EP3976081A1 - Peptides d'antigènes tumoraux hla de classe i et ii pour le traitement des carcinomes mammaires et/ou du sein - Google Patents

Peptides d'antigènes tumoraux hla de classe i et ii pour le traitement des carcinomes mammaires et/ou du sein

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Publication number
EP3976081A1
EP3976081A1 EP20734836.8A EP20734836A EP3976081A1 EP 3976081 A1 EP3976081 A1 EP 3976081A1 EP 20734836 A EP20734836 A EP 20734836A EP 3976081 A1 EP3976081 A1 EP 3976081A1
Authority
EP
European Patent Office
Prior art keywords
hla
tumor antigen
antigen peptides
tumor
patient
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
EP20734836.8A
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German (de)
English (en)
Inventor
Wolfgang Schönharting
Sybille Urban
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.)
Pmcr GmbH
Original Assignee
Pmcr GmbH
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Filing date
Publication date
Application filed by Pmcr GmbH filed Critical Pmcr GmbH
Publication of EP3976081A1 publication Critical patent/EP3976081A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • 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
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/812—Breast

Definitions

  • the present invention relates to a pharmaceutical composition for
  • HLA human leukocyte antigen
  • HLA-A tumor antigen peptides corresponding to the MHC class I complexes
  • HLA-A restricted tumor antigen peptides at least 2 tumor antigen peptides corresponding to the MHC class II complexes
  • HLA restricted tumor antigen peptides being tumor-exclusive or tumor-associated HLA antigen peptides and against the corresponding MHC complexes
  • Combinations thereof are directed to (i.e. bind to or have an affinity for them), a combination preparation (or parts thereof), a method for
  • Cancers continue to be the leading causes of death. In general, cancer is treated using established methods such as surgery
  • Tumor removal (resection), chemotherapy and / or radiation therapy.
  • Newer therapeutic concepts aim to incorporate the patient's own immune system into the overall therapeutic concept through the use of specific measures such as antibody therapy against immunosuppressors and recombinant immunoinformatics (ie treatment with information carriers).
  • the prerequisite for the success of such a strategy is the recognition of tumor-specific or tumor-associated antigens or epitopes by the immune system of the test person, whose effector functions (by the immune cells) are to be strengthened.
  • tumor cells differ significantly from their non-malignant cells of origin.
  • tumor-associated structures are recognized by the specific immune system of the tumor-bearing host, one speaks of tumor-associated epitopes.
  • Cancer / testis antigens denote a group of tumor-associated proteins that are expressed, among other things, by tumors of different histological origins (Fratta et al., Molecular Oncology, 5 (2), April 2011, 164-182). In healthy adult vertebrates, expression of these proteins is restricted to male germ cells. In cancer, however, the expression of these developmental antigens is often reactivated and can thus serve as a site for immune activation. Many of the CTAs are oncogenes and are involved in cellular processes such as cell growth and division, in the inhibition of apoptosis and in metastasis. They are often the cause of
  • CTAs Oncogenesis and malignant transformation and are therefore classified as tumor antigens.
  • the expression of CTAs in different malignancies is heterogeneous and often correlates with tumor progression, which is why they are also used as biomarkers for the course of a
  • HLA antigen peptides of such CTAs are often presented as degradation products on the surface of the tumor cells. It is known that such
  • Treatment methods can be used that combine drug treatment with anti-CTA-directed immunotherapy.
  • Human leukocyte antigens also known as HLA system, HL antigens, histocompatibility antigens, English human leukocyte antigens
  • HLA system occurs under the name Major Histocompatibility Complex (MHC) in all vertebrates.
  • MHC Major Histocompatibility Complex
  • MHCs There are two types of MHCs, namely MHC class I molecules (also referred to herein as “MHC complexes of the class or” HLA complexes of class I ') and MHC molecules of class II (herein also “MHC complexes of the class / or“ HLA complexes of the class /). Both are found on the cell surface of all cells with a nucleus in the bodies of the MHCs.
  • MHC molecules consist of two polypeptide chains, a heavy ⁇ chain and a light ⁇ chain (see also FIGS. 1 and 2).
  • Class I MHC molecules are expressed on the cell surface of all nucleated cells and recognized by CD8 + T cells (also known as killer T cells or cytotoxic T cells). MHC class II molecules are mainly based on the
  • T helper cells Cell surface exposed by antigen-presenting cells and recognized by CD4 + T cells (also known as T helper cells).
  • MHC class I molecules are on the cell surface of
  • T-killer cells also cytotoxic T-cells
  • MHC class I protein present peptides derived from cytosolic proteins
  • the route of presentation of class I MHC molecules is often referred to as the cytosolic or endogenous route.
  • HLA antigen peptides serve as mediators between the corresponding MHC complex, which is presented on the cell surface, and the T cell receptor.
  • HLA complexes of class I present intracellular antigen peptide fragments on the cell surface of the host cells (herein “HLA antigen peptides corresponding to the MHC class I complexes” or “HLA antigen peptides of type G, the 7 to 1 1, mainly comprising 9 amino acids - so-called nonamers - in their sequence) compared to T killer cells (also cytotoxic T cells), whereas HLA complexes of class II (HLA-DR, DQ and DP) exogenously derived antigen peptides (herein " HLA antigen peptides
  • HLA antigen peptides which correspond to the MHC class II complexes ”or“ HLA antigen peptides of the type 2 ”, which comprise more than 11 amino acids, preferably 12 to 17 amino acids in their sequence) to T helper cells.
  • the class I HLA antigen peptides which correspond to the MHC class I, are divided into HLA-A, HLA-B and HLA-C antigen peptides.
  • HLA complexes of class II primarily via the discrete anchor residues in the Amino acid positions 1, 4, 6/7 and 9 of the HLA antigen peptides take place (see, for example, Sinigaglia and Hammer (1995), J. Exp. Med., 181, 449-451).
  • the interaction between the peptide binding pocket motif of the HLA complex of class II and the discrete anchor residues in amino acid positions 6 and 9 of the HLA antigen peptides corresponding to the MHC class II complexes is particularly preferred.
  • HLA antigen peptides corresponding to the MHC class I complexes the amino acid positions 1, 2 and 9 are postulated as the primary anchor residues compared to the corresponding HLA complex of class I (see, for example, Binkowski et al. (2012), PLoS ONE , 7 (8), e41710; Yamada (1999), Tissue Antigens, 54 (4), 325-32).
  • cancer immunotherapies are based on the fact that the individual mutation pattern (signature) of the tumor of each individual cancer patient has to be deciphered. Based on the determined profile of the mutation pattern, synthetic vaccines, for example based on RNA, are produced for each individual patient (so-called vaccine production). The vaccines obtained in this way can then only be used for the individual treatment of this particular patient.
  • HLA antigen peptides which can be used as pharmacologically effective HLA antigen peptides or as pharmacologically active ingredients, as well as to provide pharmaceutical compositions containing them for diagnosis, prevention and / or Treatment of breast cancer and other diseases and
  • Disorders, particularly cancers, listed herein can be used; and methods for the diagnosis, prevention and / or treatment of such
  • HLA antigen peptides which are suitable for prophylactic, therapeutic and / or diagnostic use in warm-blooded animals, in particular in a mammal and very particularly in a human.
  • a pharmaceutical composition for use in the treatment or for profiling of breast / breast carcinoma, in particular locally recurring or metastatic breast carcinoma in a patient or group of patients who has or is suspected of having a breast / breast carcinoma to suffer from a breast cancer comprising a pharmacologically effective amount of 4 to 8, preferably 4, 5, 6, 7 or 8 HLA-A
  • the pharmaceutical composition consists exclusively of a carrier liquid
  • compositions of carrier liquids are known to the person skilled in the art and are, for example, in the range of 30% DMSO and 70% water), in which a pharmacologically effective amount of 4 to 8 HLA A tumor antigen peptides
  • compositions and suitable dosage forms for administering the pharmaceutically active HLA tumor antigen peptides are prepared according to standard methods known in the art and are easily applicable to any new or improved method for their preparation.
  • CA 15-3 is particularly advantageously reduced.
  • CA 15-3 (Cancer-Antigen 15-3) is a so-called glycoprotein that is used as a specific tumor marker in breast cancer.
  • the CA 15-3 value is a laboratory value that increases significantly above the threshold value in the case of certain types of cancer, especially breast cancer. In healthy people, the CA is 15-3
  • the CA 15-3 value is preferably determined by administering the pharmacologically effective amount of Tumor antigen peptides to the patient or the patient group suffering from breast cancer, below 60 U / ml, particularly preferably below 50 U / ml, very particularly preferably to a range below 40 U / ml and a normal value ( ⁇ 31 U / ml).
  • the progression-free survival of the individual is particularly preferably extended effectively, preferably by at least 2 to 5 years.
  • tumor antigen peptides which have a K D value in the range between 50 and 500 nM, contrary to conventional // is / 7 / co binding prediction models, which have viewed these as low binding, trigger effector cells (ie cytotoxic T cells) .
  • the HLA tumor antigen peptides used for the treatment are immunogenic in the patient or the patient group with at least one identical HLA allele, which is done in advance with an immunogenicity test (e.g. using Western blot, ELISA techniques , in particular by means of ELISPOT, preferably by means of interferon-gamma, interferon-alpha or interleukin (IL-2), or immunodetection with microscopic analysis).
  • HLA tumor antigen peptides corresponding to the MHC class I complexes (see particularly preferred examples in Tables 1-3)
  • HLA tumor antigen peptides corresponding to the MHC class II complexes (see particularly preferred examples in Table 4)
  • HLA Allele is not just about passive immunization (as in treatment with antibodies, eg Herceptin) but about active immunization (ie specific activation of T cells or B helper cells via information carriers). Since the specific activation of MHC class II molecules, which are mainly exposed on the cell surface of antigen-presenting cells, by means of the tumor antigen peptides corresponding to the MHC class II complexes, specifically CD4 + T cells (also known as T helper cells) and B cells are activated.
  • an HLA tumor antigen peptide of the invention usually has one or more amino acid residues or one or more stretches of amino acid residues in its amino acid sequence (ie, with each "segment” comprising two or more amino acid residues that are adjacent or are in close proximity to one another, ie in the primary or tertiary structure of the amino acid sequence), via which the amino acid sequence of the invention can bind to a T cell receptor (in particular a binding pocket thereof), the amino acid residues or sections of the
  • anchor amino acids are amino acids that form the “anchor” for binding to a T cell receptor (also referred to herein as “anchor amino acids”).
  • This “anchor” can be determined, for example, with in silico methods (e.g. the artificial neural network NNAIign, which is used in the publicly accessible NetMHC-4.0) or by targeted mutation (insertions or substitutions in the
  • the HLA tumor antigen peptides provided by this invention are preferably in substantially isolated form (as defined herein) or form part of a protein or polypeptide, which can comprise one or more HLA tumor antigen peptides of the invention or consist essentially thereof and which optionally further can comprise one or more pharmaceutically active HLA tumor antigen peptide (s) (all of which are optionally linked via one or more linkers in a so-called oligopeptide).
  • the tumor antigen peptides of the invention can be used as a binding moiety in such a protein or polypeptide, which may optionally contain one or more additional amino acid sequences that can serve as a binding moiety (i.e., against one or more targets other than a T- Cell receptor) to provide a monovalent, multivalent, or multispecific polypeptide of the invention as described herein.
  • a protein or polypeptide can also be in substantially isolated form (as defined herein).
