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WO2025233432A1 - Utilisation et dosage d'une protéine de liaison à l'antigène comprenant un tcr spécifique d'un peptide restreint par hla-a*02 - Google Patents

Utilisation et dosage d'une protéine de liaison à l'antigène comprenant un tcr spécifique d'un peptide restreint par hla-a*02

Info

Publication number
WO2025233432A1
WO2025233432A1 PCT/EP2025/062557 EP2025062557W WO2025233432A1 WO 2025233432 A1 WO2025233432 A1 WO 2025233432A1 EP 2025062557 W EP2025062557 W EP 2025062557W WO 2025233432 A1 WO2025233432 A1 WO 2025233432A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
gen
amino acid
binding protein
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/EP2025/062557
Other languages
English (en)
Inventor
Norbert Hilf
Sarah MISSEL
Andrea MAYER-MOKLER
Olga VEREMCHUK
Sebastian Bunk
Meike HUTT
Martin Hofmann
Jens Hukelmann
Lena FREUDENMANN
Heiko Schuster
Jens Fritsche
Oliver Schoor
Linus BACKERT
Sabine KASTNER
Arun SATELLI
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
Immatics US Inc
Original Assignee
Immatics Biotechnologies GmbH
Immatics US Inc
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, Immatics US Inc filed Critical Immatics Biotechnologies GmbH
Publication of WO2025233432A1 publication Critical patent/WO2025233432A1/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 and dosing 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.
  • 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 an an gen-binding protein to said pa ent, wherein the an gen-binding protein binds to a pep de according to SEQ ID NO: 25.
  • the inven on relates to the treatment of metasta c cancer.
  • the inven on relates to doses of the an gen-binding proteins administered to pa ents.
  • Cancer remains one of the most crucial challenges to modern medicine, with its pervasive impact felt globally.
  • metastases are characterized by the spread of cancerous cells from the primary tumor to distant sites within the body.
  • Metasta c cancers, in par cular present unique challenges due to their ability to infiltrate mul ple organs and systems, o en evading conven onal treatment modali es. Addressing metastases becomes impera ve, as metastases significantly worsen prognosis and diminish overall survival rates.
  • T cell therapy (WO 2017/158103) as well as soluble protein-based molecules (WO 2021/023658) that are directed against the target epitope KVLEHVVRV (SEQ ID NO: 25) have been described in the art. However, the full spectrum of effectiveness of these promising drugs has not yet been recognized. Further, suitable doses for an effective treatment with such protein-based molecules have not been described before.
  • 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, or to the 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 metasta c 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.
  • 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, wherein the an gen-binding protein comprises: a T cell receptor (TCR) alpha variable domain (V ⁇ ) and a TCR beta variable domain (V ⁇ ), wherein the V ⁇ domain 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 ⁇ domain comprises (i) a CDR ⁇ 1 comprising the amino acid sequence according to
  • the inven on relates to an gen-binding protein for use in the treatment of cancer, 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, wherein a dose of about 6.6 ⁇ g to about 10 mg, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen-binding protein is to be administered to the pa ent.
  • Example 1 it has been found that the tumor-associated pep de (TUMAP) MAG-003 (SEQ ID NO: 25) is also presented on cells of metasta c tumors although other TUMAPs are frequently downregulated in metasta c tumor cells.
  • Figure 1 shows comparable presentation levels of MAG-003 in samples derived from primary and metastatic samples, indicating that presentation of MAG-003 is maintained when the respective tumor undergoes metastasis. Accordingly, the an gen-binding proteins binding to MAG-003 are efficient in treating not only primary tumors but also metastases.
  • Example 2 summarizes the preliminary results of a Phase 1first- in-human clinical trial that tests the efficiency and safety of the bispecific antigen-binding molecule MAG-003 TCER®.
  • Table 4 doses were determined that show excellent an -tumor ac vity with acceptable side effects against different cancer types.
  • the present inven on provides therapeu c doses of the powerful an -cancer molecule MAG-003 TCER® to allow excellent and safe treatment of a wide range of cancer types.
  • pa ents that showed disease progression or stable disease upon treatment with the MAG-003 TCER® have increased PD-L1 expression (see Figure 12).
  • the effect of the MAG-003 TCER® can be further improved by combina on with a checkpoint inhibitor.
  • Pa ent 21 in Examples shows that a combina on treatment of Pembrolizumab and MAG-003 TCER® shows excellent an -tumor ac vity in pa ents.
  • the inven on provides combina ons of MAG-003 binding an gen-binding proteins and checkpoint inhibitors.
  • the MAGE-A tumor antigen of the amino acid sequence ‘KVLEHVVRV’ (SEQ ID NO: 25), also known as MAG-003 peptide, is an HLA-A*02:01-restricted cytotoxic T lymphocyte (CTL) epitope of MAGE-A4 (amino acids 286-294) and MAGE-A8 (amino acids 288-296) (Jia ZC et al. Clin Dev. Immunol.2010, 567594).
  • CTL cytotoxic T lymphocyte
  • 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.
  • 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.
  • Peptides such as 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 is thus a target for T cell based immunotherapy.
  • the present inven on thus provides dosages and dosage regimes for an gen-binding proteins which are specific for the tumor expressed an gen MAG-003 (SEQ ID NO: 25) in a complex with an MHC protein.
  • 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.
  • TCR that comprises the TCR alpha chain sequence as comprised in SEQ ID NO: 26 and the TCR beta chain sequence as comprised in SEQ ID NO: 32 is used for the treatment of metasta c cancer.
  • 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., Eur J Immunol.2012; 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.
  • 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.
  • MHC major histocompa bility complex
  • a method of treatment of cancer in a pa ent in need of such treatment comprising 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.
  • MHC major histocompa bility complex
  • the method of item 4 wherein the cancer is a metasta c cancer and/or advanced cancer and/or unresectable cancer and/or recurrent cancer and/or refractory cancer.
  • the method of item 4 or 5 wherein 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 of any one of items 1 to 3 and 7 or the method of any one of items 4 to 6, 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
  • TCR T cell receptor
  • the an gen-binding protein for use or the method of any one of items 7 to 11, 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 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, and VH and VL 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 of any of items 7 to 13, 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.
  • an gen-binding protein for use or the method of any of items 7 to 14, 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.
  • 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 of any of items 1 to 16 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 vely.
  • the an gen-binding protein for use or the method of any one of items 1 to 21, 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, about 1200 ⁇ g, about 1800 ⁇ g or about 2500 ⁇ g, about 5000 ⁇ g, or about 10 mg, preferably about 6.6 ⁇ g, about 20 ⁇ g, about 60 ⁇ g, about 180 ⁇ g, about 300 ⁇ g, about 540 ⁇ g, about 600 ⁇ g, about 1000 ⁇ g, about 1
  • a method of trea ng MAGE-A posi ve cancer, preferably MAGE-A4 or MAGE-A8 posi ve cancer in a pa ent in need of such treatment comprises administering a dose of about 6.6 ⁇ g to about 10 mg, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an an gen-binding protein to said pa ent, wherein the an gen-binding protein comprises: a TCR V ⁇ , a TCR V ⁇ , an an body VL, and an an body VH, wherein the V ⁇ domain 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 ⁇ domain comprises (i) a CDR ⁇ 1 comprising the amino acid
  • an gen-binding protein for use or the method according to item 31 or 32, 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 31 to 33, 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 acid sequence having at least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO: 43 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 34, 35, and 36, respec vely.
  • the TCR alpha chain sequence comprises a amino acid sequence according to S
  • 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, preferably metasta c cancer, 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.
  • MEL cutaneous
  • TNBC triple-nega ve breast cancer
  • HNSCC head and neck squamous cell carcinoma
  • OC ovarian cancer
  • GC gastric cancer
  • NSCLCsquam squamous cell non- small cell lung cancer
  • gallbladder adenocarcinoma and Neuroendocrine Tumor CUP
  • 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 of any of the preceding items, wherein the cancer is cutaneous melanoma, mucosal melanoma, head and neck squamous cell carcinoma (HNSCC) or Neuroendocrine Tumor CUP. 41.
  • HNSCC head and neck squamous cell carcinoma
  • 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 of any one of the preceding items, 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), preferably metasta c gastric cancer (GC), metasta c head and neck squamous cell carcinoma (HNSCC), metasta c melanoma (MEL),
  • 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 of any one of items 1 to 41, wherein an immune checkpoint inhibitor is administered before, concomitantly, simultaneously 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, preferably wherein the immune checkpoint inhibitor is a PD1 inhibitor, preferably Pembrolizumab.
  • PD1 inhibitor preferably Pembrolizumab
  • 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 binds 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 acquired 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 belongs to MHC class I. It is further preferred that the MHC protein is of the serotype group HLA-A. It is most preferred that 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. The skilled person is well aware that HLA-A*02 can be further subdivided. A preferred serotype is HLA-A*02:01.
  • 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.
  • 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 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 refers 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 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 September 2, 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 et. al., Oncology, 2003, 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., Mod. Pathol., 2014, 27, 1255-1266). Expression of the MAGE-A4 protein and mRNA has been linked to the development and prognosis of various cancers.
  • the “MAGE-A8” or “Melanoma-associated an gen 8” protein is a member of the MAGE-A superfamily and has the Uniprot accession number P43361 (as available on September 2, 2024).
  • 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., Nucleic Acids Res., 1997, 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 cancer is treated that presents the pep de according to SEQ ID NO:25 in complex with a MHC protein.
  • 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.
  • 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).
  • MHC major histocompa bility complex
  • metalastasiza on” or “metastases forma on” relates to the spread of cancerous cells or ssues from a primary tumor. Some mes also the term “metastasis” is used for the spread of cancerous cells or ssues from a primary tumor.
  • Cancer occurs a er cells are gene cally altered to proliferate rapidly and indefinitely. The cells may eventually undergo metaplasia, followed by dysplasia then anaplasia, resul ng in a malignant phenotype, which is o en called “primary tumor”. Some cells from the primary tumor acquire the ability to penetrate the walls of lympha c vessels or blood vessels and then circulate through the bloodstream to other sites and ssues in the body.
  • metastasis relates to a breast cancer as primary tumor, that releases cancer cells into the body, which may or may not setle and form metastases in the same or other organs or ssues.
  • breast cancer metastasis relates to a metastasis in either the breast or another organ or ssue which has spread from a breast cancer as primary tumor. This nomenclature relates to all other tumor or cancer types or metastasis as well, like e.g. (i) metasta c lung cancer, (ii) lung cancer metastasis, and/or (i) metasta c liver cancer, (ii) liver cancer metastasis, and so forth. Accordingly, in diagnosis, a metastasis found somewhere in the body may be referred to as a e.g.
