular 90%, 95%, 97%, 99% or 100%) to the framework region of a naturally occurring an gen-binding protein, such as a naturally occurring human an body or human TCR.
  • a func onal fragment or deriva ve of an an body refers to a modified form of the an body molecule that retains some or all of its func onal proper es but may have altered characteris cs such as size or structure. These modifica ons can be made to enhance the an body's therapeu c poten al, improve its stability, reduce immunogenicity or enable specific interac ons with target molecules. Fragments of an bodies may comprise a por on of an intact an body, in par cular the an gen-binding region or variable region of the intact an body.
  • an body fragment examples include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv and sc(Fv)2.
  • a fragment of an an body may also be a single domain an body, such as a heavy chain an body (including nanobodies) or VHH.
  • 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.
  • native Fc 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 lgG1 or lgG2, most preferably lgG1.
  • 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 number of 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., lgG1, lgG2, lgG3, IgA1, and lgGA2).
  • class e.g., IgG, IgA, and IgE
  • subclass e.g., lgG1, lgG2, lgG3, IgA1, and lgGA2
  • native Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG.
  • native Fc as used herein is generic to the monomeric, dimeric, and multimeric forms.
  • the "hinge” or “hinge region” or “hinge domain” refers typically to the flexible portion of a heavy chain located between the CH1 domain and the CH2 domain.
  • 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.
  • FcRn a binding site for the salvage receptor
  • FcRn nonnatal Fc receptor
  • Exemplary Fc variants, and their interaction with the salvage receptor, are known in the art.
  • the term "Fc variant” can comprise a molecule or sequence that is humanized from a non-human native Fc.
  • 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.
  • 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).
  • ADCC antibody-dependent cellular cytotoxicity
  • the two Fc domains may be of the same immunoglobulin isotype or isotype subclass or of different immunoglobulin isotypes or isotype subclasses, preferably of the same.
  • FC1 and FC2 may be of the IgG1 subclass, or of the lgG2 subclass, or of the lgG3 subclass, or of the lgG4 subclass, preferably of the lgG1 subclass, or of the lgG2 subclass, more preferably of the lgG1 subclass.
  • the Fc domain may be a Fc domain variant and thus comprises one or more of the amino acid substitutions described herein below.
  • the Fc domain may comprise or further comprise the “RF” and/or “Knob-into-hole” mutation, preferably the “Knob-into-hole” 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.
  • the RF mutation may be in one or both, preferably in one Fc domain.
  • the “Knob-into-Hole” or also called “Knob-into-Hole” technology refers to amino acid substitutions T366S, L368A and Y407V (Hole) and T366W (Knob) both in the CH3-CH3 interface to promote heteromultimer formation.
  • ar ficially introduced cysteine bridges may (further) improve the stability of the (bispecific) an gen-binding proteins, op mally without interfering with the binding characteris cs of the (bispecific) an gen-binding proteins. Such cysteine bridges can further improve heterodimeriza on.
  • the knob-into-hole mutation can be further stabilized by the introduction of additional cysteine amino acid substitutions Y349C and S354C.
  • the “Knob-into-Hole” technology together with the stabilizing cysteine amino acid substitutions has been described in patents US5731168 and US8216805.
  • the Fc domain of one polypeptide of the described antigen-binding proteins for example FC1 may comprise the amino acid substitution T366W (Knob) in its CH3 domain and the Fc domain of the other polypeptide, for example FC2, may comprise the amino acid substitution T366S, L368A and Y407V (Hole) in its CH3 domain or vice versa.
  • the Fc domain of one of the polypeptides, for example FC1 may comprise or further comprise the amino acid substitution S354C in its CH3 domain and the Fc domain of the other polypeptide, for example FC2, may comprise or further comprise the amino acid substitution Y349C in its CH3 domain or vice versa.
  • the Fc domain of one of the polypeptides, for example FC1 may comprise the amino acid substitutions S354C and T366W (Knob) in its CH3 domain
  • the Fc domain of the other polypeptide, for example FC2 may comprise the amino acid substitution Y349C, T366S, L368A and Y407V (Hole) in its CH3 domain or vice versa.
  • the skilled person is readily capable to determine to which positions in the described antigen- binding proteins said positions correspond. In other words, the skilled person can readily determine where said amino acid substitutions are to be introduced in the described antigen- binding proteins.
  • the “Knob” mutation together with the cysteine amino acid substitution S354C is, for example, present in the Fc domain comprising or consisting of the amino acid sequence of SEQ ID NO: 19 and the “Hole” mutation together with the cysteine amino acid substitutions Y349C is present in the Fc domain comprising or consisting amino acid sequence of SEQ ID NO: 20.
  • This set of amino acid substitutions can be further extended by inclusion of the amino acid substitutions K409A on one polypeptide and F405K in the other polypeptide as described by Wei et al. (Wei et al., Oncotarget, 2017, 8(31):51037-51049).
  • the Fc domain of one of the polypeptides, for example FC1 may comprise or further comprise the amino acid substitution K409A in its CH3 domain
  • the Fc domain of the other polypeptide, for example FC2 may comprise or further comprise the amino acid substitution F405K in its CH3 domain or vice versa.
  • the Fc domain of one of the polypeptides may comprise or further comprise the charge pair substitutions E356K, E356R, D356R, or D356K and D399K or D399R
  • the Fc domain of the other polypeptide, for example FC2 may comprise or further comprise the charge pair substitutions R409D, R409E, K409E or K409D and N392D, N392E, K392E or K392D or vice versa.
  • 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.
  • FcyR Fc gamma receptor
  • Such alterations may include L234A or L235A.
  • 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, FcgRIlb, FcgRI 11) binding with differing affinities to epitopes displayed by Fc-parts of IgG-molecules.
  • FcgRI, FcgRIla, FcgRIlb, FcgRI 11 binding with differing affinities to epitopes displayed by Fc-parts of IgG-molecules.
  • 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
  • Fc-variants and mutations to ablate FcgR-binding have been identified.
  • 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 and 331S) wherein the recombinant antibody is capable of binding the target molecule without triggering significant complement-dependent lysis or cell-mediated destruction of the target.
  • 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.
  • the Fc domain may comprise or further comprise the amino acid substitution N297Q, N297G or N297A, preferably N297Q.
  • the amino acid substitution “N297Q”, “N297G” or “N297A” refer to amino acid substitutions at position 297 that abrogate the native N-Glycosylation site within the Fc-domain. This amino acid substitution prevents Fc-gamma-receptor interaction and decreases the variability of the final protein products, i.e. the bispecific antigenbinding 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).
  • the Fc domain may comprise or further comprise the amino acid substitution C220S.
  • the amino acid substitution "C220S” deletes the cysteine forming the Cm-CL disulfide-bridge.
  • the Fc domain may comprise or further comprise at least two additional cysteine residues, for example S354C and Y349C or L242C and K334C, wherein S354C is in the Fc-domain of one polypeptide, such as FC1, and Y349C is in the Fc domain of the other polypeptide, such as FC2, to form a heterodimer and/or wherein L242C and K334C are located in the same Fc-domain, either in the FC1 or FC2 of one or both polypeptides to form a intradomain C-C bridge.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, or to the pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein comprises or consists of an an body or a func onal fragment or deriva ve thereof and wherein said an gen-binding protein is administered in combina on with a pro-inflammatory substance.
  • MHC major histocompa bility complex
  • the an gen-binding protein for use or the methods according to the inven on comprises or consists of a T cell receptor (TCR) or a func onal fragment or deriva ve thereof.
  • 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 ⁇ and ⁇ forms, which are structurally similar but have quite distinct anatomical locations and probably functions.
  • the extracellular portion of native heterodimeric ⁇ TCR and ⁇ 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 domains contain the highly polymorphic loops analogous to the complementarity determining regions (CDRs) of antibodies.
  • 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. Fragments of a TCR comprise a por on of an intact or na ve TCR, in par cular the an gen- binding region or variable region of the intact or na ve TCR.
  • TCR fragments include fragments of the ⁇ , ⁇ , ⁇ , ⁇ chain, such as V ⁇ - C a or V ⁇ - C ⁇ or por ons thereof, such fragments might also further comprise the corresponding hinge region or single variable domains, such as V ⁇ , V ⁇ , V ⁇ , V ⁇ , or single chain V ⁇ V ⁇ fragments.
  • Fragments of a TCR may exert iden cal func ons compared to the naturally occurring full-length TCR, i.e. fragments selec vely and specifically bind to their target pep de. It is also envisaged herein that the TCR is a single chain TCR (scTCR).
  • scTCR herein denotes a protein wherein the variable domains of the TCR, such as the V ⁇ and V ⁇ or V ⁇ and V ⁇ are 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.
  • linker typically comprises 5 to 20, such as 5 to 15 amino acids.
  • Na ve as used for example in the wording “na ve TCR” refers to a wildtype TCR. Na ve alpha-beta heterodimeric TCRs have an alpha chain and a beta chain.
  • 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.
  • CDRs Complementarity Determining Regions
  • the alpha variable domain CDRs may be referred to as CDRa1, CDRa2 and CDRa3 or CDR ⁇ 1, CDR ⁇ 2 and CDR ⁇ 3
  • the beta variable domain CDRs may herein referred to as CDRb1, CDRb2 and CDRb3 or CDR ⁇ 1, CDR ⁇ 2 and CDR ⁇ 3.
  • a conven onal TCR an gen-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 CDR3 sequences are relevant for the recogni on and binding of the pep de an gen that is bound to the HLA protein and the CDR2 sequences are relevant for the recogni on and binding of the HLA protein.
  • TCR framework regions refer to amino acid sequences interposed between CDRs, i.e. to those por ons 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 FR1-a, FR2-a, FR3-a, FR4-a, and FR1-b, FR2-b, FR3-b, FR4-b, respec vely.
  • the alpha chain variable domain may thus be designated as (FR1-a)-(CDRa1)-(FR2-a)-(CDRa2)-(FR3-a)-(CDRa3)-(FR4-a)
  • the beta chain variable domain may thus be designated as (FR1-b)-(CDRb1)-(FR2-b)-(CDRb2)-(FR3-b)- (CDRb3)-(FR4-b).
  • CDR/FR defini on in an ⁇ or ⁇ chain is to be determined based on IMGT defini on (Lefranc et al. Dev. Comp. Immunol., 2003, 27(1):55-77; www.imgt.org).
  • na ve gamma-delta heterodimeric TCRs have a gamma chain and a delta chain.
  • the inven on relates an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein comprises or consists of a T cell receptor (TCR) or a func onal fragment or deriva ve thereof and wherein said an gen- binding protein is administered in combina on with a pro-inflammatory substance.
  • MHC major histocompa bility complex
  • the inven on relates an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25 bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein comprises or consists of a T cell receptor (TCR) or a func onal fragment or deriva ve thereof, wherein the T cell receptor (TCR), the func onal fragment or the deriva ve thereof is part of a host cell, preferably a T cell and wherein said an gen-binding protein is administered in combina on with a pro- inflammatory substance
  • the an gen-binding protein for use according to the inven on comprises a T cell receptor (TCR) alpha variable domain (V ⁇ ).
  • TCR T cell receptor
  • V ⁇ “ and “V ⁇ domain” may be used synonymously herein.
  • the V ⁇ domain may comprise a CDR ⁇ 1 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 16.
  • the V ⁇ domain may comprise a CDR ⁇ 2 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 17.
  • the V ⁇ domain may comprise a CDR ⁇ 3 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 18.
  • Said CDRs may comprise one, two or three amino acid muta ons, wherein the muta on may be a dele on, an inser on, or a subs tu on, preferably a conserva ve subs tu on.
  • the an gen-binding protein for the use and the methods according to the inven on may comprise a V ⁇ domain comprising a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17 and/or a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18.
  • the an gen-binding protein for the use and the methods according to the inven on may comprise a V ⁇ domain comprising a CDR ⁇ 1 consis ng of the amino acid sequence according to SEQ ID NO: 16, a CDR ⁇ 2 consis ng of the amino acid sequence according to SEQ ID NO: 17 and/or a CDR ⁇ 3 consis ng of the amino acid sequence according to SEQ ID NO: 18. It is further envisaged that the an gen-binding protein for use according to the inven on comprises a TCR beta variable domain (V ⁇ ). “V ⁇ “ and “V ⁇ domain” may be used synonymously herein.
  • the V ⁇ domain may comprise a CDR ⁇ 1 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 12.
  • the V ⁇ domain may comprise a CDR ⁇ 2 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 13.
  • the V ⁇ domain may comprise a CDR ⁇ 3 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 14.
  • Said CDRs may comprise one, two or three amino acid muta ons, wherein the muta on may be a dele on, an inser on, or a subs tu on, preferably a conserva ve subs tu on.
  • an gen-binding protein for the use and the methods according to the inven on may comprise a V ⁇ domain comprising a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 12, a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 13 and/or a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 14.
  • the an gen-binding protein for the use and the methods according to the inven on may comprise a V ⁇ domain comprising a CDR ⁇ 1 consis ng of the amino acid sequence according to SEQ ID NO: 12, a CDR ⁇ 2 consis ng of the amino acid sequence according to SEQ ID NO: 13 and/or a CDR ⁇ 3 consis ng of the amino acid sequence according to SEQ ID NO: 14. Accordingly, it is envisaged that the an gen-binding protein for use according to the inven on comprises a V ⁇ and a V ⁇ .
  • the an gen-binding protein for the use and the method according to the inven on comprises a V ⁇ and a V ⁇ wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and/or (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 12, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 13, and/or (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 14;
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or bind
  • the an gen-binding protein for use according to the inven on comprises a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 15. It is envisaged that the an gen-binding protein comprises a V ⁇ comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 15.
  • the an gen-binding protein comprises a V ⁇ comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 15 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 16, 17, and 18, respec vely.
  • the an gen-binding protein for use according to the inven on comprises a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 11.