  • a pharmaceutical composition comprising a specific combination disclosed herein of HLA tumor antigen peptides corresponding to the MHC class I complexes and HLA tumor antigen peptides corresponding to the MHC class II complexes is particularly advantageous because it on the one hand it is suitable for activating specifically T cells as well as specifically B cells.
  • the present invention also relates to a pharmaceutical composition, a kit (or parts thereof), a method for
  • polypeptides and pharmaceutical compositions of the present invention can be used in particular for the prevention and treatment of cancer diseases,
  • breast / breast carcinomas which are characterized by mutation (s) (herein “amino acid exchange”), modified wild-type HLA antigen peptides corresponding to the MHC class I complexes and / or corresponding to the MHC class II complexes ( so-called HLA tumor antigen peptides, as defined herein).
  • amino acid exchange modified wild-type HLA antigen peptides corresponding to the MHC class I complexes and / or corresponding to the MHC class II complexes
  • HLA tumor antigen peptides as defined herein.
  • cancer diseases of the invention of a patient or a group of patients are treated in advance by classical methods such as
  • Chemotherapy radiation therapy and / or cancer immunotherapy.
  • Classic methods of treating cancer of the invention are, for example, surgical removal of tumors (resection), chemotherapy and / or radiation therapy, with two or even all three treatment methods being used simultaneously in one
  • lymphocytes are taken from the test person, cultivated ex vivo and then injected back into the test person. Not all cells are treated during treatment of the tumor and its metastases are destroyed, the further treatment of cancer diseases is made significantly more difficult by the formation of resistance.
  • the present invention therefore also comprises a pharmaceutical composition for the treatment of cancer diseases, as previously described, which follows the classic methods for the treatment of cancer diseases, namely after unsuccessful surgical tumor removal (resection), chemotherapy and / or radiation therapy.
  • the pharmaceutical composition to be administered comprises HLA antigen peptides which are presented on the surface of the tumor cells of the breast cancer of the patient or of the patient group, which is prior to application and
  • Ultra high performance liquid chromatography in conjunction with ESI
  • MS Mass spectrometry
  • At least 60%, preferably at least 80%, very particularly preferably 90%, ideally all HLA tumor antigen peptides that are contained in the pharmaceutical composition to be administered, are on the surface of the tumor cells of the breast carcinoma of the patient or group of patients presented as determined by methods as described herein.
  • the HLA antigen peptides corresponding to the MHC class I complexes are selected from the group consisting of the amino acid sequences given in SEQ ID No. 1 to 35 or have an amino acid identity of at least 85% with respect to these amino acid sequences. on.
  • the HLA antigen peptides corresponding to the MHC class II complexes are selected from the group consisting of the amino acid sequences given in SEQ ID Nos. 36 to 48. It has been found by the inventors of the present invention that the HLA-A antigen peptides explicitly disclosed herein are suitable in accordance with MHC class I in particular for use in the treatment of breast carcinomas in test subjects or a patient group with at least one identical HLA allele that have the subtype A * 01 and / or A * 02. This means that the HLA-A
  • Tumor antigen peptides preferentially bind to the corresponding MHC class I complex of subtype A * 01 and / or A * 02.
  • the individuals have the haplotype with the subgroup A * 01: 01 and / or A * 02:01.
  • the individuals particularly preferably have the haplotype with the subgroup B * 44:01 and / or A * 18:01.
  • Tumor antigen peptides corresponding to the MHC class I complexes can be used particularly advantageously for the treatment of breast cancer.
  • Composition in the treatment of a patient or a group of patients with at least one identical HLA allele can be achieved by adding a pharmacologically effective amount of at least one HLA-B tumor antigen peptide, preferably 1, 2, 3, 4 or 5 HLA- B tumor antigen peptide (s) corresponding to the MHC class I complexes and / or at least one HLA-C
  • HLA-B tumor antigen peptides or HLA-C tumor antigen peptides are also selected according to the specific haplotype of the patient or patient group with at least one identical HLA allele for treatment or profiling.
  • composition according to the invention at least 6, 7, 8, 9, 10, 11 or 12 HLA antigen peptides corresponding to the MHC class I complexes and / or MHC class II complexes and / or at least one HLA antigen peptide that is analogous to at least one on the cell surface of cells from malignant and / or neoplastic tissue
  • HLA antigen peptide which, in its amino acid sequence, has at least one
  • Neoantigen peptide and at least a 3-fold increased specific affinity for the T cell receptor of the body's own T cells (measured accordingly and / or expressed as K D value). Particularly good results could be achieved with pharmaceutical
  • compositions are achieved which had at least 10, 11 or 12 HLA antigen peptides corresponding to the MHC class I complexes and / or MHC class II complexes.
  • compositions are particularly preferred which are composed of a pharmacologically effective amount of 4 to 8, preferably 4, 5, 6, 7 or 8 HLA-A and / or HLA-B tumor antigen peptides corresponding to MHC class I - Complexes, in particular neoantigen peptides thereof and 1, 2, 3 or 4
  • Tumor antigen peptides corresponding to the MHC class II complexes in particular
  • Neoantigen peptides consist thereof.
  • At least one HLA-A antigen peptide of the composition is a tumor-exclusive HLA-A antigen peptide (ie a cancer testis antigen (CTA) that is found in healthy / normal tissue of the patient / patient group beyond the immunoprivileged spermatocytes (no longer) appears or a so-called neoantigen peptide), and the specific binding of the tumor-exclusive HLA-A antigen peptide with a specific dissociation (KD) in the range of 10 to 50 nM, as determined by surface plasmon resonance.
  • CTA cancer testis antigen
  • KD specific dissociation
  • a pharmaceutical composition based on HLA antigen peptides is particularly effective if both T lymphocytes (T cells for short) and B lymphocytes (B cells for short) ) to be activated.
  • T cells belong to the cell group of lymphocytes and play an important role in the human immune system. T cells recognize antigens through a specific receptor, the so-called T cell receptor (TCR). To do this, however, the antigen must be offered by an antigen-presenting cell (APC).
  • APC antigen-presenting cell
  • T cells that carry the CD4 trait are also referred to as CD4 positive T cells or T helper cells.
  • CD4 + T cells make up 27-57% of the lymphocytes, i.e. about 310-1570 cells / mI.
  • CD8-positive (CD8 +) T cells which also includes regulatory T cells, includes cytotoxic T cells or T killer cells. They play a special role in killing the body's own cells that are infected by viruses. This property of the cellular immune defense is of crucial importance in the present invention, since the molecular biological and genetic engineering
  • B cells are the only cells capable of producing antibodies and, together with T cells, make up the decisive component of the adaptive immune system. While T cells are involved in the cell-mediated immune response, the B cells are the carriers of the humoral immune response (and for the formation of
  • a pharmaceutical composition comprises the tumor-associated HLA antigen peptides whose expression level in the tumor cells is at least three times higher than in the healthy cells of the patient or the specifically determined patient group with at least one identical HLA allele, as determined for example with qPCR, and wherein the tumor-associated HLA antigen peptides are associated with the proliferation, invasiveness, angiogenesis and an increase in cytokeratin production of the breast / breast carcinoma, have particularly effective pharmacological effects in the treatment of breast / breast carcinomas.
  • Composition in an absolute concentration i.e. administration dose of at least 100 to 600 mg, preferably from 300 to 600 mg.
  • composition which per HLA tumor antigen peptide has an absolute concentration of>
  • 600 mg i.e. contain at least 700 to 1,200 mg, preferably from 800 to 1,200 mg, is very particularly preferred, since this greatly intensifies the information (the activation and / or training of the immune system). This is particularly advantageous if the immune system of the subject to be treated has been pretreated with a
  • Standard therapy e.g. at least one operation, radiation, chemotherapy and / or hormone therapy
  • the absolute concentration is pro HLA tumor antigen peptide is preferred, since this substantially minimizes the influence of the degradation of the HLA tumor antigen peptides (for example by ligases) after their application to the test subject.
  • the pharmaceutical composition comprises an adjuvant which, when the composition is applied to a patient, is suitable for forming a granuloma at the site of application.
  • the advantage of forming a granuloma is that a depot effect can be achieved, with the HLA tumor antigen peptides being advantageously stored in the form of a reservoir at the point of application and being able to be released to the subject's organism over a longer period of time.
  • the pharmaceutical composition according to the invention is not administered weekly.
  • the application of the pharmaceutical composition for the treatment of cancer within the meaning of the invention therefore only has to be carried out every 2 weeks, particularly preferably only once a month, when used over a longer period of time.
  • the pharmaceutical composition is preferably applied subcutaneously or intradermally and, preferably essentially simultaneously, to at least 2, particularly preferably to at least 3 application sites, usually to 3 to 4 application sites away from a tumor lesion and / or the cancerous lymph node area.
  • the essentially simultaneous (successive) application to several application sites has the advantage that, especially when applying high absolute concentrations of the individual HLA antigen peptides (ie administration dose) in the range of> 600 ⁇ g, which means that larger application volumes are required to completely dissolve the individual HLA antigen peptides ( >
  • the application solution which has only a limited shelf life after opening, is applied at the same time as possible.
  • the pharmaceutical composition containing each individual HLA antigen peptide in the composition in an absolute concentration i.e.
  • Administration dose of 300 to 600 yug, only once every 2 weeks, preferably once every 4 weeks over a period of at least one year intradermally or subcutaneously to a patient or a specifically determined group of patients with at least one identical HLA allele.
  • a pharmaceutical composition in which at least one HLA tumor antigen peptide has at least one mutation with respect to the wild type of the HLA tumor antigen peptide which leads to an increase in the affinity, preferably to ⁇ 500 nm, very particularly preferably ⁇ 50 nm of the specific binding affinity for the T cell receptor (K D value) of the HLA tumor antigen peptide treated individual compared to the wild type of the HLA antigen peptide, show particularly advantageous effects in the treatment of breast cancer.
  • the pharmaceutical composition is used for the treatment of breast / breast carcinomas as monotherapy or in combination with other known therapies and / or compounds for the treatment of breast / breast carcinomas.
  • the pharmaceutical composition is administered as a first-line therapy to the patient or group of patients with at least one identical HLA allele (so-called adjuvant monotherapy).
  • the patient or patient group to be treated with the pharmaceutical composition with at least one identical HLA allele has already received at least one standard therapy method (e.g. at least one operation, radiation, chemotherapy and / or hormone therapy) in advance.
  • at least one standard therapy method e.g. at least one operation, radiation, chemotherapy and / or hormone therapy
  • the breast cancer to be treated is particularly preferably a hormone-positive, HER2 / neu or triple negative breast cancer.
  • the present invention also includes HLA tumor antigen peptides corresponding to the MHC class I complexes or MHC class II complexes, in particular for use in the treatment or profiling of breast carcinomas in a patient or a group of patients who / who has or is suspected of having a breast / breast cancer or for a
  • HLA tumor antigen peptides from the group consisting of the in SEQ ID No. 13 to 35 and SEQ ID No. 36 to 48, in particular those in SEQ ID No. 13 to SEQ ID No. 26, SEQ ID No. 28, SEQ ID No. 29 and SEQ ID No. 32 to SEQ ID No. 48 or which have at least one mutation, preferably an amino acid exchange, compared to one of these amino acid sequences.
  • HLA tumor antigen peptides in a method for the treatment of breast carcinomas, in particular locally recurring or metastatic breast carcinomas in a patient or a group of patients with at least one identical HLA allele, is particularly preferred, the method comprising administering / applying a treatment regime to the Patient or the patient group comprises a pharmacologically effective amount of at least one of the aforementioned HLA tumor antigen peptides.