  • metastasis may refer to the process of metasta c lesion forma on or to the metasta c lesion itself.
  • the metastases or metasta c lesions may occur in one or more vital organs.
  • the vital organ may be at least one selected from the group consis ng of brain, spinal cord, heart, lungs, liver, bone marrow, blood, trachea, skin, kidneys, pancreas and intes nes.
  • the metastases or metasta c lesions may have a diameter of 1 cm or more.
  • Such metastases or metasta c lesions may occur in vital organs. 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more or 10 or more metastases or metasta c lesions may be found in the pa ent, preferably 11 or more.
  • Advanced cancer refers to cancer that has progressed beyond its ini al stage and may have spread from its site of origin to other parts of the body. Advanced cancer may be metasta c cancer. In advanced cancer, cancer cells may have invaded nearby ssues or organs and may have the ability to travel through the bloodstream or lympha c system to form tumors in distant areas of the body. It is pointed out that when it is herein referred to e.g.
  • treatment of metasta c cancer it is meant that the metasta c cancer (i.e. the primary cancer that releases cancer cells into the body) and also the metastases (i.e. cancer cells that have been released into the body from the primary tumor) may be treated.
  • the same applies vice versa when it is referred to e.g. “treatment of metastases” it is meant that the primary tumor that (releases tumor cells into the body) and the metastases themself may be treated.
  • Unresectable cancer may refer to a type of cancer that cannot be surgically removed or excised completely due to various reasons such as the tumor's size, loca on, involvement of cri cal structures or the spread of cancer to mul ple sites in the body.
  • a tumor may be considered unresectable if surgery would pose significant risks to the pa ent's health or if the cancer has spread extensively beyond its primary site.
  • Recurrent cancer also known as cancer recurrence, may refer to the return of cancer a er a period of me during which it was either par ally or completely eliminated following ini al treatment. Recurrence may happen locally (in the same loca on as the original tumor), regionally (in nearby lymph nodes or ssues) or distantly (in distant organs or ssues). Cancer recurrence may occur for various reasons. Some cancer cells may remain in the body a er ini al treatment, leading to recurrence.
  • Cancer cells may spread to other parts of the body before or during treatment, leading to distant recurrence. Also, cancer cells may acquire gene c muta ons that allow them to become resistant to previous treatments, leading to recurrence.
  • Refractory cancer may refer to a type of cancer that does not respond to treatment or stops responding a er an ini al period of response. In other words, the cancer con nues to grow, spread or recur despite undergoing treatment(s). There are several reasons why cancer may become refractory to treatment. Cancer cells may develop resistance to the effects of certain drugs or therapies over me, making them less effec ve in controlling the disease. Changes in the gene c makeup of cancer cells may lead to the development of resistance to treatment.
  • cancer and carcinoma may be used synonymously but the term cancer may also encompass e.g. carcinoma and sarcoma.
  • the cancer or tumor to be treated presents certain pep des on its surface. It is envisaged that the cancer to be treated presents certain pep des of MAGE-A on its surface. When a cancer presents pep des of MAGE-A on its surface said cancer is referred to as MAGE-A posi ve cancer. It is in par cular envisaged that 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 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.
  • 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 Na onal Cancer Ins tute (NCI).
  • NCI Na onal Cancer Ins tute
  • 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.
  • 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.
  • MHC major histocompa bility complex
  • the inven on further relates to a method of treatment of a metasta c cancer and/or advanced cancer and/or unresectable cancer and/or recurrent cancer and/or refractory 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.
  • MHC major histocompa bility complex
  • the inven on further relates to a method of 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 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.
  • 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 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. There are two types of light chain, lambda (l) and kappa (k).
  • 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 lgA2).
  • class e.g., IgG, IgA, and IgE
  • subclass e.g., lgG1, lgG2, lgG3, IgA1, and lgA2
  • One example of a 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 comprises 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.
  • artificially introduced cysteine bridges may (further) improve the stability of the (bispecific) antigen-binding proteins, optimally without interfering with the binding characteristics of the (bispecific) antigen-binding proteins. Such cysteine bridges can further improve heterodimerization.
  • 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 and 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 antigen-binding proteins described herein, due to sugar residues as described for example in Tao and Morrison (Tao and Morrison, J Immunol., 1989, 143(8):2595-601.).
  • 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 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 an an body or a func onal fragment or deriva ve thereof.
  • 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.
  • a TCR is a heterodimeric cell surface protein of the immunoglobulin super-family, which is associated with invariant proteins of the CD3 complex involved in mediating signal transduction.
  • TCRs exist in ⁇ 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 occuring 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 and 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.
  • 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.
  • TCR T cell receptor
  • TCR T cell receptor
  • 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 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 acid sequence according to SEQ ID NO: 8, (ii) a CDRH2 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 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 least 85%, 90%, 95%, 98% or 99% iden ty to SEQ ID NO
  • 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.
  • 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.
  • at least one 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; 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.
  • 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 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
  • 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 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 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.
  • 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 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.
  • 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.
  • SEQ ID NO: 21 represents the upper hinge of SEQ ID NOs: 19 and 20.
  • 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.
  • 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 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
  • 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 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 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 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 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 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 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.
  • the present inventors made it plausible that combina ons of the herein described an gen-binding molecules and immune checkpoint inhibitors are suitable and efficient for cancer treatment.
  • 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. However, 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 inven on relates to the herein described an gen-binding proteins for use in the treatment of a cancer, wherein said an gen-binding protein is administered in combina on with an immune checkpoint inhibitor.
  • the inven on relates to the described an gen-binding proteins for use in the treatment of cancer, wherein an immune checkpoint inhibitor is administered before, concomitantly, simultaneously or a er administra on of the an gen-binding protein.
  • “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 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.
  • 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 immune checkpoint inhibitor) 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 immune checkpoint inhibitor 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 immune checkpoint inhibitor 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 proteins for use in the treatment of cancer, wherein the an gen-binding protein is administered in combina on with an immune checkpoint inhibitor, wherein the an gen-binding protein and the immune checkpoint inhibitor are each present in an amount effec ve to achieve a synergis c therapeu c effect when administered in combina on.
  • the inven on relates to the described an gen-binding proteins for use in the treatment of cancer, wherein the immune checkpoint inhibitor is administered before, concomitantly to, concurrently to, simultaneously to or a er administra on of the an gen- binding protein.
  • the e.g. described an gen-binding protein and the immune checkpoint inhibitor may be provided in different formula ons/composi ons.
  • the inven on relates to the described an gen-binding proteins for use in the treatment of cancer, wherein the an gen-binding protein is administered in combina on with a immune checkpoint inhibitor and wherein the an gen-binding protein formulated in a first pharmaceutical composition and the immune checkpoint inhibitor is formulated in a second pharmaceutical composition.
  • 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 the an gen-binding protein is administered in combina on with an immune checkpoint inhibitor, 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 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 an immune checkpoint inhibitor, 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:
  • 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 an immune checkpoint inhibitor, 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.
  • 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.
  • Immune checkpoint inhibitors used in context of the present inven on may target and inhibit proteins such as PD-1 (programmed death-1), PD-L1 (programmed death-ligand 1), Lymphocyte- ac va on gene 3 (LAG-3) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4).
  • an immune checkpoint inhibitor used in context of the present inven on may be a PD-1 inhibitor, a PD-L1 inhibitor, LAG-3 inhibitor or a CTLA-4 inhibitor.
  • a PD-1 inhibitor may be selected from the group consis ng of Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Re fanlimab-dlwr and Tislelizumab, preferably Pembrolizumab.
  • a PD-L1 inhibitor may be selected from the group consis ng of Atezolizumab, Durvalumab and Avelumab.
  • a LAG-3 inhibitor may be Relatlimab.
  • a 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.
  • bispecific monoclonal an bodies like Cadonilimab targe ng PD-1 and CTLA-4 may be used.
  • the immune checkpoint inhibitor is administered every two weeks. It is envisaged that the immune checkpoint inhibitor is administered every three weeks. It is envisaged that the immune checkpoint inhibitor is administered every four weeks. It is envisaged that the immune checkpoint inhibitor is administered everyfive weeks. It is also envisaged that the immune checkpoint inhibitor is administered every six weeks. It is envisaged that Nivolumab is administered every two weeks. It also is envisaged that Nivolumab is administered every four weeks.
  • Pembrolizumab is administered every three weeks. It also is 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. Accordingly, when Pembrolizumab is administered every six weeks Pembrolizumab is administered in week -1, the an gen-binding protein is administered in week 1, 2, 3, 4, 5 and the an gen-binding protein and Pembrolizumab are administered in week 6, the an gen-binding protein is administered in week 7, 8, 9, 10, 11 and the an gen-binding protein and Pembrolizumab are administered in week 12 and so forth.
  • thefirst Pembrolizumab administra on may also be performed together with the first administra on of the described an gen-binding proteins. Accordingly, when Pembrolizumab is administered every six weeks Pembrolizumab and the an gen-binding protein are administered in week 1 and the an gen binding protein is administered in week 2, 3, 4, 5, 6 and the an gen-binding protein and Pembrolizumab are administered in week 7 and and so forth. 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 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 Pembrolizumab, 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,
  • 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 Pembrolizumab, 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, op onally wherein a dose of 200 mg or 400 mg Pembrolizumab is administered. All the herein described an gen-binding proteins may be administered in the below described doses and/or administra on schemes.
  • 1000 ⁇ g (as a target dose) of the herein described an gen-binding proteins may be used for the combina on treatment with checkpoint inhibitors, in par cular Pembrolizumab.
  • checkpoint inhibitors in par cular Pembrolizumab.
  • 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 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
  • 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.
  • This weight adjusted doses may also be used 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 weight is below 50 kg or 60 kg.
  • a dose of 324 ⁇ g may be administered for pa ents below 50 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 a dose of 73.3 ng/kg to about 111.1 ⁇ g/kg 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 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, about 1000 ⁇ g, about 1200 ⁇ g, about 1800 ⁇ g or about 2500
  • 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 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, (iii
  • 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 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, about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of the an gen-binding protein is to be administered.
  • 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 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 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) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 13, and (
  • 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 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 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 are to be administered.
  • 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 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 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 1250 ⁇ g, about 1255 ⁇ g, about 1260 ⁇ g, about 1265 ⁇ g
  • 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, 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.
  • 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 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. It is preferred that the glucocor coid is administered before administra on of the an gen-binding protein.
  • 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 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 minutes 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, 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 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.
  • the appended examples provide examples for administra on schemes and regimes for the herein described uses and methods.
  • 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 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 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 an gen-binding protein in the described uses is administered bi-weekly, every 3 weeks, every 4 weeks or every 6 weeks.