  • the an gen-binding protein comprises a V ⁇ comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 11. It is also envisaged that the an gen-binding protein comprises a V ⁇ comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 11 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 12, 13, and 14, respec vely.
  • an gen-binding protein for use according to the inven on comprises a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 15 and a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 11.
  • the an gen-binding protein for use according to the inven on comprises a V ⁇ comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 15 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 16, 17, and 18, respec vely and a V ⁇ comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 11 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 12, 13, and 14, respec vely
  • the inven on thus, relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably
  • the an gen-binding protein for use according to the inven on may comprise a TCR domain, preferably a TCR variable region comprising a V ⁇ and a V ⁇ . Said TCR domain may form afirst binding side.
  • the an gen-binding protein for use according to the inven on may further comprise an an body domain, preferably an an body variable region comprising VL and VH. Said an body domain may form a second binding side of the an gen-binding protein of the inven on.
  • the an body domain binds to an alpha/beta TCR/CD3 complex, e.g. as presented on the surface of a T-cell.
  • the an body domain may bind to any part or epitope of the alpha/beta TCR/CD3 complex.
  • the an gen-binding protein for use according to the inven on comprises an an body variable light chain domain (VL).
  • the VL may comprise a CDRL1 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 4.
  • the VL may comprise a CDRL2 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 5.
  • the VL may comprise a CDRL3 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 6.
  • Said CDRs may comprise one, two or three amino acid muta ons, wherein the muta on may be a dele on, an inser on, or a subs tu on, preferably a conserva ve subs tu on.
  • the an gen-binding protein for use according to the inven on may comprise a VL comprising a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 5 and/or a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 6.
  • the an gen-binding protein for use according to the inven on may comprise a VL comprising a CDRL1 consis ng of the amino acid sequence according to SEQ ID NO: 4, a CDRL2 consis ng of the amino acid sequence according to SEQ ID NO: 5 and/or a CDRL3 consis ng of the amino acid sequence according to SEQ ID NO: 6. It is further envisaged that that the an gen-binding protein for use according to the inven on comprises an an body variable heavy chain domain (VH).
  • the VH may comprise a CDRH1 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 8.
  • the VH may comprise a CDRH2 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 9.
  • the VH may comprise a CDRH3 comprising or consis ng of the amino acid sequence according to SEQ ID NO: 10.
  • Said CDRs may comprise one, two or three amino acid muta ons, wherein the muta on may be a dele on, an inser on, or a subs tu on, preferably a conserva ve subs tu on.
  • the an gen-binding protein for use according to the inven on may comprise a VH comprising a CDRH1 comprising the amino acid sequence according to SEQ ID NO: 8, a CDRH2 comprising the amino acid sequence according to SEQ ID NO: 9, a CDRH3 comprising the amino acid sequence according to SEQ ID NO: 10.
  • the an gen-binding protein for use according to the inven on may comprise a VH comprising a CDRH1 consis ng of the amino acid sequence according to SEQ ID NO: 8, a CDRH2 consis ng of the amino acid sequence according to SEQ ID NO: 9 and/or a CDRH3 consis ng of the amino acid sequence according to SEQ ID NO: 10.
  • the inven on thus, relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein said an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises an an body variable light chain domain (VL), and an an body variable heavy chain domain (VH), wherein the VL comprises (i) a CDRL1 comprising the amino acid sequence according to SEQ ID NO: 4, (ii) a CDRL2 comprising the amino acid sequence according to SEQ ID NO: 5, and/or (iii) a CDRL3 comprising the amino acid sequence according to SEQ ID NO: 6; and wherein the VH comprises (i) a CDRH1 comprising the amino
  • the an gen-binding proteins for use according to the inven on may comprise a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 3.
  • the an gen-binding proteins for use according to the inven on may also comprise a VL comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 3.
  • the an gen-binding proteins for use according to the inven on may comprise a VL comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 3 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respec vely. It is evident for the skilled person that under certain condi ons a glutamine amino acid residue may be converted into pyro-glutamate. In par cular, N-terminal glutamine may be converted into pyro-glutamate.
  • the present applica also encompasses the described an gen-binding proteins with pyro- glutamate at the N-terminus instead of glutamine.
  • an an gen-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.
  • 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: 24 (with pyro-glutamate at the N- terminus).
  • the an gen-binding proteins for use according to the inven on may comprise a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 24.
  • the an gen-binding proteins for use according to the inven on may also comprise a VL comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 24.
  • the an gen-binding proteins for use according to the inven on may comprise a VL comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 24 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respec vely.
  • VL comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 24 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respec vely.
  • SEQ ID NO: 40 encompassing glutamin and pyro-glutamate at the N-terminus
  • SEQ ID NO: 40 and “SEQ ID NO: 3 or SEQ ID NO: 24” may be used interchangeably herein.
  • SEQ ID NO: 40 when it is referred to SEQ ID NO: 40 it may also be referred to as “SEQ ID NO: 3 and SEQ ID NO: 24” or “SEQ ID NO: 3 or SEQ ID NO: 24”. It is evident for the skilled person that the herein described an gen-binding proteins may be a mixture of molecules with pyro-glutamate at the N-terminus and molecules with glutamine at the N-terminus.
  • an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 40 it is evident for the skilled person that it may be referred to a composi on comprising an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 3 and op onally comprising an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 24.
  • an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 40 it is evident for the skilled person that it may be referred to a composi on comprising an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 24 and op onally comprising an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 3.
  • an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 40 it is evident for the skilled person that it may be referred to a composi on comprising an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 3 and op onally comprising at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of an an gen-binding protein comprising a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 24.
  • the an gen-binding proteins for use according to the inven on may comprise a VH comprising or consis ng of the amino acid sequence according to SEQ ID NO: 7.
  • the an gen-binding proteins for use according to the inven on may comprise a VH comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 7.
  • the an gen-binding proteins for use according to the inven on may comprise a VH comprising or consis ng of an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 7 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 8, 9, and 10, respec vely. Accordingly, the an gen-binding proteins for use according to the inven on may comprise a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 3 and a VH comprising or consis ng of the amino acid sequence according to SEQ ID NO: 7.
  • the an gen- binding proteins for use according to the inven on may comprise a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 24 and a VH comprising or consis ng of the amino acid sequence according to SEQ ID NO: 7.
  • the an gen-binding proteins for use according to the inven on may comprise a VL comprising or consis ng of the amino acid sequence according to SEQ ID NO: 40 and a VH comprising or consis ng of the amino acid sequence according to SEQ ID NO: 7.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein said an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises a VL comprising or consis ng 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% iden ty to SEQ ID NO: 40 and comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respec vely; and a VH comprising or consis ng of the amino acid sequence according to SEQ ID NO: 7 or an amino acid sequence having at
  • the “percentage of iden ty” may be calculated using a global pairwise alignment (i.e. the two sequences are compared over their en re length). Methods for comparing the iden ty 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) tofind the op mum alignment (including gaps) of two sequences when considering their en re 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 publica on EMBOSS: The European Molecular Biology Open Software Suite (2000) Rice, P. Longden, I. and Bleasby, A. Trends in Gene cs 16, (6) pp. 276—277.
  • the percentage of iden ty between two polypep des, in accordance with the inven on, 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.
  • Proteins having an amino acid sequence “having at least 85%, 90%, 95%, 98% or 99% iden ty” to a reference sequence may comprise amino acid muta ons such as dele ons, inser ons and/or subs tu ons compared to the reference sequence.
  • Amino acid subs tu ons may be conserva ve or non-conserva ve.
  • subs tu ons are conserva ve subs tu ons, in which one amino acid is subs tuted for another amino acid with similar structural and/or chemical proper es.
  • conservea ve subs tu ons may include those, which are described by Dayhoff in “The Atlas of Protein Sequence and Structure. Vol.5”, Natl.
  • amino acids which belong to one of the following groups, can be exchanged for one another, thus, cons tu ng a conserva ve exchange:
  • Group 1 alanine (A), proline (P), glycine (G), asparagine (N), serine (S), threonine (T);
  • Group 2 cysteine (C), serine (S), tyrosine (Y), threonine (T);
  • Group 3 valine (V), isoleucine (I), leucine (L), methionine (M), alanine (A), phenylalanine (F);
  • Group 4 lysine (K), arginine (R), his dine (H);
  • Group 5 phenylalanine (F), tyrosine (Y), tryptophan (W), his dine (H);
  • Group 6 aspar c acid (D), glutamic acid
  • a conserva ve amino acid subs tu on may be selected from the following of T ⁇ A, G ⁇ A, A ⁇ I, T ⁇ V, A ⁇ M, T ⁇ I, A ⁇ V, T ⁇ G, and/or T ⁇ S.
  • a conserva ve amino acid subs tu on may also include the subs tu on of an amino acid by another amino acid of the same class, for example, (1) nonpolar: Ala, Val, Leu, Ile, Pro, Met, Phe, Trp; (2) uncharged polar: Gly, Ser, Thr, Cys, Tyr, Asn, Gln; (3) acidic: Asp, Glu; and (4) basic: Lys, Arg, His.
  • an gen-binding proteins for the herein described uses and methods are mul specific, e.g. bispecific an gen-binding proteins.
  • the term “bispecific” in connec on with the herein described an gen-binding proteins refers to an gen-binding proteins with at least two valences and binding specifici es for two different an gens and, thus, comprise at least two an gen-binding sites.
  • the term “valence” refers to the number of binding sites of an an gen-binding protein, e.g.
  • a bivalent an gen- binding protein relates to an an gen-binding protein that has two binding sites.
  • 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 an gen-binding protein may be monospecific, i.e. binding one target, or bispecific, i.e. binding two different targets.
  • Targets may be an gens, such as (target) pep des.
  • a specificity of the an gen- binding sites is derived from a TCR, more par cularly, that at least one an gen-binding site comprises the TCR derived CDRs as described herein.
  • bispecific in the context of the present inven on may refer to an an gen-binding protein which combines at least one an gen-binding site comprising TCR derived CDRs, and at least one further an gen-binding site, wherein said at least one further an gen-binding site, may be derived from an an body and thus comprises an body CDRs, or from a further TCR and thus comprises the CDRs of a further TCR, preferably said further an gen-binding site, is derived from an an body and thus comprises an body CDRs.
  • a preferred format is the TCER® format.
  • format refers to an an gen-binding protein comprising a specific number and type of domains that are present in said an gen-binding protein and the spa al organiza on thereof.
  • formats typically include non-limi ng examples, such as diabodies, Cross-Over-Dual-Variable-Domain (CODV) and/or Dual variable domain (DVD) proteins.
  • CODV Cross-Over-Dual-Variable-Domain
  • DVD Dual variable domain
  • the DVD format is, for example, disclosed in the following scien fic ar cles: Wu C et al. Nat Biotechnol 2007; 25:1290-7; PMID:17934452; Wu C. et al. MAbs 2009; 1:339-47; Lacy SE et al. MAbs 2015; 7:605-19; PMID:25764208; Craig RB et al. PLoS One 2012; 7:e46778; PMID:23056448; and Piccione EC et al. MAbs 2015.
  • the CODV is for example disclosed in Onuoha SC et al.
  • an gen-binding proteins for use according to the inven on are bispecific.
  • an gen-binding proteins afirst an gen-binding site may bind to a MAGE-A an genic pep de, preferably a MAGE-A4 and/or MAGE-A8 an genic pep de more preferably an an genic pep de according to SEQ ID NO: 25.
  • an genic pep de is in a complex with a (human) MHC protein, preferably HLA-A*02.
  • Said an gen-binding site may be TCR-derived.
  • a V ⁇ and V ⁇ may form afirst an gen-binding site that specifically binds to a MAGE-A4 or MAGE-A8 an genic pep de according to SEQ ID NO: 25 in a complex with a human MHC protein.
  • Corresponding variable domains and CDRs are described throughout this applica on.
  • a second an gen-binding site may bind to a T cell receptor complex, preferably an alpha/beta TCR/CD3 complex.
  • Said an gen-binding site may be an body-derived. Accordingly, a VH and VL may form a second an gen-binding site that specifically binds to a T cell receptor complex. Binding of the second an gen-binding site that specifically binds to a T cell receptor complex may ac vate the T cell. Corresponding variable domains and CDRs are described throughout this applica on.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein said an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein V ⁇ and V ⁇ form afirst an gen-binding site that specifically binds to a MAGE-A4 or MAGE-A8 an genic pep de according to SEQ ID NO: 25 in a complex with a human MHC protein, and VH and VL form a second an gen-binding site that specifically binds to a T cell receptor complex.
  • MHC major histocompa bility complex
  • T cell receptor complex refers to an e.g. alpha/beta TCR/CD3 complex, e.g. as presented on the surface of a T-cell.
  • the an body domain may bind to any part or epitope of the alpha/beta TCR/CD3 complex.
  • the below described formats are envisaged for the an gen-binding proteins for use according to the inven on.
  • the an gen-binding protein may comprises or consists of afirst polypep de chain comprising a structure represented by the formula: VL-L1-V ⁇ [I]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-VH [II]; wherein L1 and L2 are linkers.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises or consists of afirst polypep de chain comprising a structure represented by the formula: VL-L1-V ⁇ [I]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-VH [II]; wherein L1 and L2 are linkers.
  • MHC major histocompa bility complex
  • VL may comprise or consist 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% iden ty to SEQ ID NO: 40 and preferably comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respec vely.
  • L1 may comprise or consist of SEQ ID NO: 22.
  • V ⁇ may comprise or consist of the amino acid sequence according to SEQ ID NO: 11 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 11 and preferably comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 12, 13, and 14, respec vely.
  • V ⁇ may comprise or consist of the amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 15 and preferably comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 16, 17, and 18, respec vely.
  • L2 may comprise or consist of SEQ ID NO: 22.
  • VH may comprise or consist of the amino acid sequence according to SEQ ID NO: 7 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 7 and comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 8, 9, and 10, respec vely.