  • the immune system of the individual to whom the HLA tumor antigen peptides or the pharmaceutical composition is administered is still fully functional and thus easier to train, it is advantageous if the individual has not yet received any radiation, chemotherapy and / or hormone therapy against the Has received breast cancer, particularly locally recurrent or metastatic breast cancer and / or has not received previous adjuvant chemotherapy in recurrence for 12 months or less since the last dose of a chemotherapeutic agent.
  • HLA-A antigen peptides and HLA-A neoantigen peptides A) HLA-A antigen peptides and HLA-A neoantigen peptides
  • HLA-A tumor antigen peptide corresponding to the MHC class I complexes is defined herein as an "HLA antigen peptide of the invention or" amino acid sequence of the invention (as defined herein), which comprises: a) an amino acid sequence consisting of 7 up to 1 1 amino acids; and / or b) a neoantigen peptide with an amino acid sequence consisting of 7 to 11
  • Amino acids that i) analogously to at least one on the cell surface of cells from malignant
  • HLA-A antigen peptide a polypeptide having at least one amino acid substitution in its amino acid sequence compared to the wild type of this HLA-A neoantigen peptide (so-called "HLA-A neoantigen peptide" ) and iii) has at least a 3-fold increased specific affinity for the T cell receptor of the body's own T cells
  • Neoantigen peptides which in their amino acid sequence have at least one amino acid exchange in amino acid positions 1 (N-terminus), 2, 7/8 and / or the C-terminus compared to the wild type of this HLA-A antigen peptide, at least 4-fold, especially preferably at least 5-fold, very particularly preferably at least 8-fold increased specific affinity (K D ) for the T cell receptor of the body's own T cells and are therefore particularly preferably used for the composition according to the invention.
  • the amino acid exchange in the amino acid sequence of the HLA-A antigen peptide is particularly preferably a single amino acid exchange in the amino acid position 1 (N terminus), 2, 7/8 or the C terminus.
  • the amino acid exchange in the amino acid sequence of the HLA-A neoantigen compared to the wild type of this HLA-A antigen peptide is preferably a C / Y, A / V, D / Y, E / K, P / L, N / D or T / M exchange.
  • the HLA-A peptide or the HLA-A neoantigen preferably has a specific activity (K D ) against the T cell receptor which, by any suitable detection method known to the person skilled in the art, is less than 100 nM, particularly preferably less than 75 nM or very particularly preferably less than 50 nM, such as, for example, less than 40 nM, 35 nM, 30 nM, 25 nM or 20 nM.
  • the HLA-A tumor antigen peptide or the HLA-A neoantigen is preferred in the pharmaceutical composition according to the invention with a concentration, as defined above, of at least 100 to 600 pg, alternatively preferably in absolute
  • HLA-A tumor antigen peptides or HLA-A neoantigens are preferably selected as defined above under point (b).
  • an “HLA-A neoantigen peptide” is preferred which comprises the following framework sequence:
  • Has sequence identity or similarity to the native HLA-A antigen peptide such as at least 85%, particularly preferably at least 90% sequence identity (as defined herein) with an amino acid sequence selected from the group of SEQ ID NO:
  • HLA-A tumor antigen peptide and one HLA-A, HLA-B and / or HLA-C tumor antigen peptide and / or corresponding neoantigens consist of these, in which the HLA
  • Antigen peptides are optionally connected to one another by suitable linkers (so-called oligopeptides).
  • HLA-A tumor antigen peptides as defined under (b), (d) and (e) are very particularly preferred.
  • the HLA-A tumor antigen peptides are preferably defined as described under (a) or (d). In the event that the HLA-A
  • Tumor antigen peptides and / or neoantigens, as defined under (e), are connected to one another via a linker, suitable linkers are known to the person skilled in the art from the prior art.
  • Peptide sequences consisting of HLA tumor antigen peptides and / or HLA neoantigens have the further advantage that the longer amino acid sequences of the compounds, constructs, proteins or polypeptides cause a longer residence time in the tissue of the test subject after application, the compounds, constructs, proteins or polypeptides after application to the test person, for example by endogenous enzymes in smaller fragments (pharmaceutically active form, comprising at least 7 to 1 1
  • Amino acids which have a biologically desired function within the meaning of the invention can be broken down. This means that the individual fragments of the oligopeptide have an activity as HLA-A, HLA-B or HLA-C tumor antigen peptides and thus contribute to the activation of T cells.
  • any HLA-A peptide sequence can be a humanized and / or sequence-optimized sequence, as further described herein.
  • HLA-B antigen peptide is defined herein as an "HLA-B antigen peptide of the invention or" amino acid sequence of the invention (as defined herein) that comprises: a) an amino acid sequence consisting of 12 to 17 amino acids; and / or b) a neoantigen peptide with an amino acid sequence consisting of 12 to 17
  • HLA-B antigen peptide a polypeptide having at least one amino acid replacement in its amino acid sequence compared to the wild type of this HLA-B antigen peptide (so-called "HLA-B neoantigen peptide" ) and iii) has at least a 3-fold increased specific affinity for the T cell receptor of the body's own T cells
  • HLA-B neoantigen peptides which have at least one amino acid exchange in amino acid positions 3, 8 and / or 10 in their amino acid sequence compared to the wild type of this HLA-B antigen peptide, at least 4-fold, particularly preferably at least 7 -fold increased specific affinity for the T cell receptor of the body's own T cells and are therefore particularly preferably used for the formulation according to the invention.
  • the amino acid exchange in the amino acid sequence of the HLA-B antigen peptide is particularly preferably a single amino acid exchange in the amino acid position 3, 8 or 10.
  • the amino acid exchange in the amino acid sequence of the HLA-B neoantigen compared to the wild type of this HLA-B antigen peptide is preferably an E / A, E / K, R / W or D / A
  • the HLA-B antigen peptide or the HLA-B neoantigen peptide preferably has a specific activity (K D ) with respect to the T cell receptor, which is achieved by any suitable
  • Detection methods known to the person skilled in the art from less than 100 nM, particularly preferably less than 75 nM or very particularly preferably less than 50 nM, such as less than 40 nM, 35 nM, 30 nM,
  • composition according to the invention with a concentration, as defined above, of at least 100 to 600 pg, alternatively preferably in absolute
  • HLA-B peptides or HLA-B neoantigens are preferably selected as defined above under point b).
  • an “HLA-B neoantigen” is preferred, which comprises the following framework sequence:
  • amino acid sequence with an amino acid sequence which is at least 80%, such as at least 85%, particularly preferably at least 90% sequence identity (as defined herein) with an amino acid sequence selected from the group of SEQ ID NO: 6, 7, 8, 20 , 21, 22 and 35; and or
  • Amino acid substitution with respect to the amino acid sequence (s) selected from the group of SEQ ID Nos .: 6, 7, 8, 20, 21, 22 and 35 comprises or consists essentially thereof; and or
  • HLA-B tumor antigen peptide and one HLA-A, HLA-B and / or HLA-C tumor antigen peptide and / or corresponding neoantigens consist of these, in which the HLA
  • Antigen peptides are optionally connected to one another by suitable linkers (so-called oligopeptides).
  • HLA-B peptides as defined under (a), (c) and (d) are very particularly preferred.
  • the HLA-B peptides are preferably defined as described under (a) or (c).
  • suitable linkers are known to the person skilled in the art from the prior art.
  • Peptide sequences consisting of HLA tumor antigen peptides and / or HLA neoantigens have the further advantage that the longer amino acid sequences of the compounds, constructs, proteins or polypeptides cause a longer residence time in the tissue of the test subject after application, the compounds, constructs, proteins or polypeptides after application to the test person, for example by endogenous enzymes in smaller fragments (pharmaceutically active form, comprising at least 7 to 1 1
  • Amino acids which have a biologically desired function within the meaning of the invention can be broken down. That is, the individual fragments of the oligopeptide have an activity as HLA-A, HLA-B or HLA-C tumor antigen peptides and thus contribute to the activation of T cells.
  • any HLA-B peptide sequence can be a humanized and / or sequence-optimized sequence, as further described herein.
  • HLA-C antigen peptides and HLA-C neoantigen peptides
  • HLA-C antigen peptide is defined herein as an“ HLA antigen peptide of the invention or “amino acid sequence of the invention (as defined herein), which comprises: a) an amino acid sequence consisting of 8 to 11 amino acids; and / or b) a neoantigen peptide with an amino acid sequence consisting of 8 to 11
  • Amino acids that i) analogously to at least one on the cell surface of cells from malignant
  • HLA-C antigen peptide a protein derived from human cells
  • neoplastic tissue in particular of breast / breast carcinoma
  • HLA-C antigen peptide at least one amino acid exchange in its amino acid sequence compared to the wild type of this HLA-C peptide (so-called "HLA-C neoantigen peptide” ) and iii) has at least a 3-fold increased specific affinity for the T cell receptor of the body's own T cells
  • HLA-C neoantigen peptides which in their amino acid sequence compared to the wild type of this HLA-C antigen peptide have at least one amino acid exchange in amino acid positions 1 (N-terminus), 4 and / or the C-terminus, at least one Have 4-fold, particularly preferably at least 5-fold, very particularly preferably at least 7-fold increased specific affinity for the T cell receptor of the body's own T cells and are therefore used with particular preference for the formulation according to the invention.
  • the amino acid exchange in the amino acid sequence of the HLA-C antigen peptide is particularly preferably a single amino acid exchange in amino acid position 1 (N terminus), 4 or the C terminus.
  • amino acid exchange in the amino acid sequence of the HLA-C is preferred
  • Neoantigen peptide versus the wild type of this HLA-C antigen peptide has a C / Y, A / P, L / F or T / M exchange.
  • the HLA-C antigen peptide or the HLA-C neoantigen peptide preferably has a specific activity (K D ) with respect to the T cell receptor, which is achieved by any suitable
  • Detection methods known to the person skilled in the art from less than 100 nM, particularly preferably less than 75 nM or very particularly preferably less than 50 nM, such as less than 40 nM, 35 nM, 30 nM,
  • the HLA-C tumor antigen peptide or the HLA-C neoantigen is preferred in the pharmaceutical composition according to the invention with a concentration, as defined above, of at least 100 to 600 pg, alternatively preferably in absolute terms
  • HLA-C antigen peptides or HLA-C neoantigen peptides are preferably selected as defined above under point b).
  • an “HLA-C neoantigen peptide” is preferred, which comprises the following framework sequence:
  • Amino acid substitution with respect to the amino acid sequence (s) selected from the group of SEQ ID NOS: 9 to 12 and 23 to 26 comprises or consists essentially thereof; and or
  • HLA-C tumor antigen peptide identical or different peptide sequences of at least one HLA-C tumor antigen peptide and one HLA-A, HLA-B and / or HLA-C tumor antigen peptide and / or corresponding neoantigens consist of these, in which the HLA
  • Antigen peptides are optionally connected to one another by suitable linkers (so-called oligopeptides).
  • HLA-C peptides as defined under (a), (c) and (d) are very particularly preferred.
  • the HLA-C antigen peptides are preferably defined as described under (a) or (c).
  • suitable linkers are known to the person skilled in the art from the prior art.
  • Peptide sequences consisting of HLA tumor antigen peptides and / or HLA neoantigens have the further advantage that the longer amino acid sequences of the compounds, constructs, proteins or polypeptides cause a longer residence time in the tissue of the test subject after application, the compounds, constructs, proteins or polypeptides after application to the test person, for example by endogenous enzymes in smaller fragments (pharmaceutically active form, comprising at least 7 to 1 1
  • Amino acids which have a biologically desired function within the meaning of the invention can be broken down. This means that the individual fragments of the oligopeptide have an activity as HLA-A, HLA-B or HLA-C tumor antigen peptides and thus contribute to the activation of T cells.