  • Bi-weekly administra on may be preferred.
  • 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 to be administered bi- weekly, every 3 weeks, every 4 weeks or every 6 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 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
  • the 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 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 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 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 consists of afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 23, 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 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 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-binding protein is to be administered.
  • 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 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 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an gen-binding protein is to
  • 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 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 1200 ⁇ g to about 2500 ⁇ g of an gen-binding protein is to be administered.
  • 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 ⁇ 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 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, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ 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 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 ⁇ 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 ⁇ g to about 4000 ⁇ g, such as about 1000 ⁇ g to about 2
  • a pa ent may receive 40-800 ⁇ g, preferably 300 ⁇ g, of the an gen-binding protein for thefirst applica on, 120-1000 ⁇ g, preferably 600 ⁇ g of the an gen-binding protein for the second applica on and 600-6000 ⁇ g, 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, about 2300 ⁇ g, about 2400 ⁇ g, about 2500 ⁇ g, about 2600 ⁇ g, about 2700 ⁇ g, about 2800 ⁇ g, about 2900 ⁇ g, about 3000 ⁇ g, about 3100 ⁇ g, about 3200 ⁇ g, about 3300 ⁇ g, about 3400 ⁇ g, about 3500 ⁇
  • the an gen-binding protein may be administered weekly for thefirst four weeks and then administered bi-weekly.
  • thefirst four administra ons are within four weeks and thefi h administra on is in week six and the sixth administra on is in week eight and so forth.
  • 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 the herein described an gen-binding protein for use in the treatment of cancer, wherein the treatment comprises administra on to the pa ent of a) at least onefirst dose in the range of about 40 ⁇ g to about 800 ⁇ g of said an gen- binding protein, preferably 300 ⁇ g; b) at least one second dose in the range of about 120 ⁇ g to about 1000 ⁇ g of said an gen- binding protein, preferably 600 ⁇ g; 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, about 2300 ⁇ g, about 2400 ⁇ g,
  • the inven on also relates to the herein described an gen-binding protein for use in the treatment of cancer, wherein the treatment comprises administra on to the pa ent of a) at least onefirst dose in the range of about 40 ⁇ g to about 800 ⁇ g of said an gen- binding protein; b) at least one second dose in the range of about 120 ⁇ g to about 1000 ⁇ 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; and wherein the second dose is higher than thefirst dose and the third dose is higher than the second dose; and op onally wherein the doses are administered weekly, bi-weekly, every three weeks, every four weeks, everyfive weeks or every six weeks or administered weekly for thefirst four administra ons and then administered bi-weekly.
  • the inven on also relates to the herein described an gen-binding protein for use in the treatment of cancer, 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, about 2300 ⁇ g, about 2400 ⁇ g, about 2500 ⁇ g, about 2600 ⁇ g, about 2700 ⁇ g, about 2800 ⁇ g, about 2900
  • the inven on also relates to the herein described an gen-binding protein for use in the treatment of cancer, 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, about 2300 ⁇ g, about 2400 ⁇ g, about 2500 ⁇ g, about 2600 ⁇ g, about 2700 ⁇ g, about 2800 ⁇ g, about 2900
  • the inven on also relates to the herein described an gen-binding protein for use in the treatment of cancer, wherein the treatment comprises administra on to the pa ent of a) onefirst dose of about 300 ⁇ g of said an gen-binding protein; b) one second dose of about 600 ⁇ g of said an gen-binding protein; c) one third dose and all subsequent doses 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, about 2300 ⁇ g, about 2400 ⁇ g, about 2500 ⁇ g, about 2600 ⁇ g, about 2700 ⁇ g, about 2800 ⁇ g, about 2900
  • 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 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 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 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 protein is to be administered.
  • MHC major histocompa bility complex
  • the inven on also relates to a method of trea ng MAGE-A posi ve cancer, preferably MAGE-A4 or MAGE-A8 posi ve cancer in a pa ent in need of such treatment, wherein the method comprises administering a dose of about 6.6 ⁇ g to about 10 mg, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an an gen-binding protein to said pa ent, wherein the an gen-binding protein comprises: a TCR V ⁇ , a TCR V ⁇ , an an body VL, and an an body VH, wherein the V ⁇ domain 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
  • the inven on also relates to a method of trea ng MAGE-A posi ve cancer, preferably MAGE- A4 or MAGE-A8 posi ve cancer in a pa ent in need of such treatment, wherein the method comprises administering a dose of about 6.6 ⁇ g to about 10 mg, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an an gen-binding protein to said pa ent, wherein the an gen-binding protein comprises: afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39 and a second polypeptide chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • the inven on further relates to a method of trea ng MAGE-A posi ve cancer, preferably MAGE-A4 or MAGE-A8 posi ve cancer in a pa ent in need of such treatment, wherein the method comprises administering 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 an gen-binding protein to said pa ent, wherein the an gen-binding protein comprises: afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39 and a second polypeptide chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • the inven on relates, for example, also 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 immune checkpoint inhibitor, 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,
  • MHC major histocompa bility complex
  • the inven on thus, 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 an immune checkpoint inhibitor, 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 invention also relates to pharmaceutical compositions.
  • the invention relates to pharmaceutical compositions comprising the herein described antigen-binding proteins in the herein described doses.
  • the inven on relates to a pharmaceu cal composi on comprising about 6.6 ⁇ g to about 10 mg, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an an gen-binding protein, wherein the an gen-binding protein comprises a TCR V ⁇ , a TCR V ⁇ , an an body VL, and an an body VH, wherein the V ⁇ domain 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 ⁇ domain comprises (i) a CDR ⁇ 1 comprising the amino acid sequence
  • the inven on also relates to a pharmaceu cal composi on comprising about 6.6 ⁇ g to about 10 mg, such as about 1000 ⁇ g to about 2500 ⁇ g or about 1200 ⁇ g to about 2500 ⁇ g of an an gen-binding protein, wherein the an gen-binding protein comprises afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39 and a second polypeptide chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • the inven on also relates to a pharmaceu cal composi on comprising 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 an gen-binding protein, wherein the an gen-binding protein comprises afirst polypep de chain that consists of the amino acid sequence according to SEQ ID NO: 39 and a second polypeptide chain that consists of the amino acid sequence according to SEQ ID NO: 2.
  • 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, 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 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 may be dissolved or dispersed in a pharmaceu cally acceptable carrier or aqueous medium.
  • the inven on relates to a pharmaceu cal composi on, wherein the herein described an gen-binding protein is 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.
  • the form must be sterile and must befluid to the extent that administra on via a syringe is possible. It must be stable under the condi ons of manufacture and storage and must be preserved against the contamina ng ac on of microorganisms, such as bacteria and fungi.
  • 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 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) 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.
  • the inven on also relates to the use of the described an gen-binding proteins and/or to a pharmaceu cal composi on, in the manufacture of a medicament.
  • the inven on also relates to the use of the described an gen-binding protein and/or to a pharmaceu cal composi on, in the manufacture of a medicament for the treatment of cancer.
  • pharmaceu cal composi ons comprising the herein described nucleic acids, vectors and host cells are also encompassed. It is of course envisaged that not only bispecific formats are used in the treatment of cancer but also T-cell receptors (TCRs). Accordingly, it is envisaged that 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 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 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: 30; and wherein the V ⁇ or V ⁇ domain comprises (i) a CDR1 comprising the
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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%, 98% or 99% iden ty to SEQ ID NO: 44 and comprising the CDR ⁇ 1, CDR ⁇ 2, and
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 histocompatibility 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 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 invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 histocompatibility complex
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 consisting of an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region consisting of an amino acid sequence according to SEQ ID NO: 37.
  • MHC major histocompatibility complex
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 identity to an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a V ⁇ comprising or
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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% identity to SEQ ID NO: 41 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 28, 29, and 30, respectively; 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 CDR1, CDR2,
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 histocompatibility complex
  • TCR sequences with and without signal peptide 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 peptide.
  • SEQ ID NO: 27 corresponds to SEQ ID NO: 42 with signal peptide.
  • SEQ ID NO: 32 corresponds to SEQ ID NO: 43 with signal peptide.
  • SEQ ID NO: 33 corresponds to SEQ ID NO: 44 with signal peptide.
  • the skilled person is readily capable to identify signal peptide sequences in polypeptides (e.g. by the software SignalP 6.0 as provided by DTU Health Tech).
  • TCRs presented on the cell surface do usually not comprise the signal peptide 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 therapeutic activity when located on the surface of an immune cell) it is usually referred to the TCR sequences without signal peptide. However, the skilled person knows that under certain circumstances it is more reasonable to refer to the sequence with signal peptide (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 peptide to be transported to the cell membrane).
  • TCRs are used in combina on with immune checkpoint inhibitors for the treatment of cancer. Accordingly, it is envisaged that 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 combina on with immune checkpoint inhibitors in the treatment of cancer. Accordingly, it is envisaged that TCR-engineered T cells may be infused into cancer pa ents in combina on with an immune checkpoint inhibitor.
  • 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 an immune checkpoint inhibitor, 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: 30
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-binding protein is administered in combination with an immune checkpoint inhibitor, wherein the antigen-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%, 98% or 99% iden ty
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-binding protein is administered in combination with an immune checkpoint inhibitor, wherein the antigen-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 histocompatibility complex
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-binding protein is administered in combination with an immune checkpoint inhibitor, wherein the antigen-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% identity to SEQ ID NO: 41 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 28, 29, and 30, respectively; 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
  • the invention also relates to an antigen-binding protein for use in the treatment of a cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-binding protein is administered in combination with an immune checkpoint inhibitor, wherein the antigen-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 histocompatibility complex
  • 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 cells 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, ex vivo or in vivo.
  • Numerous forms of viral vectors are known in the art.
  • Useful viral vectors include vectors based on retroviruses, lentiviruses, adenoviruses, adeno-associated viruses, herpes viruses, vectors based on SV40, papilloma virus, Epstein Barr virus, vaccinia virus vectors and Semliki Forest virus (SFV).
  • retroviruses lentiviruses
  • adenoviruses adeno-associated viruses
  • herpes viruses vectors based on SV40, papilloma virus, Epstein Barr virus, vaccinia virus vector
  • 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, preferably a metasta c cancer.
  • 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, preferably a metasta c cancer.