  • the an gen-binding protein may also comprise or consist of afirst polypep de chain comprising a structure represented by the formula: VL–L1-V ⁇ -L3-FC1 [III]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-VH-L4-FC2 [IV]; wherein L1, L2, L3 and L4 are linkers and may be present or absent, and FC1 and FC2 are Fc- domains and may be the same or different.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises or consists of afirst polypep de chain comprising a structure represented by the formula: VL–L1-V ⁇ -L3-FC1 [III]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-VH-L4-FC2 [IV]; wherein L1, L2, L3 and L4 are linkers and may be present or absent, and FC1 and FC2 are Fc- domains and may be the same or different.
  • MHC major histocompa bility complex
  • an gen-binding protein comprises or consists of afirst polypep de chain comprising a structure represented by the formula: VL–L1-V ⁇ -FC1 [III]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-VH-FC2 [IV]; wherein L1 and L2 are linkers, and FC1 and FC2 are Fc-domains and may be the same or different.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises or consists of afirst polypep de chain comprising a structure represented by the formula: VL–L1-V ⁇ -FC1 [III]; and a second polypep de chain comprising a structure represented by the formula: V ⁇ -L2-VH-FC2 [IV]; wherein L1 and L2 are linkers, and FC1 and FC2 are Fc-domains and may be the same or different.
  • MHC major histocompa bility complex
  • FC1 may comprises or consists of the amino acid sequence according to SEQ ID NO: 19 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 19.
  • FC2 may comprises or consists of the amino acid sequence according to SEQ ID NO: 20 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 20.
  • FC1 may comprises or consists of the amino acid sequence according to SEQ ID NO: 19 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 19.
  • VL may comprise or consist of the amino acid sequence according to SEQ ID NO: 40 an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 40 and preferably comprising the CDRL1, CDRL2, and CDRL3 according to SEQ ID NOs: 4, 5, and 6, respec vely.
  • L1 may comprise or consist of SEQ ID NO: 22.
  • V ⁇ may comprise or consist of the amino acid sequence according to SEQ ID NO: 11 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 11 and preferably comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 12, 13, and 14, respec vely.
  • FC1 may comprises or consists of the amino acid sequence according to SEQ ID NO: 19 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 19.
  • V ⁇ may comprise or consist of the amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 15 and preferably comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 16, 17, and 18, respec vely.
  • L2 may comprise or consist of SEQ ID NO: 22.
  • VH may comprise or consist of the amino acid sequence according to SEQ ID NO: 7 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 7 and preferably comprising the CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 8, 9, and 10, respec vely.
  • FC2 may comprises or consists of the amino acid sequence according to SEQ ID NO: 20 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 20.
  • Thefirst polypep de chain [III] of the an gen-binding proteins for use according to the inven on may comprise or consist 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% iden ty to SEQ ID NO: 1 and comprising the CDRL1, CDRL2, CDRL3, CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respec vely.
  • the glutamine residue in SEQ ID NO: 1 may be converted to pyro-glutamate.
  • SEQ ID NO: 23 represents SEQ ID NO: 1 with a pyro-glutamate instead of a glutamine at the most N-terminal posi on.
  • Thefirst polypep de chain [III] of the an gen-binding proteins for use according to the inven on may comprises or consists of the amino acid sequence according to SEQ ID NO: 23 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 23 and comprising the CDRL1, CDRL2, CDRL3, CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respec vely.
  • SEQ ID NO: 39 encompassing glutamin and pyro- glutamate at the N-terminus
  • SEQ ID NO: 39 and SEQ ID NO: 1 or SEQ ID NO: 23 may be used interchangeably herein.
  • SEQ ID NO: 39 it may also be referred to as “SEQ ID NO: 1 and SEQ ID NO: 23” or “SEQ ID NO: 1 or SEQ ID NO: 23”.
  • an gen-binding protein 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 an gen-binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 39 it is evident for the skilled person that it may be referred to a composi on comprising an an gen-binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 1 and op onally comprising an an gen- binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 23.
  • an an gen-binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 39 it is evident for the skilled person that it may be referred to a composi on comprising an an gen-binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 23 and op onally comprising an an gen- binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 1.
  • an an gen-binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 39 it is evident for the skilled person that it may be referred to a composi on comprising an an gen-binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 1 and op onally comprising at least at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of an an gen-binding protein comprising a polypep de comprising or consis ng of the amino acid sequence according to SEQ ID NO: 23.
  • the second polypep de chain [VI] of the an gen-binding proteins for use according to the inven on may comprise or consist of the amino acid sequence according SEQ ID NO: 2 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 2 and comprising the CDR ⁇ 1, CDR ⁇ 2, CDR ⁇ 3, CDRH1, CDRH2, and CDRH3 according to SEQ ID NOs: 16, 17, 18, 8, 9, and 10, respec vely
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises or consists of afirst poly
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2.
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises or consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 1, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 23, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • an gen-binding protein may comprise a modifica on of the N-terminal and/or C-terminal amino acid(s). Accordingly, the herein described an gen-binding proteins with a modifica on of the N- terminal and/or C-terminal amino acid(s) are encompassed by the scope of this applica on. In par cular modifica ons of N-terminal glutamine residues are also encompassed. In par cular variants of the herein described an gen-binding proteins in which the N-terminal glutamine is subs tuted by a pyro-glutamate are encompassed.
  • an gen-binding proteins in which the N-terminal glutamine of thefirst polypep de chain (e.g. [I] or [III]) is subs tuted by a pyro-glutamate. All the herein described an gen-binding proteins may be administered in the below described doses and/or administra on schemes.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein a dose of about 6.6 ⁇ g to about 10 mg or about 65 pmol to about 98 nmol of the an gen-binding protein is to be administered to the pa ent.
  • MHC major histocompa bility complex
  • the doses may also be provided as weight-adjusted dose.
  • a dose of 6.6 ⁇ g would be a weight-adjusted dose of 73.3 ng/kg and a dose of 10 mg would be a weight-adjusted dose of 111.1 ⁇ g/kg.
  • These weight-adjusted doses may also be used for e.g. for pa ents with underweight so that they do not receive too high doses, e.g.
  • a reduced dose may be administered if the pa ent’s weight is below 50 kg or below 60 kg.
  • the inven on thus, relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein a dose of 73.3 ng/kg to about 111.1 ⁇ g/kg of the an gen-binding molecule is to be administered.
  • MHC major histocompa bility complex
  • the inven on thus, relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein a dose of about 6.6 ⁇ g, about 10 ⁇ g, about 20 ⁇ g, about 30 ⁇ g, about 40 ⁇ g, about 50 ⁇ g, about 60 ⁇ g, about 80 ⁇ g, about 100 ⁇ g, about 120 ⁇ g, about 140 ⁇ g, about 150 ⁇ g, about 160 ⁇ g, about 180 ⁇ g, about 200 ⁇ g, about 250 ⁇ g, about 300 ⁇ g, about 350 ⁇ g, about 400 ⁇ g, about 450 ⁇ g, about 500 ⁇ g, about 540 ⁇ g, about 600 ⁇ g
  • the described an gen-binding proteins may be administered at doses of at least 10 mg, of at least 12 mg, of at least 20 mg, of at least 24 mg or of at least 30 mg.
  • the described an gen- binding proteins may be administered at doses higher than 10 mg, higher than 12 mg, higher than 24 mg or higher than 30 mg.
  • Doses of about 12 mg, about 20 mg or about 30 mg of the described an gen-binding proteins may be used/administered.
  • Doses of about 6 mg to about 8 mg of the described an gen-binding proteins may be administered.
  • Doses of about 6 mg to about 10 mg of the described an gen-binding proteins may be administered.
  • Doses of about 8 mg to about 10 mg of the described an gen-binding proteins may be administered.
  • Doses of about 8 mg to about 12 mg of the described an gen-binding proteins may be administered. Doses of about 10 mg to about 20 mg of the described an gen-binding proteins may be used/administered, such as 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. Doses of about 8 mg to about 15 mg of the described an gen-binding proteins may be administered. Doses of about 12 mg to about 15 mg of the described an gen-binding proteins may be administered. Doses of about 12 mg to about 20 mg of the described an gen-binding proteins may be administered. Doses of about 15 mg to about 20 mg of the described an gen-binding proteins may be administered.
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises: a V ⁇ and a V ⁇ , wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (i
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g, about 1200 ⁇ g, about 1800 ⁇ g, about 2500 ⁇ g, or about 5000 ⁇ g, or about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen-binding protein is
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises: a V ⁇ and a V ⁇ , wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 12, (i
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g or all values in between such as about 1951 ⁇ g of the an
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen-binding protein are to be administered.
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g or all values in between such as about 1750 ⁇ g of the an gen-binding protein
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen- binding protein are to be administered.
  • an gen-binding proteins may be administered in the described uses and methods at a dose of about 1200 ⁇ g, about 1205 ⁇ g, about 1210 ⁇ g, about 1215 ⁇ g, about 1220 ⁇ g, about 1225 ⁇ g, about 1230 ⁇ g, about 1235 ⁇ g, about 1240 ⁇ g, about 1245 ⁇ g, about 1250 ⁇ g, about 1255 ⁇ g, about 1260 ⁇ g, about 1265 ⁇ g, about 1270 ⁇ g, about 1275 ⁇ g, about 1280 ⁇ g, about 1285 ⁇ g, about 1290 ⁇ g, about 1295 ⁇ g, about 1300 ⁇ g, about 1305 ⁇ g, about 1310 ⁇ g, about 1315 ⁇ g, about 1320 ⁇ g, about 1325 ⁇ g, about 1330 ⁇ g, about 1335 ⁇ g, about 1340 ⁇ g, about 1345 ⁇ g, about 1350 ⁇ g, about 1355 ⁇ g, about 1360 ⁇ g
  • the inven on thus, in par cular relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA- A*02, wherein the an gen-binding protein is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1200 ⁇ g, about 1205 ⁇ g, about 1210 ⁇ g, about 1215 ⁇ g, about 1220 ⁇ g, about 1225 ⁇ g, about 1230 ⁇ g, about 1235 ⁇ g, about 1240 ⁇ g, about 1245 ⁇ g, about
  • glucocor coids such as dexamethasone or prednisone
  • glucocor coids is commonly employed in cancer treatment to mi gate various adverse reac ons associated with chemotherapy, radia on therapy or biological agents.
  • medica ons are administered to prevent or alleviate side effects such as nausea, vomi ng, allergic reac ons, inflamma on (including severe reac ons such as cytokine release syndrome), edema, hypersensi vity reac ons, fa gue, pain, neutropenia and appe te suppression.
  • Glucocor coids func on by suppressing immune responses and reducing inflamma on, making them effec ve in managing a spectrum of treatment-related complica ons and symptoms. Accordingly, it is envisaged that the herein described uses and methods are combined with glucocor coid treatment.
  • the skilled person understands that although he present applica on is directed to the combina on of the described an gen-binding proteins with pro-inflammatory substances it may s ll be reasonable to administer also an -inflammatory glucocor coids. While the pro- inflammatory substance may induce an inflammatory state the glucocor coid may prevent or alleviate certain side effect without completely counterac ng the pro-inflammatory substance.
  • glucocor coids may be administered before, concomitantly, simultaneously or a er administra on of the an gen-binding protein in the herein described uses.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein a glucocor coid is administered before, concomitantly, simultaneously or a er administra on of the an gen-binding protein, preferably wherein the glucocor coid is Dexamethasone.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a glucocor coid, preferably Dexamethasone is administered, preferably before administra on of the an gen-binding protein.
  • MHC major histocompa bility complex
  • the skilled person e.g. an oncologist is readily capable to tailor the dose and ming of glucocor coid (pre)medica on according to the specific treatment regimen and individual pa ent factors to op mize benefits while minimizing risks.
  • the glucocor coid may be administered 0 to 60 minutes before infusion of the described an gen-binding proteins, preferably 30 to 60 min before infusion of the described an gen-binding proteins.
  • a preferred dose for Dexamethasone is 8 mg but the dose may be increased up to 20 mg such as 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg or 19 mg.
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA- A*02, wherein the an gen-binding protein is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein 8 mg Dexamethasone is administered before administra on of the an gen- binding protein.
  • MHC major histocompa bility complex
  • Dexamethasone is administered before thefirst four administra ons of the an gen-binding protein.
  • Administra on schemes and regimes for the herein described uses and methods are described herein.
  • the an gen-binding protein may be administered weekly.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein is to be administered weekly.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen- binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen- binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein the an gen-binding protein is to be administered weekly.
  • MHC major histocompa bility complex
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein is to be administered bi-weekly, every 3 weeks or every 4 weeks, preferably bi-weekly.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein the an gen-binding protein is to be administered bi-weekly, every 3 weeks, every 4 weeks or every 6 weeks, preferably bi-weekly.
  • MHC major histocompa bility complex
  • an gen-binding protein may be administered weekly for thefirst four weeks and then administered bi-weekly.
  • the an gen-binding protein may be administered in week 1, 2, 3, 4, 6, 8, 10, 12, 14 and so forth.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen- binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen- binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein is to be administered weekly for thefirst four weeks and then administered bi-weekly or every three weeks.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen- binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen- binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein the an gen-binding protein is to be administered weekly for thefirst four weeks and then administered bi-weekly or every three weeks.
  • MHC major histocompa bility complex
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein is to be administered weekly for thefirst eight weeks and then administered bi-weekly or every three weeks.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen- binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein the an gen-binding protein is to be administered weekly for thefirst eight weeks and then administered bi-weekly or every three weeks.
  • MHC major histocompa bility complex
  • the me between administra ons is increased. For example it is envisaged that a er six months of treatment the an gen-binding protein is administered every six weeks.
  • the skilled person can determine whether each administra on of the an gen-binding proteins is accompanied by administra on of a pro-inflammatory substance. In other words, there may be administra ons of described an gen-binding molecule that are not directly combined with a pro-inflammatory substance. In s ll other words, there may be more administra ons of the described an gen-binding proteins than administra ons of the pro-inflammatory substance.