  • any HLA-C antigen peptide sequence can be a humanized and / or sequence-optimized sequence, as further described herein.
  • HLA antigen peptide of class lt ' is defined herein as an“ HLA peptide of the invention ”or“ amino acid sequence of the invention (as defined herein), which comprises the following: a) an amino acid sequence consisting of 13 to 20 amino acids, particularly preferably 13 up to 17 amino acids; and / or b) a neoantigen with an amino acid sequence consisting of 13 to 20 amino acids, particularly preferably 13 to 17 amino acids, the following: a) an amino acid sequence consisting of 13 to 20 amino acids, particularly preferably 13 up to 17 amino acids; and / or b) a neoantigen with an amino acid sequence consisting of 13 to 20 amino acids, particularly preferably 13 to 17 amino acids, the
  • HLA neoplastic tissue in particular of breast / breast carcinoma
  • / or neoplastic tissue in particular of breast / breast carcinoma
  • the exposed HLA peptide of class II is the exposed HLA peptide of class II, and ii) at least one amino acid substitution in its amino acid sequence compared to the wild type of this HLA peptide of class II (so-called "HLA neoantigen of Class lf ') and
  • HLA neoantigens of class II which in their amino acid sequence compared to the wild type of this HLA peptide of class II, are particularly preferred in amino acid positions 3, 6, 10, 12, 13 and / or 14 the amino acid positions 12 and / or 14, have an at least 4-fold increased specific affinity for the T cell receptor of the body's own T cells and are therefore used with particular preference for the formulation according to the invention.
  • amino acid exchange in the amino acid sequence of the HLA peptide of class II is particularly preferably a single amino acid exchange in amino acid position 12 or 14.
  • the amino acid exchange in the amino acid sequence of the HLA neoantigen of class II compared to the wild type of this HLA peptide of class II is an E / K, E / A, D / Y or T / M exchange.
  • the HLA peptide of class II or the HLA neoantigen of class II preferably has a specific activity (K D ) against the T cell receptor, which can be determined by any suitable detection method known to the person skilled in the art from the prior art less than 100 nM, particularly preferably less than 75 nM or very particularly preferably less than 50 nM, such as less than 40 nM, 35 nM, 30 nM,
  • composition according to the invention with a concentration, as defined above, of at least 100 to 600 gg, alternatively preferably in absolute
  • HLA peptide (s) of class II or HLA neoantigen (s) of class II are preferably selected as defined above under point b).
  • an “HLA neoantigen of class II” is preferred, which comprises the following framework sequence:
  • a neoantigen having an amino acid sequence which has at least 80%, such as at least 85%, particularly preferably at least 90% sequence identity (as defined herein) an amino acid sequence selected from the group of SEQ ID NO: 36 to 48; exhibit; and or
  • HLA peptide sequences of class II exist, in which the HLA antigen peptides of class II are connected to one another by suitable linkers (so-called oligopeptides).
  • Class II antigen peptide sequence and an HLA class II antigen peptide sequence, HLA-A, HLA-B and / or HLA-C antigen peptide sequence and / or corresponding neoantigens consist of these, in which the HLA antigen peptides are optionally linked by suitable linkers (so-called oligopeptides ).
  • HLA antigen peptides of class II as defined under (a), (c) and (d) are very particularly preferred.
  • the HLA antigen peptides of class II are preferably defined as described under (a) or (c). In the event that the HLA
  • Class II tumor antigen peptides and / or corresponding neoantigens, as defined under (d), are linked to one another via a linker, then suitable linkers are known to the person skilled in the art from the prior art.
  • Peptide sequences consisting of HLA tumor antigen peptides and / or HLA neoantigens have the further advantage that the longer amino acid sequences of the compounds, constructs, proteins or polypeptides cause a longer residence time in the tissue of the test subject after application, the compounds, constructs, proteins or polypeptides after application to the test person, for example by endogenous enzymes in smaller fragments (pharmaceutically active form, comprising at least 7 to 1 1
  • Amino acids which have a biologically desired function within the meaning of the invention can be broken down. That is, the individual fragments of the oligopeptide have an activity as HLA-A, HLA-B or HLA-C tumor antigen peptides and thus contribute to the activation of T cells.
  • any HLA peptide sequence of class II can be a humanized and / or sequence-optimized sequence, as further described herein.
  • HLA tumor antigen peptides of class II for the treatment of breast cancer has the significant advantage that B cells are also activated in a targeted manner in the test subject to be treated.
  • HLA tumor antigen peptides of class II has the further advantage that HLA antigen peptides, which have a longer amino acid sequence compared to HLA tumor antigen peptides of class I, are broken down into smaller fragments (comprising at least 7 to 1 fragments) after application to the test subject, for example by endogenous enzymes 1 amino acids), which have an activity as HLA-A, HLA-B or HLA-C antigen peptides and thus contribute to the activation of T cells.
  • fragment is meant a portion of a polypeptide that is preferably at least 10%, 20%, 30%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more of the total Contains length of the reference polypeptide.
  • a fragment can contain 7, 8, 9, 10, 11 or more amino acids.
  • amino acid sequences and polypeptides of the invention are preferred as defined in the claims and those in which: at least one HLA tumor antigen peptide analogous to at least one on the cell surface of cells from malignant and / or neoplastic tissue of the tissue to be treated
  • Amino acid sequence has at least one amino acid exchange compared to the wild type of this HLA tumor antigen peptide (i.e. HLA neoantigen peptide) and compared to the wild type of this HLA tumor antigen peptide has at least a 3-fold increased specific affinity for the T cell receptor of the body's own T cells.
  • HLA neoantigen peptide i.e. HLA neoantigen peptide
  • the pharmaceutical composition according to the invention therefore preferably comprises at least six, very particularly preferably at least eight, very particularly preferably ten of the aforementioned HLA tumor antigen peptides corresponding to the MHC complexes of class I and / or II.
  • a monovalent amino acid sequence (or a polypeptide which comprises only one amino acid sequence of the invention) which is used in the invention is preferably such that it binds to a T cell receptor of the body's own T cells with a compared to the corresponding wild-type Binding HLA peptide sequence 3-fold increased specific affinity.
  • HLA-A, HLA-B and / or HLA-C tumor antigen peptides and / or corresponding neoantigen peptides in a single polypeptide of the invention have unique binding properties (cf. FIG. 3).
  • KD specific activity of the polypeptides of the invention which contain more than one component of the amino acid sequence of HLA-A, HLA-B and / or HLA-C
  • Tumor antigen peptides and / or neoantigen peptides corresponding to the MHC complexes of class I or II are determined by one of the detection methods described above / below, the compounds, constructs, proteins or polypeptides of the invention preferably having a specific activity that corresponds to the specific activity of each of their constituents, ie a specific activity that is similar to the specific activity of each of the (individual components of) Class I or II amino acid sequences contained in the compounds, constructs, proteins or polypeptides of the invention.
  • Some specific, but non-limiting examples of the preferred compounds, constructs, proteins or polypeptides mentioned above are compounds, constructs, proteins or polypeptides which either i) a wild-type HLA tumor antigen peptide corresponding to the MHC complexes of class I (HLA-A, HLA -B or HLA-C peptide) and / or II; or ii) a neoantigen corresponding to the MHC complexes of class I (HLA-A, HLA-B or HLA-C neoantigen) and / or II with an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 48 are selected; or
  • neoantigen corresponding to the MHC complexes of class I HLA-A, HLA-B or
  • HLA-C neoantigen HLA-C neoantigen
  • / or II with an amino acid sequence which has at least 80% sequence identity (as defined herein) with an amino acid sequence selected from the group of SEQ ID NO: 1 to 48; or
  • Amino acid sequence selected from the group of SEQ ID NO: 1 to 48 comprises or consists essentially thereof; or
  • HLA antigen peptide sequences exist, in which the HLA peptides are optionally connected to one another by suitable linkers; or a suitable combination thereof.
  • HLA tumor antigen peptides corresponding to the MHC complexes of class I and II can be used and are effective for the treatment of a cancer disease, as disclosed herein, in particular for the treatment of breast carcinomas.
  • the HLA tumor antigen peptide (in each case) is in the form of a single-membered amino acid sequence, i. not as an element of compounds, constructs, proteins or polypeptides which consist of at least two identical or different amino acid sequences for HLA tumor antigen peptides / neoantigens, in which the HLA tumor antigen peptides / neoantigens are connected to one another by suitable linkers.
  • the HLA tumor antigen peptides of the invention have specific activity against T cell receptors (T cells are used for this) which can be determined by any suitable detection method known to those skilled in the art is known, as can be determined, for example, using EliSpot AlphaScreen detection methods (as described herein) or cell-based detection methods (as described herein).
  • the blocking activity is preferably determined using a cell-based detection method, as described, for example, in exemplary embodiments 3 and 4.
  • Invention which comprise an amino acid sequence of an HLA antigen peptide of the invention and belong to MHC class I (as defined herein), preferably having a specific affinity of 10 to 50 nM for the corresponding T cell receptor.
  • amino acid sequence of the invention is attached to two or more MHC complexes of class I or II, epitopes,
  • MHC complexes, epitopes, components, domains or subunits of an MHC complex to which the amino acid sequences and / or polypeptides of the invention bind can be substantially the same or different (and in the latter case the amino acid sequences and polypeptides can of the invention to such different complexes, epitopes, components, domains or subunits of an MHC complex of class I or II including combinations thereof with an affinity and / or specificity which may be the same or different).
  • polypeptides of the invention will generally bind to any naturally occurring or synthetic analogs, variants, mutants, components and fragments of an MHC complex of Class I or II, respectively. Even in such a case, the amino acid sequences and polypeptides of the invention can bind to such analogs, variants, mutants, alleles, components and fragments with an affinity and / or specificity that corresponds to the affinity and specificity with which the amino acid sequences of the invention are bound to the wild types of MHC complexes of class I or II bind the same or different.
  • amino acid sequences and polypeptides of the invention bind to some analogs, variants or mutants of an MHC complex of class I or II, but not to others.
  • compounds, constructs, proteins or polypeptides comprising an HLA tumor antigen peptide of the invention may have an increased half-life in serum compared to the amino acid sequence from which they were derived.
  • an amino acid sequence of this invention can (chemically or otherwise) with one or more groups or units which extend the half-life (such as for example PEG), so that they are a derivative of an amino acid sequence of the invention with an increased half-life.
  • the compounds or polypeptides of the invention with increased half-life preferably have a half-life that is at least 1.5 times, preferably at least 2 times, such as at least 5 times, for example at least 10 times or more than 20 times higher is called the half-life of the corresponding
  • the compounds or polypeptides of the invention with increased half-life have a half-life that is more than 1 hour, preferably more than 2 hours, more preferably more than 6 hours, such as more than 12 hours or even more than 24, 48 or 72 hours is higher compared to the corresponding amino acid sequence of the invention per se.
  • an HLA tumor antigen peptide of the invention (or a compound, construct, or polypeptide comprising the same) is intended for administration to a patient (e.g., for therapeutic and / or diagnostic purposes, as defined herein)
  • a patient e.g., for therapeutic and / or diagnostic purposes, as defined herein
  • this is preferred either an amino acid sequence that is not naturally occurring in the patient; or, if this occurs naturally in the patient, it is in a substantially isolated and at the same time concentrated form (as defined herein).