  • 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. 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 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 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 sequence according to SEQ ID NO: 18; and wherein the V ⁇ comprises (i) a CDR
  • 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 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 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 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 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 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 invention relates to an an gen-binding protein for use in the treatment of a cancer, 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 antigen-binding protein, and e) formulating the antigen-binding protein into a pharmaceutical composition; 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 ⁇
  • the invention also relates to an an gen-binding protein for use in the treatment of a cancer, 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 antigen-binding protein, and e) formulating the antigen-binding protein into a pharmaceutical composition; 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
  • 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. 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 or fluids. 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, preferably metasta c cancer, 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, preferably 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 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: 30; and wherein the V TCR alpha
  • the invention also relates to a host cell comprising an antigen-binding protein for use in the treatment of a cancer, preferably metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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%, 98% or 99% iden ty to SEQ ID NO: 44 and
  • the invention further relates to a host cell comprising an antigen-binding protein for use in the treatment of a cancer, preferably metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 histocompatibility complex
  • the inven on also relates to a host cell comprising an an gen-binding protein for use in the treatment of a cancer, preferably 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 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 invention also relates to a host cell comprising an antigen-binding protein for use in the treatment of a cancer, preferably metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 consisting of an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region consisting of an amino acid sequence according to SEQ ID NO: 37.
  • MHC major histocompatibility complex
  • the invention also relates to a host cell comprising an antigen-binding protein for use in the treatment of a cancer, preferably metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 identity to an amino acid sequence according to SEQ ID NO: 31; and wherein the T
  • the invention also relates to a host cell comprising an antigen-binding protein for use in the treatment of a cancer, preferably metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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% identity to SEQ ID NO: 41 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 28, 29, and 30, respectively; 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
  • the invention also relates to a host cell comprising an antigen-binding protein for use in the treatment of a cancer, preferably metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 histocompatibility complex
  • 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) or salivary gland adenocarcinoma; skin cancer, preferably melanoma (MEL), preferably cutaneous melanoma or mucosal melanoma; renal cell cancer (RCC); brain cancer, preferably glioblastoma (GBM); gastric cancer (
  • 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 proteins, nucleic acids, vectors and host cells for use in the treatment of cancer, 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), squamous cell non-small cell lung cancer (NSCLCsquam) or large cell neuroendocrine tumor of the lung; liver cancer, preferably hepatocellular cancer (HCC); head and neck cancer, preferably head and neck squamous cell carcinoma (HNSCC) or salivary gland adenocarcinoma; skin cancer, preferably melanoma (MEL), preferably cutaneous melanoma or mucosal melanoma; renal cell cancer (RCC); brain cancer, preferably glioblastoma (GBM); gastric cancer (GC), preferably
  • the inven on relates to the herein described an gen-binding proteins, nucleic acids, vectors and host cells for use in the treatment of cancer, 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 head and neck squamous cell carcinoma
  • OC ovarian cancer
  • GC gastric cancer
  • NSCLCsquam squamous cell non-small cell lung cancer
  • NPN Neuroendocrine neoplasm
  • the inven on relates to the herein described an gen-binding proteins, nucleic acids, vectors and host cells for use in the treatment of cancer, wherein the cancer is cutaneous melanoma, mucosal melanoma, head and neck squamous cell carcinoma (HNSCC) or Neuroendocrine Tumor CUP.
  • cancer is cutaneous melanoma, mucosal melanoma, head and neck squamous cell carcinoma (HNSCC) or Neuroendocrine Tumor CUP.
  • HNSCC head and neck squamous cell carcinoma
  • Neuroendocrine Tumor CUP Neuroendocrine Tumor CUP.
  • 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 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, about 1000 ⁇ g, about 1200 ⁇ g, about 1800 ⁇ g or about 2500
  • 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 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) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 13, and (
  • 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 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 be administered, wherein the cancer is selected from the group consis ng of lung cancer such as small cell lung cancer
  • 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 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) a CDR ⁇ 2 comprising the amino acid sequence according to SEQ ID NO: 13, and (
  • 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 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 cancer is selected from the group consis ng of lung cancer such as small cell lung cancer (SCLC), non
  • 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 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 to about 4000 ⁇ g, such as 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 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 adenocar
  • 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 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 squamous cell carcinoma
  • MEL melanoma
  • NSCLC non-small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the inven on also relates to the herein described an gen-binding proteins, nucleic acids, vectors or host cells for use in the treatment of metasta c cancer, 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 esophageal cancer (OSCAR), metasta c renal
  • GC metasta c gastric cancer
  • HNSCC metasta c head and neck squamous cell carcinoma
  • MEL metasta c melanoma
  • NSCLC metasta c
  • the inven on 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 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: 30; and wherein the V ⁇ or V ⁇ domain comprises (i)
  • the invention also relates to an antigen-binding protein for use in the treatment of a metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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%, 98% or 99% iden ty to SEQ ID NO: 44 and comprising the CDR ⁇ 1, CDR ⁇
  • the invention also relates to an antigen-binding protein for use in the treatment of a metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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, 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 adenocarcinoma (NSCLCadeno) or squamous cell non-small cell lung cancer (NSCLCsquam), ovarian cancer (OC), esophageal 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 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, 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 (NS
  • the invention also relates to an antigen-binding protein for use in the treatment of a metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 consisting of an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a constant region consisting of an amino acid sequence according to SEQ ID NO: 37, optionally wherein the cancer is selected from the group consisting 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 squam
  • the invention also relates to an antigen-binding protein for use in the treatment of a metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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 identity to an amino acid sequence according to SEQ ID NO: 31; and wherein the TCR beta chain sequence comprises a V ⁇ compris
  • the invention also relates to an antigen-binding protein for use in the treatment of a metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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% identity to SEQ ID NO: 41 and comprising the CDR1, CDR2, and CDR3 according to SEQ ID NOs: 28, 29, and 30, respectively; 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 CDR1, C
  • the invention also relates to an antigen-binding protein for use in the treatment of a metastatic cancer, wherein the antigen-binding protein binds to a peptide according to SEQ ID NO: 25, preferably bound to a major histocompatibility complex (MHC) protein, preferably HLA-A*02, wherein the antigen-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, 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 adenocarcinoma (NSCLCadeno) or squamous cell non-small
  • the inven on further relates to an an gen-binding protein for use in the treatment of a metasta c 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 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) a CDR ⁇ 2 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 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 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 adenocarcinoma (NSCLCadeno) or squamous cell non-small cell lung cancer (NS
  • 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 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, 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 adenocarcinoma (NSCLCadeno) or squamous cell non-small cell lung cancer (NSCLCsquam),
  • the herein described an gen-binding proteins may be administered according to the doses and regimens exemplified in the appended examples. It is envisaged that the described an gen-binding proteins are administered weekly at a dose of 20 ⁇ g for thefirst 7 weeks and at a dose 60 ⁇ g from week 8 onwards. Said regimen may in par cular be used for metasta c Triple Nega ve Breast Cancer pa ents. For a metasta c synovial sarcoma pa ent 60 ⁇ g of the an gen-binding protein may be administered weekly. The described an gen-binding proteins may administered weekly at a dose of 180 ⁇ g for the first 9 weeks and at a dose 540 ⁇ g from week 10 onwards.
  • Said regimen may in par cular be used for metasta c head and neck cancer pa ents.
  • the described an gen-binding proteins may administered weekly at a dose of 180 ⁇ g for the first 10 weeks and at a dose 540 ⁇ g from 11 onwards. From week 32 onwards 1200 ⁇ g (and op onally 1800 ⁇ g from week 56 onwards) may be administered bi-weekly.
  • Said regimen may in par cular be used for metasta c cutaneous melanoma pa ents.
  • the described an gen-binding proteins may administered weekly at a dose of 540 ⁇ g for the first 27 weeks and at a dose 1200 ⁇ g from 28 onwards (and op onally at a dose of 1800 ⁇ g from week 50 onwards). From week 29 the an gen-binding protein may be administered bi- weekly. Said regimen may in par cular be used for metasta c cutaneous melanoma pa ents. For a metasta c cutaneous melanoma pa ent 540 ⁇ g of the an gen-binding protein may be administered weekly.
  • the described an gen-binding proteins may administered at a dose of 300 ⁇ g in week 1, at a dose of 540 ⁇ g in week 2 and at a dose of 1200 ⁇ g from week 3 onwards (and op onally at a dose of 1800 ⁇ g from week 26 onwards).
  • a er thefirst 4 infusions the an gen-binding protein may be administered bi-weekly.
  • Said regimen may in par cular be used for Neuroendocrine Cancer with unknown primary cancer pa ents.
  • the described an gen-binding proteins may administered at a dose of 300 ⁇ g in week 1, at a dose of 600 ⁇ g in week 2 and at a dose of 1200 ⁇ g from week 3 onwards (and op onally at a dose of 1800 ⁇ g week 20 onwards).
  • a er thefirst 4 infusions the an gen-binding protein may be administered bi-weekly.
  • Dexamethasone may be administered at a dose of 8 mg intravenously as premedica on (e.g. at week 2-4).
  • Said regimen may in par cular be used for metasta c mucosal melanoma pa ents.
  • the described an gen-binding proteins may administered at a dose of 300 ⁇ g in week 1, at a dose of 600 ⁇ g in week 2 and at a dose of 2500 ⁇ g from week 3 onwards. It may be switched to bi-weekly treatment schedule from week 6. The dose may be decreased to 1200 ⁇ g in case of adverse events (and op onally increased again to a dose of 1800 ⁇ g).
  • Dexamethasone may be administered at a dose of 8 mg intravenously as premedica on (e.g. at week 11, 12 and 14). Said regimen may in par cular be used for metasta c gastric cancer pa ents.
  • the described an gen-binding proteins may administered at a dose of 300 ⁇ g in week 1, at a dose of 600 ⁇ g in week 2 and at a dose of 2500 ⁇ g from week 3 onwards. It may be switched to bi-weekly treatment schedule from week 4. Said regimen may in par cular be used for metasta c squamous non-small cell lung cancer pa ents.
  • the described an gen-binding proteins may administered at a dose of 300 ⁇ g in week 1, at a dose of 600 ⁇ g in week 2 and at a dose of 1200 ⁇ g from week 3 onwards (and op onally at a dose of 1800 ⁇ g from week 16 onwards). It may be switched to bi-weekly treatment schedule from week 4.
  • Dexamethasone may be administered at a dose of 8 mg intravenously as premedica on (e.g. at week 1-4 and 6). Said regimen may in par cular be used for metasta c ovarian cancer pa ents.
  • the described an gen-binding proteins may administered at a dose of 300 ⁇ g in week 1, at a dose of 600 ⁇ g in week 2 and at a dose of 1800 ⁇ g from week 3 onwards (and op onally further increased to 2000 ⁇ g). It may be switched to bi-weekly treatment schedule from week 4.
  • Dexamethasone may be administered at a dose of 8 mg intravenously as premedica on (e.g. at thefirst four infusions).
  • Said regimen may in par cular be used for metasta c cutaneous melanoma pa ents, metasta c squamous head and neck cancer pa ents and large cell neuroendocrine tumor of the lung (LCNEC lung) pa ents.