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2, wherein the an gen-binding protein is to be administered weekly and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an gen-
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2, wherein the an gen-binding protein is to be administered bi-weekly, every 3 weeks, every 4 weeks or every 6 weeks, preferably bi-weekly and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO:39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2, wherein the an gen-binding protein is to be administered weekly for thefirst four weeks or eight weeks and then administered bi-weekly or every three weeks and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about
  • step dosing may be used in the herein described uses and methods.
  • the dose to be administered can vary between the applica on events. That means that a pa ent may receive e.g.300 ⁇ g of the an gen-binding protein for thefirst applica on and e.g. 600 ⁇ g for the second applica on.
  • the dose of the third applica on may be s ll higher.
  • the dose of the third applica on may be used for all subsequent applica ons. In this case the dose of the third and all subsequent applica ons may be referred to as target dose. All the herein described doses may be the target dose.
  • a pa ent may receive 300 ⁇ g of the an gen-binding protein for thefirst applica on and 600 ⁇ g of the an gen-binding protein for the second applica on and about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g for the third applica on and all subsequent applica ons.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein 300 ⁇ g of the an gen-binding protein are to be administered for thefirst applica on, 600 ⁇ g ⁇ g of the an gen-binding protein are to be administered for the second applica on and about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g,
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2, wherein the an gen-binding protein is to be administered weekly and wherein 300 ⁇ g of the an gen-binding protein are to be administered in thefirst week (week 1), 600 ⁇ g of the an gen-binding protein are to be administered in the second week (week 2) and about 1000 ⁇ g to about 4000 ⁇ g or about 1200
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein is to be administered intravenously.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein an gen-binding protein is to be administered intravenously.
  • MHC major histocompa bility complex
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen- binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2, wherein an gen-binding protein is to be administered intravenously and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an gen-binding
  • the pro-inflammatory substance may be also administered intravenously or via a different route.
  • the inven on also relates to the herein described an gen-binding protein for use in the treatment of cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the treatment comprises administra on to the pa ent of a) at least onefirst dose of about 300 ⁇ g of said an gen-binding protein; b) at least one second dose of about 600 ⁇ g of said an gen-binding protein; c) at least one third dose in the range of about 600 ⁇ g to about 6000 ⁇ g of said an gen- binding protein, such as about 1000 ⁇ g, about 1100 ⁇ g, about 1200 ⁇ g, about 1300 ⁇ g, about 1400 ⁇ g, about 1500 ⁇ g about 1600 ⁇ g, about 1700 ⁇ g, about 1800 ⁇ g, about 1900 ⁇ g, about 2000 ⁇ g, about 2100 ⁇ g, about 2200 ⁇ g,
  • the invention also relates to pharmaceutical compositions.
  • the invention relates to pharmaceutical compositions comprising the herein described antigen-binding proteins in the herein described doses.
  • Said pharmaceutical compositions may be administered in combination with a pro-inflammatory substance.
  • TCRs T-cell receptors
  • TCRs binding to pep des of MAGE-A, in par cular of MAGE-A4 and/or MAGE-A8, in par cular to the pep de ‘KVLEHVVRV’ (SEQ ID NO: 25) are used in the treatment of cancer.
  • TCR gene therapy typically allows for equipping subjects’ (pa ents’) own T cells as well as T cells from a (healthy) donor with desired specifici es and for genera ng sufficient numbers of T cells in a short period of me, avoiding their exhaus on.
  • the TCR will be transduced into potent T cells (e.g. central memory T cells or T cells with stem cell characteris cs), which may ensure beter persistence, preserva on and func on upon transfer.
  • TCR-engineered T cells will be infused into cancer pa ents rendered lymphopenic by chemotherapy or irradia on, allowing efficient engra ment of engineered T cells while avoiding immune suppression.
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises: a T cell receptor (TCR) alpha variable domain (V ⁇ ) and a TCR beta variable domain (V ⁇ ) or a TCR gamma variable domain (V ⁇ ) and a TCR delta variable domain (V ⁇ ), wherein the V ⁇ or V ⁇ domain comprises (i) a CDR1 comprising the amino acid sequence according to SEQ ID NO: 28, (ii) a CDR2 comprising the amino acid sequence according to SEQ ID NO: 29, and (iii) a CDR3 comprising the amino acid sequence according to SEQ ID NO:
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises: a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 42 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 42 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 28, 29, and 30, respec vely; and a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 44 or an amino acid sequence having at least 85%, 90%, 95%,
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein comprises: a V ⁇ consis ng of the amino acid sequence according to SEQ ID NO: 42; and a V ⁇ consis ng of the amino acid sequence according to SEQ ID NO: 44.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a constant region having at least 70% sequence iden ty to an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region having at least 70% sequence iden ty to an amino acid sequence according to SEQ ID NO: 37.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a constant region comprising an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region comprising an amino acid sequence according to SEQ ID NO: 37.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a constant region consis ng of an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region consis ng of an amino acid sequence according to SEQ ID NO: 37.
  • MHC major histocompa bility complex
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 42 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 42 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 28, 29, and 30, respec vely; and a constant region having at least 70% sequence
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a amino acid sequence according to SEQ ID NO: 41 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 41 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 28, 29, and 30, respec vely; and wherein the TCR beta chain sequence comprises an amino acid sequence according to SEQ ID NO: 43 or an amino
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence consists of an amino acid sequence according to SEQ ID NO: 41; and wherein the TCR beta chain sequence consists of an amino acid sequence according to SEQ ID NO: 43.
  • MHC major histocompa bility complex
  • TCR sequences with and without signal pep de that mediates transport of the TCR to the cell membrane and that is cleaved off before the TCR is presented on the cell.
  • SEQ ID NO: 26 corresponds to SEQ ID NO: 41 with signal pep de.
  • SEQ ID NO: 27 corresponds to SEQ ID NO: 42 with signal pep de.
  • SEQ ID NO: 32 corresponds to SEQ ID NO: 43 with signal pep de.
  • SEQ ID NO: 33 corresponds to SEQ ID NO: 44 with signal pep de.
  • the skilled person is readily capable to iden fy signal pep de sequences in polypep des (e.g. by the so ware SignalP 6.0 as provided by DTU Health Tech).
  • TCRs presented on the cell surface do usually not comprise the signal pep de because it has been cleaved off upon transport to the membrane. Accordingly, when it is referred herein to TCRs presented on the cell surface (usually the TCR exerts its therapeu c ac vity when located on the surface of an immune cell) it is usually referred to the TCR sequences without signal pep de. However, the skilled person knows that under certain circumstances it is more reasonable to refer to the sequence with signal pep de (e.g. when it is referred to the TCR chain amino acid sequence that is produced by a host cell because the TCR chains may require a signal pep de to be transported to the cell membrane).
  • nucleic acids and/or vectors encoding the herein described an gen-binding proteins may be used for the treatment of cancer.
  • nucleic acids and/or vectors encoding the herein described an gen- binding proteins may be used for the herein described uses and methods.
  • the polypep des of the an gen-binding proteins may be encoded by nucleic acids and expressed in vivo, ex vivo or in vitro.
  • 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 an gen-binding proteins.
  • One nucleic acid molecule may encode one part or monomer of an an gen-binding protein (for example one of two chains of a TCR), and another nucleic acid molecule may encode another part or monomer of an an gen-binding protein (for example the other one of two chains of the TCR).
  • the nucleic acid may encode two or more an gen-binding protein polypep de chains, for example, at least two TCR chains.
  • Nucleic acids encoding mul ple an gen-binding protein polypep de chains may include a nucleic acid cleavage site between at least two chain encoding sequences, may encode a transcrip on or transla on start site, such as an internal ribosomal entry site (IRES) between two or more chain sequences, and/or may encode a proteoly c target site between two or more an gen-binding protein chains. If two or more an gen-binding protein polypep de chains are encoded on one nucleic acid molecule, the two or more an gen-binding protein polypep de chains may be under the control of the same promoter or under the control of separate promoters.
  • IVS internal ribosomal entry site
  • nucleic acid refers in the context of this inven on to single- or double-stranded oligo- or polymers of deoxyribonucleo de or ribonucleo de bases or both.
  • Nucleo de monomers are composed of a nucleobase, afive-carbon sugar (such as but not limited to ribose or 2'-deoxyribose), and one to three phosphate groups.
  • a nucleic acid is formed through phosphodiester bonds between the individual nucleo de monomers.
  • nucleic acid includes but is not limited to ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) molecules but also includes synthe c forms of nucleic acids comprising other linkages (e.g., pep de nucleic acids as described in Nielsen et al. (Science 254:1497-1500, 1991).
  • nucleic acids are single- or double-stranded molecules and are composed of naturally occurring nucleo des.
  • the depic on of a single strand of a nucleic acid also defines (at least par ally) the sequence of the complementary strand.
  • the nucleic acid may be single or double stranded or may contain por ons of both double and single stranded sequences.
  • nucleic acid molecules can have 3' or 5' overhangs and as such are not required or assumed to be completely double-stranded over their en re length.
  • nucleic acid is used herein in the broadest sense and comprises chromosomes or chromosomal segments. Unless otherwise indicated, a par cular nucleic acid sequence comprises or encodes complementary sequences, in addi on to any sequence explicitly indicated.
  • 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 par ally purified or substan ally pure form.
  • a nucleic acid is "isolated” or “rendered substan ally 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 amplifica on, and reverse transcrip on 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.
  • 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.
  • operatively linked 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.
  • vectors for TCRs or antibodies, are known in the art and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • 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.
  • 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.
  • Non-viral vectors and systems include plasmids, cosmids, episomes, and artificial chromosomes.
  • 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.
  • plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance plIC, pcDNA, pBR, and the like.
  • 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.
  • 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 WO 95/14785, WO 96/22378, US 5,882,877, US 6,013,516, US 4,861,719, US 5,278,056 and WO 94/19478.
  • the inven on relates to a nucleic acid or separate nucleic acids encoding an an gen-binding protein as described herein for use in the treatment of cancer, wherein the nucleic acid or separate nucleic acids are administered in combina on with a pro- inflammatory substance.
  • the inven on further relates to a vector comprising the nucleic acid or the separate nucleic acids as described herein or separate vectors comprising the separate nucleic acids as described herein for use in the treatment of cancer, wherein the vector or separate vectors are administered in combina on with a pro-inflammatory substance.
  • 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. It is pointed out that the invention also relates to an antigen-binding protein for use in the treatment of cancer, wherein the antigen-binding protein is produced by any one of the herein described host cells (and administered in combina on with a pro-inflammatory substance). Accordingly, the invention also relates to an antigen-binding protein for use in the treatment of cancer, wherein the antigen-binding protein is produced by a host cell transfected with (a) nucleic acid(s) or (a) vector(s) encoding the herein described antigen-binding proteins.
  • the invention relates to an antigen-binding protein for use in the treatment of cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the antigen-binding protein is produced by a) providing a suitable host cell, b) transfec ng said suitable host cell with (a) nucleic acid(s) or (a) vector(s) encoding the antigen-binding protein, c) producing the antigen-binding protein, optionally d) purifying the antigen-binding protein, and e) formulating the antigen-binding protein into a pharmaceutical composition.
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the antigen-binding protein is produced by a) providing a suitable host cell, b) transfec ng said suitable host cell with (a) nucleic acid(s) or (a) vector(s) encoding the antigen-binding protein comprising: a V ⁇ and a V ⁇ , wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR ⁇ 3 comprising the amino acid
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the antigen-binding protein is produced by a) providing a suitable host cell, b) transfec ng said suitable host cell with (a) nucleic acid(s) or (a) vector(s) encoding the antigen-binding protein comprising or consis ng of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2, c) producing the antigen-binding protein, optionally d) purifying the anti
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the antigen-binding protein is produced by a) providing a suitable host cell, b) transfec ng said suitable host cell with (a) nucleic acid(s) or (a) vector(s) encoding the antigen-binding protein consis ng of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2, c) producing the antigen-binding protein, optionally d) purifying the antigen-binding protein, and e) formulating the antigen-binding protein into a pharmaceutical composition.
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the antigen-binding protein is produced by a) producing the antigen-binding protein by a host cell transfected with (a) nucleic acid(s) or (a) vector(s) encoding the antigen-binding protein consis ng of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2, b) purifying the antigen-binding protein, and optionally c) formulating the antigen-binding protein into a pharmaceutical composition.
  • the invention relates to an antigen-binding protein for use in the treatment of cancer, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance and wherein the antigen-binding protein is produced by a) providing a suitable host cell, b) transfec ng said suitable host cell with (a) nucleic acid(s) or (a) vector(s) encoding the antigen-binding protein, c) producing the antigen-binding protein, optionally d) purifying the antigen-binding protein, and e) formulating the antigen-binding protein into a pharmaceutical composition; and wherein any of the herein described doses of the an gen-binding protein is to be administered.
  • 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.
  • 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.
  • the host cell can be of any cell type, can originate from any type of tissue, and can be of any developmental stage, the host cell preferably is a peripheral blood leukocyte (PBL) or a peripheral blood mononuclear cell (PBMC). More preferably, the host cell is a lymphocyte, such as a T cell, a T cell progenitor or a NK cell.
  • NK cells are naturally occurring lymphoid non- T cells that can rapidly kill virally infected cells and tumour cells.
  • NK cells can be engineered to express a tumor-specific TCR for use as a cell therapy product in cancer therapy (Shimasaki et al., Nat Rev Drug Discov.2020 Mar; 19(3):200-218).
  • the host cell is a T cell, for example a CD4 or CD8 positive T cell.
  • the T cell can be any T cell, such as a cultured T cell, e.g., a primary T cell, or a T cell from a cultured T cell line, e.g., Jurkat, SupT1, etc., or a T cell obtained from a mammal, preferably a T cell or T cell precursor from a human pa ent or donor. If obtained from a mammal, the T cell can be obtained from numerous sources, including but not limited to blood, bone marrow, lymph node, the thymus, or other ssues orfluids. T cells can also be enriched for or purified.