  • Constructs and polypeptides comprising the same) directed against a human T cell receptor including combinations thereof as defined in the claims; wherein, for veterinary purposes, the polypeptides of the invention are preferably directed against a T cell receptor including combinations thereof (as defined in the claims) from the species to be treated or at least cross reactive with a T cell receptor including combinations thereof of those to be treated Species are.
  • the breast carcinoma to be treated is preferably a hormone-positive,
  • the present invention also includes a method for determining pharmaceutically effective HLA tumor antigen peptides for use in the treatment or for profiling of breast / breast carcinomas or in a pharmaceutical according to the invention
  • a composition comprising the method monitoring a tissue section of a patient or a group of patients who is suffering from a breast / breast cancer or is suspected of having a breast / breast cancer, the method comprising the following steps:
  • tissue sample from a tissue section, preferably a breast carcinoma of the patient or group of patients, wherein the cells of the tissue sample express MHC complexes of class I and / or II and these are presented on their surface, the said
  • Method step (a) of providing the tissue sample itself does not involve any surgical intervention in the patient or one of the patients
  • Patient group includes;
  • transcriptome of the tissue sample provided for determining all DNA sequences transcribed in mRNA sequences and for
  • the specific HLA haplotype preferably including the HLA haplosubtypes of the patient or the patient group, and very particularly preferably in relation to the MHC class I complexes, and optionally deriving the preferred anchor positions of the MHC class I complexes (as defined herein);
  • HLA antigen peptides to the patient or the patient group is prevented (obtaining a healthy Tissue sample of the patient or the patient group can take place, for example, by taking a blood sample with nucleated cells);
  • step (iii) the ligandome for determining the HLA tumor antigen peptides determined in step (iii) that are presented on the surface of the cells of the breast carcinoma
  • HLA antigen peptides which are presented on the surface of cells of a healthy tissue sample of the patient or the patient group;
  • Tumor antigen peptides compared to the corresponding MHC complex of class I and / or II, which is expressed in the cells of the tissue sample, preferably a breast carcinoma, and presented on the surface of these cells, using a database and / or a ranking algorithm; and or
  • step (iv) optionally the immunogenicity of the HLA tumor antigen peptides determined in step (iv) by means of an immunogenicity test, in particular by means of Western blot, ELISA techniques, in particular by means of ELISPOT, AFM or immunodetection with microscopic analysis;
  • HLA tumor antigen peptides preferably at least 4 to 8 HLA-A tumor antigen peptides corresponding to the MHC class I complexes and at least 2 antigen peptides corresponding to the MHC class II complexes which meet the criteria according to the in step (b ) meet defined parameters and which are expressed in the cells of the tissue sample provided and presented on the surface of these cells.
  • the method for determining pharmaceutically active HLA tumor antigen peptides takes place immediately after the provision of the Tissue sample of the patient or the patient group in step (a) the examination of the genes BRCA1 and BRCA2 for the presence of mutations.
  • the determination of whether the HLA tumor antigen peptides are presented on the surface of the cells of the tissue sample provided in step a) of the patient or of the patient group takes place by means of ultra-high-performance liquid chromatography (UHPCL) in conjunction with ESI mass spectrometry (MS).
  • UHPCL ultra-high-performance liquid chromatography
  • MS ESI mass spectrometry
  • the method for determining an HLA peptide of class I and / or II in step (b) comprises creating a transcriptome of the
  • the transcriptome is preferably created by means of RT-PCR, with a DNA microarray or DNA sequencing subsequently being carried out.
  • the method for determining an HLA antigen peptide of class I and / or II in step (b) particularly preferably comprises the creation of an exome sequencing for this
  • the method for determining a pharmaceutically active HLA tumor antigen peptide of class I and / or II in step (b) includes the alignment of the determined amino acid sequences of the HLA antigen peptides corresponding to the MHC complexes of class I and / or II a series, collection or library of
  • T-cell receptor of the body's own T-cells
  • content factors for tumor progression such as invasiveness, Angiogenesis, but also the escape mechanisms of the tumor against the immune attack.
  • the method also includes comparing the determined parameters
  • Amino acid sequences an appropriate set, collection or library of
  • the range, collection, or library of Amino acid sequences a series, collection or library of HLA tumor antigen peptides and / or MHC complexes of class I and class II (as described herein), such as, for example, a native series, collection or library of HLA tumor antigen peptides and / or MHC complexes Be class I and class II; a synthetic or semisynthetic series, collection or library of HLA tumor antigen peptides and / or MHC complexes of Class I and Class II and / or a series; a collection or library of HLA tumor antigen peptides and / or MHC class I and class II complexes that have undergone affinity maturation.
  • the determination method according to the invention determines an immunogenicity test, in particular by means of Western blot, ELISA techniques, in particular by means of ELISPOT, AFM or immunodetection with microscopic analysis.
  • the present invention also comprises a method for determining the regression, the course or the occurrence of a disease of a breast / breast carcinoma, comprising the monitoring of a tissue section, in particular a breast tissue of a patient who is sick with or is suspected of having a breast / breast carcinoma stands to develop breast cancer, the method comprising the following steps:
  • Tissue sample express HLA complexes of class I and / or II and present on their cell surface;
  • immunogenicity of the determined HLA-A antigen peptides and the class II antigen peptides by means of an immunogenicity test (e.g. by means of Western blot, ELISA techniques, in particular by means of ELISPOT or immunodetection with microscopic analysis);
  • step (c) Matching the determined amino acid sequences of the HLA antigen peptides with a series, collection or library of amino acid sequences on amino acid sequences which are linked to MHC class I complexes or MHC class II complexes, including combinations thereof, determined in step (i) , bind or have an affinity for it.
  • Another, in particular, cost-reduced aspect of the method according to the invention for determining at least one HLA tumor antigen peptide corresponding to the MHC complexes of class I and / or II for a pharmaceutical composition according to the invention provides that only (ie without prior creation of a transcriptome, exome sequencing) the HLA -Tumor antigen peptides of the class I and / or II are determined, which are on the cell surface of cells from malignant and / or
  • neoplastic tissue of the individual to be treated are exposed to neoplastic tissue of the individual to be treated (so-called determination of the ligandome).
  • the procedure consists of the following steps:
  • sequence and / or the sequence combination is an HLA tumor antigen peptide corresponding to the MHC class I complexes and / or MHC class II complexes or a combination of HLA tumor antigen peptides thereof, and the individual sequences from the sequences of a database with nucleic acids can be selected.
  • a pharmaceutical composition is to be understood here as a so-called informatics that can be administered to a patient or a group of patients with at least one identical HLA allele and that contains the inventive combination of HLA tumor antigen peptides in the concentration disclosed herein, an HLA tumor antigen peptide having a Represents information carrier.
  • the in vitro or in vivo loading of MHC class I complexes or MHC class II complexes of the tumor cells with the HLA tumor antigen peptides of the pharmaceutical composition according to the invention which have an identical or slightly modified amino acid sequence with HLA tumor antigen peptides , or the contacting of T cells with these HLA tumor antigen peptides, tumor cells sensitive to the lysis of the tumor cells of the tissue or the tissue section by specific cytotoxic or specifically activated T lymphocytes.
  • the primary aim of the present invention is not the in vitro or in vivo loading of tumor cells with HLA tumor antigen peptides, but the targeted activation and training of the immune system, in particular of T cells and B cells
  • the pharmaceutical composition according to the invention is preferably subcutaneous or intradermal and, preferably im
  • Tumor cells that present these HLA tumor antigen peptides on their surface, recognize and lyse.
  • the method according to the invention therefore has the advantage that in the event that the signals that the tumor sends out to the immune system are too weak (passive) or that the tumor actively releases substances that promote its growth (stimulate macrophages) (active e.g. TREX or BD1 start up), the immune system, especially the T cells, can be trained for the presence of the tumor, even if the signals sent by the tumor are too weak.
  • the signals that are sent out by the tumor are too weak when the HLA antigen peptides are presented on the
  • the cell surface of the tumor cells is small or decreases in response to cytotoxic T cell attacks (escape mechanism).
  • an HLA antigen peptide is an HLA tumor antigen peptide if it is a tumor-exclusive (i.e. HLA antigen peptide that is exclusively expressed and / or exposed by tumor cells; a cancer testis antigen (CTA), which in the
  • Tumor-exclusive H LA antigen peptides are mutated HLA antigen peptides that arise, for example, from a mutation of a gene, the mutation of the gene for the
  • Tumor growth is causative and / or related to oncogenesis.
  • the mutated gene product in the tumor is specific for the individual patient or a certain group of patients with at least one identical HLA allele.
  • Tumor-associated HLA antigen peptides include non-mutated HLA antigen peptides that, in the adult stage, only occur in some tissues of the patient or a specific tissue
  • Tolerance immune tolerance
  • HLA antigen peptides that are only associated with tumors.
  • An immunogenic HLA tumor antigen peptide is also referred to herein as an “epitope”.
  • the MHC complexes corresponding to the tumor-associated HLA antigen peptides are associated with the proliferation, invasiveness, angiogenesis and an increase in the cytokeratin production of the breast carcinoma.
  • the person skilled in the art is familiar with corresponding databases and literature in which these effects are listed (e.g. the databases of the National Center for Biotechnology Information (NCBI)).
  • the at least one HLA tumor antigen peptide in the context of the present invention is especially formulated for subcutaneous administration.
  • composition therefore denotes the provision of at least one HLA tumor antigen peptide and an adjuvant in a pharmaceutical formulation that enables good applicability and includes solutions, in particular injection solutions and infusion solutions, concentrates for the production of injection and infusion preparations, powder for the production of injection and infusion preparations Infusion preparations and subcutaneous implants.
  • compositions are prepared by adding the determined HLA tumor antigen peptides in a carrier liquid (i.e. a pharmacologically acceptable vehicle), optionally with the addition of other auxiliaries such as wetting agents, dyes,
  • Permeation promoters are dissolved or suspended.
  • the carrier liquid is preferably from the group consisting of sodium chloride injection solution, Ringier's injection solution, isotonic dextrose, sterile water, Dextrose solution, Lactated Ringer's solution for injection, distilled water, or mixtures thereof, selected for local injection.
  • Preferred permeation promoters are dimethyl sulfoxide (DMSO),
  • composition water a pharmaceutically acceptable one
  • Saline and / or DMSO are suitable for application
  • compositions containing a mixture of about 30% DMSO and 70% water.
  • HLA tumor antigen peptide (corresponding to the MHC complexes) of the class, as used here, denotes a peptide sequence which is bound to the MHC complex (in humans to the HLA complex) of class I or is immunogenic.
  • the HLA protein complex of class I is used to present the antigen on the cell surface and comprises a heavy chain with 3 domains (a1, a2 and a3) and ß2-microglobulin (ß2M).
  • HLA tumor antigen peptide (corresponding to the MHC complexes) of class it‘ denotes a polypeptide sequence which is bound or immunogenic to the MHC complex (in humans to the HLA complex) of class II.
  • the HLA protein complex of class II is used for the antigen presentation on the cell surface and consists of two chains of almost the same size, an ⁇ -chain and a non-covalently bound ß-chain, each chain having two extracellular domains (a1 and a2 as well as ß1 and ß2 ).
  • polypeptides and pharmaceutical compositions of the present invention can be used in prevention and/or
  • cancer Treatment of breast cancer (also referred to herein as “cancer”).