  • the described an gen-binding proteins may administered at a dose of 300 ⁇ g in week 1, at a dose of 600 ⁇ g in week 2 and at a dose of 2500 ⁇ g from week 3 onwards. In case of neutropenia the dose may be decreased again to 1800 ⁇ g. It may be switched to bi-weekly treatment schedule from week 4.
  • Dexamethasone may be administered at a dose of 8 mg intravenously as premedica on (e.g. at thefirst four infusions).
  • Said regimen may in par cular be used for gallbladder adenocarcinoma pa ents.
  • the described an gen-binding proteins may administered at afirst dose of 300 ⁇ g, at a second dose of 600 ⁇ g at a third dose of 1200 ⁇ g, at a fourth dose of 1500 ⁇ g, at afi h dose of 1800 ⁇ g and at a sixth and all subsequent doses of 2000 ⁇ g.
  • the dose may be decreased again to 1800 ⁇ g, 1500 ⁇ g or 1200 ⁇ g. It may be switched to bi-weekly treatment schedule from week 4.
  • Dexamethasone may be administered at a dose of 8 mg intravenously as premedica on (e.g. at thefirst four infusions).
  • Said regimen may in par cular be used for metasta c head and neck cancer or salivary gland adenocarcinoma pa ents.
  • an gen-binding protein When the herein described an gen-binding protein is administered to a pa ent the an gen- binding protein may have the PK values as depicted in Table 1.
  • the an gen-binding protein may have a C max of about 1 ng/ml serum to about 1500 ng/ml serum or all values in between such as about 1.9 ng/ml, about 2.2 ng/ml, about 3.1 ng/ml, about 4.4 ng/ml, about 6.7 ng/ml, about 10.7 ng/ml, about 20 ng/ml, about 20.2 ng/ml, about 20.3 ng/ml, about 44.7 ng/ml, about 39 ng/ml, about 52.8 ng/ml, about 60 ng/ml, about 77.6 ng/ml, about 80.8 ng/ml, about 87.1 ng/ml, about 88.4 ng/ml, about 88.7 ng/ml, about 90.1 ng/ml, about 94.2 ng/ml, about 95.3 ng/ml, about 100 ng/ml, about 106 ng/ml, about a C max of
  • the an gen-binding protein may have a C max of about 20.3 ng/ml to about 357.0 ng/ml, such as 89.4 ng/ml.
  • the C max may be normalized to 1 ⁇ g of an gen-binding protein administered to the pa ent.
  • the an gen-binding protein may have a C max of about 0.05 ng/ml serum per ⁇ g an gen-binding protein to about 1.5 ng/ml serum per ⁇ g an gen-binding protein or all values in between such as 0.62 ng/ml serum per ⁇ g an gen-binding protein, preferably 0.07 ng/ml serum per ⁇ g an gen-binding protein to about 1.29 ng/ml serum per ⁇ g an gen-binding protein, such as 0.30 ng/ml serum per ⁇ g an gen-binding protein.
  • the an gen-binding protein may have a C trough of about 1 ng/ml serum to about 600 ng/ml serum or all values in between such as about 1.9 ng/ml, about 5.5 ng/ml, about 6.5 ng/ml, about 7 ng/ml, about 14 ng/ml, about 15.7 ng/ml, about 15.8 ng/ml, about 20.2 ng/ml, about 28.2 ng/ml, about 29.9 ng/ml, about 32.5 ng/ml, about 36.5 ng/ml, about 36.6 ng/ml, about 39.4 ng/ml, about 42.7 ng/ml, about 43.7 ng/ml, about 47.6 ng/ml, about 49.5 ng/ml, about 50 ng/ml, about 117 ng/ml, about 131 ng/ml, about 148 ng/ml, about 164 ng/ml, about
  • the C trough may be normalized to 1 ⁇ g of an gen-binding protein administered to the pa ent.
  • the an gen-binding protein may have a C trough of about 0.01 ng/ml serum per ⁇ g an gen-binding protein to about 0.5 ng/ml serum per ⁇ g an gen-binding protein or all values in between such as 0.12 ng/ml serum per ⁇ g an gen-binding protein, preferably 0.02 ng/ml serum per ⁇ g an gen-binding protein to about 0.39 ng/ml serum per ⁇ g an gen-binding protein, such as 0.10 ng/ml serum per ⁇ g an gen-binding protein.
  • the an gen-binding protein may have a half-life T 1/2 of about 4 days to about 60 days, such as about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days
  • Table 1 Summary of PK parameters from pa ents treated with MAG-003 TCER® in DL1-DL7.
  • the theore cal C max is calculated by assuming the ini al distribu on of the applied amount of MAG-003 TCER® within the blood plasma, assuming a volume of 3L.
  • 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 terms “comprising”/"including”/”having” encompass the terms “consis ng of” and “consis ng essen ally of”. Thus, whenever the terms “comprising”/"including”/”having” are used herein, they can be replaced by “consis ng essen ally of” or, preferably, by “consis ng of”.
  • 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.
  • the immune checkpoint inhibitor always also mul ple immune checkpoint inhibitors are encompassed.
  • GC gastric cancer
  • HNSCC head and neck squamous cell carcinoma
  • MEL melanoma
  • NSCLCadeno non-small cell lung cancer adenocarcinoma
  • OC ovarian cancer
  • OSCAR esophageal cancer
  • RCC renal cell carcinoma
  • SARC synovial sarcoma
  • UBC urinary bladder carcinoma
  • UEC uterine endometrial cancer
  • MAG-003 (SEQ ID NO: 25) shows comparable presentation levels in samples derived from primary and metastatic samples, indicating that presentation of MAG-003 is maintained when the respective tumors undergo metastasis.
  • Figure 2 Presentation of a KRT5 peptide (SEQ ID NO: 38) in different tumor metastases This Figure shows the presentation of a KRT5 peptide (SEQ ID NO: 38) in different tumor metastases compared to the respective primary tumor sample. Median MS signal intensities from technical replicate measurements are plotted as dots for single primary tumor (left part of Figure) and metastatic samples (right part of Figure) of the KRT5 peptide identifications on HLA-A*02-positive tumor samples.
  • Boxes display median, 25th and 75th percentile of normalized signal intensities, while whiskers extend to the lowest data point still within 1.5 interquartile range (IQR) of the lower quartile, and the highest data point still within 1.5 IQR of the upper quartile.
  • IQR interquartile range
  • HNSCC head and neck squamous cell carcinoma
  • MEL melanoma
  • NSCLsquam squamous non-small cell lung cancer
  • OC ovarian cancer
  • OSCAR esophageal cancer
  • Figure 3 Absolute copies of MAG-003 (SEQ ID NO: 25) in samples from primary and metastatic This Figure shows the absolute presentation of MAG-003. Median absolute copies from technical replicate measurements are plotted as dots for single primary tumor (left part of Figure) and metastatic samples (right part of Figure) of the MAG-003 identifications on HLA- A*02-positive tumor samples. Boxes display median, 25th and 75th percentile of copies, while whiskers extend to the lowest data point still within 1.5 interquartile range (IQR) of the lower quartile, and the highest data point still within 1.5 IQR of the upper quartile.
  • IQR interquartile range
  • HNSCC head and neck squamous cell carcinoma
  • OC ovarian cancer
  • OSCAR esophageal cancer
  • RCC renal cell carcinoma
  • MAG-003 SEQ ID NO: 25
  • Figure 4 Absolute lymphocyte counts (ALC) for DL6 and DL7 pa ents with step dosing (D1: 300 ⁇ g; D8: 600 ⁇ g; D15, D22, D36, D50, D64, D78: target dose [1200 ⁇ g (DL6) or 2500 ⁇ g (DL7)].
  • Visits (all pre-dose if not otherwise indicated): Cycle1 (C1) Visit 1 (V1) on D1 (pre-dose and 6h a er MAG-003 TCER® dosing); C1V2 on D2; C1V3 on D3; C1V5 on D8; C1V6 on D15; C1V7 on D22; C1V9 on D36 (pre-dose and 6h a er MAG-003 TCER® dosing); C1V10 on D37; C1V11 on D38; C1V13 on D43; C1V14 on D50; C1V15 on D64, C1V16 on D78.
  • C1V10 Visit 1 (V1) on D1 (pre-dose and 6h a er MAG-003 TCER® dosing); C1V2 on D2; C1V3 on D3; C1V5 on D8; C1V6 on D15; C1V7 on D22; C1V9 on D
  • Figure 5 Change of absolute number of CD3+ T cells in whole blood samples rela ve to the baseline value. T cell margina on is seen a er thefirst MAG-003 TCER® applica on and again a er the 5 th MAG-003 TCER® applica on (second dense profile). Dosing: D1: 300 ⁇ g; D8: 600 ⁇ g: D15: 2500 ⁇ g; D22: 2500 ⁇ g; D36: 2500 ⁇ g
  • Figure 6 Increase in ac vated (CD69+) T cells in blood a er 1 st MAG-003 TCER® applica on as early as 6 h a er infusion and peaking around day 2.
  • DL4 180 ⁇ g
  • DL5 540 ⁇ g
  • Figure 7 PK profiles for DL4 pa ents 3 and 4 (180 ⁇ g weekly) for thefirst MAG-003 TCER® infusion and for the 4 th MAG-003 TCER® infusion.
  • Figure 8 PK profiles for DL5 pa ents 5, 6 and 14 (540 ⁇ g weekly or 324 ⁇ g weekly for Pa ent 14 with a body weight below 50 kg) for thefirst MAG-003 TCER® infusion and for the 4 th MAG- 003 TCER® infusion.
  • Figure 9 PK profiles for pa ent 17 receiving DL6 (weekly infusions, 2 nd profile a er 4 th applica on) and pa ents 7 and 18 receiving DL5/6.
  • DL5/6 pa ents received ini al 4 applica ons in weekly distance and further applica on in biweekly intervals.
  • Second PK profile measured a er 5 th applica on for DL5/6 pa ents.
  • Figure 10 PK profiles for DL7 pa ents 9, 10, and 19. Step-up dosing (300 ⁇ g MAG-003 TCER® followed by 600 ⁇ g) was applied before the full target dose was given (2500 ⁇ g; target dose for pa ent 19 was reduced to 1800 ⁇ g).
  • Figure 12 Box plot for PD-L1 expression in trial pa ents. The expression is measured using qPCR and is grouped into PR/cPR vs. PD/SD. Details described below.