  • the T cell is a human T cell. More preferably, the T cell is a T cell isolated from a human.
  • the T cell can be any type of T cell and can be of any developmental stage, including but not limited to, CD4-posi ve helper T cells, e.g., Th1 and Th2 cells, CD8-posi ve T cells (e.g., cytotoxic T cells), tumor infiltra ng cells (TILs), memory T cells, naive T cells, and the like.
  • CD4-posi ve helper T cells e.g., Th1 and Th2 cells
  • CD8-posi ve T cells e.g., cytotoxic T cells
  • TILs tumor infiltra ng cells
  • memory T cells naive T cells, and the like.
  • the inven on relates to a host cell comprising the described an gen-binding protein, the described nucleic acid or separate nucleic acids, or the described vector or the separate vectors for use in the treatment of cancer, wherein said host cell is administered in combina on with a pro-inflammatory substance, preferably wherein the host cell is a lymphocyte, more preferably a T lymphocyte or T lymphocyte progenitor, most preferably a CD4 or CD8 posi ve T-cell.
  • the inven on relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein comprises: a T cell receptor (TCR) alpha variable domain (V ⁇ ) and a TCR beta variable domain (V ⁇ ) or a TCR gamma variable domain (V ⁇ ) and a TCR delta variable domain (V ⁇ ), wherein the V ⁇ or V ⁇ domain comprises (i) a CDR1 comprising the amino acid sequence according to SEQ ID NO: 28, (ii) a CDR2 comprising the amino acid sequence according to SEQ ID NO: 29, and (iii) a CDR3 comprising the amino acid sequence according to S
  • the inven on also relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein comprises: a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 42 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 42 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 28, 29, and 30, respec vely; and a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 44 or an amino acid sequence having at least 85%, 90%, 9
  • the inven on further relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein comprises: a V ⁇ consis ng of the amino acid sequence according to SEQ ID NO: 41; and a V ⁇ consis ng of the amino acid sequence according to SEQ ID NO: 43.
  • MHC major histocompa bility complex
  • the inven on also relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a constant region having at least 70% sequence iden ty to an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region having at least 70% sequence iden ty to an amino acid sequence according to SEQ ID NO: 37.
  • MHC major histocompa bility complex
  • the inven on also relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a constant region consis ng of an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region consis ng of an amino acid sequence according to SEQ ID NO: 37.
  • MHC major histocompa bility complex
  • the inven on also relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a V ⁇ comprising or consis ng of the amino acid sequence according to SEQ ID NO: 42 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 42 and comprising the CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 28, 29, and 30, respec vely; and a constant region having at least 70%
  • the inven on also relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a amino acid sequence according to SEQ ID NO: 41 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 41 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 28, 29, and 30, respec vely; and wherein the TCR beta chain sequence comprises an amino acid sequence according to SEQ ID NO: 43 or
  • the inven on also relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, wherein said host cell is administered in combina on with a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence consists of an amino acid sequence according to SEQ ID NO: 41; and wherein the TCR beta chain sequence consists of an amino acid sequence according to SEQ ID NO: 43.
  • MHC major histocompa bility complex
  • the described an gen-binding molecules may have to be expressed with a signal pep de to be presented on the surface of the host cell. Accordingly, the skilled person can easily determine which constructs need to be expressed in the host cell. For example, it may be necessary to transfect a host cell with a nucleic acid encoding SEQ ID NO: 26 and SEQ ID NO: 32 so that the host presents a TCR on its surface comprising SEQ ID NO: 41 and SEQ ID NO: 43. As men oned the present inventors found that the therapeu c ac vity of the herein described an gen-binding molecules can be enhanced by co-administra on of a pro-inflammatory substance.
  • “Co-administra on”, “administered in combina on”, “administra on of a combina on”, “co-administra on of a combina on”, “combined therapy” and/or “combined treatment regimen” is used herein in the broadest sense and refers to at least two therapeu cally ac ve drugs/agents/substances or composi ons which may be administered or co-administered, simultaneously, in either separate or combined formula ons, or sequen ally at different mes separated by minutes, hours or days, but in some way act together to provide the desired therapeu c response.
  • act together may mean that one drug maximizes the effec veness of the other drug, i.e. the pro- inflammatory substance increases the presenta on of the target an gen on tumor cells of the described an gen-binding proteins.
  • the an gen-binding protein has a higher an -tumor ac vity when administered in combina on with a pro-inflammatory substance because the pro-inflammatory substance increases the presenta on of the target an gen on the tumor cells.
  • the described an gen-binding protein the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell and the pro-inflammatory substance may be administered or co-administered, simultaneously, in either separate or combined formula ons, or sequen ally at different mes separated by minutes, hours or days.
  • Simultaneous administra on means that the therapeu cally ac ve agents (the described an gen-binding protein and the pro-inflammatory substance) can be administered at the same me. This can occur either by combining them into a single formula on/composi on or by administering them separately but concurrently or concomitantly.
  • the described an gen-binding protein and the pro-inflammatory substance may be administered in separate formula ons which means that the ac ve agents may be provided in different formula ons/composi ons, meaning each drug or composi on retains its own dis nct form. Even though they are administered together or in close succession, they are not physically combined into one dosage form (e.g. pharmaceu cal composi on). Sequen al administra on means that the described an gen-binding protein and the pro- inflammatory substance may be administered at different mes. This could mean administering them minutes, hours, or even days apart. Despite this staggered ming, the agents are considered part of a combined therapy because they interact or work in concert to achieve the desired therapeu c effect.
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell and the pro-inflammatory substance are each present in an amount effec ve to achieve a synergis c therapeu c effect when administered in combina on.
  • the inven on also relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro- inflammatory substance, wherein the pro-inflammatory substance increases the presenta on level of the pep de according to SEQ ID NO: 25.
  • the inven on also relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro- inflammatory substance, wherein the subject benefits from an increase of the presenta on level of the pep de according to SEQ ID NO: 25.
  • the inven on relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pro-inflammatory substance is administered before, concomitantly to, concurrently to, simultaneously to or a er administra on of the an gen- binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell.
  • the e.g. described an gen-binding protein and the pro-inflammatory substance may be provided in different formula ons/composi ons.
  • the inven on relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance and wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell are formulated in a first pharmaceutical composition and the pro-inflammatory substance is formulated in a second pharmaceutical composition.
  • pharmaceu cal composi on or “therapeu c composi on” as used herein refer to a compound or composi on capable of inducing a desired therapeu c effect when properly administered to a subject.
  • the subject may also be referred to as pa ent.
  • Such therapeu c or pharmaceu cal composi ons may comprise a therapeu cally effec ve amount of an an gen-binding protein and/or pro-inflammatory substance, in admixture with a pharmaceu cally or physiologically acceptable formula on agent, carrier or aqueous medium selected for suitability with the mode of administra on.
  • the an gen-binding protein and/or pro-inflammatory substance will usually be supplied as part of a sterile, pharmaceu cal composi on which may include a pharmaceu cally acceptable carrier.
  • "Pharmaceu cally” or “pharmaceu cally acceptable” refers to molecular en es and composi ons that do not produce an adverse, allergic or other untoward reac on when administered to a mammal, especially a human, as appropriate.
  • a pharmaceu cally acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquidfiller, diluent, encapsula ng material or formula on auxiliary of any type.
  • a “pharmaceu cally-acceptable carrier” may also be referred to as “pharmaceu cally acceptable diluent” or “pharmaceu cally acceptable vehicle“ and may include solvents, bulking agents, stabilizing agents, dispersion media, coa ngs, an bacterial and an fungal agents, isotonic and absorp on delaying agents, and the like which are physiologically compa ble.
  • the carrier may be an aqueous carrier or an aqueous medium.
  • the pharmaceu cal composi ons 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 instruc ons for use.
  • the pharmaceu cal composi ons may contain vehicles, which are pharmaceu cally acceptable for a formula on suitable for injec on. These may be in par cular isotonic, sterile, saline solu ons (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze- dried composi ons which upon addi on, depending on the case, of sterilized water or physiological saline, permit the cons tu on of injectable solu ons.
  • vehicles which are pharmaceu cally acceptable for a formula on suitable for injec on.
  • These may be in par cular isotonic, sterile, saline solu ons (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze- dried composi ons which upon addi on, depending on the case, of steriliz
  • an effec ve amount of the an gen-binding protein and/or pro-inflammatory substance may be dissolved or dispersed in a pharmaceu cally acceptable carrier or aqueous medium.
  • the pharmaceu cal forms suitable for injectable use include sterile aqueous solu ons or dispersions; formula ons including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous prepara on of sterile injectable solu ons or dispersions. In all cases, the form must be sterile and must befluid to the extent that administra on via a syringe is possible.
  • Solu ons of the ac ve 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 condi ons of storage and use, these prepara ons may contain a preserva ve to prevent the growth of microorganisms.
  • An an gen-binding protein described herein and/or pro-inflammatory substance may be formulated into a composi on in a neutral or salt form using pharmaceu cally acceptable salts.
  • Sterile injectable solu ons are prepared by incorpora ng the ac ve compounds (an gen- binding proteins and/or pro-inflammatory substance) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed byfiltered steriliza on.
  • dispersions are prepared by incorpora ng the various sterilized ac ve ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of prepara on are vacuum-drying and freeze-drying techniques which yield a powder of the ac ve ingredient plus any addi onal desired ingredient from a previously sterile-filtered solu on thereof.
  • the prepara on of more, or highly concentrated solu ons for direct injec on is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetra on, delivering high concentra ons of the ac ve agents to a small tumor area. It is pointed out that pharmaceu cal composi ons comprising the herein described nucleic acids, vectors and host cells are also encompassed.
  • the pharmaceutical composition comprising the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is in a different vessel than the pharmaceutical composition comprising a pro-inflammatory substance.
  • the inven on relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell are formulated in a first pharmaceutical composition contained in a first vessel and the pro- inflammatory substance is formulated in a second pharmaceutical composition contained in a second vessel.
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell are formulated in a first pharmaceutical composition contained in a first vessel and the pro-inflammatory substance is formulated in a second pharmaceutical composition contained in a second vessel, wherein thefirst vessel and/or second vessel is a vial or a syringe.
  • the skilled person is readily capable of choosing suitable pro-inflammatory substances that may be used in context of the present inven on.
  • the pro-inflammatory substances may be (human) interferons, interferon analogs, interferon agonists, substances that increases pro-inflammatory (e.g. IFN- ⁇ , TNF- ⁇ ) cytokine expression, an viral agents, chemotherapeu c agents, immune checkpoint inhibitors, interleukins and vaccines, in par cular mRNA-based vaccines.
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the pro-inflammatory substance is selected from group consis ng of (human) interferons, interferon analogs, interferon agonists, substances that increases pro-inflammatory (e.g. IFN- ⁇ , TNF- ⁇ ) cytokine expression, an viral agents, chemotherapeu c agents, immune checkpoint inhibitors, and interleukins.
  • a pro-inflammatory substance is selected from group consis ng of (human) interferons, interferon analogs, interferon agonists, substances that increases pro-inflammatory (e.g. IFN- ⁇ , TNF- ⁇ ) cytokine expression, an viral agents
  • Interferons are a group of signaling proteins produced and released by cells in response to the presence of pathogens, such as viruses, bacteria, parasites, or tumor cells.
  • pathogens such as viruses, bacteria, parasites, or tumor cells.
  • IFN- ⁇ and IFN- ⁇ Type I interferons
  • IFN- ⁇ Type II interferon
  • IFN- ⁇ Type III interferons
  • IFN- ⁇ Type I interferons, including IFN- ⁇ (produced mainly by leukocytes and plasmacytoid dendri c cells) and IFN- ⁇ (primarily produced byfibroblasts and epithelial cells), are involved in the early immune response to viral infec ons.
  • Type II interferon, IFN- ⁇ is produced by T cells and NK cells and plays a cri cal role in ac va ng macrophages, enhancing an gen presenta on, and coordina ng the adap ve immune response.
  • Type III interferons, par cularly IFN- ⁇ have a more targeted ac on, especially in mucosal surfaces like the lungs and gut, which are common entry points for pathogens, playing a key role in an viral defense at these sites.
  • the key func ons of interferons include an viral ac vity, where they inhibit viral replica on within infected cells by inducing the produc on of an viral proteins; immunomodula on, where they enhance the ac vity of immune cells like NK cells and macrophages and promote an gen presenta on to T cells; an -prolifera ve effects, where they inhibit the prolifera on of cells, including tumor cells; and ac va on of immune responses, where they help regulate and coordinate the adap ve immune response, ensuring the body can efficiently respond to and eliminate pathogens.
  • the interferon used in context of the present inven on is a Type I interferon (IFN- ⁇ and IFN- ⁇ ), a Type II interferon (IFN- ⁇ ) or a Type III interferon (IFN- ⁇ ).
  • the interferon used in context of the present inven on is interferon- ⁇ (IFN- ⁇ ), interferon- ⁇ (IFN- ⁇ ) or interferon- ⁇ (IFN- ⁇ ).
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the pro-inflammatory substance is an interferon, preferably IFN- ⁇ , IFN- ⁇ or IFN- ⁇ .
  • the pro-inflammatory substance is IFN- ⁇ .
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen- binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the pro-inflammatory substance is IFN- ⁇ .