  • cancer of the invention can be considered
  • Tumor antigen peptide or a pharmaceutical composition of the invention (and in particular a pharmaceutically effective amount thereof) to a subject (ie a person with the disease or disorder or at least one symptom thereof and / or who are at risk of contracting or developing such a disease or disorder).
  • a “peptide sequence” (e.g. an HLA antigen peptide) with a “native sequence” comprises in the sense of the present invention a peptide sequence with the same (i.e. unmodified) amino acid sequence as a peptide sequence naturally occurring in the patient.
  • Such a peptide sequence with a “native sequence” can be isolated from nature or produced recombinantly or synthetically.
  • the term peptide sequence having a "native sequence” specifically includes naturally occurring truncated or secreted forms of the peptide sequence (e.g., an extracellular domain sequence), natural
  • amino acid sequences used in the invention are individual variable FILA antigen peptide domains (“FILAs” or “FILA complex”).
  • FILAs individual variable FILA antigen peptide domains
  • FILA complex individual variable FILA antigen peptide domains
  • HLAs of the invention Amino acid sequences or regions within the amino acid sequence of a protein of the invention that are FILAs are also referred to herein as "HLAs of the invention.
  • neoantigen peptides i.e. FILA antigen peptides expressed and / or exposed exclusively by tumor cells
  • FILA antigen peptides which have less than 100% sequence identity or similarity to the native FILA antigen peptide
  • FILA antigen peptides which have less than 100% sequence identity or similarity to the native FILA antigen peptide are preferably distinguished in the context of the present invention by an amino acid exchange in the amino acid sequence.
  • amino acid exchange denotes the exchange of an amino acid for another amino acid within the
  • Percentage of sequence identity or identity or similarity with respect to this amino acid sequence is defined herein as the percentage of amino acid residues in the amino acid sequence of the polypeptide that are identical (i.e., same residue) or similar (i.e., amino acid residues from the same group based on common
  • the amino acid exchange for the HLA antigen peptide corresponding to the MHC complexes of class I and / or II comprises at least one D / Y, one C / Y, one A / V, one T / M , an I / O or a D / O exchange at any position within the amino acid sequence to the wild type of this HLA peptide.
  • amino acids used herein are generally accepted
  • the percentage of "sequence identity" between a first amino acid sequence and a second amino acid sequence can be calculated or determined by dividing the number of amino acids in the first amino acid sequence that correspond to the amino acids in the corresponding positions in the second Amino acid sequence are identical by dividing [the total number of amino acids in the first amino acid sequence] and multiplying by [100%], with any deletion, insertion, substitution or addition of an amino acid in the second amino acid sequence - compared to the first amino acid sequence - is considered to be a difference from a single amino acid (position).
  • An HLA tumor antigen peptide is "immunogenic" if the tumor cells expose on their cell surface at least one corresponding MHC class I complex and / or at least one corresponding MHC class II complex that recognizes and binds the HLA tumor antigen peptide, i.e. the HLA tumor antigen peptide has a high specific activity towards this MHC class I complex and / or MHC class II complex.
  • the immunogenicity of the HLA tumor antigen peptide can take place by means of Western blot, ELISA techniques, in particular by means of ELISPOT or immunodetection with microscopic analysis.
  • the HLA tumor antigen peptides of the present invention are preferably immunogenic and are therefore also referred to as immunogenic HLA tumor antigen peptides (“epitopes”).
  • the immunogenicity of the HLA tumor antigen peptides can be determined by suitable detection methods. Such methods are known to the person skilled in the art and / or are described herein.
  • TCR T cell receptor
  • the “specific affinity” of the HLA antigen peptide can also be determined via in silico
  • At least one HLA-A tumor antigen peptide is a tumor-exclusive HLA-A tumor antigen peptide (i.e. a cancer testis antigen (CTA) that is present in the healthy / normal tissue of the patient / the tumor-exclusive HLA-A tumor antigen peptide (i.e. a cancer testis antigen (CTA) that is present in the healthy / normal tissue of the patient / the tumor-exclusive HLA-A tumor antigen peptide (i.e. a cancer testis antigen (CTA) that is present in the healthy / normal tissue of the patient / the tumor-exclusive HLA-A tumor antigen peptide (i.e. a cancer testis antigen (CTA) that is present in the healthy / normal tissue of the patient / the tumor-exclusive HLA-A tumor antigen peptide (i.e. a cancer testis antigen (CTA) that is present in the healthy / normal tissue of the patient / the tumor-exclusive HLA-A tumor antigen peptide
  • Patient group no longer occurs or a so-called neoantigen peptide), and the specific binding affinity of the tumor-exclusive HLA-A tumor antigen peptide is determined compared to the corresponding MHC class I complex with a K D in the range of 10 to 50 nM, as determined with surface plasmon resonance .
  • tumor antigen peptides with a K D of ⁇ 50 nM are generally regarded as strongly binding and those with a K D between 50 and 500 nM as weakly binding tumor antigen peptides.
  • K D the K D value
  • Tumor antigen peptides that had a KD value in the range between 50 and 500 nM triggered effector cells (i.e. cytotoxic T cells), contrary to conventional / n-s /// co-binding prediction models, which considered them to be low-binding. It is therefore essential for the effectiveness of the tumor antigen peptides that the tumor antigen peptides are immunogenic.
  • active ingredient enhancer / adjuvant refers to an auxiliary substance that triggers and / or enhances the effect of the HLA peptides in the first place.
  • all conventional adjuvants known to the person skilled in the art are for the production of an inventive one
  • Montanide ISA 51 VG has proven to be particularly suitable.
  • this forms a so-called granuloma that advantageously stores the HLA peptides in the form of a reservoir at the site of application and releases them to the test subject's organism over a longer period of time. Therefore, weekly applications of the (medicament) formulation according to the invention are particularly advantageously dispensed with.
  • the (pharmaceutical) formulation for the treatment of cancer within the meaning of the invention must therefore preferably be applied only every 2 weeks, particularly preferably only once a month, when used over a longer period of time.
  • subject also referred to herein as “subject” or “patient”
  • subject refers to any mammal that is being treated for an abnormal physiological condition or has been diagnosed with a disease.
  • test person in the context of the present invention include mammals such as, for example, a rodent, a carnivore, an even-toed ungulate, an odd-toed ungulate or a primate.
  • the test subject is a human.
  • a “patient group” a group of individuals, preferably people, is always in question, who all have at least one, preferably at least two, very particularly preferably at least three identical HLA allele (s). It is permissible for the patients to be treated with the pharmaceutical composition to have received a standard therapeutic procedure (for example at least one operation, radiation, chemotherapy and / or hormone therapy).
  • the pharmaceutical composition can also be administered as a first-line therapy to the patient or the specifically determined patient group with at least one identical HLA allele.
  • the individual has not yet received chemotherapy for locally recurring or metastatic breast cancer and / or has not received any previous adjuvant chemotherapy in recurrence for 12 months or less since the last dose.
  • the individual particularly preferably has the haplotype with the subgroup A * 01 or A * 02.
  • a “haplotype” (an abbreviation for “haploid genotype”) is the sum of the
  • a certain haplotype can be individual, population or species-specific.
  • the transcriptome comprises the sum of all genes transcribed in a cell at a certain point in time, i.e. transcribed from the DNA sequence into mRNA sequences, i.e. the totality of all and the quantification of the individual mRNA molecules produced in a cell .
  • the creation of the transcriptome does not yet permit any statement about the “correctness” of the rewritten mRNA sequences.
  • the term “creating a transcriptome” in the present disclosure denotes the analysis of the transcriptome as the sum of all genes transcribed in a cell at a certain point in time, preferably using quantitative real-time (RT) PCR and a subsequent DNA microarray or subsequent DNA Sequencing.
  • the creation of the transcriptome of the tissue sample which is provided in step (a) of the determination method according to the invention, usually comprises the acquisition of more than 40,000 coding DNA sequences (raw data).
  • the exome is the entirety of the exons of an organism, i.e. all sections that potentially encode proteins. In humans, the exome comprises around 23,000 genes with around 50 million nucleobases. In Whole Exome Sequencing (WES), all exons, ie the sections in the genome that code for proteins, become one
  • Tissue section i.e. healthy tissue or tumor tissue of a subject
  • the genetic diagnosis focuses on this 1 -2% of the
  • the exome analysis accordingly includes the sequencing of the exome of the patient (and possibly other relatives), the evaluation of the sequence data and the
  • the proteome denotes the entirety of all proteins of at least one cell in a malignant or neoplastic tissue / tissue section or a cell compartment thereof, under exactly defined conditions and at a specific point in time.
  • the proteome of a cell can be determined by proteome sequencing and is linked to the genome of this cell via the transcriptome.
  • Immunotherapies are based on the fact that the individual mutation pattern (signature) of the tumor of each cancer patient is deciphered. On the profile of the individual mutation pattern (signature) of the tumor of each cancer patient is deciphered. On the profile of the individual mutation pattern (signature) of the tumor of each cancer patient is deciphered. On the profile of the individual mutation pattern (signature) of the tumor of each cancer patient is deciphered.
  • Mutation patterns are produced according to conventional treatment approaches for each individual patient, synthetic vaccines, for example on an RNA basis (i.e. vaccine production or production of the computer science according to the invention). These are then used for the individual treatment of the patient.
  • these novel vaccines are not suitable for other patients with the same tumor, but can only be used for the patient whose mutanom was previously used for the vaccine production or the production of the computer science according to the invention was analyzed. Therefore, it is an outstanding achievement of the inventors to have recognized that different patients have overlaps in the mutanoma of the malignant or neoplastic tissue / tissue section thereof. Different patients can advantageously be divided into uniform patient groups so that at least 50% of the HLA peptides of the formulation according to the invention have the mutanoma of
  • Patient group is compatible.
  • HLA HLA antigen peptides that are presented on the cell surface via MHC molecules. It is assumed that more than 10 5 HLA molecules are expressed on the cell surface and the number of identical HLA peptides presented can vary between a few and up to 10,000 copies per cell. As a result, approximately 10,000 different HLA peptides are presented in different proportions on a cell.
  • the ligandome is influenced by various physiological, intrinsic and pathological (e.g. cancer or necrosis) factors such as the cell type or tissue type, infection or transformation of the cell or simply the current state of the cell, which depends on the nutrient situation or external stress factors leads to changes in the HLA peptides presented.
  • physiological, intrinsic and pathological factors e.g. cancer or necrosis
  • pathological factors such as the cell type or tissue type, infection or transformation of the cell or simply the current state of the cell, which depends on the nutrient situation or external stress factors leads to changes in the HLA peptides presented.
  • the Edman degradation can be used to gain initial knowledge about the presented peptides.
  • the ligandome can be analyzed by using modern mass spectrometers in proteomics, with which it is possible to clearly determine the sequences of many individual ligands.
  • Two methods are used for the ionization of the peptides or proteins required here: electrospray ionization (ESI) and matrix-assisted laser desorption / ionization (MALDI). Coupling with an RP-HPLC system is common with ESI.
  • capillary electrophoresis (CE) was also used as an analytical separation method.
  • ESI mass spectrometry In ESI mass spectrometry, the direct coupling of HPLC and ESI interface enables the sample to be separated online, which in combination with an autosampler enables the measurement procedure to be fully automated. Because of the continuous flow of solvent from the HPLC, the samples can be measured in a relatively short time.
  • ESI mass spectrometry uses a wide range of instruments for analysis, such as quadrupole time-of-flight mass spectrometers, linear quadrupole ion traps, triple quadrupoles or ion trap-Orbitrap hybrid systems. This advantageously allows hundreds of HLA peptides to be identified in one measurement.