  • Figure 13 Waterfall plot showing the efficacy outcomes of the MAG-003 TCER® Phase 1first- in-human clinical trial as of April 25, 2025. Includes IMA401 pa ents who received at least four IMA401 infusions and completed at least one scan with disease response assessment. The Examples illustrate the inven on. Examples Example 1 Identification and quantitation of tumor-associated peptides presented on the cell surface Tissue samples Patients’ tissues were obtained from: BioIVT (Detroit, MI, USA & Royston, Herts, UK); Bio- Options Inc.
  • Tissues were shock-frozen immediately after excision and stored until isolation of TUMAPs at -70°C or below. Isolation of HLA peptides from tissue samples HLA peptide pools from shock-frozen tissue samples were obtained by immune precipitation from solid tissues according to a slightly modified protocol (Falk et al. Nature, 1991; 351(6324):290-296; Seeger et al.
  • Peptide pools were loaded directly onto the analytical fused-silica micro- capillary column (75 ⁇ m i.d. x 250 mm) packed with 1.7 ⁇ m C18 reversed-phase material (Waters) applying a flow rate of 400 nL per minute. Subsequently, the peptides were separated using a two-step 180 minute-binary gradient from 10% to 33% B at a flow rate of 300 nL per minute. The gradient was composed of solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile). A gold coated glass capillary (PicoTip, New Objective) was used for introduction into the nanoESI source.
  • the LTQ-Orbitrap mass spectrometers were operated in the data-dependent mode using a TOP5 strategy.
  • Tandem mass spectra were interpreted by SEQUEST at a fixed false discovery rate (q ⁇ 0.05) and additional manual control.
  • SEQUEST a fixed false discovery rate (q ⁇ 0.05) and additional manual control.
  • the identified peptide sequence was uncertain it was additionally validated by comparison of the generated natural peptide fragmentation pattern with the fragmentation pattern of a synthetic sequence-identical reference peptide.
  • Label-free relative LC-MS quantitation was performed by ion counting i.e., by extraction and analysis of LC-MS features (Mueller et al. Proteomics. 7 (2007): 3470-3480). The method assumes that the peptide’s LC-MS signal area correlates with its abundance in the sample. Extracted features were further processed by charge state deconvolution and retention time alignment (Mueller et al., J Proteome.Res. 7 (2008): 51-61; Sturm et al., 2008 BMC.Bioinforma cs.9 (2008): 163). Finally, all LC-MS features were cross-referenced with the sequence identification results to combine quantitative data of different samples and tissues to peptide presentation profiles.
  • the quantitative data were normalized in a two-tier fashion according to central tendency to account for variation within technical and biological replicates. Thus, each identified peptide can be associated with quantitative data allowing relative quantification between samples and tissues. In addition, all quantitative data acquired for peptide candidates was inspected manually to assure data consistency and to verify the accuracy of the automated analysis. A presentation profile was calculated showing the mean sample presentation as well as replicate variations.
  • HNSCC head and neck squamous cell carcinoma
  • MEL melanoma
  • OC ovarian cancer
  • OSCAR esophageal cancer
  • RCC renal cell carcinoma
  • SARC synovial sarcoma
  • UBC urinary bladder carcinoma
  • UEC uterine endometrial cancer
  • MAG-003 shows comparable presentation levels in samples derived from primary and metastatic samples ( Figure 1), indicating that presentation of MAG-003 is maintained when the respective tumors undergo metastasis. Conversely, it can be seen that the presentation of the KRT5 peptide (SEQ ID NO: 38) is completely lost when comparing primary tumors to metastases: While the KRT5 peptide is detected in several primary HNSCC, MEL, NSCLCsquam and OSCAR tumor samples, it is completely absent in the metastatic HNSCC, MEL, NSCLCsquam and OSCAR tumor samples analyzed.
  • Absolute quantitation of tumor-associated peptides presented on cell surface The generation of binders, such as antibodies and/or TCRs, is a laborious process, which may be conducted only for a number of selected targets.
  • selection criteria include, but are not restricted to, exclusiveness of presentation and the density of peptide presented on the cell surface.
  • the inventors analyzed absolute peptide copies per cell as described in WO 2016/107740.
  • TUMAP tumor-associated peptide
  • the quantitation of tumor-associated peptide (TUMAP) copies per cell in solid tumor samples requires the absolute quantitation of the isolated TUMAP, the efficiency of the TUMAP isolation process, and the cell count of the tissue sample analyzed.
  • Peptide quantitation by nano LC-MS/MS For an accurate quantitation of peptides by mass spectrometry, a calibration curve was generated for SEQ ID NO: 25, using two different isotope-labeled peptide variants (one or two isotope-labeled amino acids are included during TUMAP synthesis). These isotope-labeled variants differ from the tumor-associated peptide only in their mass but show no difference in other physicochemical properties (Anderson et al., J.
  • the calibration curves were prepared in at least three different matrices, i.e., HLA peptide eluates from natural samples similar to the routine MS samples, and each preparation was measured in duplicate MS runs.
  • MS signals were normalized to the signal of the internal standard and a calibration curve was calculated by logistic regression.
  • the respective samples were also spiked with the internal standard; the MS signals were normalized to the internal standard and quantified using the peptide calibration curve.
  • Efficiency of peptide-MHC isolation As for any protein purification process, the isolation of proteins from tissue samples is associated with a certain loss of the protein of interest.
  • peptide-MHC complexes were generated for all TUMAPs selected for absolute quantitation.
  • singly isotope-labeled versions of the TUMAPs were used, i.e., one isotope-labeled amino acid was included in TUMAP synthesis.
  • These complexes were spiked into the freshly prepared tissue lysates, i.e., at the earliest possible point of the TUMAP isolation procedure, and then captured like the natural peptide-MHC complexes in the following affinity purification.
  • This method is applicable to a wide range of samples of different origin and, most importantly, frozen samples (Alcoser et al., BMC Biotechnol., 2011, 16;11:124; Forsey and Chaudhuri, Biotechnol Lett., 2009, 31(6):819-23; 2009; Silva et al., Anal Chem., 2013, 85(20):9536-42).
  • a tissue sample is processed to a homogenous lysate, from which a small lysate aliquot is taken. The aliquot is divided in three parts, from which DNA is isolated (QiaAmp DNA Mini Kit, Qiagen, Hilden, Germany).
  • the total DNA content from each DNA isolation is quantified using a fluorescence-based DNA quantitation assay (Qubit dsDNA HS Assay Kit, Life Technologies, Darmstadt, Germany) in at least two replicates.
  • a DNA standard curve from aliquots of isolated healthy blood cells from several donors, with a range of defined cell numbers, has been generated.
  • the standard curve is used to calculate the total cell content from the total DNA content from each DNA isolation.
  • the mean total cell count of the tissue sample used for peptide isolation is then extrapolated considering the known volume of the lysate aliquots and the total lysate volume.
  • OSCAR Esophageal Squamous cell Carcinoma metastasis Met.
  • MAG-003 shows very high copies per cell in both samples derived from primary tumor and metastases, with comparable median copy numbers for the respective primary and metastatic samples from each tumor entity.
  • Example 2 Clinical study Clinical Data MAG-003 TCER®, a bispecific T Cell Engaging Receptor Molecule targe ng MAGEA4/8 (more specifically the pep de MAG-003 according to SEQ ID NO:25) is evaluated in a Phase 1first- in-human clinical trial to assess the safety, tolerability, pharmacokine c proper es and ini al an -tumor ac vity of various doses and applica on schedules in pa ents with advanced and/or metasta c and/or recurrent and/or refractory solid tumors.
  • A. Pa ent Popula on The trial popula on consists of HLA-A*02:01-posi ve, HLA-A*02:XX (other than A*02:01; exclusion alleles) nega ve pa ents with MAGEA4 and/or MAGEA8 posi ve recurrent and/or refractory and/or metasta c solid tumors who have received all available indicated standard- of-care (SoC) treatments.
  • SoC standard- of-care
  • Pa ents may have received any number and any kind of prior lines of therapy before start of the trial treatment with a break (wash out period) defined for different therapy categories long enough to not interfere with MAG-003 TCER® treatment (previously received treatments are listed in Table 3.
  • Inclusion Criteria No Inclusion criterion 1 Patients must have voluntarily signed a written informed consent formular (ICF), be able to understand and comply with clinical trial procedures. 2 Patients ⁇ 18 years old 3 Patients must have pathologically confirmed and documented advanced and/or metastatic solid tumor. Note: There is no limitation on type and number of prior anti-tumor treatments. 4 Patients must have a lesion considered accessible for a biopsy unless adequate archival FFPE tumor tissue samples for target determination is available. 5 Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
  • ICF written informed consent formular
  • HLA genotype HLA-A*02:01 positive and at the same time not positive for another HLA-A*02:XX sub allele (repeat assessment allowed).
  • 7 Patients’ tumor must express MAG-003 (SEQ ID NO: 25) 8 Life expectancy > 2 months.
  • Adequate hematological values 11
  • Adequate hepatic function 12
  • Adequate renal function 13
  • Acceptable coagulation status 14
  • Patients must have recurrent and/or refractory solid tumors and must have received or not be eligible for all available indicated standard-of-care treatments (e.g., radiation, surgery, chemotherapy, immunotherapy or targeted therapy). There is no limitation on type and number of prior anti-tumor treatments patients may have received.
  • the patient is known to have any of the clinically relevant cardiac conditions. 7 Clinically significant pulmonary dysfunction, that, in the investigator’s judgement, would compromise the patient’s ability to tolerate protocol therapy or significantly increase the risk for complications. No Exclusion criterion 8 The patient has concurrent severe and/or uncontrolled medical disease that could compromise participation in the trial (e.g., uncontrolled diabetes, severe malnutrition). 9 History of, or current, immunodeficiency disease or prior treatment relevantly compromising immune function, at the discretion of the investigator.
  • Table 3 Pa ent popula on and prior treatments # Indica on All Prior an -Cancer Treatment lines 1 TNBC 1. Letrozole 2. Capecitabine 3. Gemcitabine 2 Syn. Sarcoma 1. Melphalan, Tumor Necrosis Factor Alpha 2. Ifosfamide, Doxorubicin 3 HNSCC 1. Carboplatin, Fluorouracil, Pembrolizumab 2. Docetaxel, Cetuximab 4 Cut. Melanoma 1. Nivolumab 2. Dabrafenib, Trametinib Nivolumab 3. Encorafenib, Binimetinib Nivolumab 4. Talimogen Laherparepvec 5. Ipilimumab, Nivolumab Cut. Melanoma 1.
  • Pembrolizumab 2. Ipilimumab, Nivolumab Cut. Melanoma 1. Pembrolizumab 2. Nivolumab, Ipilimumab, Talimogene Laherparepvec Nivolumab, Ipilimumab 3. dacarbazine Citrate 4. Nivolumab, Ipilimumab 5. Trametinib NE Tumor CUP 1. Dota-tyr(3)-octreotid; Lutetium (Lu 177) 2. Dota-tyr(3)-octreotid; Lutetium (Lu 177) 3. Temozolomide 4. Everolimus Gastric Cancer 1.