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein said an gen- binding protein is administered in combina on with interferon, preferably IFN- ⁇ and wherein the an gen-binding protein comprises: a V ⁇ and a V ⁇ , wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to
  • the inven on relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with interferon, preferably IFN- ⁇ and wherein the an gen-binding protein comprises or consists of afirst polypep de chain that 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% iden ty to SEQ ID NO: 39 and comprising the CDRL1, CDRL2, CDRL3, CDR ⁇ 1, CDR ⁇ 2, and CDR ⁇ 3 according to SEQ ID NOs: 4, 5, 6, 12, 13, and 14, respec vely; and a second polypep de chain that comprises or consists of the amino acid
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with interferon, preferably IFN- ⁇ , and wherein the an gen-binding protein comprises or consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • the inven on relates to an an gen-binding protein (or a host cell comprising said an gen-binding protein) for use in the treatment of a cancer, wherein said an gen-binding protein (or said host cell) is administered in combina on with interferon, preferably IFN- ⁇ , wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein comprises: a T cell receptor (TCR) alpha variable domain (V ⁇ ) and a TCR beta variable domain (V ⁇ ) or a TCR gamma variable domain (V ⁇ ) and a TCR delta variable domain (V ⁇ ), wherein the V ⁇ or V ⁇ domain comprises (i) a CDR1 comprising the amino acid sequence according to SEQ ID NO: 28, (ii) a CDR2 comprising the amino
  • the inven on relates to an an gen-binding protein (or a host cell comprising said an gen-binding protein) for use in the treatment of a cancer, wherein said an gen-binding protein (or said host cell) is administered in combina on with interferon, preferably IFN- ⁇ , wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence comprises a amino acid sequence according to SEQ ID NO: 41 or an amino acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 41 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 28, 29, and 30,
  • the inven on relates to an an gen-binding protein (or a host cell comprising said an gen-binding protein) for use in the treatment of a cancer, wherein said an gen-binding protein (or said host cell) is administered in combina on with interferon, preferably IFN- ⁇ , wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is a TCR comprising at least one TCR alpha and one TCR beta chain sequence, wherein the TCR alpha chain sequence consists of an amino acid sequence according to SEQ ID NO: 41; and wherein the TCR beta chain sequence consists of an amino acid sequence according to SEQ ID NO: 43.
  • MHC major histocompa bility complex
  • the pro-inflammatory substances used in context of the inven on may be immune checkpoint inhibitors.
  • Immune checkpoint inhibitors are well known in the art.
  • An immune checkpoint inhibitor is a type of drug used in cancer therapy to help the immune system recognize and atack cancer cells more effec vely.
  • the immune system has checkpoints—molecules on certain immune cells—that need to be ac vated (or inac vated) to start an immune response. These checkpoints help prevent the immune system from atacking normal cells in the body.
  • cancer cells can exploit these checkpoints to avoid being atacked by the immune system.
  • Immune checkpoint inhibitors work by blocking these checkpoint proteins from interac ng with their partners, thereby allowing immune cells, par cularly T-cells, to iden fy and destroy cancer cells more effec vely.
  • Common targets for these inhibitors include proteins such as PD-1 (programmed death-1), PD-L1 (programmed death-ligand 1), and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4).
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the pro-inflammatory substance is an immune checkpoint inhibitor.
  • the invention also relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the pro-inflammatory substance is an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, LAG-3 inhibitor or a CTLA-4 inhibitor.
  • the PD-1 inhibitor may be selected from the group consis ng of Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Re fanlimab-dlwr and Tislelizumab.
  • the PD-L1 inhibitor may be selected from the group consis ng of Atezolizumab, Durvalumab and Avelumab.
  • the LAG-3 inhibitor may be Relatlimab.
  • the CTLA-4 inhibitor may be Ipilimumab or Tremelimumab. It is evident for the skilled person that also combina ons of checkpoint inhibitors may be used in context of the inven on.
  • Nivolumab and Relatlimab may be used.
  • the bispecific monoclonal an body Cadonilimab targe ng PD- 1 and CTLA-4 may be used.
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the pro-inflammatory substance is an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is selected from the group consis ng of Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Re fanlimab- dlwr, Tislelizumab, Atezolizumab, Durvalumab, Avelumab, Relatlimab, Ipilimumab and Tremelimumab, preferably Pembrolizumab.
  • the immune checkpoint inhibitor is administered every three weeks. It is also envisaged that the immune checkpoint inhibitor is administered every six weeks. It is envisaged that Pembrolizumab is administered every three weeks. It is also envisaged that Pembrolizumab is administered every six weeks. It is also envisaged that thefirst administra on of Pembrolizumab is performed seven days before thefirst administra on of the herein described an gen-binding protein. It is envisaged that a dose of 200 mg Pembrolizumab is administered to the pa ent. It is in par cular envisaged that a dose of 200 mg Pembrolizumab is administered to the pa ent every three weeks.
  • the pro-inflammatory substances used in context of the inven on may be interleukins.
  • Interleukins are well known in the art and are a group of cytokines (signaling molecules) that are produced by immune cells and other cells in the body. They play a cri cal role in regula ng the immune system by facilita ng communica on between cells, promo ng the growth and differen a on of immune cells, and orchestra ng the body's response to infec ons, inflamma on, and other immune challenges.
  • the invention relates to the described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with a pro-inflammatory substance, wherein the pro-inflammatory substance is an interleukin.
  • the interleukin is interleukin-2 (IL-2), interleukin- 12 (IL-12) or interleukin-18 (IL-18).
  • the invention relates to the described an gen- binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is administered in combina on with interleukin, wherein the interleukin is interleukin-2 (IL-2), interleukin-12 (IL-12) or interleukin-18 (IL-18).
  • the pro-inflammatory substances may also be cytokines in general.
  • pro-inflammatory substances may also be administered to the pa ent in form of nucleic acids or vectors encoding said pro- inflammatory substances.
  • the skilled person is well aware or can readily determine which cancer may be treated by the herein described an gen-binding proteins, nucleic acids, vectors and host cells.
  • Non-limi ng examples of cancer types are 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); 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); pancrea c cancer (PACA); prostate cancer (PRAD); leukemia, preferably acute myeloid leukemia (AML)
  • the cancer may also be selected from the group consis ng of adrenocor cal carcinoma, bladder cancer, preferably (urinary) bladder carcinoma or bladder urothelial carcinoma, brain tumor, in par cular glioblastoma, primary brain cancer, or atypical meningioma, breast cancer, in par cular triple-nega ve breast cancer or breast carcinoma, cervical carcinoma, in par cular cervical squamous cell carcinoma or endocervical adenocarcinoma, cholangiocellular carcinoma, colorectal cancer, in par cular colon cancer, endometrial cancer, in par cular 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 junc on cancer (GEJC), fallopian tube cancer, gallbladder
  • pylori-induced MALT non- Hodgkin lymphoma, malignant peripheral nerve sheath tumors, skin cancer, in par cular melanoma, in par cular amelano c melanoma, uveal melanoma, mucosal melanoma or cutaneous melanoma, mesothelioma, oral cavity carcinomas, oral squamous carcinoma, ovarian cancer, in par cular 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 par cular restricted to serous, clear cell, and endometrioid subtypes, prostate cancer, renal cancer, in par cular renal carcinoma, in par cular renal clear cell carcinoma, renal papillary cell carcinoma, salivary duct carcinoma,
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is/are administered in combina on with a pro- inflammatory substance, wherein the cancer is selected from the group consis ng 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) or 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); skin cancer, preferably melanoma (
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is/are administered in combina on with a pro-inflammatory substance, wherein the cancer is selected from the group consis ng of (cutaneous or mucosal) melanoma (MEL); triple-nega ve breast cancer (TNBC); head and neck squamous cell carcinoma (HNSCC); synovial sarcoma; ovarian cancer (OC); gastric cancer (GC); squamous cell non-small cell lung cancer (NSCLCsquam); and Neuroendocrine neoplasm (NEN), preferably Neuroendocrine Tumor CUP.
  • MEL cutaneous or mucosal
  • TNBC triple-nega ve breast cancer
  • HNSCC
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is/are administered in combina on with a pro-inflammatory substance, wherein the cancer is cutaneous melanoma, mucosal melanoma, head and neck squamous cell carcinoma (HNSCC) or Neuroendocrine Tumor CUP.
  • HNSCC head and neck squamous cell carcinoma
  • the inven on thus, relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein a dose of about 6.6 ⁇ g, about 10 ⁇ g, about 20 ⁇ g, about 30 ⁇ g, about 40 ⁇ g, about 50 ⁇ g, about 60 ⁇ g, about 80 ⁇ g, about 100 ⁇ g, about 120 ⁇ g, about 140 ⁇ g, about 150 ⁇ g, about 160 ⁇ g, about 180 ⁇ g, about 200 ⁇ g, about 250 ⁇ g, about 300 ⁇ g, about 350 ⁇ g, about 400 ⁇ g, about 450 ⁇ g, about 500 ⁇ g, about 540 ⁇ g, about 600 ⁇ g
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises: a V ⁇ and a V ⁇ , wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 12, (i
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g, about 1200 ⁇ g, about 1800 ⁇ g, about 2500 ⁇ g, or about 5000 ⁇ g or about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen-binding protein is to
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance wherein the an gen-binding protein comprises: a V ⁇ and a V ⁇ , wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 12, (ii
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen-binding protein are to be administered, wherein
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein a dose of about 1000 ⁇ g to about 4000 ⁇ g or about 1200 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen- binding protein are to be administered, wherein the cancer is selected from the group
  • the inven on further relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein specifically recognizes, is reac ve with, or binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with interferon, preferably IFN- ⁇ , wherein the an gen-binding protein comprises: a V ⁇ and a V ⁇ , wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR ⁇ 3 comprising the amino acid sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to SEQ ID NO
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with interferon, preferably IFN- ⁇ , wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2 and wherein the cancer is selected from the group consis ng 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) or s
  • the inven on also relates to an an gen-binding protein for use in the treatment of a cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with interferon, preferably IFN- ⁇ , wherein the an gen-binding protein consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 2 and wherein the cancer is selected from the group consis ng 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) or squamous cell non-
  • the inven on also relates to the herein described an gen-binding proteins, nucleic acids, vectors and host cells for use in the treatment of cancer, wherein the an gen-binding proteins, nucleic acids, vectors and host cells are administered in combina on with a pro-inflammatory substance, wherein the cancer is selected from the group consis ng of gastric cancer (GC), head and neck squamous cell carcinoma (HNSCC), melanoma (MEL), non-small cell lung cancer (NSCLC), such as non-small cell lung cancer adenocarcinoma (NSCLCadeno) or squamous cell non-small cell lung cancer (NSCLCsquam), ovarian cancer (OC), esophageal cancer (OSCAR), renal cell cancer (RCC), sarcoma (SARC), such as synovial sarcoma, urinary bladder cancer (UBC) and uterine cancer (UEC).
  • GC gastric cancer
  • HNSCC head and neck squa
  • metasta c cancers are to be treated by the herein described an gen-binding proteins, nucleic acids, vectors or host cells.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is/are administered in combina on with a pro-inflammatory substance, wherein the cancer is metasta c cancer and/or advanced cancer and/or unresectable cancer and/or recurrent cancer and/or refractory cancer.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of metasta c cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is/are administered in combina on with a pro-inflammatory substance, wherein the metasta c cancer is selected from the group consis ng of metasta c gastric cancer (GC), metasta c head and neck squamous cell carcinoma (HNSCC), metasta c melanoma (MEL), metasta c non-small cell lung cancer (NSCLC), such as metasta c non-small cell lung cancer adenocarcinoma (NSCLCadeno) or metasta c squamous cell non-small cell lung cancer (NSCLCsquam), metasta c ovarian cancer (OC), metasta c c gastric cancer
  • the inven on also relates to an an gen-binding protein for use in the treatment of a metasta c cancer, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, wherein the an gen-binding protein is administered in combina on with a pro-inflammatory substance, wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2, op onally wherein the cancer is selected from the group consis ng of gastric cancer (GC), head and neck squamous cell carcinoma (HNSCC), melanoma (MEL), non-small cell lung cancer (NSCLC), such as non-small cell lung cancer adenocarcino
  • the inven on also relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of metasta c cancer, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is/are administered in combina on with a pro-inflammatory substance, wherein the subject to be treated is a mammal, preferably a human.
  • kits comprising the described an gen-binding proteins and the described pro-inflammatory substances. The kits are useful for carrying out any of the embodiments described herein as they may contain any of the combina ons described herein.
  • kits may contain the an gen-binding protein and the pro-inflammatory substance combined in a single vessel or separated in two or more separate vessels. Accordingly, the kits may contain the an gen-binding protein and the pro-inflammatory substance combined in a single pharmaceu cal composi on or separated in two or more separate pharmaceu cal composi ons.
  • the kits may contain instruc ons for administering the combina ons to a subject. For example, when the an gen-binding protein and the pro-inflammatory substance are provided separately in the kit the kit may contain instruc ons when to administer each of the an gen-binding protein and the pro-inflammatory substance, e.g.
  • the inven on relates to a kit comprising an an gen-binding protein and a pro- inflammatory substance, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25, preferably bound to a major histocompa bility complex (MHC) protein, preferably HLA-A*02, preferably wherein the an gen-binding protein comprises or consists of afirst polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 39, and a second polypep de chain that comprises or consists of the amino acid sequence according to SEQ ID NO: 2.
  • MHC major histocompa bility complex
  • an inflammatory state refers to a condi on in which the body's immune system is ac vely responding to a (perceived) threat, such as an infec on, injury, cancer or other harmful s muli.
  • a (perceived) threat such as an infec on, injury, cancer or other harmful s muli.
  • This response is characterized by the ac va on of immune cells, the release of signalling molecules (like cytokines), and changes in bloodflow to the affected area.
  • the primary purpose of inflamma on is to eliminate the ini al cause of cell injury, clear out damaged cells and ssues, and ini ate ssue repair.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer in a pa ent, wherein the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell is/are administered in combina on with a pro-inflammatory substance, wherein the pa ent has an inflammatory state.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state.
  • the inven on relates to a method of trea ng a pa ent having an inflammatory state, comprising administering to the pa ent an effec ve amount of the an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell as described herein.
  • the skilled person is well aware how determine whether a pa ent has an inflammatory state or is in an inflammatory state.