  • the expression “deriving a ranking” relates to the determination / selection of the quantity and the affinity of the HLA peptides which are exposed on the cell surface of the cells of the removed tissue (or a tissue section thereof).
  • a cumulative ranking for the HLA antigen peptides with regard to protein quality and specific affinity (K D ) for the T cell receptor of the body's own T cells is derived.
  • Protein quality especially content-related factors for tumor progress, such as invasiveness, angiogenesis, but also the escape mechanisms of the tumor in relation to the
  • a cumulative ranking system is used by the algorithm
  • a cumulative (predictive) ranking is used to eliminate sequences that
  • the highest-ranking sequence possibilities can be further qualified by their existence in a database of possible HLA antigen peptides with a high specific affinity for the endogenous T-cell receptors (as defined herein), which are predicted from sequence data, in particular one which is restricted to the organism / test person from which the HLA antigen peptide was obtained.
  • the highest ranking can be further qualified by their existence in a database of possible HLA antigen peptides with a high specific affinity for the endogenous T-cell receptors (as defined herein), which are predicted from sequence data, in particular one which is restricted to the organism / test person from which the HLA antigen peptide was obtained.
  • Sequence options through the separation coordinates of the HLA antigen peptide e.g. isoelectric point and molecular weight of a protein
  • Sequence options through the separation coordinates of the HLA antigen peptide e.g. isoelectric point and molecular weight of a protein
  • sequence options through the separation coordinates of the HLA antigen peptide e.g. isoelectric point and molecular weight of a protein
  • monomer composition can be further qualified.
  • HLA tumor antigen peptides synthetic or isolated HLA tumor antigen peptides, which were derived from the cumulative ranking for the production of the (drug) formulations of the present invention and for the production of the pharmaceutical composition (as so-called informatics), can in principle be used .
  • Another object of the present invention are also
  • Preferred pharmaceutical formulations are tablets, chewable tablets, chewing gum, coated tablets, capsules, drops, juices, syrups, suppositories, transmucal therapeutic systems, transdermal therapeutic systems, solutions, injections, emulsions, suspensions, easily reconstitutable dry preparations, powders or sprays.
  • Particularly preferred pharmaceutical formulations are injections or solutions.
  • the drug formulation is in a suitable application device, preferably as a lyophilisate in a syringe, which allows an in s / fu reconstitution with a pharmaceutically acceptable solution (e.g. saline solution).
  • a pharmaceutically acceptable solution e.g. saline solution
  • the (drug) formulations according to the invention are preferably suitable for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal,
  • compositions for parenteral administration can include, for example, excipients, sterile water, or
  • polyalkylene glycols such as polyethylene glycols, oils of vegetable origin, or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds.
  • Other potentially useful parenteral delivery systems for the anti-prion therapeutic compounds include ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Invasiveness is the extent of the growth of a malignant tumor that penetrates tissue from its place of origin into adjacent tissue structures.
  • Angiogenesis describes the emergence of new blood vessels from an existing blood vessel system and is part of both physiological processes (e.g. embryogenesis, wound healing) and pathological processes (e.g. diabetic retinopathy, chronic polyarthritis, tumor growth). It has long been known that new blood vessels (angiogenesis) occur in cancer, which is known as tumor angiogenesis. Tumors are made up of cells that, like all other cells in the body, provide nutrients and
  • metastases When a tumor develops, it does not initially have its own blood vessels. Its growth is therefore severely restricted. Without its own blood vessels, it will not be larger than 1 to 2 millimeters. The formation of metastases also interacts with tumor angiogenesis, because tumor cells have to get into the surrounding blood vessels for this. Only then can they be transported to distant body regions and form metastases there.
  • HLA peptide of the invention or a composition or formulation containing the same can be used for modulating an HLA complex of Class I or II, including combinations thereof, either in vitro (e.g. in an in vitro or cellular
  • Detection method or in vivo (e.g. in a unicellular or in a multicellular organism and in particular in a mammal and very particularly in one
  • human beings such as in a human being at risk of or suffering from a cancer of the invention.
  • Modulating essentially the increase in the specific affinity of T cells towards a tumor-exclusive or tumor-associated MHC class I complex or MHC class II complex of the malignant and / or neoplastic tissue, such as on the basis of a suitable in vitro -, cellular or / nv / Vo detection methods measured (such as those mentioned herein).
  • modulating means increasing the specific affinity of the patient's or patient group's own T cells compared to a tumor-exclusive or tumor-associated MHC class I complex or MHC class II complex of the malignant and / or or neoplastic tissue, by at least 1%, preferably at least 5%, such as 10% or at least 25%, for example by at least 50%, at least 60%, at least 70%, at least 80% or 90% or more compared to the affinity of T cells versus a tumor-exclusive or tumor-associated MHC class I complex or MHC class II complex of the malignant and / or neoplastic tissue in the same detection method among the same
  • Tumor antigen peptides of the pharmaceutical composition according to the invention (as defined herein).
  • the invention comprises the above-mentioned method, the expression profile of at least five, preferably at least six, very particularly of at least 6 marker genes, as shown in SEQ ID NO: 1 to SEQ ID NO: 48, being determined.
  • the marker genes are also defined by variants, which in turn are shown in Tables 2 to 4.
  • This expression profile is preferably compared with the expression profile of a “reference”.
  • a reference can, for example, be the expression profile of healthy tissue (for example intestinal tissue or tissue of the liver, lungs, etc.) Individuals (test subjects) can be used, whereby it is known of this tissue that it is not proliferatively changed or even metastatic. Corresponding examples are shown in the experimental part of the invention. However, data from tissues from foreign individuals, preferably healthy people, can also be used as “reference” or “reference value”.
  • At least 6, but preferably at least 8, very particularly preferably at least 10 of the HLA antigen peptides shown here corresponding to the MHC class I complexes or MHC class I complexes should be used in the method for detecting a carcinoma (selected from the group of the polypeptides / polypeptide segments, as shown in SEQ ID Nos .: 1 to 48). Further embodiments can be found in the experimental section.
  • the present invention also includes a method of making a
  • composition according to the invention or a
  • Tumor antigen peptides corresponding to the MHC class II complexes the definition of each HLA tumor antigen peptide being the same as defined above;
  • the present invention also includes the use of the pharmaceutical composition according to the invention or the (medicament) formulation for the production of a medicament or a combination preparation for the treatment of malignancies, leukemia and neoplasms, in particular breast cancer.
  • the invention also encompasses a pharmaceutical composition which comprises an HLA peptide within the meaning of the invention and a pharmaceutically acceptable excipient.
  • the invention also relates to an HLA antigen peptide or a neoantigen peptide of the invention for use in the preparation of a formulation (such as, for example, without limitation to a pharmaceutical formulation, as further described herein) for the treatment of cancer diseases, either in vitro (e.g. B. in an in vitro or cellular detection method) or in vivo (z. B. in a unicellular or multicellular organism and in particular in a mammal and especially in one
  • a formulation such as, for example, without limitation to a pharmaceutical formulation, as further described herein
  • human beings such as a human being at risk of or suffering from cancer of the inventions.
  • the present invention furthermore also comprises a combination preparation for use in the treatment of breast cancer with simultaneous, separate or sequential administration,
  • the combination preparation comprises the following two separate preparations (a) and (b):
  • a second preparation which, together with a pharmaceutically acceptable carrier or diluent, an anti-cancer agent selected from the group consisting of anti-cancer alkylating agents, anti-cancer anti-metabolites, anti-cancer antibiotics, herbal anti-cancer drugs, platinum-coordinated anti-cancer complexes, anti-cancer camptothecin derivatives, anti-cancer tyrosine kinase inhibitors, Interleukins, biological response modifiers and other anti-cancer agents or a pharmaceutically acceptable salt thereof.
  • an anti-cancer agent selected from the group consisting of anti-cancer alkylating agents, anti-cancer anti-metabolites, anti-cancer antibiotics, herbal anti-cancer drugs, platinum-coordinated anti-cancer complexes, anti-cancer camptothecin derivatives, anti-cancer tyrosine kinase inhibitors, Interleukins, biological response modifiers and other anti-cancer agents or a pharmaceutically acceptable salt thereof.
  • the combination preparation according to the invention is particularly suitable for use in the treatment or profiling of breast / breast carcinomas, in particular locally recurring or metastatic breast carcinomas in a patient or a group of patients who is ill with or is suspected of having a breast / breast carcinoma, to suffer from breast cancer.
  • the first preparation of the invention is particularly preferred
  • composition in combination with a
  • monoclonal antibodies in particular against immunosuppressive proteins selected from the group consisting of CTLA4 (here e.g. Ipilimumab - Yervoy®), PDL1 (here e.g. Nivolumab - Opdivo), PD1 -L, also EpCam, IDO, MIC, Fas and TRAIL; specifically: as an estrogen inhibitor for hormone-positive patients from the group of aromatase inhibitors - (herein e.g. letrozole and / or the estrogen blocker fulvestrant); as antibodies against HER2-positive patients: Herceptin (TDM-1) as the second preparation.
  • CTLA4 here e.g. Ipilimumab - Yervoy®
  • PDL1 here e.g. Nivolumab - Opdivo
  • PD1 -L also EpCam
  • IDO MIC
  • Fas and TRAIL specifically: as an estrogen inhibitor for hormone-positive patients from the group of aromata
  • Fig. 1 Schematic representation of an HLA-A-mediated connection of a T-
  • Fig. 2 Schematic representation of an HLA-B-mediated connection of a T-
  • Tumor antigen peptides according to embodiment 3 (INC 14/1713; Stern) which map the epitopes of the primary tumor MC-HER2 / Neu.
  • the illustrated course spans 26 weeks.
  • Liver marker Gamma GT after application of specific immune information through the composition of tumor antigen peptides according to embodiment 3 (INC 14/1713; vertical line), which map the specific metastatic epitopes of the liver metastases of the scattered MC-HER2 / Neu.
  • the illustrated course spans 34 weeks.
  • HLA tumor antigen peptides all of which have been tested and are immunogenic.
  • SEQ ID NOs: 13 to 48 list some preferred but non-limiting examples of amino acid sequences of tumor antigen peptides of the invention, each of these examples representing a further aspect of the present invention.
  • table 1 [comparative example]:
  • the transcriptome analysis was carried out in all patients using the
  • PANTHER chip analysis (44K chip) from Agilent Technologies.
  • the 44K chip used contains 44,000 gene probes, so that the activity of> 34,000 gene expression markers per patient could be analyzed with this chip. 1,000 genes with increased relevance were determined ten times.
  • Exome sequencing is carried out from the patient's standard frozen preparation from which the tumor DNA is extracted.
  • Next-generation sequencing of the exome is carried out from the tumor sample with coverage of over 95% of the entire coding exon area of humans. For this purpose, i.a. > 290,000 relevant
  • Sections of DNA are selectively amplified and sequenced by semiconductor sequencing technology.
  • the aim of the analysis is to define possible mutations for the design of an individual tumor antigen peptide immunization.
  • SNPs Single Nucleotide Polymorphism
  • the DNA is simultaneously isolated from the patient's blood cells containing nuclei and sequenced using the same method. The differentiation of possible neoantigen candidates took place in the following six steps:
  • Embodiment 1 peptides with a low expression relevance in the tumor can be excluded.
  • peptides 20 are defined and submitted to the HLA paratope affinity analysis NetMHC. -25 * 12 nonapeptide pairs (each mutated and wild type) are submitted to the affinity analysis for analysis in 9 HLA loci each. From this, 5814 affinities (2907 pairs) are examined. In 40 pairs, an affinity at least twice as high in the mutated peptide than in the wild-type peptide is detected.