  • the pa ents listed in Table 4 illustrate the diverse pa ent popula on and treatment outcomes observed in individuals receiving MAG-003 TCER® across a range of doses. These pa ents experienced clinical benefit, including stable disease or par al response, sugges ng the poten al efficacy of the treatment in pa ents with solid tumors refractory to standard therapies. Addi onally, the stepwise escala on of doses demonstrates the feasibility and safety of dose op miza on strategies in this pa ent popula on. A overview of all treatment outcomes is shown in Figure 13.
  • Table 4 Summary of pa ents with stable disease (SD) or tumor response (par al response; PR), including change in sum of target lesions, treatment dose and schedule per pa ent, including op onal glucocor coid premedica on. Best overall tumor response is assessed according to RECIST1.1 and/or iRECIST. Note that the mepoint denoted for the poten al dose change and for the treatment outcome are rela ve to the week a er thefirst MAG-003 TCER® infusion and not rela ve to day 1 of the clinical study treatment. Pat.
  • NCI CTCAE v5.0 are used for all grading except for cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), which should follow the recommendation by Lee et al., and Neelapu et al. (Lee et al., Biology of Blood an Marrow Transplantation 201925:625- 638; Neelapu, Hematological Oncolgy 201937(S1):48-52), and except for TLS, which should follow recommendation by Cairo et al. (Cairo and Bishop, Br J Haematol.2004 Oct;127(1):3-11).
  • DLT dose limiting toxicity
  • Grade ⁇ 3 treatment emergent adverse events were reported in 26 pa ents (74%) with 19 pa ents (54%) experiencing events at least possibly related to MAG-003 TCER® (11x lymphopenia, 5x neutropenia, 4x anemia, 2x leukopenia, 2x thrombocytopenia, febrile neutropenia, 2x facial pain, neutrophil count decreased, platelet count decreased, headache, and hypertension).
  • Step-up dosing has been introduced at dose level 6, consis ng of 300 ⁇ g (wk1), 600 ⁇ g with some modifica on in some pa ents (wk2) before star ng the target dose of 1200 ⁇ g (wk3, wk4 and onwards biweekly).
  • the step-up dosing regimen showed that ini al dosing in this range can support clinical responses while assuring good tolerability. No CRS Grade ⁇ 2 has been observed with step-up dosing.
  • glucocor costeroid e.g., Dexamethasone 8 mg, i.v.
  • Hematology values (lymphocytes, white blood cells, neutrophils, platelets, hemoglobin and red blood cells ) were measured for patients over the time course of treatment.
  • T cell populations and their phenotype were also assessed from whole blood samples at selected time points using flow cytometry.
  • Transient neutropenia was seen when highest doses where reached DL6/7 in some pa ents without glucocor costeroid pre-medica on. Other blood cell popula ons did not show significant changes upon MAG-003 TCER® treatment.
  • Assessment of ac va on and other phenotype markers revealed that early T cell ac va on (upregula on of CD69) can be measured in blood a er thefirst applica on of MAG-003 TCER® (shown for DL4/5 pa ents in Figure 6).
  • PK Pharmacokinetics
  • MSD Meso Scale Discovery
  • LLOQ 0.15 ng/mL high sensitivity
  • the long median terminal half-life of MAG-003 TCER® jus fies applica on intervals for MAG-003 TCER® ranging from weekly (q1w) injec ons to every 2-4 weeks (q2w-q4w).
  • the long terminal half-life also supports less frequent maintenance dosings, every 4 weeks to every 6 weeks (q4w-q6w) and longer (e.g.6 weeks to 8 weeks).
  • Apparent dose dependency of T 1/2 a erfirst applica on or later applica ons was not observed.
  • Deduced PK parameters for pa ents treated in dose levels DL1 to DL7 are provided in Table 5.
  • Table 5 Summary of PK parameters from pa ents treated with MAG-003 TCER® in DL1-DL7.
  • the theore cal C max is calculated by assuming the ini al distribu on of the applied amount of MAG-003 TCER® within the blood plasma, assuming a volume of 3L.
  • Clinical Benefit Maintained SD for 2.5 months being treated in rela ve low dose level, with no moderate or severe safety events reported as related to the study treatment by the trea ng Inves gator. Only mild nausea and mild diarrhea (grade 1) were observed as related to MAG- 003 TCER®.
  • Pa ent 2 Diagnosis: Metasta c synovial sarcoma, 49 years old female pa ent Previous Treatments: mul ple surgeries for primary tumor any metastasis resec on, cura ve and pallia ve radiotherapy, adjuvant targeted therapy and one line of chemotherapy for metasta c disease.
  • MAG-003 TCER® Dose 60 ⁇ g in the DL3, the pa ent was receiving the treatment on weekly basis during the en re treatment dura on, in total 3 months.
  • Baseline tumor sites lung, pleura.
  • Response Achieved Stable Disease (SD), which was evaluated at the week 7 and week 13.
  • Clinical Benefit Achieved SD at thefirst staging and maintained it during 3 months being treated in rela ve low dose level, the pa ent was clinically completely stable and developed only one G2 AE during the en re treatment.
  • MAG-003 TCER® Dose Started at 180 ⁇ g in the DL4, escalated to 540 ⁇ g (DL5) from the week 10once the next dose level was confirmed as safe.
  • the pa ent was receiving the treatment on weekly basis during the en re treatment dura on.
  • Baseline tumor sites so ssue, lymph nodes, bone.
  • Response demonstrated SD at week 7, during the next CT disease progression was observed, however the principal inves gator (PI) and the pa ent preferred to con nue the study treatment un l progression is confirmed due to the pa ent good clinical status.
  • Clinical Benefit no treatment related AEs were observed during the en re MAG-003 TCER® treatment dura on.
  • Pa ent 4 Diagnosis: Metasta c cutaneous melanoma, 75 years old male pa ent. Previous Treatments: mul ple surgeries for metastasis resec on,five lines of targeted and immuno-therapy in metasta c se ng.
  • the pa ent was receiving the treatment on weekly basis un l the week 32 and switched to bi-weekly schedule when such schedule was implemented by the protocol.
  • Baseline tumor sites liver, spleen, thoracic wall, lymph nodes.
  • Response achieved Par al response 8 weeks a er the treatment start, a erfirst 4 infusions the pa ent had 6 weeks interrup on in treatment due to appendici s which did not impact efficacy.
  • the tumor is s ll responding to the treatment with Par al Response more than two years a er the therapy start with – 69% reduc on of tumor burden, some lesions disappeared.
  • Clinical Benefit deep and durable tumor response, the pa ent is in good clinical condi on for a long me, only several cases of expected low grade adverse events were reported as related to MAG-003 TCER®, the pa ent is con nuing the study treatment since more than two years.
  • Pa ent 5 Diagnosis: Metasta c cutaneous melanoma, 78 years old male pa ent. Previous Treatments: mul ple surgeries for metastasis resec on, two lines of immuno-therapy in metasta c se ng.
  • the pa ent was receiving the treatment on weekly basis un l the week 29 and switched to bi- weekly schedule when such schedule was implemented by the protocol.
  • Baseline tumor sites so ssue, peritoneum, pleura, lymph nodes.
  • Previous Treatments mul ple surgeries for metastasis resec on, adjuvant radiotherapy,five lines of chemotherapy and immuno-therapy in adjuvant (1) and metasta c (4) se ng.
  • MAG-003 TCER® Dose: 540 ⁇ g in the DL5.
  • the pa ent was receiving the treatment on weekly basis.
  • Baseline tumor sites lung, peritoneum, lymph nodes.
  • Response achieved Par al response 7 weeks fromthe treatment start with – 30,6% reduc on of tumor burden.
  • Clinical Benefit the pa ent received the study treatment un l the week 14. She developed radiologic progression a er the ini al par al response but remained longer on study due to stable condi on and willingness to con nue treatment.
  • the pa ent is s ll alive to date, approximately two years a er star ng MAG-003 TCER® treatment.
  • Pa ent 7 Diagnosis: Neuroendocrine tumor, Cancer of unknown primary (CUP), 60 years old female pa ent.
  • Previous Treatments radiotherapy in neo-adjuvant se ng, radiopharmaceu cal therapy and chemotherapy, in total 4 lines of previous an -cancer therapy for metasta c disease.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule.
  • the pa ent started at 300 ⁇ g as thefirst step and received the target dose of 540 ⁇ g at the week 2 in the DL5, escalated to 1200 ⁇ g (DL6) from the week 3 and to 1800 ⁇ g (DL6a) from the week 26 when the next dose level was confirmed as safe.
  • the pa ent switched to bi-weekly treatment schedule a er the ini al 4 infusions.
  • Baseline tumor sites liver, lung, bone, pancreas, adrenal gland, lymph nodes.
  • Response Achieved PR at the week 7, which was confirmed at week 13 and con nued around 9 months a er treatment start with tumor load reduc on of – 66%.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule.
  • the pa ent started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 1200 ⁇ g at week 3 in the DL6, escalated to 1800 ⁇ g (DL6a) from the week 20 when the next dose level was confirmed as safe
  • the pa ent switched to bi-weekly treatment schedule from week 4 onwards.
  • Dexamethasone 8 mg i.v. premedica on was given at week 2-4 Baseline tumor sites: nasal cavity.
  • Response stabiliza on of disease achieved 7 and 13 weeks a er the treatment, improving to Par al Response at the week 21 with – 50% decrease of tumor burden.
  • the pa ent started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 2500 ⁇ g at week 3 in the DL7.
  • the pa ent switched to bi-weekly treatment schedule from the week 6.
  • the target dose was decreased to 1200 ⁇ g at the week 8 due to AE neutropenia, which did not re-occur a er dose reduc on.
  • Dexamethasone 8 mg i.v. premedica on was given at week 11, 12 and 14.
  • the dose was increased to 1800 ⁇ g (DL6a) from the week 24 when this dose level was confirmed as safe.
  • Baseline tumor sites abdomen, peritoneum, lung, lymph nodes.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule: The pa ent started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 2500 ⁇ g at week 3 in the DL7. The pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol. Baseline tumor sites: mul ple lung lesions . Response: stable disease was achieved at the week 7, which was confirmed at the next staging at the week 13.
  • the pa ent started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 1200 ⁇ g at week 3 in the DL6.
  • the pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol.
  • Dexamethasone 8 mg i.v. premedica on was given at week 1 – 4, 6.
  • the dose was increased to 1800 ⁇ g (DL6a) from the week 16 when this dose level was confirmed as safe.