  • the inflammatory state may be determined/iden fied/diagnosed systemically, in liquid biopsies or within the tumor.
  • a systemic inflammatory state may affect the en re body, involving mul ple organs and ssues and may be detected for example in the blood or the plasma by parameters described below.
  • Liquid biopsies refer to the collec on of tumor cells circula ng in the blood. Accordingly, it is envisaged that the inflammatory state is determined in tumor cells circula ng in the blood. Said liquid biopsies may be especially useful to determine inflamma on localized to the tumor.
  • An inflammatory state within the tumor may mean that the inflamma on is localized to the tumor and its immediate microenvironment not involving the en re body. Inflamma on within a tumor may be caused by the body’s immune response to the tumor cells, which are recognized as abnormal and atract immune cells.
  • An inflammatory state within the tumor may be diagnosed through ssue biopsies showing infiltra on of immune cells (e.g., macrophages, T cells) within the tumor, elevated levels of specific cytokines in the tumor microenvironment or imaging studies showing increased metabolic ac vity in the tumor area.
  • An inflammatory state within the tumor may be determined/iden fied/diagnosed by elevated/increased expression of interferon regulatory factor 1 (IRF1, ENSG00000125347).
  • IRF1, ENSG00000125347 interferon regulatory factor 1
  • Transcrip on of IRF1 is induced upon s mula on of cells, including tumor cells, with interferon triggering downstream effects including increased HLA class I expression (Schroder at al., J Leukoc Biol.
  • IRF1 expression may be determined for example from Figure 8.
  • Figure 12 also show IRF1 expression levels can be used to determine whether MAG-003 presenta on is under- or overes mated based on MAGEA4/8 expression. Under an inflammatory state MAG-003 presenta on may be higher than predicted based on MAGEA4/8 expression.
  • Figure 12B shows that samples with IRF1 dCT values of ⁇ 3 show on average posi ve residuals indica ng an underes ma on of MAG-003 CpC based on its exon expression. Accordingly, pa ents having IRF1 dCT values of ⁇ 3 may have higher MAG-003 presenta on levels than es mated based on MAGEA4/8 expression and may benefit par cularly from the herein described MAG-003 an gen binding proteins.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an IRF1 dCT value of ⁇ 5.5, ⁇ 5.0, ⁇ 4.5, ⁇ 4, ⁇ 3.5, ⁇ 3, ⁇ 2.5 or ⁇ 2.0, preferably ⁇ 3.
  • the IRF1 expression may be determined in blood samples or tumor samples of the pa ent.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied systemically, in liquid biopsies and/or within the tumor.
  • the inflammatory state is iden fied by one or more of the following parameters: elevated levels of C-reac ve protein (CRP), elevated erythrocyte sedimenta on rate (ESR), elevated levels of pro-inflammatory cytokines including TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, type I interferons, type II interferons and type III interferons, elevated white blood cell count, elevated plasmafibrinogen, elevated serum amyloid A (SAA), elevated levels of adhesion molecules such as ICAM-1 and VCAM-1, elevated levels of nitric oxide, elevated oxida ve stress markers such as malondialdehyde (MDA) and 8-isoprostane andflu-like symptoms.
  • CRP C-reac ve protein
  • ESR erythrocyte sedimenta on rate
  • pro-inflammatory cytokines including TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, type I interferons, type II interferons and type III interferons
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by one or more of the following parameters: elevated levels of C-reac ve protein (CRP), elevated erythrocyte sedimenta on rate (ESR), elevated levels of pro-inflammatory cytokines including TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, type I interferons, type II interferons and type III interferons, elevated white blood cell count, elevated plasma fibrinogen, elevated serum amyloid A (SAA), elevated levels of adhesion molecules such as ICAM-1 and VCAM-1, elevated levels of nitric oxide, elevated oxida ve stress markers such as malondialdehyde (MDA) and 8-isoprostane andflu-like symptoms.
  • CRP C-
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of C-reac ve protein (CRP) of 5 mg/l to 10 mg/l blood or higher.
  • CRP C-reac ve protein
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by a erythrocyte sedimenta on rate (ESR) of 15 mm/hr or higher.
  • ESR erythrocyte sedimenta on rate
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of TNF- ⁇ of 8.1 pg/ml blood or higher, levels of IL-1 ⁇ of 5.0 pg/ml blood or higher, levels of IL-6 of 7.0 pg/ml blood or higher and/or levels IL-8 is 62 pg/ml or higher.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of plasmafibrinogen of 400 mg/dl plasma or higher.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of serum amyloid A (SAA) of 10 mg/l blood or higher.
  • SAA serum amyloid A
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of ICAM-1 of 650 ng/ml blood or higher.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of VCAM-1 of 800 ng/ml blood or higher.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of nitric oxide of 50 ⁇ mol/l blood or higher.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of malondialdehyde (MDA) of 10 pg/ml plasma or higher.
  • MDA malondialdehyde
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by levels of 8-isoprostane of 2.5 ⁇ mol/l blood or higher.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied by a white blood cell count of 8000 cells/ ⁇ l blood to 13000 cells/ ⁇ l blood or higher, such as 10000 cells/ ⁇ l blood or higher.
  • the above described thresholds are non-limi ng. It is evident for the skilled person that the thresholds may not be universal.
  • the thresholds may be determined by the laboratory performing the corresponding tests or may be determined rela ve to what has been determined in the same pa ent in the absence of inflamma on.
  • Theflu-like symptoms may be fever, chills, headache, fa gue, myalgia and arthralgia.
  • the inven on relates to the herein described an gen-binding protein, the nucleic acid, the separate nucleic acids, the vector, the separate vectors or the host cell for use in the treatment of cancer, wherein the pa ent to be treated has an inflammatory state and wherein the inflammatory state is iden fied byflu-like symptoms such as fever, chills, headache, fa gue, myalgia and/or arthralgia.
  • the terms "comprising”, “including”, “having” or gramma cal variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addi on of one or more addi onal features, integers, steps, components or groups thereof.
  • the term “consis ng essen ally of” means that specific further components (or likewise features, integers, steps and the like) can be present, namely those not materially affec ng the essen al characteris cs of the product, composi on, device or method.
  • the term “consis ng essen ally of” (which can be interchangeably used herein with the term “comprising substan ally”), allows the presence of other components in the product, composi on, device or method in addi on to the mandatory components (or likewise features, integers, steps and the like), provided that the essen al characteris cs of the product, composi on, device or method are not materially affected by the presence of other components.
  • the term "about” refers to ⁇ 10%.
  • “a” or “an” may mean one or more. Importantly, when it is referred herein to a or the pro-inflammatory substance always also mul ple pro-inflammatory substances are encompassed.
  • IFN- ⁇ elevates IRF1 and HLA-A expression in vivo.
  • A RNA expression of IFN- ⁇ , IRF1 and HLA-A over the course of 27 days.
  • RNAseq data provided as normalized transcripts per million (TPM) values were used as input for rela ve gene expression analysis over me.
  • TPM transcripts per million
  • TPM normalized transcripts per million
  • Interferon- ⁇ (IFN- ⁇ ) expression was induced around day 8 and reached its plateau on day 14. Simultaneously, enhanced transcrip on of interferon regulatory factor-1 (IRF1) (up to a fold change of 18) and HLA-A (up to a fold change of 10) were observed.
  • IRF1 interferon regulatory factor-1
  • HLA-A up to a fold change of 18
  • HLA-A up to a fold change of 10
  • B HLA-A-02:01 CpC determined from day 1 – 27.
  • absolute HLA- A*02:01 copies per cell (CpC) were quan fied and used to assess changes in HLA levels over me. For study day 4, 8, 14 and 27 mean and standard devia on of two independent analyses is displayed (one (pool) tumor sample from mice humanized with donor 1 and donor 2 PBMCs each).
  • HLA-A*02-associated presenta on of DCTN3-003, MUM- 001, MCMB-002 and PPP6R3-001 presenta on peaked on day 14 or 27, respec vely (5-18 fold change vs. day 1).
  • MAG-003 heavily increased between day 8 and 14, which was maintained un l the end of the study at day 27. Compared with day 1, this equals a fold change of more than 50 for MAG-003 on both study day 14 and 27.
  • Figure 3 Heatmap of log 2 fold changes across the mul -omics in vivo dataset. Individual fold changes displayed infigure 1 and 2 were summarized here for the three inves gated omics layers RNA, protein, and HLA-presented pep de.
  • FIG. 4 Results of an LDH-release assay with the MAG-003-specific TCER® molecule.
  • An LDH-release assay with the bispecific TCER® targeting tumor-associated peptide MAG-003 (MAG-003 TCER®) presented on HLA-A*02 was performed.
  • PBMCs isolated from a healthy donor were co-incubated with the cancer cell line Hs695T (with or without IFN- ⁇ (100 U/mL for 2 days) pretreatment) at an effector:target ratio of 10:1, in the presence of increasing concentrations of the TCER® molecule.
  • TCER® molecule targeting an unrelated peptide was used. After 48 hours of co-culture, target cell lysis was quantified utilizing LDH-release assays according to the manufacturer’s instructions (Promega). Cytotoxicity on the IFN- ⁇ pre-treated cell line was 4-fold higher compared to untreated Hs695T tumor cells. In contrast, the control TCER® molecule was not able to induce higher T cell-dependent target cell killing on IFN- ⁇ pre-treated tumor cells.
  • Figure 5 IFNGR1 and IFNGR2 show robust expression across primary and recurrent tumors and metastases. RNAseq data are provided as normalized transcripts per million (TPM) values.
  • AML acute myeloid leukemia
  • BRCA breast cancer
  • CCC cholangiocellular carcinoma
  • CLL chronic lymphocy c leukemia
  • CRC colorectal cancer
  • GBC gallbladder cancer
  • GBM glioblastoma
  • GC gastric cancer
  • GEJC gastro-esophageal junc on cancer
  • HCC hepatocellular carcinoma
  • HNSCC head-and-neck squamous cell carcinoma
  • MEL melanoma
  • NHL non-Hodgkin lymphoma
  • NSCLCadeno non-small cell lung cancer adenocarcinoma
  • NSCLCother NSCLC samples that could not unambiguously be assigned to NSCLC adeno or NSCLCsquam
  • NSCLCsquam squamous cell non-small cell lung cancer
  • IFNGR1 gene expression in primary and recurrent tumors vs. metastases A global comparison of Interferon Gamma Receptor 1 (IFNGR1) across tumors of all en es revealed iden cal RNA expression between primary and recurrent tumors and metastases.
  • B Tumor en ty-wise comparison of IFNGR1 gene expression. Also at tumor en ty-wise resolu on, there is no substan al difference of IFNGR1 RNA expression between primary and recurrent tumors vs. metastases. Please note that there may be low sample numbers for specific categories such as ‘Met. NSCLC other’.
  • C IFNGR2 gene expression in primary and recurrent tumors vs. metastases.
  • IFNGR2 Interferon Gamma Receptor 2
  • TPM normalized transcripts per million
  • AML acute myeloid leukemia
  • BRCA breast cancer
  • CCC cholangiocellular carcinoma
  • CLL chronic lymphocy c leukemia
  • CRC colorectal cancer
  • GBC gallbladder cancer
  • GBM glioblastoma
  • GC gastric cancer
  • GEJC gastro-esophageal junc on cancer
  • HCC hepatocellular carcinoma
  • HNSCC head-and-neck squamous cell carcinoma
  • MEL melanoma
  • NHL non-Hodgkin lymphoma
  • NSCLCadeno non-small cell lung cancer adenocarcinoma
  • NSCLCother NSCLC samples that could not unambiguously be assigned to NSCLC adeno or NSCLCsquam
  • NSCLCsquam squamous cell non-small cell lung cancer
  • C JAK2 gene expression in primary and recurrent tumors vs. metastases.
  • RNAseq data are provided as normalized transcripts per million (TPM) values.
  • AML acute myeloid leukemia
  • BRCA breast cancer
  • CCC cholangiocellular carcinoma
  • CLL chronic lymphocy c leukemia
  • CRC colorectal cancer
  • GBC gallbladder cancer
  • GBM glioblastoma
  • GC gastric cancer
  • GEJC gastro-esophageal junc on cancer
  • HCC hepatocellular carcinoma
  • HNSCC head-and-neck squamous cell carcinoma
  • MEL melanoma
  • NHL non-Hodgkin lymphoma
  • NSCLCadeno non-small cell lung cancer adenocarcinoma
  • NSCLCother NSCLC samples that could not unambiguously be assigned to NSCLC adeno or NSCLCsquam
  • NSCLCsquam squamous cell non-small cell lung cancer
  • IRF1 RNA expression posi vely correlates with MAG-003 presenta on levels.
  • IRF1, ENSG00000125347 interferon regulatory factor-1
  • RNA expression and MAG-003 pep de presenta on levels were determined.
  • RNAseq data are provided as normalized transcripts per million (TPM), whereas normalized pep de presenta on is given as arbitrary unit (a.u.).
  • TPM normalized transcripts per million
  • pep de presenta on is given as arbitrary unit (a.u.).
  • S mula on with IFN- ⁇ increases MAG-003 pep de presenta on 16-fold in A*02- posi ve melanoma cell line and thus increases cytotoxic efficacy of bispecific engagers.
  • A Increase of MAG-003 abundance upon s mula on with IFN- ⁇ as compared to untreated control.
  • Target presenta on in melanoma cell line Hs695T increases 16-fold upon IFN- ⁇ treatment.
  • IFN- ⁇ treatment does not induce any target presenta on in the target-nega ve cell line T98G, which lacks expression of MAGEA4 / MAGEA8.
  • Increase of PPP4R1-003 presenta on upon s mula on decreases the EC50 value, as a measure of efficacy, by a factor of 2 (from 664.8 pM without treatment to 317.3 pM upon IFN- ⁇ s mula on)
  • C Cytotoxicity of control TCER® molecule on T98G cells upon IFN- ⁇ s mula on.