  • Example 3 Patients with mMC (metastatic breast cancer), Type_HER2-new
  • invasive ductal bifocal breast carcinoma (Mamma-CA), right, tumor 2 cm to 5 cm in the largest extent (pT2), pN1 sn pN1 (3/5) G2, NO, ER-, PR-, HER-2 new: 3+, Ki-67: 55%
  • neoadjuvant chemotherapy (TCH w3) 6 cycles, trastuzumab;
  • Proonosis of the clinicians The patient was discharged from the clinic with a prognosis of an OS (overall survival) of probably / average 6 months.
  • tumor-specific HLA antigen peptides in the form of synthesized peptides are used.
  • targets cytotoxic CD8 + T cells
  • These effector T cells can destroy the tumor cells recognized by the HLA-presented antigens by secreting granzyme and perforin.
  • NGS next generation sequencing
  • LC-MS / MS liquid chromatography-coupled tandem mass spectrometry
  • HLA tumor antigen peptides (number 86), which were weighted with regard to their expression abnormalities / deviations from normal and their known significance for tumor proliferation -> factor 3 against normal; Significance for tumor development: growth factors, angiogenesis factors, metastasis factors.
  • Cytokeratin production of breast / breast cancer are associated.
  • Target selection for step (a) From the data records of the transcriptome, first, using the amino acid sequences of the respective proteins, amino acid sequences of the HLA tumor antigen peptides corresponding to the MHC complexes (nonamers) with the highest allele affinities (specific activity against T cell receptor [nM]). This selection criterion is used to algorithmically determine the probability with which the respective HLA tumor antigen peptide is presented in vivo on the corresponding MHC complexes (a first prerequisite for a possible cellular immune response).
  • step (b) Using the patient's alleles, nonameric variants containing the amino acid exchange were determined from the data sets of the mutation studies with regard to the highest affinities (specific activity towards T cell receptor [nM]). Polymers of 17 amino acids (oligopeptides) under the
  • Peptide concepts were produced synthetically as chemical peptides.
  • Application site left and right upper arm Administration schedule: 23 vaccinations on days 1, 2, 3, 8, 15, 22, 36, 50, 71 and further every 3 weeks up to day 365
  • Adjuvants added per application 12.5 mg imiquimod in 250 mg cream (Aldara) topically at the injection site; 200 pg ipilimumab (Yervoy), as CTLA4 increased, alternating with 300 pg nivolumab (Opdivo), as PD1 or PD-L1 increased, subcutaneously (s.c.) directly next to the application site
  • Fig. 3 shows the development of the specific tumor marker CA 15-3 in connection with the liver marker Gamma GT after specific application (id) specific pharmaceutical composition of the immune information by BITAP peptides (star line), which the specific metastatic epitopes of the liver metastases of the scattered mMC -HER2 / remap (INC 14/1713).
  • the illustrated course spans 34 weeks. the development of the specific tumor marker CA 15-3 after specific
  • Tumor antigen peptides that map the epitopes of the primary tumor MC-HER2 / Neu (INC 14/1713).
  • the illustrated course spans 26 weeks.
  • Example 4 Patients with mIBC with lymphangosis carinomatosis (metastatic inflammatory breast cancer)
  • Recurrence A first recurrence after only 3 months postoperatively:
  • Chemotherapy was canceled after 5 cycles. Locoregional tumor recurrence, 7x1 1cm along the ventrolateral chest wall. Skin and subcutaneous tissue are infiltrated and thickened over a large area.
  • Treatment method according to the invention After all the therapies available in the standard and rule canon of oncological medicine had been carried out without success, the immunological therapy approach of informing the patient's own immune system by applying tumor-associated and
  • tumor-specific antigens in the form of synthesized peptides are used.
  • targets cytotoxic CD8 + T cells
  • These effector T cells can destroy the tumor cells recognized by the FILA-presented antigens by secreting granzyme and perforin.
  • FILA class I The activation of these immune cells takes place via the ligands of FILA class I, i.e. the antigens presented as sequences of 8-10 amino acids on FILA class I molecules.
  • NGS next generation sequencing
  • LC-MS / MS liquid chromatography-coupled tandem mass spectrometry
  • Target selection for step (a) From the data records of the transcriptome, first, using the amino acid sequences of the respective proteins, amino acid sequences of the HLA tumor antigen peptides corresponding to the MHC complexes (nonamers) with the highest allele affinities (specific activity against T cell receptor [nM]). This selection criterion is used to algorithmically determine the probability with which the respective HLA tumor antigen peptide is presented in vivo on the corresponding MHC complexes (a first prerequisite for a possible cellular immune response).
  • step (b) Using the patient's alleles, nonameric variants containing the amino acid exchange were determined from the data sets of the mutation studies with regard to the highest affinities (specific activity towards T cell receptor [nM]). For this purpose, polymers of 17 amino acids were also specified under the affinity criterion. This selection criterion is used to algorithmically determine the probability with which the respective tumor antigen peptide corresponding to the MHC complexes is presented in vivo on the corresponding MHC complexes (a second prerequisite for a possible cellular immune response).
  • Peptide concepts were produced synthetically as chemical peptides.
  • Adjuvants added per application Montanide ISA 51 VG (1.5 ml), mixture 1: 1 with peptide vial (1.5 ml); 300 pg nivolumab (Opdivo), as PD1 or PD-L1 increased, subcutaneously (sc) directly next to the injection site, 30 min before the peptide / montanide injection.
  • Embodiment 4 is shown in FIG.
  • the graph shows the development of the tumor markers CEA (bar 1) and CA15-3 (bar 2) as well as the liver value Gamma-GT (bar 3) and the leukocyte count (bar 4) during a period of 8 months after the application of the pharmaceutical
  • Lymphangiosis Carcinomatosis The application was carried out with a 1: 1 mixture of
  • the peptide composition is the initial application (followed by 4 further applications; see arrows in FIG. 5).
  • the 10 peptides contained in the pharmaceutical composition according to embodiment 4 are tumor antigen peptides (or also neoantigens).
  • antigens nos. 1-4 and 10 have become epitopes, i.e. it was possible to activate the corresponding T cell receptors (TCR) and to develop effector and memory cells.
  • TCR T cell receptors

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  • Gastroenterology & Hepatology (AREA)
  • Cell Biology (AREA)
  • Endocrinology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Reproductive Health (AREA)
  • Analytical Chemistry (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Zoology (AREA)
  • Gynecology & Obstetrics (AREA)

Abstract

La présente invention concerne une composition pharmaceutique destinée à être utilisée lors du traitement ou de la prophylaxie des carcinomes mammaires et/ou du sein, notamment des carcinomes mammaires localement récurrents ou métastatiques chez un patient ou un groupe de patients, qui est/sont atteint(s) ou suspecté(s) d'être atteint d'un carcinome mammaire et/ou du sein, comprenant au moins 4 à 8 peptides d'antigènes tumoraux HLA-A correspondant aux complexes CMH de classe I et au moins 2 peptides d'antigènes tumoraux correspondant aux complexes CMH de classe Il. Les peptides d'antigènes tumoraux HLA sont des peptides d'antigène HLA exclusifs à une tumeur ou associés à une tumeur et sont dirigés contre au moins un complexe CMH, y compris des combinaisons de celui-ci. La présente invention concerne également une composition pharmaceutique, un kit (ou des parties de celui-ci), un procédé de détermination d'un peptide HLA de classe I et/ou de classe II, un procédé de préparation d'une formulation selon l'invention, et l'utilisation d'une formulation selon l'invention pour la préparation d'une composition pharmaceutique destinée au traitement de malignités, de la leucémie et de néoplasies.
EP20734836.8A 2019-06-02 2020-06-02 Peptides d'antigènes tumoraux hla de classe i et ii pour le traitement des carcinomes mammaires et/ou du sein Pending EP3976081A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102019114735.2A DE102019114735A1 (de) 2019-06-02 2019-06-02 HLA-Tumorantigenpeptiden der Klasse I und II zur Behandlung von Mamma-/Brustkarzinomen
PCT/EP2020/065235 WO2020245126A1 (fr) 2019-06-02 2020-06-02 Peptides d'antigènes tumoraux hla de classe i et ii pour le traitement des carcinomes mammaires et/ou du sein

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EP3976081A1 true EP3976081A1 (fr) 2022-04-06

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US (1) US20220313804A1 (fr)
EP (1) EP3976081A1 (fr)
CN (1) CN114222583A (fr)
CA (1) CA3140204A1 (fr)
DE (1) DE102019114735A1 (fr)
WO (1) WO2020245126A1 (fr)

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CN113406240B (zh) * 2021-07-02 2023-03-24 杭州艾儿默细胞生物科技有限公司 检测pHLA复合物中抗原肽的超滤-高效液相色谱法
WO2023246834A1 (fr) * 2022-06-24 2023-12-28 King Abdullah University Of Science And Technology Apprentissage par renforcement (rl) pour une conception de protéines

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Publication number Priority date Publication date Assignee Title
CA2393738A1 (fr) * 1999-12-10 2001-06-14 Epimmune Inc. Induction de reponses immunes cellulaires a her2/neu a l'aide de compositions renfermant des peptides et des acides nucleiques
DE10225139A1 (de) * 2002-05-29 2004-02-26 Immatics Biotechnologies Gmbh Verfahren zur Identifizierung von immunreaktiven Peptiden
EP2292638A3 (fr) * 2002-09-27 2011-03-23 Ludwig Institute For Cancer Research Peptides antigènes MAGE-C2 et leurs utilisations
US7348007B2 (en) * 2004-02-09 2008-03-25 Ludwig Institute For Cancer Research Mage C2 antigenic peptides and uses thereof
EP2337795A2 (fr) * 2008-10-01 2011-06-29 Dako Denmark A/S Multimères de mhc dans des vaccins et la surveillance immunitaire contre le cancer
GB201004551D0 (en) * 2010-03-19 2010-05-05 Immatics Biotechnologies Gmbh NOvel immunotherapy against several tumors including gastrointestinal and gastric cancer
KR102041381B1 (ko) * 2012-03-12 2019-11-27 젬백스 에이에스 능동적인 면역치료법을 이용한 비-소세포성 폐암의 치료
KR20180010229A (ko) * 2015-05-20 2018-01-30 더 브로드 인스티튜트, 인코퍼레이티드 공유 신생항원
BR112018067565A2 (pt) * 2016-03-04 2019-02-05 Univ New York vetores de vírus que expressam múltiplos epítopos de antígenos associados a tumor para induzir imunidade antitumor
US20190307868A1 (en) * 2016-03-31 2019-10-10 Neon Therapeutics, Inc. Neoantigens and methods of their use
CR20190388A (es) * 2017-01-27 2019-10-16 Immatics Biotechnologies Gmbh Nuevos péptidos y nuevas combinaciones de péptidos para el uso en la inmunoterapia contra el cáncer de ovario y otros tipos de cáncer
AU2018348165A1 (en) * 2017-10-10 2020-05-21 Gritstone Bio, Inc. Neoantigen identification using hotspots
MX2020004935A (es) * 2017-11-14 2020-09-25 Arcellx Inc Terapias con celulas inmunitarias multifuncionales.

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WO2020245126A1 (fr) 2020-12-10
CA3140204A1 (fr) 2020-12-10
DE102019114735A1 (de) 2020-12-03
US20220313804A1 (en) 2022-10-06
CN114222583A (zh) 2022-03-22

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