  • Baseline tumor sites peritoneum, pleura, lymph nodes, thoracic wall.
  • Response demonstrated stabiliza on of disease at the week 7 and week 13 with – 19.6 % tumor reduc on.
  • Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment begin, started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 1800 ⁇ g at week 3 in the DL6a.
  • the pa ent received 8 mg dexamethasone i.v. as premedica on for the fourfirst infusions with MAG-003 TCER®.
  • the pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol.
  • Baseline tumor sites lung, lymph nodes, skin.
  • Pa ent 13 Diagnosis: Metasta c cutaneous melanoma, 62 years old female pa ent Previous Treatments: pallia ve radia on of metasta c disease, four lines of immune-therapy and chemotherapy in metasta c se ng.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment begin, started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 1800 ⁇ g at week 3 in the DL6a, the pa ent switched to DL 6b at the week 44 once it was cleared as safe. The pa ent received 8 mg dexamethasone i.v.
  • the pa ent switched to bi-weekly treatment schedule from week 4 according to the protocol.
  • Baseline tumor sites abdomen, lymph nodes, lung.
  • Response demonstrated stabiliza on of disease (SD) un l week 53 and is con nuing the study treatment post progression due to good clinical status.
  • Clinical Benefit The pa ent is in improved and stable clinical condi on and con nues study treatment, performance status is 0.
  • One Grade 1 related AE occurred a er thefirst infusion and no AEs developed since March 2024.
  • the pa ent is con nuing the study treatment as of April 2025, more than 1 year a er the treatment start.
  • Pa ent 14 Diagnosis: Metasta c squamous head and neck cancer, 63 years old male pa ent. Previous Treatments: mul ple surgeries, several courses of pallia ve radiotherapy, three lines of chemotherapy combined with targeted therapy or check point inhibitor for metasta c disease.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment begin, started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 1800 ⁇ g at week 3 in the DL6a, the pa ent switched to DL 6b at the week 48 once it was cleared as safe. The pa ent received 8 mg dexamethasone i.v.
  • the pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol.
  • Baseline tumor sites lung.
  • Response Achieved PR at the week 7, which was confirmed at the next staging at the week 13 and 21 and con nued 7 months a er the treatment start with tumor load reduc on of 61.5%.
  • Clinical Benefit The pa ent achieved improved and stable clinical condi on, with performance status 1. Several AEs occurred, mostly low grade, overall the treatment is very well tolerated. Due to good and stable clinical status the pa ent is con nuing the study treatment more than a year a er the treatment start, even a er radiologic tumor progression at week 37.
  • Pa ent 15 Diagnosis: LCNEC Lung Previous treatments: surgery, several courses of pallia ve radiotherapy, two lines of chemotherapy, one of which combined with a CPI.
  • the pa ent received 8 mg dexamethasone i.v. as premedica on for the fourfirst infusions with MAG-003 TCER®.
  • the pa ent switched to bi-weekly treatment schedule from week 4 according to the protocol.
  • Baseline tumor sites brain, lymph nodes, so ssue.
  • Response demonstrated stabiliza on of disease at the week 7, the staging for the week 13 was missed, stable disease was also observed at the week 21.
  • Clinical Benefit The pa ent achieved improved and stable clinical condi on with performance status of 1. Few low grade AEs occurred a er thefirst infusion and no AEs developed since April 2024. The pa ent received the study treatment for around 7 months.
  • Pa ent 16 Diagnosis: Gallbladder Adenocarcinoma Previous treatments: mul ple surgeries and courses of pallia ve radiotherapy, four lines of chemotherapy and two lines of CPI given with and without chemotherapy.
  • Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment start, with 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2, target dose of 2500 ⁇ g at week 3 in the DL7.
  • the dose was decreased to 1800 ⁇ g from the week 6 due to neutropenia.
  • the pa ent received 8 mg dexamethasone i.v. as premedica on for the fourfirst infusions with MAG-003 TCER® and a er neutropenia development un l the week 14.
  • the pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol.
  • Baseline tumor sites adrenal gland, bone, so ssue, lymph nodes, brain Response: demonstrated stabiliza on of disease at the week 7 and developed progressing in brain metastases at the week 13.
  • Clinical Benefit The pa ent achieved stable clinical condi on.
  • Several AEs including transient G3-4 neutropenia developed a er the target dose of 2500 ⁇ g, that was mi gated by the dose decrease and dexamethasone premedica on.
  • a er resolu on neutropenia did not re-occur also a er the treatment re-start.
  • the pa ent discon nued the study treatment due to disease progression.
  • Pa ent 17 Diagnosis: Bladder Urothelial Carcinoma, 44 years old male pa ent
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment start, with 300 ⁇ g as thefirst step dose at week 1, 600 ⁇ g as the second step at week 2, target dose of 2000 ⁇ g at week 3 in DL6b. The dose was decreased to 1800 ⁇ g from the week 6 due to neutropenia and then resumed at the week 14 to 2000 ⁇ g again.
  • the pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol.
  • Baseline tumor sites mul ple lymph nodes.
  • Response demonstrated stabiliza on of disease at the week 7 and 13, with decrease in target lesions of -25% developed progression due to new lymph node lesions at week 21.
  • Clinical Benefit The pa ent achieved stable clinical condi on for more than 3 months and con nued treatment post progression.
  • Several AEs including transient G3-4 neutropenia and thrombocytopenia developed a er the target dose of 2000 ⁇ g, that was mi gated by the dose decrease and dexamethasone premedica on.
  • Pa ent 18 Diagnosis: Metasta c squamous head and neck cancer, 54 years old male pa ent.
  • Previous Treatments cura ve radiotherapy, two lines of previous treatment including chemotherapy combined with targeted therapy.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment start, with 300 ⁇ g as thefirst step dose at week 1, 600 ⁇ g as the second step at week 2 and target dose of 1200 ⁇ g at week 3 in DL6.
  • the pa ent received 8 mg dexamethasone i.v. as premedica on for thefivefirst infusions with MAG-003 TCER®.
  • the pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol.
  • Baseline tumor sites lesions in tongue and mandibula.
  • Response Achieved SD at the week 7 with -10% reduc on of target lesions.
  • Clinical Benefit Several treatment related AEs occurred, mostly low grade, the pa ent discon nued the treatment due to inves gator decision.
  • Pa ent 19 Diagnosis: Metasta c head and neck cancer, Salivary gland Adenocarcinoma, 62 years old male pa ent. Previous Treatments: cura ve radiotherapy and one line of chemotherapy.
  • Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment start, with 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2, 1200 ⁇ g as the third step at the week 3 and target dose of 1500 ⁇ g at week 4 in INT DL1500, the dose was escalated to 1800 ⁇ g at the week 7 and to 2000 ⁇ g at the week 8.
  • the pa ent received 8 mg dexamethasone i.v. as premedica on for the twofirst target doses with MAG-003 TCER®.
  • the pa ent switched to bi-weekly treatment schedule from the week 4 according to the protocol Baseline tumor sites: several lesions in lung.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment start, with 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2, 1200 ⁇ g as the third step at the week 3 and target dose of 1500 ⁇ g at week 4 in the INT DL1500.
  • Baseline tumor sites orbital and lower eyelid lesions.
  • Response Achieved SD at the week 7.
  • Clinical Benefit Several treatment related AEs occurred, the pa ent discon nued the treatment due to progressive disease.
  • Pa ent 21 Diagnosis: Metasta c squamous non-small cell lung cancer, 63 years old male pa ent.
  • MAG-003 TCER® Dose Step dosing and bi-weekly treatment schedule: The pa ent started at 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2 and received the target dose of 1000 ⁇ g at week 3 in the Pembro-1000 cohort, Pembrolizumab was given one week before MAG-003 TCER®first dose . The pa ent switched to bi-weekly treatment schedule from week 4 according to the protocol. Baseline tumor sites: skin, lung, lymph nodes . Response: Par al Response was achieved at the week 7 with – 38.8% tumor lesion reduc on.
  • Step dosing and bi-weekly treatment schedule were implemented by the me of the treatment start, with 300 ⁇ g as thefirst step at week 1, 600 ⁇ g as the second step at week 2, 1200 ⁇ g as the third step at week 3 and target dose of 1500 ⁇ g at week 6 in the INT DL1500.
  • the pa ent received 8 mg dexamethasone i.v. as premedica on for the four first doses with MAG-003 TCER®.
  • the pa ent switched to bi-weekly treatment schedule from week 4 according to the protocol.
  • Baseline tumor sites tongue and lymph node lesions .
  • Response Achieved SD at the week 7 with tumor load reduc on of -22%.
  • Clinical Benefit The pa ent was in stable clinical condi on, performance status is 1.
  • the pa ent discon nued the study treatment due to tumor progression a er approximately 3 months.
  • H. Clinical tes ng for non-target genes The clinical pa ents' gene expression is tested not only for MAG-003 but also for PD-L1. This is done if enough RNA is extracted and the tes ng material is from a fresh frozen biopsy.
  • the tes ng is performed using a quan ta ve polymerase chain reac on (qPCR) and a PD-L1 specific probe set.
  • the data presented in Figure 13 show that individuals who responded to the treatment exhibited a lower expression of PD-L1 as compared to those who did not respond.
  • T cell margina on and ac va on data confirm that MAG-003 TCER® in the clinically tested dose range is well able to ac vate T cells and to ini ate their extravasa on to ssues and the tumor.
  • MAG-003 TCER® recruits by its ac on even more T cells to the tumor site which can then be engaged by MAG-003 TCER® to efficiently eradicate tumor cells.
  • This is in line with thefinding that pa ents receiving doses from 180 ⁇ g to 2500 ⁇ g achieved tumor shrinkage classified as PR (more than -30% tumor reduc on) or SD (up to -20% tumor reduc on).
  • PR more than -30% tumor reduc on
  • SD up to -20% tumor reduc on

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Abstract

La présente invention concerne de manière générale l'utilisation et le dosage 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. L'invention concerne également une méthode de traitement du cancer chez un patient nécessitant un tel traitement, la méthode comprenant l'administration d'une protéine de liaison à l'antigène audit patient, la protéine de liaison à l'antigène se liant à un peptide selon SEQ ID NO : 25. Plus particulièrement, l'invention concerne le traitement d'un cancer métastatique. En outre, l'invention concerne des doses des protéines de liaison à l'antigène administrées à des patients.
PCT/EP2025/062557 2024-05-07 2025-05-07 Utilisation et dosage d'une protéine de liaison à l'antigène comprenant un tcr spécifique d'un peptide restreint par hla-a*02 Pending WO2025233432A1 (fr)

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EP24199010 2024-09-06
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