  • Increase of PPP4R1-003 presenta on upon s mula on increases the EC50 value, as a measure of efficacy, by a factor of 2 (from 968.4 pM without treatment to 1731 pM upon IFN- ⁇ s mula on).
  • IRF1 as a marker for inflammatory condi ons favoring MAG-003 presenta on
  • A Correla on between MAGEA4/8 expression and MAG-003 presenta on. Individual data points show expression of the exon encoding MAG-003 and MAG-003 presenta on on tumor and cell line samples. Ver cal dashed line indicates threshold used for assessing target posi vity. Solid line depicts linear regression. Hollow square highlights Hs695T control cell line sample, solid square highlights Hs695T cell line sample treated without or with interferon gamma.
  • B Correla on between IRF1 expression and residuals of linear regression of MAGEA4/8 expression and MAG-003 presenta on.
  • 1 ⁇ 10 7 Hs695T cancer cells human amelano c melanoma cell line
  • tumor volumes were measured with a caliper and calculated by (length x width 2 ) / 2.
  • PBMCs Human peripheral blood mononuclear cells
  • MAG-003-specific TCER® under IFN- ⁇ treatment in vitro
  • the ac vity of the MAG-003-targe ng bispecific TCER® molecule (MAG-003 TCER®; SEQ ID NO: 39 + SEQ ID NO: 2) regarding the induc on of tumor cell lysis was evaluated by assessing human PBMC-mediated lysis of the of Interferon- ⁇ pretreated (100 U/mL) human cancer cell line Hs695T as determined by lactate dehydrogenase (LDH) release assay.
  • LDH lactate dehydrogenase
  • PBMCs isolated from a healthy donor were co-incubated with the cancer cell line Hs695T (with or without IFN- ⁇ (100 U/mL for 2 days) pretreatment) at an effector:target ra o of 10:1, in the presence of increasing concentra ons of TCER® molecules.
  • As control molecule a non-MAG-003-specific TCER® molecule (SEQ ID NO: 45 + SEQ ID NO: 46) targe ng an unrelated pep de (PPP4R1-003; SEQ ID NO: 47) was used.
  • a er 48 hours of co-culture, target cell lysis was quan fied u lizing LDH-release assays according to the manufacturer’s instruc ons (Promega).
  • MAG-003 modula on upon addi on of Pembrolizumab PBMCs were thawed in RPMI 1640 supplemented with GlutaMAXTM and 10% heat-inactivated human serum, washed, and cultured for 24 ⁇ h before treatment.
  • PBMCs were thawed in RPMI 1640 supplemented with GlutaMAXTM and 10% heat-inactivated human serum, washed, and cultured for 24 ⁇ h before treatment.
  • cells were stimulated with anti-CD3/anti-CD28 TransAct® (1:300) and 10 ⁇ g/mL Pembrolizumab; negative controls received anti-CD3/anti-CD28 TransAct® alone.
  • RNA isola on and sequencing Total RNA was isolated and purified in-house using the AllPrep DNA/RNA/miRNA Universal Kit (QIAGEN, Hilden, Germany) according to the manufacturer’s protocol.
  • RNA samples with a concentra on of ⁇ 25 ng/ ⁇ l and a RNA Integrity Number (RIN) of ⁇ 6.0 were considered acceptable for downstream library prepara on and sequencing.
  • Library prepara on, including mRNA selec on, RNA fragmenta on, cDNA conversion and addi on of sequencing adaptors, as well as the sequencing process itself were performed by GENEWIZ Germany GmbH (Leipzig, Germany). Sequencing libraries were generated using the NEBNext® UltraTM II Direc onal RNA Library Prep Kit for Illumina (New England Biolabs, Ipswich, MA, USA) following the manufacturer’s instruc ons.
  • HLA class I pep des were eluted from an body-resin by acid treatment and, if applicable, purified by ultrafiltra on.
  • pHLA abundance for the pep de of interest was determined using the AbsQuant® method (disclosed in US10545154B2) based on the number of cells within the inves gated ssue, total amount of the isolated pep de, and pep de-specific pHLA isola on efficiency.
  • AbsQuant® method Dislosed in US10545154B2
  • pHLA isola on efficiency was determined experimentally.
  • the number of cells was determined on the basis of quan ta on of DNA content.
  • DNA was isolated using the QIAamp DNA Mini Kit (QIAGEN) from lysate aliquots, which were sampled during the isola on of HLA-restricted pep des from tumor ssue samples.
  • the DNA yield was quan fied using the Qubit dsDNA High Sensi vity (HS) Assay Kit (Applied Biosystems/Thermo Fisher Scien fic), and the number of cells was interpolated from DNA content using a standard curve derived from peripheral blood mononuclear cells. In case of cell lines, cell count was assessed by manual cell coun ng. For absolute quan ta on, a series of targeted nanoLC-MS/MS measurements was performed on an Orbitrap mass spectrometer (Thermo Fisher Scien fic). Two differently isotopically labeled pep de equivalents were synthesized.
  • One of the isotopically labeled equivalents was used as an absolute quan ty reference and was spiked into reten on vials of each sample, which was used for absolute quan ta on.
  • the other isotopically labeled equivalent was used to generate the pep de-specific standard curve. Thereby, one of the isotopically labeled equivalents was trated, and the other one was used as men oned before as an absolute quan ty reference.
  • the MS/MS spectra were acquired using parallel reac on monitoring restric ng to labeled pep de masses for the analysis of standard curves and labeled and na ve pep de masses for the analysis of xenogra tumor ssue samples.
  • the MS/MS signals of selected fragment ions were extracted using Skyline 4.2.0 and translated into an absolute pep de amount using pep de-specific standard curves.
  • the efficiency of pHLA isola on was established by spiking of refolded pHLA complex of the inves gated pep de into sample lysate during the pep de isola on procedure and subsequent detec on and quan ta on of the pep de by nanoLC- MS/MS as described above for quan ta on of na vely presented pep de. 1.6.
  • Hs695T-xeno-309_2 Hs695T-xeno-309_1 1 none Hs695T-xeno-310_2 Hs695T-xeno-310_1 4 1 Hs695T-xeno-313_2 Hs695T-xeno-313_1 4 2 Hs695T-xeno-311_2 Hs695T-xeno-311_1 8 1 Hs695T-xeno-314_2 Hs695T-xeno-314_1 8 2 Hs695T-xeno-312_2 Hs695T-xeno-312_1 14 1 Hs695T-xeno-315_2 Hs695T-xeno-315_1 14 2 Hs695T-xeno-316_2 Hs695T-xen
  • IFN- ⁇ s mulates IRF-1 and HLA expression in vivo Immunodeficient animal models such as the NOG mouse develop Gra versus host disease (GvHD) upon humaniza on with human PBMCs.
  • Human PBMCs recognize murine ssues as ‘foreign’ and an allo-reac on is ini ated.
  • ac vated immune cells including CD8 + and CD4 + T cells secrete pro-inflammatory cytokines such as Interferon- ⁇ (IFN- ⁇ ) (Elhage et al., Biosci Rep 30, 2022, 42 (9): BSR20211986; Kaplan et al., Proc Natl Acad Sci USA.
  • IFN- ⁇ Interferon- ⁇
  • RNA sequencing of Hs695T xenogra tumor explants of the in vivo study performed herein confirms the induc on of IFN- ⁇ expression around study day eight. Between day eight and 14, IFN- ⁇ further increases and remains at constant levels for almost two weeks ( Figure 1 A). Accordingly, this model is suitable to study pep de presenta on by HLA under IFN- ⁇ condi ons, i.e. inflammatory condi ons. Induc on of IFN- ⁇ expression coincides with enhanced transcrip on of interferon regulatory factor-1 (IRF1) as well as elevated HLA expression on RNA and protein level from day eight.
  • IRF1 interferon regulatory factor-1
  • HLA expression While IRF1 expression is slightly reduced on day 27 compared with day 14, HLA expression remains at constantly high levels for almost two weeks (Figure 1 A, Figure 1 B). Within thefirst two weeks of the study, IRF1 expression increased up to a fold change of 18. S mula on of HLA expression came up to a fold change of 9 (RNA level) / 5 (HLA-A*02 protein CpC) between study day 1 and 14 in vivo. 2.2.
  • Target gene expression and target pep de presenta on under IFN- ⁇ in vivo MAG-003 is an HLA-A*02-presented pep de encoded by both MAGE-A4 and MAGE-A8.
  • MAG-003 showed a completely different behaviour under the influence of IFN- ⁇ . That is, MAG-003 presenta on heavily increased between day 8 and 14, which was maintained un l the end of the study at day 27. Compared with day 1, this equals a fold change of more than 50 on both study day 14 and 27 ( Figure 2 B, Figure 3). This strongly exceeds the increase in HLA expression so that the observed effect cannot be solely HLA-driven ( Figure 1, Figure 3). Amplifica on of target pep de presenta on as observed for MAG-003 increases the number of target pep de-HLA complexes accessible for pHLA-targe ng moie es thus having a direct impact on therapeu c effec veness.
  • MAG-003 the inherent poten al of MAG-003 to be excessively presented on (surface) HLA molecules under inflammatory condi ons renders it a prime candidate for a combina on of MAG-003-targe ng therapies with pro-inflammatory substances (e.g. IFN(- ⁇ ) itself as well as drugs or treatments promo ng IFN(- ⁇ ) expression).
  • pro-inflammatory substances e.g. IFN(- ⁇ ) itself as well as drugs or treatments promo ng IFN(- ⁇ ) expression.
  • IFN- ⁇ treatment boosts efficacy of MAG-003-specific TCER® in vitro
  • the MAG-003 TCER® construct induced a concentra on-dependent lysis of the MAG-003 posi ve tumor cell line.
  • intracellular signal transduc on is ini ated via ac va on of the Janus kinases (JAK) 1 and 2 then ac va ng the JAK1/JAK2/STAT1 signaling pathway (Negishi et al., Cold Spring Harb Perspect Biol. 2017, 10(11):1–16; Gao et al., Cell 2017, 167(2):397–404; Jorgovanovic et al., Biomark Res. 2020, 29;8:49; Platanias and Lurie, Nat Rev Immunol, 2005, 5, 375–386).
  • JAK1/JAK2/STAT1 signaling pathway Negishi et al., Cold Spring Harb Perspect Biol. 2017, 10(11):1–16; Gao et al., Cell 2017, 167(2):397–404; Jorgovanovic et al., Biomark Res. 2020, 29;8:49; Platanias and Lurie, Nat Rev Immunol, 2005, 5, 375–386).
  • IRF1 interferon regulatory factor-1
  • RNAseq data generated from a large number of human tumor ssues show that both primary and recurrent tumors as well as metastases are capable of responding to IFN(- ⁇ ) s mula on, i.e. pro-inflammatory s muli.
  • This conclusion is based on the observa on that IFNGR1, IFNGR2, JAK1, JAK2, and STAT1 represen ng relevant elements of the IFN- ⁇ pathway leading to transcrip on of IRF1 show robust expression in primary and recurrent tumors as well as metastases across tumors of all en es ( Figure 5 A, Figure 5 C, Figure 6 A, Figure 6 C, Figure 7 A).
  • IRF1 expression as marker to iden fy especially well treatable pa ents due to high MAG-003 presenta on levels
  • IRF1 ENSG00000125347
  • RNA expression and MAG-003 pep de presenta on levels were determined.
  • the observed predic ve value of IRF1 expression for MAG-003 pep de presenta on demonstrates its usage for pa ent stra fica on, i.e.
  • RNA expression and MAG-003 pep de presenta on levels were determined.
  • FIG 12A there is a posi ve correla on between MAGEA4/8 exon expression and MAG-003 presenta on on HLA but outliers can show much higher MAG-003 presenta on levels than expected by MAGEA4/8 expression.
  • IRF1 expression can hence be used to iden fy inflammatory state dynamics where tumor cells present higher MAG-003 CpC as expected by using MAGEA4/8 expression alone. This is demonstrated by Hs695T: while MAGEA4/8 expression overes mates the measured MAG-003 in the untreated sample with IRF1 dCT of 5.5 (above IRF1 dCT threshold of 3), the treated sample with IRF1 dCT of 1.1 (below IRF1 dCT threshold of 3) shows higher MAG-003 CpC than expected. 2.6.
  • IFN- ⁇ also termed IFNg
  • Efficacy of TCER® molecules depends on target pep de density S mula on with IFN- ⁇ (also termed IFNg) significantly enhances pep de presenta on and cytotoxic efficacy of bispecific T cell engagers in A*02-posi ve cell lines, with observed cytotoxic effects driven by treatment-induced changes in pep de presenta on.
  • IFN- ⁇ increases MAG-003 pep de presenta on 16-fold in the Hs695T melanoma cell line, while no presenta on is detected in the MAGEA4/8-nega ve T98G line (Figure 9A).

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Abstract

La présente invention concerne de manière générale l'utilisation de molécules anticancéreuses. L'invention concerne une protéine de liaison à l'antigène destinée à être utilisée dans le traitement d'un cancer, la protéine de liaison à l'antigène se liant à un peptide selon SEQ ID No : 25, ladite protéine de liaison à l'antigène étant administrée en combinaison avec une substance proinflammatoire. L'invention concerne également une méthode de traitement du cancer chez un patient ayant besoin d'un tel traitement, la méthode consistant à administrer une combinaison d'une protéine de liaison à l'antigène et d'une substance proinflammatoire audit patient, la protéine de liaison à l'antigène se liant à un peptide selon SEQ ID No : 25. De plus, l'invention concerne une protéine de liaison à l'antigène destinée à être utilisée dans le traitement d'un cancer, la protéine de liaison à l'antigène se liant à un peptide selon SEQ ID No : 25, le patient à traiter présentant un état inflammatoire.
PCT/EP2025/062540 2024-05-07 2025-05-07 Utilisation de molécules anticancéreuses Pending WO2025233420A1 (fr)

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